Long-term 2007-2013 monitoring of reproductive disturbance in the dun sentinel Assiminea grayana with regard to polymeric materials pollution at the coast of Lower Saxony, North Sea, Germany.
During biological effect monitoring studies of endocrine active compounds with the snail Assiminea grayana in 2007-2013, reproductive disorders including atresia, transformation of capsule/albumen glands into prostates in females and ovotestis, transformation of prostates to capsule/albumen glands, disruption of spermatogenesis, and calcification of tubules in males, were encountered in several years. The search of sources of endocrine active substances was first directed to antifouling biocides from paint particles and extended to leaching compounds from polymeric materials. In contrast to the reference sites, most of the observed disorders occurred at a station near harbors and dockyards polluted with residues from antifouling paints and polymeric materials. Beside of investigations about the potential ingestion of polymer particles by the snails, further investigations of compounds of polymeric materials with endocrine potential should follow.


Synthesis of peptides of Carapax Trionycis and their inhibitory effects on TGF-β1-induced hepatic stellate cells.
We previous identified the antifibrotic active ingredients from Carapax Trionycis as two peptides. Here, we synthesized these two peptides (peptide 1 and peptide 2) by a solid phase method and examined their effects on proliferation and activation of cultured hepatic stellate cells (HSC) which are the main ECM (extracellular matrix)-producing cells in fibrosis progression. We demonstrated that peptide 1 and peptide 2 significantly reduced HSC proliferation and activation in a dose dependent manner. Further, peptide 1 and peptide 2 could interfere with TGF-signaling by down-regulating Smad 3 phosphorylation. Thus, these synthetic peptides of Carapax Trionycis could inhibit proliferation and activation of HSC and might be used as a candidate for treatment of liver fibrosis.


PAMELA results on the cosmic-ray antiproton flux from 60 MeV to 180 GeV in kinetic energy.
The satellite-borne experiment PAMELA has been used to make a new measurement of the cosmic-ray antiproton flux and the antiproton-to-proton flux ratio which extends previously published measurements down to 60 MeV and up to 180 GeV in kinetic energy. During 850 days of data acquisition approximately 1500 antiprotons were observed. The measurements are consistent with purely secondary production of antiprotons in the Galaxy. More precise secondary production models are required for a complete interpretation of the results.


Dietary Sulforaphane in Cancer Chemoprevention: The Role of Epigenetic Regulation and HDAC Inhibition.
Sulforaphane, produced by the hydrolytic conversion of glucoraphanin after ingestion of cruciferous vegetables, particularly broccoli and broccoli sprouts, has been extensively studied due to its apparent health-promoting properties in disease and limited toxicity in normal tissue. Recent Studies: Recent identification of a sub-population of tumor cells with stem cell-like self-renewal capacity that may be responsible for relapse, metastasis, and resistance, as a potential target of the dietary compound, may be an important aspect of sulforaphane chemoprevention. Evidence also suggests that sulforaphane may target the epigenetic alterations observed in specific cancers, reversing aberrant changes in gene transcription through mechanisms of histone deacetylase inhibition, global demethylation, and microRNA modulation. In this review, we discuss the biochemical and biological properties of sulforaphane with a particular emphasis on the anticancer properties of the dietary compound. Sulforaphane possesses the capacity to intervene in multistage carcinogenesis through the modulation and/or regulation of important cellular mechanisms. The inhibition of phase I enzymes that are responsible for the activation of pro-carcinogens, and the induction of phase II enzymes that are critical in mutagen elimination are well-characterized chemopreventive properties. Furthermore, sulforaphane mediates a number of anticancer pathways, including the activation of apoptosis, induction of cell cycle arrest, and inhibition of NFκB. Further characterization of the chemopreventive properties of sulforaphane and its capacity to be selectively toxic to malignant cells are warranted to potentially establish the clinical utility of the dietary compound as an anti-cancer compound alone, and in combination with clinically relevant therapeutic and management strategies.


Quality of life in women who use pessaries for longer than 12 months.
Pessaries are an effective treatment for pelvic organ prolapse and urinary incontinence; however, few data exist describing long-term pessary use. Our aim was to describe symptom bother and quality of life (QoL) in women using pessaries for urinary incontinence and/or prolapse for at least 12 months. Consecutive women who met inclusion criteria were approached for this observational cross-sectional study. Wilson and Cleary's Health-Related Quality of Life Model guided the inclusion of biologic, functional, and individual factors that impact the health-related QoL. Consenting participants completed a generalized QoL index, the Center for Epidemiologic Depression Symptoms, Medical Outcomes Study Social Support Survey, and condition-specific measures; the Pelvic Floor Distress Inventory (PFDI-20-SF) and the Pelvic Floor Impact Questionnaire. Fifty-six women, mean age 74.4 years (range, 47-89 years), completed the survey. Mean length of time for pessary use was 4.5 years (1-15 years). Most of the women (n = 31, 55.4%) returned to the clinic for pessary care every 3 months. There was no difference in generalized QoL nor condition-specific total PFDI-20 in women performing self-care versus routine follow-up. Almost one third (29%) of participants reported complications related to pessary use (eg, vaginal erosion), and 41%were considering surgical repair in the near future. Women who were considering surgery had higher PFDI-20 scores relating to more bothersome prolapse symptoms than those not considering surgery (Pelvic Organ Prolapse Distress Inventory 6, 33.91 vs 24.73, P = 0.03). Pessaries can be used to control pelvic floor symptoms for extended periods. Complication rates in this study were lower than previously reported, even in women not doing self-care. Not surprisingly, women considering surgical intervention reported greater symptom bother despite pessary use.


Agonist synergism in airway smooth muscle contraction.
Hyperreactive responses of asthmatics to bronchoconstrictor agonists are caused by mediators produced by a variety of cell types within the airways. Nerves, mast cells, eosinophils, airway epithelia and airway smooth muscle cells probably all interact to increase bronchomotor tone in response to challenge with allergenic stimuli. In addition to important cell-cell interactions, there may be a significant postjunctional component of airway hyperreactivity in which mediators interact at the level of airway smooth muscle cells. To test this hypothesis, I investigated synergistic interactions of methacholine (MCH), histamine and serotonin using intact and chemically skinned canine tracheal smooth muscle. A threshold concentration of histamine (100 nM) significantly increased force when it was added 20 min after or 10 min before stimulation with low concentrations of MCH (1-10 nM). A threshold concentration of serotonin (10 nM) also significantly increased contractions induced by MCH. Serotonin (10 nM) added during a steady-state contraction induced by 6 or 10 nM MCH increased force and increased fura-2 fluorescence, which suggests that force increases in part because myoplasmic Ca++ increases. I also tested the hypothesis that mechanisms beyond the initial steps of signal transduction contribute to synergism by permeabilizing tracheal smooth muscle fibers with staphylococcal alpha-toxin. Histamine (30 microM), MCH (1 microM), GTP-gamma-S (100 microM) and phorbol dibutyrate (1 microM) all potentiated contractions induced by 1 microM Ca++ in skinned fibers. These data suggest that postjunctional components of airway hyperreactivity may be a combination of synergistic effects of agonists occurring at the level of excitation-contraction coupling as well as sensitization of contractile proteins to Ca++.


Rotaviral antibodies in the treatment of acute rotaviral gastroenteritis.
The efficacy of hyperimmune bovine colostrum received from cows immunized with simian rotavirus SA11 in the treatment of rotavirus gastroenteritis was compared in a randomized double-blind trial to colostrum and ordinary milk preparations. One hundred and thirty-five children aged 6-30 months with rotaviral gastroenteritis received either hyperimmune bovine colostrum (n=42), ordinary colostrum (n=42) or milk (n=41) as a 100 ml solution four times/d for 4 d. Even though the differences were in favour of hyperimmune bovine colostrum in all the variables evaluated [greater weight gain (403 vs 343 g), shorter duration of diarrhoea (3.1 vs 3.6 d), fewer stools during 6 d (11.5 vs 13.6) and fewer stools during the first 3 d (9.3 vs 11.3)], all the differences were statistically insignificant. Differences of this size are clinically unimportant in well-nourished immunocompetent children, but we suggest that the hyperimmune bovine colostrum tested in our trial had some effects in the treatment of acute rotaviral gastroenteritis and should be evaluated further.


Quantitative determination of decursin, decursinol angelate, and decursinol in mouse plasma and tumor tissue using liquid-liquid extraction and HPLC.
The pyranocoumarin compound decursin and its isomer decursinol angelate (DA) are the major hydrophobic phytochemicals in the root of Angelica gigas Nakai (AGN, Korean Angelica), a major traditional medicinal herb. The ethanol extract of AGN and especially the purified decursin and DA have been shown to exhibit antitumor activities by our collaborative team and others. Although decursinol has been identified as a major hydrolysis metabolite of decursin and DA in vivo in previous pharmacokinetic studies with mouse and rat, other recently published results sharply disputed this conclusion. In this study, we set up a practical method for the concurrent analysis of decursin, DA, and decursinol in mouse plasma and tumor tissues by liquid-liquid extraction and HPLC-UV and applied the method to several animal experiments. Plasma or tumor homogenate was extracted directly with ethyl acetate. The extraction efficiency for decursin/DA (quantitated together) and decursinol was between 82-95 % in both mouse plasma and tumor homogenate. The lower limit of quantitation (LLOQ) was approximately 0.25 µg/mL for decursin/DA and 0.2 µg/mL for decursinol in mouse plasma. In a pilot pharmacokinetic study, male C57BL/6 mice were given a single dose of 4.8 mg decursin/DA mixture (~240 mg/kg) per mouse either by oral gavage or intraperitoneal injection. Maximum plasma concentrations for decursin/DA and decursinol were 11.2 and 79.7 µg/mL, respectively, when decursin/DA was administered via intraperitoneal injection, and 0.54 and 14.9 µg/mL via oral gavage. Decursin/DA and decursinol contents in the tumor tissues from nude mouse xenografts correlated very well with those in plasma. Overall, our results confirm the conclusion that the majority of decursin/DA hydrolyze to decursinol in rodent models with a tiny fraction remaining as the intact compounds administered.


