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Barriers and facilitators to the integration of mental health services into primary health care: a systematic review protocol.

Mental health is an integral part of health and well-being and yet health systems have not adequately responded to the burden of mental disorders. Integrating mental health services into primary health care (PHC) is the most viable way of closing the treatment gap and ensuring that people get the mental health care they need. PHC was formally adapted by the World Health Organization (WHO), and they have since invested enormous amounts of resources across the globe to ensure that integration of mental health services into PHC works. This review will use the SPIDER (Sample, Phenomenon of Interest, Design, Evaluation, Research type) framework approach to identify experiences of mental health integration into PHC; the findings will be reported using the "Best fit" framework synthesis. PubMed, EMBASE, PsycINFO, and Cochrane Central Register of Controlled trials (CENTRAL) will be searched including other sources like the WHO website and OpenGrey database. Assessment of bias and quality will be done at study level using two separate tools to check for the quality of evidence presented. Data synthesis will take on two synergistic approaches (qualitative and quantitative studies). Synthesizing evidence from countries across the globe will provide useful insights into the experiences of integrating mental health services into PHC and how the barriers and challenges have been handled. The findings will be useful to a wide array of stakeholders involved in the implementation of the mental health integration into PHC. The SPIDER framework has been chosen for this review because of its suitable application to qualitative and mixed methods research and will be used as a guide when selecting articles for inclusion. Data extracted will be synthesized using the "Best fit" framework because it has been used before and proved its suitability in producing new conceptual models for explaining decision-making and possible behaviors. Synthesizing evidence from countries across the globe will provide useful insights into the experiences of integrating mental health services into PHC and how the barriers and challenges have been handled. PROSPERO CRD42016052000.

Barriers and facilitators;Integration;Mental health services;Primary health care

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OCT layered tomography of the cornea provides new insights on remodeling after photorefractive keratectomy.

OCT (optical coherence tomography) of corneal layers was generated to analyze the remodeling of the epithelium and stroma after photorefractive keratectomy (PRK). Myopic PRK was performed in 15 patients. One eye underwent manual scraping of epithelium while the other was treated with Epi clear. Epi clear allowed a gentler removal of the epithelium compared to manual scraping. Scheimpflug (Pentacam, OCULUS Optikgerate Gmbh, Wetzlar, Germany) and OCT (RTVue, Optovue Inc., Fremont, California, USA) scans of the cornea were performed before and after PRK (3 months). The OCT scanner and Pentacam acquired 8 and 25 radial 2-D scans of the cornea, respectively. The results showed similar topographic changes on the anterior corneal surface between Scheimpflug and OCT imaging. The curvature of the underlying anterior surface of the stroma after PRK was similar to the anterior corneal surface (air-epithelium interface), when measured with OCT. Aberrometric changes were mostly similar between Scheimpflug and OCT. However, Scheimpflug imaging reported greater changes in spherical aberration and corneal higher order aberrations than OCT after PRK. This is the first study to quantify the curvatures of the stromal layers with OCT after PRK. New insights were gained, which could be useful for refinement of surgical ablation algorithms, refractive procedures and detection of ectasia.

aberrations;cornea;curvature;optical coherence tomography;photorefractive keratectomy

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Bilateral patellar tuberculosis masquerading as infected infrapatellar bursitis.

A 30-year-old woman presented to our outpatient department with complaints of pain and swelling in bilateral infrapatellar regions and a discharging sinus in the right knee over the duration of one year. Radiographs showed lytic regions in bilateral patellae. Samples sent from material curetted from sinus yielded no organism but histopathology reported granulomatous inflammation. Following a fresh magnetic resonance imaging (MRI) scan that revealed the infrapatellar pad of fat communicating with the patellar lesions, an exploration and evacuation was done. Material sent revealed epithelioid cell granulomas with caseous necrosis consistent with tuberculosis (TB). The patient was put on first line anti-tubercular treatment (ATT) and has responded favourably with healing of sinus and patellar lesions. Bilateral infrapatellar bursitis is not rare. However patellar TB as a cause for OMIT is not a common diagnosis. A bilateral patellar involvement has not been reported in literature to the best of our knowledge.

Tuberculosis (TB);infrapatellar bursitis;osteoarticular

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Numerical Development.

In this review, we attempt to integrate two crucial aspects of numerical development: learning the magnitudes of individual numbers and learning arithmetic. Numerical magnitude development involves gaining increasingly precise knowledge of increasing ranges and types of numbers: from nonsymbolic to small symbolic numbers, from smaller to larger whole numbers, and from whole to rational numbers. One reason why this development is important is that precision of numerical magnitude knowledge is correlated with, predictive of, and causally related to both whole and rational number arithmetic. Rational number arithmetic, however, also poses challenges beyond understanding the magnitudes of the individual numbers. Some of these challenges are inherent; they are present for all learners. Other challenges are culturally contingent; they vary from country to country and classroom to classroom. Generating theories and data that help children surmount the challenges of rational number arithmetic is a promising and important goal for future numerical development research.

arithmetic;conceptual understanding;logarithmic-to-linear shift;mathematics achievement;numerical magnitudes;rational numbers

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Early or delayed reconstruction in multi-ligament knee injuries: A systematic review and meta-analysis.

Whether early or delayed surgical intervention in patients with multi-ligament injuries results in better outcomes, is of current and controversial debate. The purpose of this study was to perform a meta-analysis comparing early versus late surgical treatment of multi-ligament knee injuries. We performed a systematic review of Medline, Embase, Scopus, and Google Scholar to identify relevant studies in the English and German literature. Eligibility criteria included studies comparing early or delayed surgical interventions for multi-ligament knee injuries, with a minimum follow-up of two years, reporting the primary clinical outcome using a validated functional scoring system and range of motion. Exclusion criteria were patients treated with multi-trauma, head injury, non-union, lower extremity fractures, or a documented history of previous knee injuries. Publication bias was assessed by funnel plot, and the risk of bias was established using the Cochrane Collaboration's risk of bias tool. Heterogeneity was assessed using χ² and I₂ statistic. Eight studies (n=260 patients) were included in the analysis. 149 patients were treated early with a mean of 10.6days; 111 patients were treated late with a mean of 294days. The pooled estimate for clinical outcome demonstrated that early surgery resulted in significantly higher Lysholm scores (SMD 0.669, 95% CI: 0.379 to 0.959, p=0.0001, I₂=0%). Thirty-one per cent of all patients with early surgery had a normal or near normal knee, whereas only 15% of patients with late reconstruction reported the knee to be normal or near normal. The pooled estimates for total ROM did not demonstrate a significant difference between the groups (SMD 0.113, 95% CI: -0.271 to 0.498, p=0.564, I₂=35.57%). The results of this meta-analysis suggest that early surgical intervention in multi-ligament injuries of the knee produces a significantly superior clinical outcome, compared to late reconstruction. Although an overall trend of improved total range of knee motion was also demonstrated, this was very small and unlikely to be clinically relevant. Level 4; Systematic review and meta-analysis.

Early reconstruction;Knee dislocation;Late reconstruction;Meta-analysis;Multi-ligament knee injuries;Systematic review

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Longitudinal study of the protective effect of hope on reducing body image distress in cancer patients.

Body image distress is well-documented in patients with cancer, but little is known about the course of body image distress over time and the role of psychosocial resources such as hope. This prospective study sought to explore the dynamics between trajectories of body image distress and hope across time. Cancer patients receiving outpatient treatment at a cancer center completed self-reported measures of body image distress (Body Image Scale) and hope (Adult Hope Scale) at baseline (within three months of their cancer diagnosis) and follow-up (six months post-baseline; N = 111). Trajectories of intra-individual change (improved, stable, and declined) for body image distress were calculated based on the minimal clinically important difference (±0.5 baseline SD). There was a significant increase in body image distress at follow-up (p < .05); hope remained stable. Rank-transformed mixed-factor repeated measures analyses of variance revealed significant interactions between body image distress trajectory groups and time on hope, suggesting that patients experiencing improvements in body image distress reported higher levels of hope than those who had stable or deteriorating levels of body image distress F(2,108) = 3.25, p < .05. The findings of this exploratory study suggest that psychosocial resources like hope may also reduce body image distress across time in a sample of cancer patients, although the mechanisms of interaction require further examination. Supportive care could lend greater focus to improving patients' hope to alleviating body image distress.

body image distress;cancer patients;hope;longitudinal;psychological resources

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Cardiac Implantable Electronic Device Infections: Added Complexity and Suboptimal Outcomes With Previously Abandoned Leads.

This study sought to assess the impact of previously abandoned leads on the clinical management of cardiac device infections, notably transvenous lead extraction and subsequent clinical course. The population of patients with cardiac implantable electronic devices continues to grow with a disproportionate increase in device infections, which are invariably life threatening. A potentially complicating issue is the widely practiced strategy of device lead abandonment at the time of system revision, change, or upgrade, which is affecting an increasing number of patients. The study assessed the impact of previously abandoned leads in a prospectively maintained registry of consecutive patients undergoing percutaneous extraction of infected cardiac devices at the Cleveland Clinic between August 1996 and September 2012. The primary clinical endpoint was complete procedural and clinical success defined as the successful removal of the device and all lead material from the vascular space, in the absence of a major complication. Of 1,386 patients with infected cardiac devices, 323 (23.3%) had previously abandoned leads. Failure to achieve the primary endpoint occurred more frequently in patients with abandoned leads (13.0% vs. 3.7%; p < 0.0001). This was primarily due to retention of lead material (11.5% vs. 2.9%; p < 0.0001), which was associated with poor clinical outcomes including higher rates of 1-month mortality (7.4% vs. 3.5% in those without lead remnants). Lead extraction procedures in patients with previously abandoned leads were longer (p < 0.0001), with longer fluoroscopy times (p < 0.0001), and more likely to require specialized extraction tools (94.4% vs. 81.8%; p < 0.0001) or adjunctive rescue femoral workstations (14.9% vs. 2.9%; p < 0.0001). Procedural complications occurred more frequently in patients with previously abandoned leads (11.5% vs. 5.6%; p = 0.0003), which was true for both major (3.7% vs. 1.4%; p = 0.009) and minor complications (7.7% vs. 4.4%; p = 0.02). Previously abandoned leads complicate the management of cardiac device infections, leading to worse clinical outcomes.

complications;device infection;transvenous lead extraction

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Plasma metabolomics for the diagnosis and prognosis of H1N1 influenza pneumonia.