Sarcoidosis: a state of the art review from the Thoracic Society of Australia and New Zealand.
Sarcoidosis is a systemic disease of unknown aetiology, characterised by non-caseating granulomatous inflammation. It most commonly manifests in the lungs and intrathoracic lymph nodes but can affect any organ. This summary of an educational resource provided by the Thoracic Society of Australia and New Zealand outlines the current understanding of sarcoidosis and highlights the need for further research. Our knowledge of the aetiology and immunopathogenesis of sarcoidosis remains incomplete. The enigma of sarcoidosis lies in its immunological paradox of type 1 T helper cell-dominated local inflammation co-existing with T regulatory-induced peripheral anergy. Although specific aetiological agents have not been identified, mounting evidence suggests that environmental and microbial antigens may trigger sarcoidosis. Genome-wide association studies have identified candidate genes conferring susceptibility and gene expression analyses have provided insights into cytokine dysregulation leading to inflammation. Sarcoidosis remains a diagnosis of exclusion based on histological evidence of non-caseating granulomas with compatible clinical and radiological findings. In recent years, endobronchial ultrasound-guided transbronchial needle aspiration of mediastinal lymph nodes has facilitated the diagnosis, and whole body positron emission tomography scanning has improved localisation of disease. No single biomarker is adequately sensitive and specific for detecting and monitoring disease activity. Most patients do not require treatment; when indicated, corticosteroids remain the initial standard of care, despite their adverse side effect profile. Other drugs with fewer side effects may be a better long term choice (eg, methotrexate, hydroxychloroquine, azathioprine, mycophenolate), while tumour necrosis factor-α inhibitors are a treatment option for patients with refractory disease.


Open Access uptake by universities worldwide.
The implementation of policies promoting the adoption of an open science (OS) culture must be accompanied by indicators that allow monitoring the uptake of such policies and their potential effects on research publishing and sharing practices. This study presents indicators of open access (OA) at the institutional level for universities worldwide. By combining data from Web of Science, Unpaywall and the Leiden Ranking disambiguation of institutions, we track OA coverage of universities' output for 963 institutions. This paper presents the methodological challenges, conceptual discrepancies and limitations and discusses further steps needed to move forward the discussion on fostering OA and OS practices and policies.


Accuracy of genotypic value predictions for marker-based selection in biparental plant populations.
The availability of cheap and abundant molecular markers has led to plant-breeding methods that rely on the prediction of genotypic value from marker data, but published information is lacking on the accuracy of genotypic value predictions with empirical data in plants. Our objectives were to (1) determine the accuracy of genotypic value predictions from multiple linear regression (MLR) and genomewide selection via best linear unbiased prediction (BLUP) in biparental plant populations; (2) assess the accuracy of predictions for different numbers of markers (N(M)) and progenies (N(P)) used in estimation; and (3) determine if an empirical Bayes approach for modeling of the variances of individual markers and of epistatic effects leads to more accurate predictions in empirical data. We divided each of four maize (Zea mays L.) datasets, one Arabidopsis dataset, and two barley (Hordeum vulgare L.) datasets into an estimation set, where marker effects were calculated, and a test set, where genotypic values were predicted based on markers. Predictions were more accurate with BLUP than with MLR. Predictions became more accurate as N(P) and N(M) increased, until sufficient genome coverage was reached. Modeling marker variances with the empirical Bayes method sometimes led to slightly better predictions, but the accuracy with different variants of the empirical Bayes method was often inconsistent. In nearly all cases, the accuracy with BLUP was not significantly different from the highest accuracy across all methods. Accounting for epistasis in the empirical Bayes procedure led to poorer predictions. We concluded that among the methods considered, the quick and simple BLUP approach is the method of choice for predicting genotypic value in biparental plant populations.


The current role of telomerase in the diagnosis of bladder cancer.
Bladder cancer has an incidence of 15 cases per 100,000 persons in the global population and is the most common tumor of the urinary tract. Imaging techniques, cytoscopy, and cytology are either invasive or not sufficiently accurate to detect early stage tumors, and the need for new diagnostic markers still remains. Among the markers most recently proposed to improve diagnostic accuracy and especially sensitivity, increasing attention has been focused on the role of the ribonucleoprotein, telomerase. Relevant papers on the etiology, diagnosis, and evaluation of bladder cancer using telomerase in urine were searched for and considered. The PubMed search was performed using the text terms "bladder cancer", "diagnosis", and "telomerase". Previous studies have shown that the quantitative Telomerase Repeat Amplification Protocol (TRAP) assay performed in voided urine is an important non-invasive tool for the diagnosis of bladder tumors since it has very high sensitivity and specificity, even for early stage and low grade tumors. The main limitation of this test is the rate of false positive results due to the presence of inflammatory or non-tumor cells (i.e., epithelial cells from the lower genital tract), which express telomerase activity (TA). Consequently, an in situ analysis would seem to be important to identify the nature of telomerase-positive cells. Immunocytochemical detection of the hTERT subunit by a specific antibody seemed to open up the possibility to identify different cellular components of urine. However, the lack of a strict relationship between hTERT protein expression and telomerase activity has, to a certain extent, made this approach less relevant. In conclusion, telomerase activity in urine determined by TRAP seems to be marker of great potential, even more advantageous in cost/benefit terms when used in selected symptomatic patients or professionally high-risk subgroups.


Systematic Modification of Zingerone Reveals Structural Requirements for Attraction of Jarvis's Fruit Fly.
Tephritid fruit flies are amongst the most significant horticultural pests globally and male chemical lures are important for monitoring and control. Zingerone has emerged as a unique male fruit fly lure that can attract dacine fruit flies that are weakly or non-responsive to methyl eugenol and cuelure. However, the key features of zingerone that mediate this attraction are unknown. As Jarvis's fruit fly, Bactrocera jarvisi (Tryon), is strongly attracted to zingerone, we evaluated the response of B. jarvisi to 37 zingerone analogues in a series of field trials to elucidate the functional groups involved in attraction. The most attractive analogues were alkoxy derivatives, with isopropoxy being the most attractive, followed by ethoxy and trifluoromethoxy analogues. All of the phenolic esters tested were also attractive with the response typically decreasing with increasing size of the ester. Results indicate that the carbonyl group, methoxy group, and phenol of zingerone are key sites for the attraction of B. jarvisi and identify some constraints on the range of structural modifications that can be made to zingerone without compromising attraction. These findings are important for future work in developing and optimising novel male chemical lures for fruit flies.


Phosphorus sorption and availability in soils amended with animal manures and sewage sludge.
Soils that receive large applications of animal wastes and sewage sludge are vulnerable to releasing environmentally significant concentrations of dissolved P available to subsurface flow owing to the gradual saturation of the soil's P sorption capacity. This study evaluated P sorption (calculated from Langmuir isotherms) and availability of P (as CaCl2-P and resin P) in soils incubated for 20 d with poultry litter, poultry manure, cattle slurry, municipal sewage sludge, or KH2PO4, added on a P-equivalent basis (100 mg P kg(-1)). All the P sources had a marked negative effect on P sorption and a positive effect on P availability in all soils. In the cattle slurry- and KH2PO4-treated soils, the decreases in P sorption maximum (19-66%) and binding energy (25-89%) were consistently larger than the corresponding decreases (7-41% and 11-30%) in poultry litter-, poultry manure-, and sewage sludge-treated soils. The effects of cattle slurry and KH2PO4 on P availability were, in most cases, larger than those of the other P sources. In the poultry litter, poultry manure, and sewage sludge treatments, the increase in soil solution P was inversely related (R2 = 0.75) to the input of Ca from these relatively high Ca (13.5-42 g kg(-1)) sources. Correlation analyses implied that the magnitude of the changes in P sorption and availability was not related to the water-extractable P content of the P sources. Future research on the sustainable application of organic wastes to agricultural soils needs to consider the non-P- as well as P-containing components of the waste.


Smokeless tobacco use among patients with tuberculosis in Karnataka: the need for cessation services.
India is home to the largest population of patients with tuberculosis and tobacco users in the world. Smokeless tobacco use exceeds smoking and is increasing. There is no study to date that reports smokeless tobacco use before and after the diagnosis and treatment of tuberculosis. We assessed smokeless tobacco use among former patients of tuberculosis in Karnataka, India. We conducted a community-based, cross sectional study among 202 men, who had been diagnosed and treated for tuberculosis (mean age 48 years), selected by multistage, random sampling. Using a semi-structured interview schedule, retrospective smoking and smokeless tobacco use were captured at eight time-points before and after the diagnosis and treatment of tuberculosis. Most patients suspended tobacco use during treatment. A high 44% prevalence of smokeless tobacco use 6 months before diagnosis was reduced to just 8% during the intensive phase of treatment and climbed to 27% 6 months after treatment. The tobacco use relapse rate 6 months after completion of treatment was higher for smokeless tobacco use (52%, 95% CI 41%-62%) than for smoking (36%, 95% CI 26%-45%). We also found that many patients who were advised to quit smoking continued using smokeless tobacco after completion of treatment. Additionally, new smokeless tobacco use was documented. Of the 11 new exclusive smokeless tobacco users, 10 shifted from smoking to smokeless tobacco use as a form of harm reduction. Patients with tuberculosis are advised by their doctors, at the time of diagnosis, to quit smoking. Several patients shift from smoking to smokeless tobacco use, which needs to be addressed while providing tobacco cessation services.


REPRODUCTIVE TOXICOLOGY: Pregnancy exposure to endocrine disrupting chemicals: implications for women's health.
Women are ubiquitously exposed to non-persistent endocrine disrupting chemicals (EDCs) from food contact materials and personal care products. Understanding the impacts of exposure to these chemicals on pregnancy and long-term health outcomes in women is a critical area of research that has been largely overlooked. This brief review focuses on the epidemiologic literature exploring associations of non-persistent EDCs - including phthalates, parabens, bisphenols, and triclosan - with maternal pregnancy outcomes and long-term health outcomes in women. We focus on the challenges of this research, particularly assessing non-persistent EDC exposures, aspects of study design, and statistical approaches. We conclude by reviewing the best practices for non-persistent EDC research with regards to pregnancy and women's health. Though limited, we found some evidence indicating that exposure to non-persistent EDCs is associated with pregnancy health. However, findings from these studies have been inconsistent and require corroboration. Recent studies have also proposed that non-persistent EDC exposures in pregnancy may adversely affect postnatal maternal health. To date, only a few studies have been conducted and have only focused on postpartum weight. More research is needed in this area to inform efforts to promote optimal health across the lifespan of women.