Metabolomics is a tool that has been used for the diagnosis and prognosis of specific diseases. The purpose of this study was to examine if metabolomics could be used as a potential diagnostic and prognostic tool for H1N1 pneumonia. Our hypothesis was that metabolomics can potentially be used early for the diagnosis and prognosis of H1N1 influenza pneumonia. ¹H nuclear magnetic resonance spectroscopy and gas chromatography-mass spectrometry were used to profile the metabolome in 42 patients with H1N1 pneumonia, 31 ventilated control subjects in the intensive care unit (ICU), and 30 culture-positive plasma samples from patients with bacterial community-acquired pneumonia drawn within the first 24 h of hospital admission for diagnosis and prognosis of disease. We found that plasma-based metabolomics from samples taken within 24 h of hospital admission can be used to discriminate H1N1 pneumonia from bacterial pneumonia and nonsurvivors from survivors of H1N1 pneumonia. Moreover, metabolomics is a highly sensitive and specific tool for the 90-day prognosis of mortality in H1N1 pneumonia. This study demonstrates that H1N1 pneumonia can create a quite different plasma metabolic profile from bacterial culture-positive pneumonia and ventilated control subjects in the ICU on the basis of plasma samples taken within 24 h of hospital/ICU admission, early in the course of disease.

Biomarkers;GC-MS;H1N1 pneumonia;Metabolomics;NMR

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Analysis of phylogeny, distribution, and pathogenicity of Botryosphaeriaceae species associated with gummosis of Anacardium in Brazil, with a new species of Lasiodiplodia.

Netto, M. S. B., Lima, W. G., Correia, K. C., da Silva, C. F. B., Thon, M., Martins, R. B., Miller, R. N. G., Michereff, S. J., and Câmara, M. P. S. 2016. Analysis of phylogeny, distribution, and pathogenicity of Botryosphaeriaceae species associated with gummosis of Anacardium in Brazil, with a new species of Lasiodiplodia. We identified Botryosphaeriaceae species associated with gummosis on Anacardium in Brazil. Isolates were sampled and identified on the basis morphology and phylogeny, through analysis of a partial translation elongation factor 1-α sequence, ribosomal DNA internal transcribed spacers, and β-tubulin gene sequence. Ten taxa were identified, namely, Lasiodiplodia brasiliense, L. euphorbicola, L. gonubiensis, L. iraniensis, L. jatrophicola, L. gravistriata sp. nov., L. pseudotheobromae, L. theobromae, Neofusicoccum batangarum, and Pseudofusicoccum stromaticum. Lasiodiplodia theobromae has been previously reported in cashew and is the most prevalent species observed. All the other species are reported here for the first time on this host. All species of Botryosphaeriaceae were pathogenic on detached green cashew shoots. Differences in aggressiveness were observed among the species, with N. batangarum, L. iraniensis, L. jatrophicola, and L. gravistriata characterized as the most aggressive species, whilst L. euphorbicola and L. pseudotheobromae were identified as the least aggressive.

Aggressiveness;Cashew;EF1-α;ITS;Tropical fruit

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The Effect of Uremic Solutes on the Organic Cation Transporter 2.

Chronic kidney disease (CKD) is characterized by the accumulation of uremic solutes; however, little is known about how these solutes affect drug absorption and disposition. The goal of this study is to evaluate the effect of uremic solutes on the organic cation transporter, OCT2, which plays a key role in the renal secretion of many basic drugs. As a second goal, we reviewed the literature to determine whether there was evidence for the effect of CKD on the renal secretion of basic drugs. We first screened 72 uremic solutes as inhibitors of [¹⁴C]-labeled metformin uptake by OCT2. Seven were identified as inhibitors and 3 of them were determined to be clinically relevant. Of the 7 solutes, dimethylamine, malondialdehyde, trimethylamine, homocysteine, indoxyl-β-d-glucuronide, and glutathione disulfide were novel OCT2 inhibitors. For 6 drugs that are known OCT2 substrates, both secretory clearance and glomerular filtration rate declined in parallel with progression of CKD from stage 2 to 4, suggesting that selective effects of uremic solutes on net tubular secretion of organic cations do not occur. Further clinical studies are warranted with a broader range of OCT2 substrates to determine whether CKD may differentially affect tubular secretion of drugs especially in patients with advanced CKD.

OCT;disease states;organic cation transporters;regulatory science;renal clearance

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Feasibility of endoscopic submandibular ganglion neurectomy for drooling.

We performed endoscopic transoral neurectomy of the submandibular and sublingual glands to treat drooling. We bilaterally operated two adult cases with treatment-resistant drooling. In these patients, conventional treatment had failed. Repeated botilinum toxin type A (BOTOX®, Abdi Ibrahim Pharmaceutical Company, Istanbul, Turkey) injections had been effective but were becoming less so. The patients benefited from surgery in that their saliva scores decreased. No issue emerged over 6 months of follow-up. Endoscopic transoral neurectomy of the submandibular and sublingual glands reduces saliva production and allows management of drooling in treatment-resistant patients. Laryngoscope, 127:1604-1607, 2017.

Drooling;saliva;sialorrhea;sublingual glands;submandibular glands

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^99m Tc-tazobactam, a novel infection imaging agent: Radiosynthesis, quality control, biodistribution, and infection imaging studies.

The radiolabeled drug ^99m Tc-tazobactam (^99m Tc-TZB) was developed and assessed as an infection imaging agent in Pseudomonas aeruginosa and Salmonella enterica infection-induced animal models by comparing with inflammation induced animal models. Radiosynthesis of ^99m Tc-TZB was assessed while changing ligand concentration, reducing agent concentration, pH, and reaction time while keeping radioactivity constant (~370 MBq). Percent labeling of the resulting complex was measured using paper chromatography and instant thin layer chromatography. The analysis of the ^99m Tc-TZB complex indicated >95% labeling yield and electrophoresis revealed complex is neutral in nature. The biodistribution study also showed predominantly renal excretion; however liver, stomach, and intestine also showed slight tracer agent uptake. The agent significantly accumulated in Pseudomonas aeruginosa and Salmonella enterica infection induced tissues 3.58 ± 0.26% and 2.43 ± 0.42% respectively at 1 hour postinjection. The inflamed tissue failed to uptake noticeable activity at 1 hour time point. The scintigraphic study results were found in accordance with biodistribution pattern. On the basis of our preliminary results, the newly developed ^99m Tc-TZB can be used to diagnose bacterial infection and to discriminate between infected and inflamed tissues.

99mTc-tazobactam;Beta-lactamases;P. aeruginosa;Radipharmaceuticals;S. enterica;infection diagnosis

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Biomimetic Total Synthesis of (±)-Homodimericin A.

A biomimetic total synthesis of racemic homodimericin A was achieved in seven steps, including two cascade reactions. Aqueous buffer solutions are found to help both the oxidative dimerization cascade and the intramolecular Diels-Alder cascade. This synthetic sequence validates key steps in the biogenetic proposal of homodimericin A.

Negishi coupling;biomimetic synthesis;cascade reactions;homodimericin;total synthesis

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Central conduction abnormalities in patients receiving levodopa-carbidopa intestinal gel infusion.

In recent years, several studies have reported a relatively high frequency of polyneuropathy in patients with Parkinson's disease (PD), in particular, in patients receiving levodopa-carbidopa intestinal gel (LCIG) infusion. In spite of the several patients investigated with nerve conduction studies, no study has prospectively explored a possible central nervous system involvement of patients receiving LCIG infusion. We prospectively evaluated eight PD patients receiving LCIG infusion, who underwent neurophysiological evaluations with nerve conduction studies, visual, somatosensory and motor evoked potentials before LCIG infusion, and 1 and 6 months after. At 6 months follow-up, we found significant reduction in sural nerve SNAP amplitude, increase of central sensory conduction time N22-P40, and increases of central motor conduction time recorded from I dorsal interosseous and tibialis anterior. In PD patients with LCIG infusion, we found a subclinical neurophysiological impairment of both peripheral and central nervous system.

Clinical neurophysiology;Electromyography (EMG);Evoked potentials;Neuropharmacology;Parkinson’s disease

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Loss of Dnmt3a and Dnmt3b does not affect epidermal homeostasis but promotes squamous transformation through PPAR-γ.

The DNA methyltransferase Dnmt3a suppresses tumorigenesis in models of leukemia and lung cancer. Conversely, deregulation of Dnmt3b is thought to generally promote tumorigenesis. However, the role of Dnmt3a and Dnmt3b in many types of cancer remains undefined. Here, we show that Dnmt3a and Dnmt3b are dispensable for homeostasis of the murine epidermis. However, loss of Dnmt3a-but not Dnmt3b-increases the number of carcinogen-induced squamous tumors, without affecting tumor progression. Only upon combined deletion of Dnmt3a and Dnmt3b, squamous carcinomas become more aggressive and metastatic. Mechanistically, Dnmt3a promotes the expression of epidermal differentiation genes by interacting with their enhancers and inhibits the expression of lipid metabolism genes, including PPAR-γ, by directly methylating their promoters. Importantly, inhibition of PPAR-γ partially prevents the increase in tumorigenesis upon deletion of Dnmt3a. Altogether, we demonstrate that Dnmt3a and Dnmt3b protect the epidermis from tumorigenesis and that squamous carcinomas are sensitive to inhibition of PPAR-γ.

DNA methylation;PPARg;cancer biology;developmental biology;enhancers;mouse;promoters;squamous cell carcinomas;stem cells;transcriptional regulation

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Feasibility study in teledermatopathology: An examination of the histopathologic features of mycosis fungoides and spongiotic dermatitis.

Digital pathology offers numerous advantages, allowing remote information sharing using whole slide imaging (WSI) to digitize an entire glass slide (GS) at high resolution, creating a digital slide (DS). In this study, we examine the concordance in diagnoses made on 40 digital slides (DSs) vs traditional GSs in differentiating between spongiotic dermatitis (SD) and patch/plaque-stage mycosis fungoides (MF). Greater interobserver concordance rate in final diagnosis of SD vs MF was observed with the utilization of DS (86.7%) compared with the utilization of GS (80%). Intraobserver concordance rate between the diagnoses rendered by a particular dermatopathologist on GS and DS was 86.7%. For all histopathological criteria, a correlation in the magnitudes of interobserver vs intraobserver discordances suggests that discordance between glass vs digital evaluation of these criteria may be largely expected subjective read variation independent of the media. Discordance in identification of histopathological features did not have a statistically significant link to discordance in diagnosis for 7 out of the 8 features. The similarity between interobserver and intraobserver discordances suggests that WSI does not introduce additional barriers or variability to accurately identify histopathologic feature and to discriminate between MF and SD beyond interobserver variability.

digital;histopathology;mycosis fungoides;spongiotic dermatitis;teledermatopathology

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Influenza virus NS1 protein mutations at position 171 impact innate interferon responses by respiratory epithelial cells.

The influenza virus NS1 protein interacts with a wide range of proteins to suppress the host cell immune response and facilitate virus replication. The amino acid sequence of the 2009 pandemic virus NS1 protein differed from sequences of earlier related viruses. The functional impact of these differences has not been fully defined. Therefore, we made mutations to the NS1 protein based on these sequence differences, and assessed the impact of these changes on host cell interferon (IFN) responses. We found that viruses with mutations at position 171 replicated efficiently but did not induce expression of interferon genes as effectively as wild-type viruses in A459 lung epithelial cells. The decreased ability of these NS1 mutant viruses to induce IFN gene and protein expression correlated with decreased activation of STAT1 and lower levels of IFN-stimulated gene (ISG) expression. These findings demonstrate that mutations at position 171 in the NS1 protein result in decreased expression of IFN and ISGs by A549 cells. Consequently, these viruses may be more virulent than the parental strains that do not contain mutations at position 171 in the NS1 protein.

A459 cells;ISG;Influenza;Interferon;NS1;STAT1

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Simultaneous determination of dechloranes, polybrominated diphenyl ethers and novel brominated flame retardants in food and serum.

A sensitive method for the simultaneous quantification of dechloranes, polybrominated diphenyl ethers (PBDEs) and novel brominated flame retardants (NBFRs) has been developed for gas chromatography (GC) coupled to tandem mass spectrometry operating in electron capture negative ionization (ECNI) mode. The major advance has been achieved by combining selected ion monitoring (SIM) and multiple reaction monitoring (MRM) modes in well-defined time windows, to determine dechloranes, PBDEs and NBFRs at picogram per gram level in one single analysis in complex matrix biological samples. From the chromatographic point of view, efforts were devoted to study several injection modes using multimode inlet (MMI) in order to obtain low instrumental detection limits, necessary for trace compounds such as Dechlorane Plus (DP) isomers. Method performance was also evaluated: calibration curves were linear from 20 fg μL^-1 to 100 pg μL^-1 for the studied compounds, with method detection limits at levels of 50 fg g^-1 for DPs. Repeatability and reproducibility, expressed as relative standard deviation, were better than 5% even in solvent vent mode for the injection of standards. The application to a wide range of complex samples (including food, human and animal serum samples) indicated a sensitive and reliable way to quantify at the picogram per gram level 4 halogenated norbornenes (HNs), Dechlorane Plus (anti-DP and syn-DP) and 2 of their homologues (Dechlorane-602 and Dechlorane-603), 11 PBDE congeners (no. 28, 47, 49, 66, 85, 99, 100, 153, 154, 183 and 209) and 5 novel BFRs, i.e. decabromodiphenyl ethane (DBDPE), 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE), hexabromobenzene (HBB), 2,3,4,5-tetrabromo-ethylhexyl-benzoate (TBB) and tetrabromophthalate (TBPH). Graphical Abstract GC-ECNI-MS/MS chromatograms showing the most sensitive transition for DPs when injecting 2 μL of a 16 fg/μL standard solution of s-DP and a-DP at three different source temperatures.

Biological matrices;Brominated flame retardants;Chemical ionization;Dechloranes;Gas chromatography;Large volume injection

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Mass spectrometric studies on selective androgen receptor modulators (SARMs) using electron ionization and electrospray ionization/collision-induced dissociation.

Selective androgen receptor modulators (SARMs) have been identified as a promising class of drug candidates potentially applicable to diverse pathological conditions commonly associated with significantly reduced muscle mass. Due to a suspected and meanwhile repeatedly proven misuse of SARMs in elite and amateur sport, sustaining constantly updated doping control analytical methods is critical for sports drug testing laboratories. These test methods predominantly utilize mass spectrometry-based instrumentations and, consequently, studies on the mass spectrometric behavior of new compounds and, where available, their metabolic products are vital for comprehensive doping controls. In this communication, the dissociation patterns of three new SARM drug candidates referred to as GSK2881078, PF-06260414, and TFM-4 AS-1 as observed under electron ionization as well as electrospray ionization/collision-induced dissociation are discussed. By means of high resolution/high accuracy tandem mass spectrometry employing quadrupole-orbitrap mass analyzers, information on precursor-product ion relationships and elemental compositions was obtained and subsequently utilized to suggest dissociation routes of the target compounds. This information can contribute to future studies concerning structure assignments of metabolites and accelerate the identification of related substances if distributed and/or illicitly used in the world of sport.

Doping;anabolics;mass spectrometry;sport

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Dysregulated metabolic enzymes and metabolic reprogramming in cancer cells.

Tumor cells carry various genetic and metabolic alterations, which directly contribute to their growth and malignancy. Links between metabolism and cancer are multifaceted. Metabolic reprogramming, such as enhanced aerobic glycolysis, mutations in the tricarboxylic acid (TCA) cycle metabolic enzymes, and dependence on lipid and glutamine metabolism are key characteristics of cancer cells. Understanding these metabolic alterations is crucial for development of novel anti-cancer therapeutic strategies. In the present review, the broad importance of metabolism in tumor biology is discussed, and the current knowledge on dysregulated metabolic enzymes involved in the vital regulatory steps of glycolysis, the TCA cycle, the pentose phosphate pathway, and lipid, amino acid, and mitochondrial metabolism pathways are reviewed.

cancer metabolism;glycolysis;lipid metabolism;metabolic enzymes;metabolic reprogramming

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Modern drug delivery strategies applied to natural active compounds.

Colloidal drug delivery systems (CDDSs) are innovative carriers that have been studied in pharmaceutical field from many years to overcome unfavorable physical and chemical features of synthetic drugs. Recently the use of CDDS as carriers for phytochemicals has seen an exponential increase which, in some cases, has led to the rediscovery of ancient and forgotten natural molecules. Area covered: This article focuses on the main features of CDDS, particularly micro- and nanoemulsions, vesicular carriers and micro- and nanoparticles, loaded with natural active compounds. A detailed review of the literature is presented, introducing the importance of these systems in terms of their capability to optimize the stability of phytochemicals, their absorption through biological membranes and their bioavailability. Expert opinion: The delivery of phytochemicals is problematic due to poor solubility, poor permeability, low bioavailability, instability in biological milieu and extensive first-pass metabolism. Global research efforts investigating nanotechnology have attempted to overcome these limitations rediscovering and, in some cases, 'discovering ex novo' unexpected virtues and benefits associated to these compounds. The 'nanotechnological approach' can definitely enhance the pharmacokinetics and therapeutic index of natural active compounds and improve their performance in therapy.

Phytochemicals;micro and nanoemulsions;polymeric nanoparticles and lipid nanoparticles;vesicular carriers

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Gold-Catalyzed Dearomatization of 2-Naphthols with Alkynes.

The site-selective dearomatization of naphthols is realized in a straightforward manner through a gold(I)-catalyzed [3,3]-sigmatropic rearrangement/allene functionalization cascade sequence. The method employs readily available naphthylpropargyl ethers as starting materials. A range of densely functionalized dihydrofurylnaphthalen-2(1H)-ones are obtained in high yields (up to 98 %) and extremely mild reaction conditions (reagent grade solvent, air, 10 minute reaction time). A complete theoretical elucidation of the reaction machinery is also proposed, providing a rationale for important issues such as regio- and chemoselectivity.

catalysis;dearomatization;gold;mechanism;naphthol

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Impact of the endoscopist's experience on the negative predictive value of capsule endoscopy.