Alternative medicine use by Canadian ambulatory gastroenterology patients: secular trend or epidemic?
To assess the prevalence and determinants of alternative medicine (AM) use in gastroenterology outpatients and those with inflammatory bowel disease (IBD). An 80-item questionnaire, addressing symptoms, general health, quality of life, and AM use, was administered and analyzed using logistic regression. 52.5% of 341 participants used AM in the previous year. Most commonly used were herbal medicine (45.2% of users; 95% CI 35.4-52.5%), chiropractor (40.7%; 95% Cl 31.4-48.0%), and massage therapy (22.9%; 95% CI 15.9-29.1%). Reasons prompting AM use were ineffective medical therapy (39.5%; 95% CI 30.4-46.8%), a greater sense of self-control (29.1%; 95% CI 21.2-35.7%), agreement with personal beliefs (19.5%; 95% CI 13.1-25.4%), and conventional drug adverse-effects (17.3%; 95% CI 11.2-22.9%). AM use was predicted as follows: (1) higher education (odds ratio (OR) 2.10; 95% CI 1.22-3.60), (2) comorbid medical conditions (OR 1.80; 95% CI 1.08-3.00), 3) poor mental component summary score of the SF-12 health survey (OR 1.04; 95% CI 1.01-1.07), and (4) higher annual income (OR 1.17; 95% CI 1.001-1.36), but was not related to response to conventional medical therapy. AM practitioners had instructed 8.6% to change prescription medications. AM usage for gastrointestinal disease was greater in patients with IBD (44.6% vs 10.0%; p < 0.05), who were more likely to cite adverse drug effects as a reason for AM use (28.9 vs 14.4%; p = 0.03). AM was used by 52.5% of gastroenterology outpatients and its use was greater in those with a higher level of education, comorbid conditions, poorer mental health-related quality of life, and higher income. Drug-related side effects also led to increased AM use.


Resilience and reactivity of global food security.
The escalating food demand by a growing and increasingly affluent global population is placing unprecedented pressure on the limited land and water resources of the planet, underpinning concerns over global food security and its sensitivity to shocks arising from environmental fluctuations, trade policies, and market volatility. Here, we use country-specific demographic records along with food production and trade data for the past 25 y to evaluate the stability and reactivity of the relationship between population dynamics and food availability. We develop a framework for the assessment of the resilience and the reactivity of the coupled population-food system and suggest that over the past two decades both its sensitivity to external perturbations and susceptibility to instability have increased.


Fuzzy tricentric pharmacophore fingerprints. 2. Application of topological fuzzy pharmacophore triplets in quantitative structure-activity relationships.
Topological fuzzy pharmacophore triplets (2D-FPT), using the number of interposed bonds to measure separation between the atoms representing pharmacophore types, were employed to establish and validate quantitative structure-activity relationships (QSAR). Thirteen data sets for which state-of-the-art QSAR models were reported in literature were revisited in order to benchmark 2D-FPT biological activity-explaining propensities. Linear and nonlinear QSAR models were constructed for each compound series (following the original author's splitting into training/validation subsets) with three different 2D-FPT versions, using the genetic algorithm-driven Stochastic QSAR sampler (SQS) to pick relevant triplets and fit their coefficients. 2D-FPT QSARs are computationally cheap, interpretable, and perform well in benchmarking. In a majority of cases (10/13), default 2D-FPT models validated better than or as well as the best among those reported, including 3D overlay-dependent approaches. Most of the analogues series, either unaffected by protonation equilibria or unambiguously adopting expected protonation states, were equally well described by rule- or pKa-based pharmacophore flagging. Thermolysin inhibitors represent a notable exception: pKa-based flagging boosts model quality, although--surprisingly--not due to proteolytic equilibrium effects. The optimal degree of 2D-FPT fuzziness is compound set dependent. This work further confirmed the higher robustness of nonlinear over linear SQS models. In spite of the wealth of studied sets, benchmarking is nevertheless flawed by low intraset diversity: a whole series of thereby caused artifacts were evidenced, implicitly raising questions about the way QSAR studies are conducted nowadays. An in-depth investigation of thrombin inhibition models revealed that some of the selected triplets make sense (one of these stands for a topological pharmacophore covering the P1 and P2 binding pockets). Nevertheless, equations were either unable to predict the activity of the structurally different ligands or tended to indiscriminately predict any compound outside the training family to be active. 2D-FPT QSARs do however not depend on any common scaffold required for molecule superimposition and may in principle be trained on hand of diverse sets, which is a must in order to obtain widely applicable models. Adding (assumed) inactives of various families for training enabled discovery of models that specifically recognize the structurally different actives.


Detection of biomarkers using recombinant antibodies coupled to nanostructured platforms.
The utility of biomarker detection in tomorrow's personalized health care field will mean early and accurate diagnosis of many types of human physiological conditions and diseases. In the search for biomarkers, recombinant affinity reagents can be generated to candidate proteins or post-translational modifications that differ qualitatively or quantitatively between normal and diseased tissues. The use of display technologies, such as phage-display, allows for manageable selection and optimization of affinity reagents for use in biomarker detection. Here we review the use of recombinant antibody fragments, such as scFvs and Fabs, which can be affinity-selected from phage-display libraries, to bind with both high specificity and affinity to biomarkers of cancer, such as Human Epidermal growth factor Receptor 2 (HER2) and Carcinoembryonic antigen (CEA). We discuss how these recombinant antibodies can be fabricated into nanostructures, such as carbon nanotubes, nanowires, and quantum dots, for the purpose of enhancing detection of biomarkers at low concentrations (pg/mL) within complex mixtures such as serum or tissue extracts. Other sensing technologies, which take advantage of 'Surface Enhanced Raman Scattering' (gold nanoshells), frequency changes in piezoelectric crystals (quartz crystal microbalance), or electrical current generation and sensing during electrochemical reactions (electrochemical detection), can effectively provide multiplexed platforms for detection of cancer and injury biomarkers. Such devices may soon replace the traditional time consuming ELISAs and Western blots, and deliver rapid, point-of-care diagnostics to market.


Unconditional cash transfers for assistance in humanitarian disasters: effect on use of health services and health outcomes in low- and middle-income countries.
Unconditional cash transfers (UCTs) are a common social protection intervention that increases income, a key social determinant of health, in disaster contexts in low- and middle-income countries (LMICs). To assess the effects of UCTs in improving health services use, health outcomes, social determinants of health, health care expenditure, and local markets and infrastructure in LMICs. We also compared the relative effectiveness of UCTs delivered in-hand with in-kind transfers, conditional cash transfers, and UCTs paid through other mechanisms. We searched 17 academic databases, including the Cochrane Public Health Group Specialised Register, the Cochrane Database of Systematic Reviews (The Cochrane Library 2014, Issue 7), MEDLINE, and EMBASE between May and July 2014 for any records published up until 4 May 2014. We also searched grey literature databases, organisational websites, reference lists of included records, and academic journals, as well as seeking expert advice. We included randomised and quasi-randomised controlled trials (RCTs), as well as cohort, interrupted time series, and controlled before-and-after studies (CBAs) on UCTs in LMICs. Primary outcomes were the use of health services and health outcomes. Two authors independently screened all potentially relevant records for inclusion criteria, extracted the data, and assessed the included studies' risk of bias. We requested missing information from the study authors. Three studies (one cluster-RCT and two CBAs) comprising a total of 13,885 participants (9640 children and 4245 adults) as well as 1200 households in two LMICs (Nicaragua and Niger) met the inclusion criteria. They examined five UCTs between USD 145 and USD 250 (or more, depending on household characteristics) that were provided by governmental, non-governmental or research organisations during experiments or pilot programmes in response to droughts. Two studies examined the effectiveness of UCTs, and one study examined the relative effectiveness of in-hand UCTs compared with in-kind transfers and UCTs paid via mobile phone. Due to the methodologic limitations of the retrieved records, which carried a high risk of bias and very serious indirectness, we considered the body of evidence to be of very low overall quality and thus very uncertain across all outcomes.Depending on the specific health services use and health outcomes examined, the included studies either reported no evidence that UCTs had impacted the outcome, or they reported that UCTs improved the outcome. No single outcome was reported by more than one study. There was a very small increase in the proportion of children who received vitamin or iron supplements (mean difference (MD) 0.10 standard deviations (SDs), 95% confidence interval (CI) 0.06 to 0.14) and on the child's home environment, as well as clinically meaningful, very large reductions in the chance of child death (hazard ratio (HR) 0.26, 95% CI 0.10 to 0.66) and the incidence of severe acute malnutrition (HR 0.44, 95% CI 0.24 to 0.80). There was also a moderate reduction in the number of days children spent sick in bed (MD - 0.36 SDs, 95% CI - 0.62 to - 0.10). There was no evidence for any effect on the proportion of children receiving deworming drugs, height for age among children, adults' level of depression, or the quality of parenting behaviour. No adverse effects were identified. The included comparisons did not examine several important outcomes, including food security and equity impacts.With regard to the relative effectiveness of UCTs compared with a food transfer providing a relatively high total caloric value, there was no evidence that a UCT had any effect on the chance of child death (HR 2.27, 95% CI 0.69 to 7.44) or severe acute malnutrition (HR 1.15, 95% CI 0.67 to 1.99). A UCT paid in-hand led to a clinically meaningful, moderate increase in the household dietary diversity score, compared with the same UCT paid via mobile phone (difference-in-differences estimator 0.43 scores, 95% CI 0.06 to 0.80), but there was no evidence for an effect on social determinants of health, health service expenditure, or local markets and infrastructure. Additional high-quality evidence (especially RCTs of humanitarian disaster contexts other than droughts) is required to reach clear conclusions regarding the effectiveness and relative effectiveness of UCTs for improving health services use and health outcomes in humanitarian disasters in LMICs.