The impact of the accumulated experience of the capsule endoscopy (CE) reader on the accuracy of this test is discussed. To determine whether the negative predictive value of CE findings changes along the learning curve. We reviewed the first 900 CE read by 3 gastroenterologists experienced in endoscopy over 8 years. These 900 CE were divided into 3 groups (300 CE each): group 1 consisted of the sum of the first 100 CE read by each of the 3 endoscopists; group 2, the sum of the second 100 and groups 3, the sum of the third 100. Patients with normal CE were monitored for at least 28 months to estimate the negative predictive value. A total of 54 (18%) CE in group 1, 58 (19.3%) in group 2 and 47 (15.6%) in group 3 were normal, although only 34 patients in group 1, 38 in group 2 and 36 in group 3 with normal CE completed follow up and were eventually studied. The negative predictive value was 88.2% in group 1, 89.5% in group 2 and 97% in group 3 (P>.05). The negative predictive value tended to increase, but remained high and did not change significantly after the first 100 when readers are experienced in conventional endoscopy and have preliminary specific training.

Capsule endoscopy;Curva de aprendizaje;Cápsula endoscópica;Entrenamiento;Hemorragia digestiva de origen oscuro;Learning curve;Lectura;Negative predictive value;Obscure gastrointestinal bleeding;Reading;Training;Valor predictivo negativo

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Automated identification of sleep states from EEG signals by means of ensemble empirical mode decomposition and random under sampling boosting.

Automatic sleep staging is essential for alleviating the burden of the physicians of analyzing a large volume of data by visual inspection. It is also a precondition for making an automated sleep monitoring system feasible. Further, computerized sleep scoring will expedite large-scale data analysis in sleep research. Nevertheless, most of the existing works on sleep staging are either multichannel or multiple physiological signal based which are uncomfortable for the user and hinder the feasibility of an in-home sleep monitoring device. So, a successful and reliable computer-assisted sleep staging scheme is yet to emerge. In this work, we propose a single channel EEG based algorithm for computerized sleep scoring. In the proposed algorithm, we decompose EEG signal segments using Ensemble Empirical Mode Decomposition (EEMD) and extract various statistical moment based features. The effectiveness of EEMD and statistical features are investigated. Statistical analysis is performed for feature selection. A newly proposed classification technique, namely - Random under sampling boosting (RUSBoost) is introduced for sleep stage classification. This is the first implementation of EEMD in conjunction with RUSBoost to the best of the authors' knowledge. The proposed feature extraction scheme's performance is investigated for various choices of classification models. The algorithmic performance of our scheme is evaluated against contemporary works in the literature. The performance of the proposed method is comparable or better than that of the state-of-the-art ones. The proposed algorithm gives 88.07%, 83.49%, 92.66%, 94.23%, and 98.15% for 6-state to 2-state classification of sleep stages on Sleep-EDF database. Our experimental outcomes reveal that RUSBoost outperforms other classification models for the feature extraction framework presented in this work. Besides, the algorithm proposed in this work demonstrates high detection accuracy for the sleep states S1 and REM. Statistical moment based features in the EEMD domain distinguish the sleep states successfully and efficaciously. The automated sleep scoring scheme propounded herein can eradicate the onus of the clinicians, contribute to the device implementation of a sleep monitoring system, and benefit sleep research.

EEG;EEMD;RUSBoost;Sleep stage classification;Statistical features

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A novel nonsense mutation in a patient with Hermansky-Pudlak syndrome type 4.

HPS4;Hermansky-Pudlak syndrome;Nonsense mutation;Novel mutation;Platelet granule secretion

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Dynamics between doctors and managers in the Italian National Health Care System.

This article focuses on the changes in the Italian NHS by concentrating on patterns in the managerialisation of doctors. It addresses a series of shortcomings in studies on the response by doctors to managerialisation. The first is a shortcoming of theoretical and analytical nature. It is necessary to adopt a broader perspective whereby analysis considers not only the interaction between doctors and managers, but also the public control and regulation agencies that operate in that field. The second shortcoming is a methodological one. The literature on managerialisation is more theoretical than applied. It is necessary to adopt a strategy based on a plurality of methodologies and sources in order to focus attention on a national case (Italy in the present study), discussing the changes over time (from the beginning of managerialisation until today) and considering different groups within the medical profession. The outcome is a complex picture of the dynamics between doctors and managers which foregrounds the managerial co-optation processes of a small group of national health service doctors, the transition from strategic adaptation to forms of resistance against managerialisation by the majority of Italian NHS doctors, and the emergence of restratification processes among self-employed doctors working with the NHS.

management;managerial co-optation;medical resistance;medicine;professionalism;strategic adaptation and professional stratification

pubmed

A turn-on competitive immunochromatographic strips integrated with quantum dots and gold nano-stars for cadmium ion detection.

Immunochromatographic strips (ICSs) are inexpensive, simple, portable, and robust, and therefore have many uses in the medicinal, agricultural, and environmental industries. For detection of small molecules, current ICSs are competitive format (competitive ICSs, CICSs), which only offer a turn-off readout mode, and therefore lead to low sensitivity when evaluating results by the naked eye. To overcome this problem, we report a turn-on CICSs that relies on the ability of gold nano-stars (AuNSs) quenching the signal of quantum dots (QDs). This turn-on CICSs device was applied to detect cadmium ions (Cd²⁺). The linear detection range (LDR) of the turn-on CICSs was 0.25ng/mL-8ng/mL, and the detection of limit (LOD) was 0.18ng/mL. Compared with traditional turn-off CICSs, the sensitivity of the turn-on CICSs was enhanced by 32 times. The turn-on CICSs also has a high specificity and high recovery for the detection of Cd²⁺ in Pearl River (95-112%) and tap water samples (103.5-116.67%). Therefore, we believe the turn-on CICSs offers great potential for the detection of other small molecules in clinical diagnostics, food safety investigations, and environment pollution monitoring.

Cadmium ion;Gold nano-stars;Quantum dots;Turn-on competitive immunochromatographic strip

pubmed

JOURNAL CLUB: Utility of Repeat Core Needle Biopsy of Musculoskeletal Lesions With Initially Nondiagnostic Findings.

The purpose of the present study is to assess the utility of repeat image-guided core needle biopsy (CNB) of musculoskeletal lesions in the setting of initially nondiagnostic CNB findings. A retrospective review was conducted of 1302 consecutive CNBs performed on bone or soft-tissue lesions at a single institution. Pediatric cases and spine lesions were not included. All cases for which a repeat biopsy of the same lesion was performed because biopsy results were nondiagnostic were included in the study. Tumor characteristics, such as lesion size and type (i.e., bone vs soft tissue), were correlated with the diagnostic yield on repeat biopsy. Technical factors, including the modality used, the number of passes performed, the gauge of the biopsy device, the time between biopsies, the radiologist performing the procedure, and the portion of the lesion biopsied, were also correlated. Twenty-six of the 1302 CNBs (2.0%) performed had been referred for repeat biopsy. A diagnosis was obtained for 10 of these 26 cases (38.5%) after repeat CNB. For five of the cases (19.2%), repeat CNB yielded a diagnosis of malignancy. Overall, 11 cases ultimately had histologic findings indicating malignancy, and five of these cases (45.4%) had diagnostic findings after rebiopsy. Of the 14 cases that were found to be benign, five (35.7%) had diagnostic findings after rebiopsy. One case was lost to follow-up. A statistically significant difference in the diagnostic yield was found in association with an increase in the number of passes (p = 0.047) and an increase in time (p = 0.020) between biopsies. Repeat CNB of musculoskeletal lesions with initially nondiagnostic biopsy findings can be useful. Increasing the number of passes on the second biopsy attempt is recommended.

core needle biopsy;diagnostic yield;musculoskeletal lesions;repeat biopsy

pubmed

Maintenance of high quality rat precision cut liver slices during culture to study hepatotoxic responses: Acetaminophen as a model compound.

Precision cut liver slices (PCLiS) represent a promising tool in reflecting hepatotoxic responses. However, the culture of PCLiS varies considerably between laboratories, which can affect the performance of the liver slices and thus the experimental outcome. In this study, we describe an easily accessible culture method, which ensures optimal slice viability and functionality, in order to set the basis for reproducible and comparable PCLiS studies. The quality of the incubated rat PCLiS was assessed during a 24h culture period using ten readouts, which covered viability (lactate dehydrogenase-, aspartate transaminase- and glutamate dehydrogenase-leakage, ATP content) and functionality parameters (urea, albumin production) as well as histomorphology and other descriptive characteristics (protein content, wet weight, slice thickness). The present culture method resulted in high quality liver slices for 24h. Finally, PCLiS were exposed to increasing concentrations of acetaminophen to assess the suitability of the model for the detection of hepatotoxic responses. Six out of ten readouts revealed a toxic effect and showed an excellent mutual correlation. ATP, albumin and histomorphology measurements were identified as the most sensitive readouts. In conclusion, our results indicate that rat PCLiS are a valuable liver model for hepatotoxicity studies, particularly if they are cultured under optimal standardized conditions.

Acetaminophen;Culture conditions;Culture setup;Hepatotoxicity;Precision cut liver slices

pubmed

Understanding aneurysmal type 1 neovascularization (polypoidal choroidal vasculopathy): a lesson in the taxonomy of 'expanded spectra' - a review.

The term aneurysmal type 1 neovascularization is derived from terminology, which is established in the literature but has fallen out of use. We believe that aneurysmal type 1 neovascularization accurately describes the lesions which define the entity known as polypoidal choroidal vasculopathy (PCV). Over the last three decades, the clinical spectrum of PCV has expanded to recognize the occurrence of the aneurysmal (polypoidal) lesions in different contexts, resulting in a complex and unwieldy taxonomy based sometimes on circumstantial findings rather than mechanistic considerations. Advances in multimodal imaging provides increasingly convincing evidence that the lesions which define various forms of PCV are indeed vascular and arise from type 1 neovascular networks. The understanding of PCV as type 1 neovascularization with aneurysms renews focus on the question as to why some patients with type 1 neovascularization develop aneurysms while others do not. Conceptual themes and potential for further study are discussed.

imaging;macular degeneration;neovascularization;pachychoroid;polypoidal

pubmed

Ca²⁺-CaMKKβ pathway is required for adiponectin-induced secretion in rat submandibular gland.

Adiponectin functions as a promoter of saliva secretion in rat submandibular gland via activation of adenosine monophosphate-activated protein kinase (AMPK) and increased paracellular permeability. Ca²⁺ mobilization is the primary signal for fluid secretion in salivary acinar cells. However, whether intracellular Ca²⁺ mobilization is involved in adiponectin-induced salivary secretion is unknown. Here, we found that full-length adiponectin (fAd) increased intracellular Ca²⁺ and saliva secretion in submandibular glands. Pre-perfusion with ethylene glycol-bis (2-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA) combined with thapsigargin (TG), an endoplasmic reticulum Ca²⁺-ATPase inhibitor, abolished fAd-induced salivary secretion, AMPK phosphorylation, and enlarged tight junction (TJ) width. Furthermore, in cultured SMG-C6 cells, co-pretreatment with EGTA and TG suppressed fAd-decreased transepithelial electrical resistance and increased 4-kDa FITC-dextran flux responses. Moreover, fAd increased phosphorylation of calcium/calmodulin-dependent protein kinase (CaMKKβ), a major kinase that is activated by elevated levels of intracellular Ca²⁺, but not liver kinase B1 phosphorylation. Pre-perfusion of the isolated gland with STO-609, an inhibitor of CaMKKβ, abolished fAd-induced salivary secretion, AMPK activation, and enlarged TJ width. CaMKKβ shRNA suppressed, whereas CaMKKβ re-expression rescued fAd-increased paracellular permeability. Taken together, these results indicate that adiponectin induced Ca²⁺ modulation in rat submandibular gland acinar cells. Ca²⁺-CaMKKβ pathway is required for adiponectin-induced secretion through mediating AMPK activation and increase in paracellular permeability in rat submandibular glands.

Adenosine monophosphate-activated protein kinase;Adiponectin;Calcium;Calcium/calmodulin-dependent protein kinase;Secretion;Submandibular gland

pubmed

Delayed risk stratification system in pT1aN0/Nx DTC patients treated without radioactive iodine.

Delayed risk stratification (DRS) system by Momesso and coworkers was accepted by the American Thyroid Association as a diagnostic tool for the risk stratification of unfavorable clinical outcomes and to monitor the clinical outcomes of differentiated thyroid cancer (DTC) patients treated without radioactive iodine (RAI). The aim of this study was to evaluate the DRS system in patients with pT1aN0/Nx stage. The study included 304 low-risk patients after thyroidectomy (<i>n</i> = 202) or lobectomy (<i>n</i> = 102) without RAI and were treated at a single center. The median age was 50.5 years, 91.1% were women and the median follow-up was 4 years. DRS of the treatment response was performed based on medical records and according to the criteria of Momesso and coworkers. Disease course (recurrence, death) and status (remission, persistent disease) on December 31, 2016 were evaluated. The relationship between unfavorable outcomes and the DRS system was evaluated. Response to initial therapy was excellent in 272 patients (89.5%), indeterminate in 31 (10.2%) and biochemical incomplete (increased TgAb levels) in one (0.3%). Two patients in the excellent response group experienced recurrence at 6 and 7 years of follow-up (after lobectomy). None of the patients with indeterminate and biochemical incomplete response developed structural disease, and none of the patients died during the follow-up. The DRS system was not useful for predicting the risk of unfavorable clinical outcomes and cannot be used to personalize the monitoring method of the disease in patients at pT1aN0/Nx stage who are not treated with RAI.

delayed risk stratification system;differentiated thyroid cancer;early stage DTC;thyroid cancer

pubmed

Reasons for family involvement in elective surgical decision-making in Taiwan: a qualitative study.

To inquire into the reasons for family involvement in adult patients' surgical decision-making processes from the point of view of the patients' family. Making a patient the centre of medical decision-making is essential for respecting individual's autonomy. However, in a Chinese society, family members are often deeply involved in a patient's medical decision-making. Although family involvement has long been viewed as an aspect of the Chinese culture, empirical evidence of the reasons for family involvement in medical decision-making has been lacking. A qualitative study. In order to record and examine reasons for family involvement in adult patients' surgical decision-making, 12 different family members of 12 elective surgery patients were interviewed for collecting and analysing data. Three major reasons for family involvement emerged from the data analyses: (1) to share responsibility; (2) to ensure the correctness of medical information; and (3) to safeguard the patient's well-being. These findings also reveal that culture is not the only reason for family involvement. Making decision to undergo a surgery is a tough and stressful process for a patient. Family may provide the patient with timely psychological support to assist the patient to communicate with his or her physician(s) and other medical personnel to ensure their rights. It is also found that due to the imbalanced doctor-patient power relationship, a patient may be unable, unwilling to, or even dare not, tell the whole truth about his or her illness or feelings to the medical personnel. Thus, a patient would expect his or her family to undertake such a mission during the informed consent and decision-making processes. The results of this study may provide medical professionals with relevant insights into family involvement in adult patients' surgical decision-making.

autonomy;decision-making;family;nurse-patient relationships;qualitative study

pubmed

Relationships between kinematics and undulatory underwater swimming performance.

Undulatory underwater swimming (UUS) is one of the major skills contributing to performance in competitive swimming. UUS has two phases- the upbeat is performed by hip extension and knee flexion, and the downbeat is the converse action. The purpose of this study was to determine which kinematic variables of the upbeat and downbeat are associated with prone UUS performance in an elite sample. Ten elite participants were filmed performing three prone 20 m UUS trials. Seven landmarks were manually digitised to calculate eighteen kinematic variables, plus the performance variable- horizontal centre of mass velocity (V_COM). Mean V_COM was significantly correlated with body wave velocity (upbeat r = 0.81, downbeat r = 0.72), vertical toe velocity (upbeat r = 0.71, downbeat r = 0.86), phase duration (upbeat r = -0.79), peak hip angular velocity (upbeat r = 0.73) and mean knee angular velocity (upbeat r = -0.63), all significant at P < 0.05. A multiple stepwise regression model explained 78% of variance in mean V_COM. Peak toe velocity explained 72% of the variance, and mean body wave velocity explained an additional 6%. Elite swimmers should strive for a high peak toe velocity and a fast caudal transfer of momentum to optimise underwater undulatory swimming performance.

Dolphin kick;body wave;maximum velocity;phase

pubmed

Generation of inhibitory monoclonal antibodies targeting matrix metalloproteinase-14 by motif grafting and CDR optimization.

Matrix metalloproteinase-14 (MMP-14) plays important roles in cancer metastasis, and the failures of broad-spectrum MMP compound inhibitors in clinical trials suggested selectivity is critical. By grafting an MMP-14 specific inhibition motif into complementarity determining region (CDR)-H3 of antibody scaffolds and optimizing other CDRs and the sequences that flank CDR-H3, we isolated a Fab 1F8 showing a binding affinity of 8.3 nM with >1000-fold enhancement on inhibition potency compared to the peptide inhibitor. Yeast surface display and fluorescence-activated cell sorting results indicated that 1F8 was highly selective to MMP-14 and competed with TIMP-2 on binding to the catalytic domain of MMP-14. Converting a low-affinity peptide inhibitor into a high potency antibody, the described methods can be used to develop other inhibitory antibodies of therapeutic significance.

CDR grafting;inhibitory antibody;matrix metalloproteinase;phage display;synthetic library

pubmed

Melting Process of the Peritectic Mixture of Lidocaine and Ibuprofen Interpreted by Site Percolation Theory Model.

Eutectic mixtures are often used in the design and delivery of drugs. In this study, we examined the peritectic mixture of lidocaine (LDC) and ibuprofen (IBP) using differential scanning calorimetry, Raman spectroscopy, and microscopy. The obtained phase diagram showed that as the mixture was heated, first LDC melted at 293 K, then IBP dissolved in the liquefied LDC at 310 K, and finally all remaining crystals melted. In the ¹H NMR spectra, the signals of the carboxyl group in IBP and amide or amine group in LDC shifted to the low magnetic field in the IBP/LDC mixtures, because of the intermolecular interaction between these moieties. Using FTIR spectroscopy, the kinetic "reaction" order of the melting process in the mixtures with excess LDC, equimolar, and excess IBP was determined to be +1/2, -1/2, and 0, respectively. The 2 contacts between the liquidus line and the higher melting line at 310 K at IBP molar fractions of 1/3 and of 2/3 were explained on the basis of the site percolation theory.

FTIR;NMR spectroscopy;Raman spectroscopy;calorimetry (DSC);interaction;kinetics;physical characterization;solid state;thermal analysis;transition

pubmed

Over-Expression of Porcine Myostatin Missense Mutant Leads to A Gender Difference in Skeletal Muscle Growth between Transgenic Male and Female Mice.

Myostatin, a transforming growth factor-β family member, is a negative regulator of skeletal muscle development and growth. Piedmontese cattle breeds have a missense mutation, which results in a cysteine to tyrosine substitution in the mature myostatin protein (C313Y). This loss-of-function mutation in myostatin results in a double-muscled phenotype in cattle. Myostatin propeptide is an inhibitor of myostatin activity and is considered a potential agent to stimulate muscle growth in livestock. In this study, we generated transgenic mice overexpressing porcine myostatin missense mutant (pmMS), C313Y, and wild-type porcine myostatin propeptide (ppMS), respectively, to examine their effects on muscle growth in mice. Enhanced muscle growth was observed in both pmMS and ppMS transgenic female mice and also in ppMS transgenic male mice. However, there was no enhanced muscle growth observed in pmMS transgenic male mice. To explore why there is such a big difference in muscle growth between pmMS and ppMS transgenic male mice, the expression level of androgen receptor (AR) mutant AR45 was measured by Western blot. Results indicated that AR45 expression significantly increased in pmMS transgenic male mice while it decreased dramatically in ppMS transgenic male mice. Our data demonstrate that both pmMS and ppMS act as myostatin inhibitors in the regulation of muscle growth, but the effect of pmMS in male mice is reversed by an increased AR45 expression. These results provide useful insight and basic theory to future studies on improving pork quality by genetically manipulating myostatin expression or by regulating myostatin activity.

androgen receptor 45;muscle growth;porcine myostatin;transgenic mice

pubmed

Evaluation of the prognostic value of liver stiffness in patients with hepatitis C virus treated with triple or dual antiviral therapy: A prospective pilot study.