SU-E-T-206: Standardization in Documentation Format Can Significantly Reduce Manual Data Entry Error in Patient Chart.
To demonstrate that standardization in documentation format can significantly reduce manual data entry error in patient chart. Due to lack of direct data link between CT on rail imaging registration software and patient R&V system, therapists have to manually enter translation correction of patient position into R&V system after performing imaging registration between CT image taken just before treatment delivery and treatment planning CT image. Approximately six months after CT on rail was placed into clinical service, we started requiring therapists to use a standard format to document the shifts when they manually enter data to reduce manual data entry error rate. The therapist manual data entry errors in R&V system before (551 entries) and after the format standardization (1645 entries) are the subjects of statistical analysis. The errors are divided into two categories (recoverable and non-recoverable errors) depending on whether a human being can recover the translation shifts in lateral, longitudinal, and vertical directions from the therapist notes. Fisher's exact test is performed to test the statistical significance of therapist's data entry error reduction after our imposing the documentation format requirement. Temporal information on when the errors were made is also analyzed to find out when errors are more likely to happen. Statistical analysis indicated that reductions in the numbers of recoverable, non-recoverable, and total errors after standardization in document format are all statistically significant with p values less than 0.05. A simple and low cost measure like standardization in document format can significantly reduce the errors operators introduce to patient R&V system when they perform manual data entry. We hope our experience will convince people to follow more disciplined documentation rule to reduce the error rate and therefore potentially can improve the quality of patient care when manual data entry is involved.


Specific binding of substance P aminoterminal heptapeptide [SP(1-7)] to mouse brain and spinal cord membranes.
Aminoterminal fragments of substance P (SP) have been previously shown to produce effects distinct, and often opposite, from those produced by the C-terminal of SP. The present investigation was initiated to determine whether N-terminal fragments interact at binding sites distinct from the neurokinin-1 (NK-1) receptor where the C-terminal sequence of SP binds with high affinity, and distinct from mu-opiate receptors, where we have previously shown the N-terminal sequence of SP to interact. A tritium-labeled aminoterminal heptapeptide of SP, 3H-SP(1-7), was synthesized, purified, and used to characterize the binding of a variety of fragments of SP and opioids in the mouse brain and spinal cord membranes. Using the reduction of SP-induced caudally directed biting and scratching behaviors as an index of biological activity, 3H-SP(1-7) was shown to be equipotent to unlabeled SP(1-7). 3H-SP(1-7) was found to bind reversibly to a saturable population of sites. Scatchard analyses of concentration-dependent saturation of binding in the brain indicated a single population of noninteracting sites with a high affinity (Kd = 2.5 nM) and a low capacity (Bmax = 29.2 fmol/mg protein). Kinetic analyses indicated an apparent dissociation equilibrium constant of 2.1 nM. Two populations of binding sites were observed in the spinal cord, one with a very high affinity (Kd = 0.03 nM) and low capacity (Bmax = 0.87 fmol/mg protein), and the other with lower affinity (Kd = 5.4 nM) and intermediate capacity (Bmax = 19.6 fmol/mg protein). Specific agonists for NK-1, NK-2, and NK-3 and delta opioid receptors, carboxyterminal fragments of SP, and a variety of other peptides did not compete at the 3H-SP(1-7) binding sites, but structurally related N-terminal peptides and (D-Ala2, NMe-Phe4, Gly-ol)-enkephalin (DAMGO) were active in displacing the ligand. The binding site for 3H-SP(1-7) appeared to be a membrane-bound complex whose specific binding was dependent on the integrity of both proteins and phospholipids. These studies are the first to characterize the binding sites for the SP N-terminal partial sequence of SP that can be generated by metabolism in vivo. The expanding body of evidence for distinct biological activities of N-terminal metabolites of SP, together with the current characterization of N-terminal binding, strongly support the existence of an N-terminal-directed SP receptor. The characteristics of SP(1-7) binding sites are consistent with those expected for an SP N-terminal receptor.


Antidepressants for treating depression in dementia.
The use of antidepressants in dementia accompanied by depressive symptoms is widespread, but their clinical efficacy is uncertain. This review updates an earlier version, first published in 2002. To determine the efficacy and safety of any type of antidepressant for patients who have been diagnosed as having dementia of any type and depression as defined by recognised criteria. We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's Specialised Register, on 16 August 2017. ALOIS contains information on trials retrieved from databases and from a number of trial registers and grey literature sources. We included all relevant double-blind, randomised trials comparing any antidepressant drug with placebo, for patients diagnosed as having dementia and depression. Two review authors selected studies for inclusion and extracted data independently. We assessed risk of bias in the included studies using the Cochrane 'Risk of bias' tool. Where clinically appropriate, we pooled data for treatment periods up to three months and from three to nine months. We used GRADE methods to assess the overall quality of the evidence. We included ten studies with a total of 1592 patients. Eight included studies reported sufficiently detailed results to enter into analyses related to antidepressant efficacy. We split one study which included two different antidepressants and therefore had nine groups of patients treated with antidepressants compared with nine groups receiving placebo treatment. Information needed to make 'Risk of bias' judgements was often missing.We found high-quality evidence of little or no difference in scores on depression symptom rating scales between the antidepressant and placebo treated groups after 6 to 13 weeks (standardised mean difference (SMD) -0.10, 95% confidence interval (CI) -0.26 to 0.06; 614 participants; 8 studies). There was probably also little or no difference between groups after six to nine months (mean difference (MD) 0.59 point, 95% CI -1.12 to 2.3, 357 participants; 2 studies; moderate-quality evidence). The evidence on response rates at 12 weeks was of low quality, and imprecision in the result meant we were uncertain of any effect of antidepressants (antidepressant: 49.1%, placebo: 37.7%; odds ratio (OR) 1.71, 95% CI 0.80 to 3.67; 116 participants; 3 studies). However, the remission rate was probably higher in the antidepressant group than the placebo group (antidepressant: 40%, placebo: 21.7%; OR 2.57, 95% CI 1.44 to 4.59; 240 participants; 4 studies; moderate-quality evidence). The largest of these studies continued for another 12 weeks, but because of imprecision of the result we could not be sure of any effect of antidepressants on remission rates after 24 weeks. There was evidence of no effect of antidepressants on performance of activities of daily living at weeks 6 to 13 (SMD -0.05, 95% CI -0.36 to 0.25; 173 participants; 4 studies; high-quality evidence) and probably also little or no effect on cognition (MD 0.33 point on the Mini-Mental State Examination, 95% CI -1.31 to 1.96; 194 participants; 6 studies; moderate-quality evidence).Participants on antidepressants were probably more likely to drop out of treatment than those on placebo over 6 to 13 weeks (OR 1.51, 95% CI 1.07 to 2.14; 836 participants; 9 studies). The meta-analysis of the number of participants suffering at least one adverse event showed a significant difference in favour of placebo (antidepressant: 49.2%, placebo: 38.4%; OR 1.55, 95% CI 1.21 to 1.98, 1073 participants; 3 studies), as did the analyses for participants suffering one event of dry mouth (antidepressant: 19.6%, placebo: 13.3%; OR 1.80, 95% CI 1.23 to 2.63, 1044 participants; 5 studies), and one event of dizziness (antidepressant: 19.2%, placebo: 12.5%; OR 2.00, 95% CI 1.34 to 2.98, 1044 participants; 5 studies). Heterogeneity in the way adverse events were reported in studies presented a major difficulty for meta-analysis, but there was some evidence that antidepressant treatment causes more adverse effects than placebo treatment does. The available evidence is of variable quality and does not provide strong support for the efficacy of antidepressants for treating depression in dementia, especially beyond 12 weeks. On the only measure of efficacy for which we had high-quality evidence (depression rating scale scores), antidepressants showed little or no effect. The evidence on remission rates favoured antidepressants but was of moderate quality, so future research may find a different result. There was insufficient evidence to draw conclusions about individual antidepressant drugs or about subtypes of dementia or depression. There is some evidence that antidepressant treatment may cause adverse events.


Oncological Outcomes After Anastomotic Leakage After Surgery for Colon or Rectal Cancer: Increased Risk of Local Recurrence.
The aim of this study was to evaluate oncological outcome for patients with and without anastomotic leakage after colon or rectal cancer surgery. The role of anastomotic leakage in oncological outcome after colorectal cancer surgery is still topic of debate and impact on follow-up and consideration for further treatment remains unclear. Patients included in the international, multicenter, non-inferior, open label, randomized, controlled trials COLOR and COLOR II, comparing laparoscopic surgery for curable colon (COLOR) and rectal (COLOR II) cancer with open surgery, were analyzed. Patients operated by abdominoperineal excision were excluded. Both univariate and multivariate analyses were performed to investigate the impact of leakage on overall survival, disease-free survival, local and distant recurrences, adjusted for possible confounders. Primary endpoints in the COLOR and COLOR II trial were disease-free survival and local recurrence at 3-year follow-up, respectively, and secondary endpoints included anastomotic leakage rate. For colon cancer, anastomotic leakage was not associated with increased percentage of local recurrence or decreased disease-free-survival. For rectal cancer, an increase of local recurrences (13.3% vs 4.6%; hazard ratio 2.96; 95% confidence interval 1.38-6.34; P = 0.005) and a decrease of disease-free survival (53.6% vs 70.9%; hazard ratio 1.67; 95% confidence interval 1.16-2.41; P = 0.006) at 5-year follow-up were found in patients with anastomotic leakage. Short-term morbidity, mortality, and long-term oncological outcomes are negatively influenced by the occurrence of anastomotic leakage after rectal cancer surgery. For colon cancer, no significant effect was observed; however, due to low power, no conclusions on the influence of anastomotic leakage on outcomes after colon surgery could be reached. Clinical awareness of increased risk of local recurrence after anastomotic leakage throughout the follow-up is mandatory.Trial Registration: Registered with ClinicalTrials.gov, number NCT00387842 and NCT00297791.