To evaluate the association between liver stiffness (LS) prior to the initiation of dual/triple therapy and viral response. LS was measured in all patients before treatment was administered. The therapeutic approach was based on hepatic, virological, and immunological evaluations and considered the fact that patients with severe fibrosis (F3) or compensated cirrhosis (F4) in Child-Pugh class A are the primary candidates for triple therapy. In total, 65 hepatitis C virus (HCV) patients were treated with Peg-interferon/ribavirin (Peg-IFN/RBV); 24 patients were classified as genotypes 1/4 (36.92%), and 41 patients were classified as genotypes 2/3 (63.08%) (dual therapy). In addition, 20 HCV treatment-experienced genotype 1 patients were treated with PegIFN-RBV and boceprevir (triple therapy). Wilcoxon rank-sum tests were used to compare the groups. LS significantly differed between dual therapy and triple therapy (P = 0.002). The mean LS value before dual therapy treatment was 8.61 ± 5.79 kPa and was significantly different between patients achieving a sustained virologic response (SVR) 24 weeks after therapy and those who did not (7.23 ± 5.18 kPa vs 11.72 ± 5.99 kPa, respectively, P = 0.0003). The relative risk of non-response to therapy was 4.45 (95%CI: 2.32-8.55). The attributable risk of non-response to therapy was 49%. The mean LS value before triple therapy treatment was 13.29 ± 8.57 kPa and was significantly different between patients achieving and not achieving SVR24 (9.41 ± 5.05 vs 19.11 ± 9.74, respectively; P = 0.008). The relative risk of non-response to therapy was 5.57% (95%CI: 1.50-20.65). The attributable risk of non-response to therapy (70%) was increased compared with dual therapy patients. Pre-treatment stiffness > 12 kPa was significantly associated with non-SVR (P < 0.025) in both groups. Pre-treatment liver stiffness may be useful for predicting the response to treatment in patients treated with either dual or triple anti-HCV therapy.

Antiviral therapy;Chronic hepatitis C;Fibrosis;Liver stiffness;Sustained virological response

pubmed

Discussion of "Combining Health Data Uses to Ignite Health System Learning".

This article is part of a For-Discussion-Section of Methods of Information in Medicine about the paper "Combining Health Data Uses to Ignite Health System Learning" written by John D. Ainsworth and Iain E. Buchan [1]. It is introduced by an editorial. This article contains the combined commentaries invited to independently comment on the paper of Ainsworth and Buchan. In subsequent issues the discussion can continue through letters to the editor. With these comments on the paper "Combining Health Data Uses to Ignite Health System Learning", written by John D. Ainsworth and Iain E. Buchan [1], the journal seeks to stimulate a broad discussion on new ways for combining data sources for the reuse of health data in order to identify new opportunities for health system learning. An international group of experts has been invited by the editor of Methods to comment on this paper. Each of the invited commentaries forms one section of this paper.

Health data reuse; secondary uses;adaptive health systems;healthcare evidence;intelligence pipelines;learning health systems;meaningful use;population health

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Modest agreement in ECG interpretation limits the application of ECG screening in young athletes.

Athlete ECG screening has been recommended by several international sporting bodies; however, a number of controversies remain regarding the accuracy of ECG screening. An important component that has not been assessed is the reproducibility of ECG interpretation. The purpose of this study was to assess the variability of ECG interpretation among experienced physicians when screening a large number of athletes. A sports cardiologist, a sports medicine physician, and an electrophysiologist analyzed 440 consecutive screening ECGs from asymptomatic athletes and were asked to classify the ECGs according to the 2010 European Society of Cardiology criteria as normal (or demonstrating training related ECG changes) or abnormal. When an abnormal ECG was identified, they were asked to outline what follow-up investigations they would recommend. The reported prevalence of abnormal ECGs ranged from 13.4% to 17.5%. Agreement on which ECGs were abnormal ranged from poor (κ = 0.297) to moderate (κ = 0.543) between observers. Suggested follow-up investigations were varied, and follow-up costs ranged from an additional A$30-A$129 per screening episode. Neither of the 2 subjects (0.45%) in the cohort with significant pathology diagnosed as a result of screening were identified correctly by all 3 physicians. Even when experienced physicians interpret athletes' ECGs according to current standards, there is significant interobserver variability that results in false-positive and false-negative results, thus reducing the effectiveness and increasing the social and economic cost of screening.

Electrocardiography;Interpreter variability;Screening;Sudden cardiac death

pubmed

Crystal structure of (E)-3-{[2-(2,4-di-chloro-benzyl-idene)hydrazin-1-yl]carbon-yl}pyridinium chloride trihydrate.

In the title hydrated salt, C13H10Cl2N3O(+)·Cl(-)·3H2O, the organic cation exhibits a dihedral angle of 8.26 (14)° between the mean planes of the pyridinium and benzene rings, and dihedral angles of 8.70 (15) and 15.93 (5)° between the mean planes of the hydrazide group and the benzene and pyridinium rings, respectively. In the crystal, N-H⋯O, N-H⋯Cl, C-H⋯O, C-H⋯Cl, O-H⋯O, O-H⋯N and O-H⋯Cl hydrogen bonds link the complex cations, chloride anions and solvent water mol-ecules into a three-dimensional network.

crystals structure;hydrazide group;hydrogen bonds;pyridinium

pubmed

A systematic approach to initial data analysis is good research practice.

Initial data analysis is conducted independently of the analysis needed to address the research questions. Shortcomings in these first steps may result in inappropriate statistical methods or incorrect conclusions. We outline a framework for initial data analysis and illustrate the impact of initial data analysis on research studies. Examples of reporting of initial data analysis in publications are given. A systematic and careful approach to initial data analysis is needed as good research practice.

data cleaning;data screening;initial data analysis

pubmed

Anti-inflammatory role of DPP-4 inhibitors in a nondiabetic model of glomerular injury.

Dipeptidyl peptidase (DPP)-4 is an enzyme that cleaves and inactivates incretin hormones capable of stimulating insulin secretion from pancreatic β-cells. DPP-4 inhibitors are now widely used for the treatment of type 2 diabetes. Experimental studies have suggested a renoprotective role of DPP-4 inhibitors in various models of diabetic kidney disease, which may be independent of lowering blood glucose levels. In the present study, we examined the effect of DPP-4 inhibitors in the rat Thy-1 glomerulonephritis model, a nondiabetic glomerular injury model. Rats were injected with OX-7 (1.2 mg/kg iv) and treated with the DPP-4 inhibitor alogliptin (20 mg·kg(-1)·day(-1)) or vehicle for 7 days orally by gavage. Alogliptin significantly reduced the number of CD68-positive inflammatory macrophages in the kidney, which was associated with a nonsignificant tendency to ameliorate glomerular injury and reduce proteinuria. Another DPP-4 inhibitor, anagliptin (300 mg·kg(-1)·day(-1) mixed with food) and a glucagon-like peptide-1 receptor agonist, exendin-4 (10 mg/kg sc), similarly reduced CD68-positive macrophage infiltration to the kidney. Furthermore, ex vivo transmigration assays using peritoneal macrophages revealed that exendin-4, but not alogliptin, dose dependently reduced monocyte chemotactic protein-1-stimulated macrophage infiltration. These data suggest that DPP-4 inhibitors reduced macrophage infiltration directly via glucagon-like peptide-1-dependent signaling in the rat Thy-1 nephritis model and indicate that the control of inflammation by DPP-4 inhibitors is useful for the treatment of nondiabetic kidney disease models.

dipeptidyl peptidase-4;glucagon-like peptide-1;nondiabetic kidney disease

pubmed

Synthesis and Preliminary Evaluation of N-Oxide Derivatives for the Prevention of Atherothrombotic Events.

Thrombosis is the main outcome of many cardiovascular diseases. Current treatments to prevent thrombotic events involve the long-term use of antiplatelet drugs. However, this therapy has several limitations, thereby justifying the development of new drugs. A series of N-oxide derivatives (furoxan and benzofuroxan) were synthesized and characterized as potential antiplatelet/antithrombotic compounds. All compounds (3a,b, 4a,b, 8a,b, 9a,b, 13a,b and 14a,b) inhibited platelet aggregation induced by adenosine-5-diphosphate, collagen, and arachidonic acid. All compounds protected mice from pulmonary thromboembolism induced by a mixture of collagen and epinephrine; however, benzofuroxan derivatives (13a,b and 14a,b) were the most active compounds, reducing thromboembolic events by up to 80%. N-oxide derivative 14a did not induce genotoxicity in vivo. In conclusion, 14a has emerged as a new antiplatelet/antithrombotic prototype useful for the prevention of atherothrombotic events.

N-oxide;antiplatelet activity;atherothrombosis;benzofuroxan;bleeding time;furoxan;genotoxicity

pubmed

Identification of novel radiation-induced p53-dependent transcripts extensively regulated during mouse brain development.

Ionizing radiation is a potent activator of the tumor suppressor gene p53, which itself regulates the transcription of genes involved in canonical pathways such as the cell cycle, DNA repair and apoptosis as well as other biological processes like metabolism, autophagy, differentiation and development. In this study, we performed a meta-analysis on gene expression data from different in vivo and in vitro experiments to identify a signature of early radiation-responsive genes which were predicted to be predominantly regulated by p53. Moreover, we found that several genes expressed different transcript isoforms after irradiation in a p53-dependent manner. Among this gene signature, we identified novel p53 targets, some of which have not yet been functionally characterized. Surprisingly, in contrast to genes from the canonical p53-regulated pathways, our gene signature was found to be highly enriched during embryonic and post-natal brain development and during in vitro neuronal differentiation. Furthermore, we could show that for a number of genes, radiation-responsive transcript variants were upregulated during development and differentiation, while radiation non-responsive variants were not. This suggests that radiation exposure of the developing brain and immature cortical neurons results in the p53-mediated activation of a neuronal differentiation program. Overall, our results further increase the knowledge of the radiation-induced p53 network of the embryonic brain and provide more evidence concerning the importance of p53 and its transcriptional targets during mouse brain development.

Alternative splicing;Development;Embryonic brain;Ionizing radiation;Neuronal differentiation;p53 targets

pubmed

Molecular evidence of apoptotic pathway activation in semen samples with high DNA fragmentation.

Male infertility is diagnosed by semen parameters, such as concentration, motility and morphology; however, these are not sufficient for the prediction of male fertility capacity. In the clinical routine, several other sperm functions have been introduced, including the sperm DNA fragmentation test. The objective of the present study was to evaluate sperm chromatin integrity in semen samples. Sperm chromatin dispersion test (SCD) was used in ejaculates from men divided into five groups: normozoospermic, oligozoospermic, asthenozoospermic, oligoasthenozoospermic and cryptozoospermic. The data obtained showed that the SCD percentage appeared to be significantly associated with oligozoospermia diagnosis. We also evaluated total testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH) and inhibin B serum hormonal levels in all samples examined, in order to assess whether DNA fragmentation increase could correlate with abnormal hormonal values. Finally we selected certain samples with an increasing DNA fragmentation and analyzed the molecular activated apoptotic pathways. A significant relationship was found between caspase-3 activation and increased DNA fragmentation.

Apoptotic pathway;DNA fragmentation;caspase;chromatin dispersion test (SCD);male infertility

pubmed

Varying strength of cognitive markers and biomarkers to predict conversion and cognitive decline in an early-stage-enriched mild cognitive impairment sample.

Several cognitive, neuroimaging, and cerebrospinal fluid (CSF) markers predict conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia. However, predictors might be more or less powerful depending on the characteristics of the MCI sample. To investigate which cognitive markers and biomarkers predict conversion to AD dementia and course of cognitive functioning in a MCI sample with a high proportion of early-stage MCI patients. Variables known to predict progression in MCI patients and hypothesized to predict progression in early-stage MCI patients were selected. Cognitive (long-delay free recall, regional primacy score), imaging (hippocampal and entorhinal cortex volumes, fornix fractional anisotropy), and CSF (Aβ1-42/t-tau, Aβ1-42) variables from 36 MCI patients were analyzed with Cox regression and mixed-effect models to determine their individual and combined abilities to predict time to conversion to AD dementia and course of global cognitive functioning, respectively. Those variables hypothesized to predict the course of early-stage MCI patients were most predictive for MCI progression. Specifically, regional primacy score (a measure of word-list position learning) most consistently predicted conversion to AD dementia and course of cognitive functioning. Both the prediction of conversion and course of cognitive functioning were maximized by including CSF Aβ1-42 and fornix integrity biomarkers, respectively, indicating the complementary information carried by cognitive variables and biomarkers. Predictors of MCI progression need to be interpreted in light of the characteristics of the respective MCI sample. Future studies should aim to compare predictive strengths of markers between early-stage and late-stage MCI patients.

Alzheimer's disease;amyloid;cerebrospinal fluid;dementia;diffusion tensor imaging;fornix (brain);magnetic resonance imaging;memory;mild cognitive impairment

pubmed

Adsorption behavior comparison of trivalent and hexavalent chromium on biochar derived from municipal sludge.

In this work, static equilibrium experiments were conducted to distinguish the adsorption performance between the two valence states of chromium on biochar derived from municipal sludge. The removal capacity of Cr(VI) is lower than 7mg/g at the initial chromium concentration range of 50-200mg/L, whereas that of Cr(III) higher than 20mg/g. It indicates that Cr(III) is much easier to be stabilized than Cr(VI). No significant changes in the biochar surface functional groups are observed before and after the adsorption equilibrium, demonstrating the poor contribution of organic matter in chromium adsorption. The main mechanism of heavy metal adsorption by biochar involves (1) surface precipitation through pH increase caused by biochar buffer ability, and (2) exchange between cations in solution (Cd(2+)) and in biochar matrix (e.g. Ca(2+) and Mg(2+)). The reduction of Cr(VI) to Cr(III) is necessary to improve removal efficiency of chromium.

Adsorption;Biochar;Heavy metal;Hexavalent chromium;Trivalent chromium

pubmed

Eating and inflicting pain out of boredom.

In the present study it was investigated whether boredom promotes eating and if so, whether this effect likely reflects an increased drive for rewarding stimulation (positive reinforcement) or more plainly the drive to escape boredom (negative reinforcement). In the latter case, the valence of the stimulation should not matter and people might even be willing to look for negative stimulation, for instance to hurt oneself, just to escape boredom. In two parallel experiments, it was tested whether induced boredom promotes the consumption of chocolate (Experiment 1) and whether participants likewise are more inclined to self-administer electrocutaneous stimuli (Experiment 2). In both experiments, a total of 30 participants attended two separate sessions watching a documentary for 1 h (neutral condition) and a monotonous repetition of a single clip from the same documentary for 1 h (boring condition), in balanced order. During Experiment 1, participants had free access to M&Ms and during Experiment 2 participants could freely self-administer brief electrical shocks. It was found that participants ate more M&Ms when bored but also that they more readily self-administered electrical shocks when bored. It is concluded that eating when bored is not driven by an increased desire for satisfying incentive stimulation, but mainly by the drive to escape monotony.

Boredom;Emotional eating;NSSI;Negative reinforcement;Self-inflicting pain;Self-injury

pubmed

Strategies to Support Sustained Breastfeeding of Late Preterm Multiple Birth Infants.

Strategies to support sustained breastfeeding in late preterm multiple birth infants include developing a family-centered feeding plan in collaboration with the medical team, assessing and supporting breastfeeding sessions, promoting lactogenesis with pumping or manual expression, and activating a support system for families.

breastfeeding;late preterm;multiple birth

pubmed

Mi-1-Mediated Nematode Resistance in Tomatoes is Broken by Short-Term Heat Stress but Recovers Over Time.

Tomato (Solanum lycopersicum L.) is among the most valuable agricultural products, but Meloidogyne spp. (root-knot nematode) infestations result in serious crop losses. In tomato, resistance to root-knot nematodes is controlled by the gene Mi-1, but heat stress interferes with Mi-1-associated resistance. Inconsistent results in published field and greenhouse experiments led us to test the effect of short-term midday heat stress on tomato susceptibility to Meloidogyne incognita race 1. Under controlled day/night temperatures of 25°C/21°C, 'Amelia', which was verified as possessing the Mi-1 gene, was deemed resistant (4.1 ± 0.4 galls/plant) and Rutgers, which does not possess the Mi-1 gene, was susceptible (132 ± 9.9 galls/plant) to M. incognita infection. Exposure to a single 3 hr heat spike of 35°C was sufficient to increase the susceptibility of 'Amelia' but did not affect Rutgers. Despite this change in resistance, Mi-1 gene expression was not affected by heat treatment, or nematode infection. The heat-induced breakdown of Mi-1 resistance in 'Amelia' did recover with time regardless of additional heat exposures and M. incognita infection. These findings would aid in the development of management strategies to protect the tomato crop at times of heightened M. incognita susceptibility.

Meloidogyne incognita;Mi-1 gene;Solanum lycopersicum;heat stress;resistance;root-knot nematode

pubmed

Association of asthma with the risk of acute leukemia and non-Hodgkin lymphoma.

An increasing incidence of hematological malignancies has been observed in children and adults worldwide over the last few decades. Asthma is a common chronic inflammatory disease. The aim of the present meta-analysis was to evaluate the potential association between a history of asthma and the risk of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) and non-Hodgkin lymphoma (NHL). A literature search was performed through PubMed and the Cochrane Database of Systematic Reviews and the Newcastle-Ottawa Scale was used to evaluate the quality of the selected studies. The I² index was used to evaluate heterogeneity and the outcome was measured as the odds ratio (OR) by the random-effects model. A total of 16 case-control studies were included. All the studies were of high quality. The OR for ALL was 0.90 [95% confidence interval (CI): 0.68-1.19; P=0.45; I²=79%]. The OR for AML was 0.85 (95% CI: 0.67-1.08; P=0.19; I²=8%). The OR for NHL was 0.91 (95% CI: 0.83-1.00; P=0.05; I²=0%). Asthma was found to be inversely associated with the risk of NHL. A negative trend of association of asthma with ALL and AML was also observed. However, additional large prospective studies are required to confirm these findings.

acute lymphoblastic leukemia;acute myeloid leukemia;asthma;non-Hodgkin lymphoma

pubmed

Increased peripheral vascular disease risk progressively constrains perfusion adaptability in the skeletal muscle microcirculation.