Smoking habits and risk of fatal stroke: 18 years follow up of the Oslo Study.
To examine the risk of fatal stroke in relation to smoking habits in men screened for the Oslo study. The Oslo study is a prospective, cohort study of the epidemiology and preventive aspects of cardiovascular diseases in middle aged men. Screening started in May 1972 and results after 18 years of follow up are reported. There were 16209 men aged 40-49 years, of whom 16173 had no stroke history. Eighty five men died from stroke, of whom 48 were daily cigarettes smokers, 7 were pipe and cigar smokers, 15 smoked cigarettes and pipe or cigars daily, 11 were previous cigarette smokers, and 4 had never smoked cigarettes. Results of proportional hazards regression analysis adjusted for age, diastolic blood pressure, and glucose concentration showed the following rate ratios (RR) (95% confidence interval) of smoking groups compared with those who had never smoked or had previously smoked: combined cigarette and cigar or pipe smokers, RR = 6.1 (3.0, 12.5); cigarettes only, RR = 4.1 (2.3,7.4); and pipe and/or cigars only RR = 2.2 (0.9,5.5). The overall, age adjusted risk of smoking cigarettes daily was 3.5 and was found to increase with increasing cigarette consumption. Regardless of their smoking group, stroke cases had increased diastolic (DBP) and systolic blood pressure (SBP) when compared with men who had not had a stroke. The absolute differences in DBP and SBP between stroke cases and others for never and previous cigarette smokers versus daily smokers were twice as large: DBP, 12.1 mmHg versus 6.5 mmHg respectively and SBP, 16.0 mmHg versus 7.1 mmHg respectively. A high BMI increased the risk of fatal stroke of never and previous cigarette smokers. Men being treated for hypertension at the time of screening had three times the crude risk of fatal stroke of men who were not taking hypertensive treatment. Daily cigarette smoking increased the risk of fatal stroke three and a half times. Combined cigarette and pipe or cigar smoking had a higher risk than smoking cigarettes only. An increased risk was found in relation to increased daily cigarette consumption.


Ultrastructure of Proteus mirabilis swarmer cell rafts and role of swarming in catheter-associated urinary tract infection.
Proteus mirabilis is a common cause of catheter-associated urinary tract infection (C-UTI). It blocks indwelling urethral catheters through the formation of extensive crystalline biofilms. The obstruction of urine flow can induce episodes of pyelonephritis, septicemia, and shock. P. mirabilis exhibits a type of motility referred to as swarming, in which multicellular rafts of elongated, hyperflagellated swarmer cells form and move rapidly in concert over solid surfaces. It has been suggested that swarming is important in the pathogenesis of C-UTI. In this study we generated a set of stable transposon mutants deficient in swarming and used them to assess the role of swarming in the migration of P. mirabilis over urinary catheters. Swarming was found to be essential for migration over all-silicone catheters. Swarming-deficient mutants were attenuated in migration over hydrogel-coated latex catheters, but those capable of swimming motility were able to move over and infect these surfaces. A novel vapor fixation technique for the preparation of specimens and scanning electron microscopy were used to resolve the ultrastructure of P. mirabilis multicellular rafts. The flagellar filaments of P. mirabilis were found to be highly organized during raft migration and were interwoven in phase to form helical connections between adjacent swarmer cells. Mutants lacking these novel organized structures failed to swarm successfully. We suggest that these structures are important for migration and formation of multicellular rafts. In addition, the highly organized structure of multicellular rafts enables P. mirabilis to initiate C-UTI by migration over catheter surfaces from the urethral meatus into the bladder.


Mechanisms of filtration failure during postischemic injury of the human kidney. A study of the reperfused renal allograft.
Postischemic filtration failure in experimental animals results primarily from depression of the transcapillary hydraulic pressure difference (delta P), a quantity that cannot be determined in humans. To circumvent this limitation we determined the GFR and each of its remaining determinants in transplanted kidneys. Findings in 12 allografts that exhibited subsequent normofiltration (group 1) were compared with those in 11 allografts that exhibited persistent hypofiltration (group 2). Determinations were made intraoperatively in the exposed graft after 1-3 h of reperfusion. GFR (6 +/- 2 vs 29 +/- 5 ml/min) and renal plasma flow by Doppler flow meter (140 +/- 30 vs 315 +/- 49 ml/min) were significantly lower in group 2 than group 1. Morphometric analysis of glomeruli obtained by biopsy and a structural hydrodynamic model of viscous flow revealed the glomerular ultrafiltration coefficient to be similar, averaging 3.5 +/- 0.6 and 3.1 +/- 0.2 ml/(min.mmHg) in group 2 vs 1, respectively. Corresponding values for plasma oncotic pressure were also similar, averaging 19 +/- 1 vs 21 +/- 1 mmHg. We next used a mathematical model of glomerular ultrafiltration and a sensitivity analysis to calculate the prevailing range for delta P from the foregoing measured quantities. This revealed delta P to vary from only 20-21 mmHg in group 2 vs 34-45 mmHg in group 1 (P < 0.001). Further morphometric analysis revealed the diameters of Bowman's space and tubular lumens, as well as the percentage of tubular cells that were necrotic or devoid of brush border, to be similar in the two groups. We thus conclude (a) that delta P depression is the predominant cause of hypofiltration in this form of postischemic injury; and (b) that afferent vasoconstriction rather than tubular obstruction is the proximate cause of the delta P depression.


Long-term benefits of appropriately corrected sagittal alignment in reconstructive surgery for adult spinal deformity: evaluation of clinical outcomes and mechanical failures.
It has been well documented that optimal sagittal alignment is highly correlated with good clinical outcomes in adult spinal deformity (ASD) surgery. However, it remains to be determined whether the clinical benefit of appropriately corrected sagittal alignment can be maintained in the long term. Therefore, the aim of this study was to investigate whether appropriately corrected sagittal alignment continues to offer benefits over time with regard to clinical outcomes and mechanical failure. Patients older than 50 years who underwent ≥ 4-level fusion for ASD and were followed up for ≥ 5 years were included in this study. Appropriateness of sagittal alignment correction was defined as pelvic incidence minus lumbar lordosis ≤ 10°, pelvic tilt ≤ 25°, and sagittal vertical axis ≤ 50 mm. Two groups were created based on this appropriateness: group A (appropriate) and group IA (inappropriate). Clinical outcomes were evaluated using the visual analog scale (VAS), Oswestry Disability Index (ODI), and Scoliosis Research Society Outcomes Questionnaire-22 (SRS-22). The development of mechanical failures, such as rod fracture and proximal junctional kyphosis (PJK), was compared between the two groups. The study included 90 patients with a follow-up duration of 90.3 months. There were 30 patients in group A and 60 patients in group IA. The clinical outcomes at 2 years were significantly better in group A than in group IA in terms of the VAS scores, ODI scores, and all domains of SRS-22. At the final follow-up visit, back VAS and ODI scores were still lower in group A than they were in group IA, but the VAS score for leg pain did not differ between the groups. The SRS-22 score at the final follow-up showed that only the pain and self-image/appearance domains and the total sum were significantly higher in group A than in group IA. The incidence of rod fracture and PJK did not differ between the two groups. The rate of revision surgery for rod fracture or PJK was also similar between the two groups. The clinical benefits from appropriate correction of sagittal alignment continued for a mean of 90.3 months. However, the intergroup difference in clinical outcomes between groups A and IA decreased over time. The development of rod fracture or PJK was not affected by the appropriateness of sagittal alignment.


Mitochondrial DNA deletion mutations in adult mouse cardiac side population cells.
We investigated the presence and potential role of mitochondrial DNA (mtDNA) deletion mutations in adult cardiac stem cells. Cardiac side population (SP) cells were isolated from 12-week-old mice. Standard polymerase chain reaction (PCR) was used to screen for the presence of mtDNA deletion mutations in (a) freshly isolated SP cells and (b) SP cells cultured to passage 10. When present, the abundance of mtDNA deletion mutation was analyzed in single cell colonies. The effect of different levels of deletion mutations on SP cell growth and differentiation was determined. MtDNA deletion mutations were found in both freshly isolated and cultured cells from 12-week-old mice. While there was no significant difference in the number of single cell colonies with mtDNA deletion mutations from any of the groups mentioned above, the abundance of mtDNA deletion mutations was significantly higher in the cultured cells, as determined by quantitative PCR. Within a single clonal cell population, the detectable mtDNA deletion mutations were the same in all cells and unique when compared to deletions of other colonies. We also found that cells harboring high levels of mtDNA deletion mutations (i.e. where deleted mtDNA comprised more than 60% of total mtDNA) had slower proliferation rates and decreased differentiation capacities. Screening cultured adult stem cells for mtDNA deletion mutations as a routine assessment will benefit the biomedical application of adult stem cells.


Selectivity of (±)-citalopram at nicotinic acetylcholine receptors and different inhibitory mechanisms between habenular α3β4* and α9α10 subtypes.
The inhibitory activity of (±)-citalopram on human (h) α3β4, α4β2, and α7 nicotinic acetylcholine receptors (AChRs) was determined by Ca2+ influx assays, whereas its effect on rat α9α10 and mouse habenular α3β4* AChRs by electrophysiological recordings. The Ca2+ influx results clearly establish that (±)-citalopram inhibits (IC50's in μM) hα3β4 AChRs (5.1 ± 1.3) with higher potency than that for hα7 (18.8 ± 1.1) and hα4β2 (19.1 ± 4.2) AChRs. This is in agreement with the [3H]imipramine competition binding results indicating that (±)-citalopram binds to imipramine sites at desensitized hα3β4 with >2-fold higher affinity than that for hα4β2. The electrophysiological, molecular docking, and in silico mutation results indicate that (±)-citalopram competitively inhibits rα9α10 AChRs (7.5 ± 0.9) in a voltage-independent manner by interacting mainly with orthosteric sites, whereas it inhibits a homogeneous population of α3β4* AChRs at MHb (VI) neurons (7.6 ± 1.0) in a voltage-dependent manner by interacting mainly with a luminal site located in the middle of the ion channel, overlapping the imipramine site, which suggests an ion channel blocking mechanism. In conclusion, (±)-citalopram inhibits α3β4 and α9α10 AChRs with higher potency compared to other AChRs but by different mechanisms. (±)-Citalopram also inhibits habenular α3β4*AChRs, supporting the notion that these receptors are important endogenous targets related to their anti-addictive activities.


Peptides from the amino terminal mdm-2-binding domain of p53, designed from conformational analysis, are selectively cytotoxic to transformed cells.
We have synthesized three peptides from the mdm-2 binding domain of human p53, residues 12-26 (PPLSQETFSDLWKLL), residues 12-20, and 17-26. To enable transport of the peptides across the cell membrane and at the same time to maximize the active mdm-2 binding alpha-helical conformation for these peptides, each was attached at its carboxyl terminus to the penetratin sequence, KKWKMRRNQFWVKVQRG, that contains many positively charged residues that stabilize an alpha-helix when present on its carboxyl terminal end. All three peptides were cytotoxic to human cancer cells in culture, whereas a control, unrelated peptide attached to the same penetratin sequence had no effect on these cell lines. The same three cytotoxic peptides had no effect on the growth of normal cells, including human cord blood-derived stem cells. These peptides were as effective in causing cell death in p53-null cancer cells as in those having mutant or normal p53. Peptide-induced cell death is not accompanied by expression of apoptosis-associated proteins such as Bax and waf(p21). Based on these findings, we conclude that the antiproliferative effects of these p53-derived peptides are not completely dependent on p53 activity and may prove useful as general anticancer agents.


Introduction to machine learning.
The machine learning field, which can be briefly defined as enabling computers make successful predictions using past experiences, has exhibited an impressive development recently with the help of the rapid increase in the storage capacity and processing power of computers. Together with many other disciplines, machine learning methods have been widely employed in bioinformatics. The difficulties and cost of biological analyses have led to the development of sophisticated machine learning approaches for this application area. In this chapter, we first review the fundamental concepts of machine learning such as feature assessment, unsupervised versus supervised learning and types of classification. Then, we point out the main issues of designing machine learning experiments and their performance evaluation. Finally, we introduce some supervised learning methods.


Strategy Use in Oral Communication with Competent Synthesis and Complex Interaction.
Strategy use is a critical competence for academic achievement and problem solving in globalised and information-based knowledge economies. It involves skills such as synthesising information from task source materials and elaborating on interlocutors' viewpoints during integrated group discussions. However, evidence from empirical studies on this topic is scarce. We recruited 171 local Hong Kong undergraduate students to participate in an integrated group discussion task in Putonghua as an L2 (i.e., second language) and to complete a strategy use inventory of the task. The students' performances and responses were analysed with multiple statistical methods. The strategy use inventory of the integrated group discussion was validated. Five categories of strategy were identified: active engagement, non-verbal, synthesis, clarification and affective strategies. These strategies significantly predicted task performance (with 19.9% variation), leading to significant improvement in oral production quality. Both the synthesis (the integrative use of information) and active engagement (including elaborating viewpoints) strategies were significantly associated with task performance, which are rarely found in existing oral communication strategy inventories. The participants with high levels of task performance demonstrated significantly more use of the active engagement, clarification and synthesis strategies (with the first two merged in the complex interaction strategy) than those with medium or low task performance levels. The implications of the results are discussed.


TTF-1/p63-Positive Poorly Differentiated NSCLC: A Histogenetic Hypothesis from the Basal Reserve Cell of the Terminal Respiratory Unit.
TTF-1 is expressed in the alveolar epithelium and in the basal cells of distal terminal bronchioles. It is considered the most sensitive and specific marker to define the adenocarcinoma arising from the terminal respiratory unit (TRU). TTF-1, CK7, CK5/6, p63 and p40 are useful for typifying the majority of non-small-cell lung cancers, with TTF and CK7 being typically expressed in adenocarcinomas and the latter three being expressed in squamous cell carcinoma. As tumors with coexpression of both TTF-1 and p63 in the same cells are rare, we describe different cases that coexpress them, suggesting a histogenetic hypothesis of their origin. We report 10 cases of poorly differentiated non-small-cell lung carcinoma (PD-NSCLC). Immunohistochemistry was performed by using TTF-1, p63, p40 (ΔNp63), CK5/6 and CK7. EGFR and BRAF gene mutational analysis was performed by using real-time PCR. All the cases showed coexpression of p63 and TTF-1. Six of them showing CK7+ and CK5/6- immunostaining were diagnosed as "TTF-1+ p63+ adenocarcinoma". The other cases of PD-NSCLC, despite the positivity for CK5/6, were diagnosed as "adenocarcinoma, solid variant", in keeping with the presence of TTF-1 expression and p40 negativity. A "wild type" genotype of EGFR was evidenced in all cases. TTF1 stained positively the alveolar epithelium and the basal reserve cells of TRU, with the latter also being positive for p63. The coexpression of p63 and TTF-1 could suggest the origin from the basal reserve cells of TRU and represent the capability to differentiate towards different histogenetic lines. More aggressive clinical and morphological features could characterize these "basal-type tumors" like those in the better known "basal-like" cancer of the breast.


Steps toward computer analysis of nucleotide sequences.
Advances in recombinant DNA technology have allowed the isolation of large numbers of biologically interesting fragments of DNA. Concomitant improvements in methods for nucleic acid sequencing have led many investigators to characterize their clones by sequencing them. This has resulted in the accumulation of such large amounts of sequence data that computer-assisted methods, with programs directed toward the manipulation of nucleic acid sequences, have become indispensable during the collection and analysis of that data.


Fitness, obesity and risk of heat illness among army trainees.
Exertional heat illness (EHI) affects military personnel, athletes and occupational groups such as agricultural workers, despite knowledge of preventive measures. To evaluate EHI diagnoses during US Army basic training and its associations with fitness and body fat on entering military service. From February 2005 to September 2006, US Army recruits at six different military entrance stations took a pre-accession fitness test, including a 5-min step test scored as pass or fail. Subsequent EHI incidence and incidence rate ratios were analysed with reference to subjects' fitness (step test performance) and whether they met (weight qualified [WQ]) or exceeded body fat (EBF) standards. Among the 8621 WQ and 834 EBF male subjects, there were 67 incidents of EHI within 180 days of entering military service. Among WQ subjects, step test failure was significantly associated with EHI (odds ratio [OR] 2.00, 95% confidence interval [CI] 1.13, 3.53). For those passing the step test, the risk of EHI was significantly higher in EBF than in WQ subjects (OR 3.98, 95% CI 2.17, 7.29). Expected ORs for the joint effects of step test failure and EBF classification under additive and multiplicative models were 4.98 and 7.96, respectively. There were too few women to evaluate their data in detail. This study demonstrated that fitness and body fat are independently associated with incident EHI, and the effect of both was substantially higher. Those with low fitness levels and/or obesity should be evaluated further before engaging in intense physical activity, especially in warmer months.


Successful participant recruitment strategies for an online smokeless tobacco cessation program.
An estimated 22% of Americans currently use smokeless tobacco (ST). Most live in small towns and rural areas that offer few ST cessation resources. Approximately 94 million Americans use the Internet for health-related information, and on-line access is growing among lower-income and less-educated groups. As part of a randomized clinical trial to assess the reach and effectiveness of Web-based programs for delivering an ST cessation intervention, the authors developed and evaluated several methods for overcoming the recruitment challenges associated with Web-based research. This report describes and evaluates these methods. Participants were recruited through: (a) Thematic promotional "releases" to print and broadcast media, (b) Google ads, (c) placement of a link on other Web sites, (d) limited purchase of paid advertising, (e) direct mailings to ST users, and (f) targeted mailings to health care and tobacco control professionals. Combined recruitment activities resulted in more than 23,500 hits on our recruitment website from distinct IP addresses over 15 months, which yielded 2,523 eligible ST users who completed the registration process and enrolled in the study. Self-reports revealed that at least 1,276 (50.6%) of these participants were recruited via mailings, 874 (34.6%) from Google ads or via search engines or links on another Web site, and 373 (14.8%) from all other methods combined. The use of thematic mailings is novel in research settings. Recruitment of study participants went quickly and smoothly. Google ads and mailings to media outlets were the methods that recruited the highest number of participants.


A Community-Based IoT Personalized Wireless Healthcare Solution Trial.
This paper presents an advanced Internet of Things point-of-care bio-fluid analyzer; a LoRa/Bluetooth-enabled electronic reader for biomedical strip-based diagnostics system for personalized monitoring. We undertake test simulations (technology trial without patient subjects) to demonstrate potential of long-range analysis, using a disposable test 'key' and companion Android app to form a diagnostic platform suitable for remote point-of-care screening for urinary tract infection (UTI). The 868 MHz LoRaWAN-enabled personalized monitor demonstrated sound potential with UTI test results being correctly diagnosed and transmitted to a remote secure cloud server in every case. Tests ranged over distances of 1.1-6.0 Km with radio path losses from 119-141 dB. All tests conducted were correctly and robustly received at the base station and relayed to the secure server for inspection. The UTI test strips were visually inspected for correct diagnosis based on color change and verified as 100% accurate. Results from testing across a number of regions indicate that such an Internet of Things medical solution is a robust and simple way to deliver next generation community-based smart diagnostics and disease management to best benefit patients and clinical staff alike. This significant step can be applied to any type of home or region, particularly those lacking suitable mobile signals, broadband connections, or even landlines. It brings subscription-free long-range bio-telemetry to healthcare providers and offers savings on regular clinician home visits or frequent clinic visits by the chronically ill. This paper highlights practical hurdles in establishing an Internet of Medical Things network, assisting informed deployment of similar future systems.


Meticulously detailed eye region model and its application to analysis of facial images.
We propose a system that is capable of detailed analysis of eye region images in terms of the position of the iris, degree of eyelid opening, and the shape, complexity, and texture of the eyelids. The system uses a generative eye region model that parameterizes the fine structure and motion of an eye. The structure parameters represent structural individuality of the eye, including the size and color of the iris, the width, boldness, and complexity of the eyelids, the width of the bulge below the eye, and the width of the illumination reflection on the bulge. The motion parameters represent movement of the eye, including the up-down position of the upper and lower eyelids and the 2D position of the iris. The system first registers the eye model to the input in a particular frame and individualizes it by adjusting the structure parameters. The system then tracks motion of the eye by estimating the motion parameters across the entire image sequence. Combined with image stabilization to compensate for appearance changes due to head motion, the system achieves accurate registration and motion recovery of eyes.


Diverse regulation of claudin-1 and claudin-4 in atopic dermatitis.
Tight junctions are important for skin barrier function. The tight junction protein claudin 1 (Cldn-1) has been reported to be down-regulated in nonlesional skin of atopic dermatitis (AD) patients. In contrast, we did not observe a significant down-regulation of Cldn-1 in nonlesional skin of the AD cohort used in this study. However, for the first time, a significant down-regulation of Cldn-1 in the upper and lower epidermal layers of lesional skin was detected. In addition, there was a significant up-regulation of Cldn-4 in nonlesional, but not lesional, AD skin. For occludin, no significant alterations were observed. In an AD-like allergic dermatitis mouse model, Cldn-1 down-regulation in eczema was significantly influenced by dermal inflammation, and significantly correlated with hallmarks of eczema (ie, increased keratinocyte proliferation, altered keratinocyte differentiation, increased epidermal thickness, and impaired barrier function). In human epidermal equivalents, the addition of IL-4, IL-13, and IL-31 resulted in a down-regulation of Cldn-1, and Cldn1 knockdown in keratinocytes resulted in abnormal differentiation. In summary, we provide the first evidence that Cldn-1 and Cldn-4 are differentially involved in AD pathogenesis. Our data suggest a role of Cldn-1 in AD eczema formation triggered by inflammation.


Frequency of viral etiology in symptomatic adult upper respiratory tract infections.
To determine the frequency of viral pathogens causing upper respiratory tract infections in non-hospitalized, symptomatic adults in the city of Rio de Janeiro. Respiratory samples (nasal/throat swabs) were collected between August 2010 and November 2012 and real time PCR was used to detect different viral pathogens. Viruses were detected in 32.1% (43/134) of samples from 101 patients. Specifically, 9% (12/134) were positive for HBoV, 8.2% (11/134) were positive for HAdV, 5.2% (7/134) were positive for HRV, and 1.5% (2/134) were positive for FLUBV or HMPV, as single infections. HRSV-A, HPIV-3, and HCoV-HKU1 were detected in one (0.75%) sample each. Co-infections were detected in 4.8% (6/134) of the samples. Peaks of viral infections were observed in March, April, May, August, and October. However, positive samples were detected all year round. Only 23.3% (10/43) of the positive samples were collected from patients with febrile illness. Results presented in this report suggest that respiratory viral infections are largely under diagnosed in immunocompetent adults. Although the majority of young adult infections are not life-threatening they may impose a significant burden, especially in developing countries since these individuals represent a large fraction of the working force.


Psychocentricity and participant profiles: implications for lexical processing among multilinguals.
Lexical processing among bilinguals is often affected by complex patterns of individual experience. In this paper we discuss the psychocentric perspective on language representation and processing, which highlights the centrality of individual experience in psycholinguistic experimentation. We discuss applications to the investigation of lexical processing among multilinguals and explore the advantages of using high-density experiments with multilinguals. High density experiments are designed to co-index measures of lexical perception and production, as well as participant profiles. We discuss the challenges associated with the characterization of participant profiles and present a new data visualization technique, that we term Facial Profiles. This technique is based on Chernoff faces developed over 40 years ago. The Facial Profile technique seeks to overcome some of the challenges associated with the use of Chernoff faces, while maintaining the core insight that recoding multivariate data as facial features can engage the human face recognition system and thus enhance our ability to detect and interpret patterns within multivariate datasets. We demonstrate that Facial Profiles can code participant characteristics in lexical processing studies by recoding variables such as reading ability, speaking ability, and listening ability into iconically-related relative sizes of eye, mouth, and ear, respectively. The balance of ability in bilinguals can be captured by creating composite facial profiles or Janus Facial Profiles. We demonstrate the use of Facial Profiles and Janus Facial Profiles in the characterization of participant effects in the study of lexical perception and production.


Enhanced HIV-1 surveillance using molecular epidemiology to study and monitor HIV-1 outbreaks among intravenous drug users (IDUs) in Athens and Bucharest.
A significant increase in HIV-1 diagnoses was reported among Injecting Drug Users (IDUs) in the Athens (17-fold) and Bucharest (9-fold) metropolitan areas starting 2011. Molecular analyses were conducted on HIV-1 sequences from IDUs comprising 51% and 20% of the diagnosed cases among IDUs during 2011-2013 for Greece and Romania, respectively. Phylodynamic analyses were performed using the newly developed birth-death serial skyline model which allows estimating of important epidemiological parameters, as implemented in BEAST programme. Most infections (>90%) occurred within four and three IDU local transmission networks in Athens and Bucharest, respectively. For all Romanian clusters, the viral strains originated from local circulating strains, whereas in Athens, the local strains seeded only two of the four sub-outbreaks. Birth-death skyline plots suggest a more explosive nature for sub-outbreaks in Bucharest than in Athens. In Athens, two sub-outbreaks had been controlled (Re<1.0) by 2013 and two appeared to be endemic (Re∼1). In Bucharest one outbreak continued to expand (Re>1.0) and two had been controlled (Re<1.0). The lead times were shorter for the outbreak in Athens than in Bucharest. Enhanced molecular surveillance proved useful to gain information about the origin, causal pathways, dispersal patterns and transmission dynamics of the outbreaks that can be useful in a public health setting.


Cognitive performance in hypertensive and normotensive older subjects.
Longitudinal studies suggest that hypertension in midlife is associated with cognitive impairment in later life. Cross-sectional studies are difficult to interpret because blood pressure can change with onset of dementia and the inclusion of subjects on treatment and with hypertensive end-organ damage can make analysis difficult. We examined cognitive performance in hypertensive and normotensive subjects without dementia or stroke >/=70 years of age. Cognitive performance was determined with the use of a computerized assessment battery in 107 untreated hypertensives (55 women, age 76+/-4 years, blood pressure, 164+/-9/89+/-7; range, 138 to 179/68 to 99 mm Hg) and 116 normotensives (51 female, age 76+/-4 years, 131+/-10/74+/-7; 108 to 149/60 to 89 mm Hg). Older subjects with hypertension were significantly slower in all tests (reaction time, milliseconds; simple, 346+/-100 versus 318+/-56, P<0.05; memory scanning, 867+/-243 versus 789+/-159, P<0.01; immediate word recognition, 947+/-261 versus 886+/-192, P<0.05; and delayed word recognition, 937+/-230 versus 856+/-184, P<0.05; picture recognition, 952+/-184 versus 894+/-137, P<0.01; spatial memory, 1390+/-439 versus 1258+/-394, P<0.01; excepting choice reaction time, 510+/-75 versus 498+/-72, P=0.08). Accuracy was also impaired in tests of number vigilance, 99.2+/-2.5% versus 99.9+/-0.9, P<0.01; delayed word recognition, 83.5+/-16 versus 87.9+/-9.8, P<0.01; and spatial memory 64+/-32 versus 79+/-20, P<0.001. Hypertension in older subjects is associated with impaired cognition in a broad range of areas in the absence of clinically evident target organ damage.


An epidemiological perspective on the future of direct-to-consumer personal genome testing.
Personal genome testing is offered via the internet directly to consumers. Most tests that are currently offered use data from genome-wide scans to predict risks for multiple common diseases and traits. The utility of these tests is limited, predominantly because they lack predictive ability and clear benefits for disease prevention that are specific for genetic risk groups. In the near future, personal genome tests will likely be based on whole genome sequencing, but will these technological advances increase the utility of personal genome testing? Whole genome sequencing theoretically provides information about the risks of both monogenic and complex diseases, but the practical utility remains to be demonstrated. The utility of testing depends on the predictive ability of the test, the likelihood of actionable test results, and the options available for the reduction of risks. For monogenic diseases, the likelihood of known mutations will be extremely low in the general population and it will be a challenge to recognize new causal variants among all rare variants that are found using sequencing. For complex diseases, the predictive ability of genetic tests will be mainly restricted by the heritability of the disease, but also by the genetic complexity of the disease etiology, which determines the extent to which the heritability can be understood. Given that numerous genetic and non-genetic risk factors interact in the causation of complex diseases, the predictive ability of genetic models will likely remain modest. Personal genome testing will have minimal benefits for individual consumers unless major breakthroughs are made in the near future.


Cutaneous expression of TREM, vitamin D receptor and HMGB1 in vitamin D deficiency.
Signaling pathways of the vitamin D receptor (VDR) and the triggering receptor expressed on myeloid cells (TREM) have been independently implicated in the biology of numerous of cutaneous pathologies. There is substantial evidence for possible crosstalk between these pathways, though the relationship between VDR and TREMs remains unclear. In this study, we characterize the effects of vitamin D-deficiency and sufficiency on the cutaneous expression of TREM-1, TREM-2, VDR, HMGB1, and RAGE. Cutaneous tissue isolated from Yucatan microswine were immunohistochemically evaluated for epidermal expression of TREM-1, TREM-2, VDR, HMGB1, and RAGE. The swine were fed a vitamin D-deficient or vitamin D-sufficient diet to examine the role of vitamin D state on levels of these markers. In vitamin D-sufficient animals, keratinocytes exhibited elevated levels of TREM-1, TREM-2. Additionally, TREM-1 expression predominated in basal cells, whereas TREM-2 levels were higher in keratinocytes, regardless of vitamin D state. Levels of HMGB1 and RAGE did not differ by vitamin D state. VDR expression was consistently higher in the cytoplasm and nuclei of basal cells, when compared to keratinocytes. Our findings suggest a role of vitamin D in signaling of TREM pathways. Additionally, the TREM ratio may play a role in keratinocyte differentiation and should be explored further. Possible signaling crosstalk between these pathways has a potential role in progression of cutaneous malignancies and other inflammatory pathologies.


Time of flight lidar measurements as an ocean probe.
Photons emitted by a narrow laser beam are followed through multiple scattering events in the ocean until registered by a detector at the source position. A realistic ocean model is used which takes account not only of molecular scattering (Rayleigh) and absorption, but also scattering and absorption by the hydrosols (Mie). The single scattering function for the hydrosols is calculated from Mie theory assuming a relative index of refraction of 1.15 and a size distribution with a modal radius of 3 micro. Targets with various surface albedos (A) are introduced at various distances from the source. The three-dimensional path of the photons is followed by a Monte Carlo technique. When A >/= 0.02 the returned flux per unit photon path length from the targets is greater than the background from the laser beam for any target distance. The returned flux is plotted as a function of the photon path length. In practice the detection distance is limited by the lowest flux that can be detected and the background of natural li ht. Inhomogeneities in the optical properties of the ocean can also be measured in this way.


Precision oncology in advanced cancer patients improves overall survival with lower weekly healthcare costs.
The impact of precision oncology on guiding treatment decisions of late-stage cancer patients was previously studied in a retrospective analysis. However, the overall survival and costs were not previously evaluated. We report the overall survival and healthcare costs associated with precision oncology in these patients with advanced cancer. Building on a matched cohort study of 44 patients with metastatic cancer who received all of their care within a single institution, we evaluated the overall survival and healthcare costs for each patient. We analyzed the outcomes of 22 patients who received genomic testing and targeted therapy (precision oncology) between July 1, 2013 and January 31, 2015, and compared to 22 historically controlled patients (control) who received standard chemotherapy (N = 17) or best supportive care (N = 5). The median overall survival was 51.7 weeks for the targeted treatment group and 25.8 weeks for the control group (P = 0.008) when matching on age, gender, histological diagnosis and previous treatment lines. Average costs over the entire period were $2,720 per week for the targeted treatment group and $3,453 per week for the control group, (P = 0.036). A separate analysis of 1,814 patients with late-stage cancer diagnoses found that those who received a targeted cancer treatment (N = 93) had 6.9% lower costs in the last 3 months of life compared with those who did not. These findings suggest that precision oncology may improve overall survival for refractory cancer patients while lowering average per-week healthcare costs, resource utilization and end-of-life costs.


Managing opioid use disorder in primary care: PEER simplified guideline.
To use the best available evidence and principles of shared, informed decision making to develop a clinical practice guideline for a simplified approach to managing opioid use disorder (OUD) in primary care. Eleven health care and allied health professionals representing various practice settings, professions, and locations created a list of key questions relevant to the management of OUD in primary care. These questions related to the treatment setting, diagnosis, treatment, and management of comorbidities in OUD. The questions were researched by a team with expertise in evidence evaluation using a series of systematic reviews of randomized controlled trials. The Guideline Committee used the systematic reviews to create recommendations. Recommendations outline the role of primary care in treating patients with OUD, as well as pharmacologic and psychotherapy treatments and various prescribing practices (eg, urine drug testing and contracts). Specific recommendations could not be made for management of comorbidities in patients with OUD owing to limited evidence. The recommendations will help simplify the complex management of patients with OUD in primary care. They will aid clinicians and patients in making informed decisions regarding their care.


Oral treatment with herbal formula B307 alleviates cardiac failure in aging R6/2 mice with Huntington's disease via suppressing oxidative stress, inflammation, and apoptosis.
Cardiac failure is often observed in aging patients with Huntington's disease (HD). However, conventional pharmacological treatments for cardiac failure in HD patients have rarely been studied. Chinese herbal medicines, especially combined herbal formulas, have been widely used to treat cardiac dysfunctions over the centuries. Thus, we assess whether oral treatment with herbal formula B307 can alleviate cardiac failure in transgenic mice with HD. After oral B307 or vehicle treatment for 2 weeks, cardiac function and cardiomyocytes in 12-week-old male R6/2 HD mice and their wild-type littermate controls (WT) were examined and then compared via echocardiography, immunohistochemistry, and Western blotting. We found that cardiac performance in aging R6/2 HD mice had significantly deteriorated in comparison with their WT (P<0.01). Cardiac expressions of superoxide dismutase 2 (SOD2) and B-cell lymphoma 2 (Bcl-2) in aging R6/2 HD mice were significantly lower than their WT (P<0.01), but cardiac expressions of tumor necrosis factor alpha (TNF-α), neurotrophin-3 (3-NT), 4-hydroxynonenal (4-HNE), Bcl-2-associated X protein (Bax), calpain, caspase 12, caspase 9, and caspase 3 of aging R6/2 HD mice were significantly higher than their WT (P<0.05). Furthermore, we found that cardiac performance in aging R6/2 HD mice had significantly improved under oral B307 treatment (P<0.05). Cardiac expressions of SOD2 and Bcl-2 of aging R6/2 HD mice were significantly higher under oral B307 treatment (P<0.01), but cardiac expressions of TNF-α, 3-NT, 4-HNE, Bax, calpain, caspase 12, caspase 9, and caspase 3 of aging R6/2 HD mice were significantly reduced under oral B307 treatment (P<0.05). Oral B307 treatment may briefly alleviate cardiac failure in aging HD R6/2 mice via suppressing cardiac oxidative stress, inflammation, and apoptosis. We suggested that the herbal formula B307 may be further developed as a potential health supplement for ameliorating cardiac failure associated with aging.


Multifocal diabetic muscle infarction: a rare complication of poorly controlled diabetes mellitus.
Diabetic muscle infarction (DMI) is a rare complication of long-standing poorly controlled diabetes mellitus. We herein describe the case of a 56-year-old man with a 10-year history of poorly controlled type 2 diabetes mellitus with multiple microvascular and macrovascular complications who presented with the sudden onset of left thigh pain and swelling. MRI suggested muscle infarction. A muscle biopsy demonstrated coagulation necrosis in the skeletal muscle with inflammation and infarction in the walls of small blood vessels. Physicians should consider DMI in the differential diagnosis of patients with diabetes who present with painful, swollen muscles without systemic signs of infection.


Influence of chronic training workload on the hematological profile: a pilot study in sedentary people, amateur and professional cyclists.
The assessment of hematological profile requires to identify possible sources of biological variability, including exercise-related variations. This study was hence aimed to evaluate hematological profile variations in amateur and professional athletes, and establish their possible dependence on cumulative training volume. The study population consisted of 59 sedentary male subjects, 78 amateur and 80 professional male cyclists, in whom a large number of hematological variables were measured at rest. Red blood cell (RBC) count and hemoglobin were decreased in the two athlete cohorts compared to sedentary subjects, but did not differ between amateur and professional cyclists. Hematocrit was gradually and significantly decreased in parallel with cumulative training volume. Amateur cyclists displayed higher mean corpuscular volume (MCV) and lower mean corpuscular hemoglobin concentration (MCHC) values than sedentary subjects and professional cyclists, whilst mean corpuscular hemoglobin (MCH) was higher in professional cyclists. The reticulocyte count and soluble transferrin receptor (sTFR) values were similar across all groups. Serum ferritin was higher in professional cyclists than in the other two groups, whilst transferrin gradually decreased from sedentary group to the two cohorts of amateur and professional cyclists. In univariate analysis, cumulative training volume was inversely associated with age, body mass index (BMI), RBC count, hematocrit, hemoglobin and transferrin, whilst a positive association was found with ferritin. In multivariate analysis, BMI, RBC count and ferritin remained significantly associated with training volume. These results show that the volume of endurance training may affect some hematological variables.


A typology of drug selling among young adults in the United States.
Although studies have found that young adults who sell drugs are more likely to be involved in risky behaviors than those who do not sell drugs, there has been relatively little research that has explored heterogeneity among young adults who sell drugs. Using a pooled sample of 18 to 25 year olds from the National Survey on Drug Use and Health (2006-2010) who report past-year drug selling (N = 5,373), this study employs latent profile analysis to specify latent groups and assess the correlates of group membership. Findings indicate substantial differences among young adults who sell drugs. In particular, the analysis found four groups of drug sellers: normative (49.6%), club drug users (23.6%), polysubstance users (16.0%), and criminal offenders (10.8%). Club drug users were characterized by high levels of ecstasy and hallucinogen use, polysubstance users were more likely to be depressed and anxious, White and female than the other groups. Criminal offenders were overwhelmingly male and more likely to be comprised of African-Americans and Hispanics. RESULTS indicate that drug selling in early adulthood varies substantially. Contrary to media and popular notions most drug sellers are not involved in crime and polysubstance using drug sellers are in clear need of mental health services. Further, most drug sellers in this age range are White. Findings suggest that policy efforts that operate under the assumption of homogeneity of drug selling may be misguided.


The Role of Hypofractionated Radiation Therapy with Photons, Protons, and Heavy Ions for Treating Extracranial Lesions.
Traditionally, the ability to deliver large doses of ionizing radiation to a tumor has been limited by radiation-induced toxicity to normal surrounding tissues. This was the initial impetus for the development of conventionally fractionated radiation therapy, where large volumes of healthy tissue received radiation and were allowed the time to repair the radiation damage. However, advances in radiation delivery techniques and image guidance have allowed for more ablative doses of radiation to be delivered in a very accurate, conformal, and safe manner with shortened fractionation schemes. Hypofractionated regimens with photons have already transformed how certain tumor types are treated with radiation therapy. Additionally, hypofractionation is able to deliver a complete course of ablative radiation therapy over a shorter period of time compared to conventional fractionation regimens making treatment more convenient to the patient and potentially more cost-effective. Recently, there has been an increased interest in proton therapy because of the potential further improvement in dose distributions achievable due to their unique physical characteristics. Furthermore, with heavier ions the dose conformality is increased and, in addition, there is potentially a higher biological effectiveness compared to protons and photons. Due to the properties mentioned above, charged particle therapy has already become an attractive modality to further investigate the role of hypofractionation in the treatment of various tumors. This review will discuss the rationale and evolution of hypofractionated radiation therapy, the reported clinical success with initially photon and then charged particle modalities, and further potential implementation into treatment regimens going forward.


Ordering self-assembly structures via intermolecular BrS interactions.
Recent research studies have shown that the halogenated benzo[1,2-b:4,5-b']dithiophene (DTBDT) unit as a polymer donor exhibits high charge carrier mobility due to the well-ordered molecular packing and high crystallinity, which is meaningful for achieving highly efficient organic solar cells (OSCs). However, it is difficult to acquire the accurate packing information of polymer materials. Herein, we investigated the self-assembled behaviors of two DTBDT derivatives, 4,8-bis(4-octadecylthiophen-2-yl)benzo[1,2-b:4,5-b']dithiophene (H-DTBDT) and 4,8-bis(5-bromo-4-octadecylthiophen-2-yl)benzo[1,2-b:4,5-b']dithiophene (Br-DTBDT), to elucidate the effect of introducing a bromine atom on molecular packing structures by STM at the 1-phenyloctane/HOPG interface. It is observed that the H-DTBDT molecules exhibit a random arrangement along each lamella, while the Br-DTBDT molecules self-assemble into a highly ordered lamellar structure. Density functional theory (DFT) analysis combined with the topological properties of the electron density at the bond critical points revealed that the existence of weak intermolecular interactions of BrS facilitates the regular packing motif of Br-DTBDT molecules. The results helped us to understand that the BrS bond generally acted as the auxiliary force and can play the primary role in the construction of supramolecular nanostructures.