To determine the impact of progressive elevations in peripheral vascular disease (PVD) risk on microvascular function, we utilized eight rat models spanning "healthy" to "high PVD risk" and used a multiscale approach to interrogate microvascular function and outcomes: healthy: Sprague-Dawley rats (SDR) and lean Zucker rats (LZR); mild risk: SDR on high-salt diet (HSD) and SDR on high-fructose diet (HFD); moderate risk: reduced renal mass-hypertensive rats (RRM) and spontaneously hypertensive rats (SHR); high risk: obese Zucker rats (OZR) and Dahl salt-sensitive rats (DSS). Vascular reactivity and biochemical analyses demonstrated that even mild elevations in PVD risk severely attenuated nitric oxide (NO) bioavailability and caused progressive shifts in arachidonic acid metabolism, increasing thromboxane A2 levels. With the introduction of hypertension, arteriolar myogenic activation and adrenergic constriction were increased. However, while functional hyperemia and fatigue resistance of in situ skeletal muscle were not impacted with mild or moderate PVD risk, blood oxygen handling suggested an increasingly heterogeneous perfusion within resting and contracting skeletal muscle. Analysis of in situ networks demonstrated an increasingly stable and heterogeneous distribution of perfusion at arteriolar bifurcations with elevated PVD risk, a phenomenon that was manifested first in the distal microcirculation and evolved proximally with increasing risk. The increased perfusion distribution heterogeneity and loss of flexibility throughout the microvascular network, the result of the combined effects on NO bioavailability, arachidonic acid metabolism, myogenic activation, and adrenergic constriction, may represent the most accurate predictor of the skeletal muscle microvasculopathy and poor health outcomes associated with chronic elevations in PVD risk.

blood flow regulation;microvascular dysfunction;peripheral vascular disease;rodent models of cardiovascular disease risk;system biology of microcirculation

pubmed

Gender differences in detoxification metabolism of polycyclic aromatic hydrocarbon (chrysene) in scallop Chlamys farreri during the reproduction period.

This study aims to investigate the effects of chrysene (CHR) on biotransformation and detoxification responses of mature scallop Chlamys farreri during the reproduction period. Scallops were exposed to 0.2, 0.8 and 3.2 μg/L CHR for 21 days; at day 10 scallops were induced to spawn. At days 1, 3, 6, 10, 11, 15 and 21, enzymatic activities of 7-ethoxyresorufin O-deethylase (EROD) and glutathione-s-transferase (GST), related mRNA expression levels of CYP1A1, GST-pi and P-glycoprotein (P-gp) in digestive glands and CHR bioaccumulation in tissues were examined by separately analyzing male and female scallops. During the pre-spawn period, CHR concentrations of the treated groups in tissues except the hemolymph increased rapidly. Levels of enzymatic activities and related gene expressions were all induced by the exposure to CHR for females and males. GST activity and GST-pi mRNA expression showed a good time- and dose-dependent relationship only in males, and P-gp mRNA expression exhibited a dose-dependent manner in both sexes. During the post-spawn period, spawning caused significant reductions of bioaccumulation in tissues but the gill and hemolymph. Enzymatic activities and related gene expressions were for females significantly depressed at day 21 at 0.8 or 3.2 μg/L CHR. Overall, females accumulated more CHR than males, while males were more sensitive than females to CHR exposure in gene expressions and enzyme activities. P-gp mRNA expression seemed to be a potential biomarker for PAH exposure. These results will offer the information on CHR biotransformation in this species, and ensure the influence of gender and reproductive status on PAH detoxification metabolism.

Bioaccumulation;CYP1A1;Chlamys farreri;Chrysene;EROD;GST;P-gp

pubmed

Commissioning, implementation and delivery of an interface secondary fracture prevention service within the NHS: Lessons learnt from the Oxfordshire Fracture Prevention Service.

To provide a case history of the service model, commissioning, implementation and delivery of an interface secondary fracture prevention service. Fracture Prevention has been identified as key to reducing the burden on the NHS from an ageing population. The need to have a systematic process for identifying, assessing and ensuring treatment adherence is vital. Delivering the service to identify patients at risk and initiate treatment is important as is the use of a database for patient tracking and the need to ensure that patients remain on treatment to ensure maximum fracture prevention benefit, and cost savings are seen. The process for implementing a Fracture Prevention service can be challenging but identifying the components and working closely with local commissioners can provide the evidence and release the resource required. The key components of a Fracture Prevention Service should include robust case-finding, assessment, treatment initiation, patient education and monitoring.

Adherence;Fracture prevention;Hip fracture;Osteoporosis;Secondary prevention

pubmed

Differential diagnosis of parotid gland tumours: which magnetic resonance findings should be taken in account?

Our aim was to define typical magnetic resonance (MRI) findings in malignant and benign parotid tumours. This study is based on retrospective evaluation of pre-surgical MRI of 94 patients with parotid gland tumours. Histology results were available for all tumours. There were 69 cases of benign (73%) and 25 cases of malignant (27%) tumours, including 44 pleomorphic adenomas, 18 Warthin's tumours, 7 various benign tumours, 6 squamous cell carcinomas, 3 carcinoma ex pleomorphic adenomas, 2 mucoepidermoid carcinomas, 1 adenoid cystic carcinoma and 13 various malignant tumours. The following MRI parameters were evaluated: shape, site, size, margins, signal intensity (SI) on T1w and T2w images, contrast enhancement, signal of cystic content, presence or absence of a capsule, perineural spread, extraglandular growth pattern and cervical adenopathy. Statistical analysis was performed to identify the MRI findings most suggestive of malignancy, and to define the most typical MRI pattern of the most common histologies. Ill-defined margins (p < 0.001), adenopathies (p < 0.001) and infiltrative grown pattern (p < 0.001) were significantly predictive of malignancy. Typical findings of pleomorphic adenoma included hyperintensity on T2w images (p = 0.02), strong contrast enhancement (p < 0.001) and lobulated shape (p = 0.04). Typical findings of Warthin's tumour included hyperintense components on T1w images (p < 0.001), location in the parotid inferior process (p < 0.001) and mild or incomplete contrast enhancement (p = 0.01). SI on T1w and T2w images and contrast enhancement enables differential diagnosis between pleomorphic adenoma and Warthin's tumour.

Differential diagnosis;Histology;Magnetic Resonance Imaging;Neoplasms;Parotid gland

pubmed

Comparative Toxicity by Sex Among Children Treated for Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group.

Epidemiologic studies find sex-based differences in incidence, survival, and long-term outcomes for children with cancer. The purpose of this study was to determine whether male and female patients differ with regard to acute treatment-related toxicities. We reviewed data collected on the Children's cancer group (CCG) high-risk acute lymphoblastic leukemia (ALL-HR) study (CCG-1961), and compared male and female patients' toxicity incidence and related variables in the first four phases of treatment. Similar analyses were performed with standard-risk ALL (ALL-SR) patients enrolled in CCG-1991. Among ALL-HR patients, females had significantly more hospital days, delays in therapy, grade 3 or 4 toxicities (e.g., gastrointestinal, liver), and supportive care interventions (e.g., transfusions, intravenous antibiotics) than males. Females were significantly more likely to have died of treatment-related causes than males (Hazard ratio = 2.8, 95%CI = 1.5-5.3, P = 0.002). Five months after beginning the treatment, the cumulative incidence of treatment-related deaths was 2.6% for females and 1.2% for males. Similar disparities were found among ALL-SR patients, with females experiencing significantly more hospital days and treatment-related toxicities than males. This study complements cancer survivorship studies that also report an increase in treatment-related late effects among females. Risk profiles appear to be different for male and female patients, with females having greater risk of developing both acute and long-term treatment-related toxicities. The underlying biological mechanisms for these sex differences are poorly understood and warrant further study in order to determine how sex-based outcome disparities can be addressed in future clinical trials and practice.

acute lymphoblastic leukemia;acute toxicities;disparities;pediatric oncology;sex

pubmed

Convection-enhanced delivery of sorafenib and suppression of tumor progression in a murine model of brain melanoma through the inhibition of signal transducer and activator of transcription 3.

OBJECT Despite recent advances, metastatic melanoma remains a terminal disease, in which life-threatening brain metastasis occurs in approximately half of patients. Sorafenib is a multikinase inhibitor that induces apoptosis of melanoma cells in vitro. However, systemic administration has been ineffective because adequate tissue concentrations cannot be achieved. This study investigated if convection-enhanced delivery (CED) of sorafenib would enhance tumor control and survival via inhibition of the signal transducer and activator of transcription 3 (Stat3) pathway in a murine model of metastatic brain melanoma. METHODS Melanoma cells treated with sorafenib in vitro were examined for signaling and survival changes. The effect of sorafenib given by CED was assessed by bioluminescent imaging and animal survival. RESULTS The results showed that sorafenib induced cell death in the 4 established melanoma cell lines and in 1 primary cultured melanoma cell line. Sorafenib inhibited Stat3 phosphorylation in HTB65, WYC1, and B16 cells. Accordingly, sorafenib treatment also decreased expression of Mcl-1 mRNA in melanoma cell lines. Because sorafenib targets multiple pathways, the present study demonstrated the contribution of the Stat3 pathway by showing that mouse embryonic fibroblast (MEF) Stat3 +/+ cells were significantly more sensitive to sorafenib than MEF Stat3 -/- cells. In the murine model of melanoma brain metastasis used in this study, CED of sorafenib increased survival by 150% in the treatment group compared with animals receiving the vehicle control (p < 0.01). CED of sorafenib also significantly abrogated tumor growth. CONCLUSIONS The data from this study indicate that local delivery of sorafenib effectively controls brain melanoma. These findings validate further investigation of the use of CED to distribute molecularly targeted agents.

B16-ffluc = firefly luciferase-expressing B16 melanoma cell line;CED = convection-enhanced delivery;DMSO = dimethyl sulfoxide;IC50 = median inhibitory concentration;IL-6 = interleukin 6;PBS = phosphate-buffered saline;Stat3;Stat3 = signal transducer and activator of transcription 3;brain;convection-enhanced delivery;melanoma;mice;oncology;pStat3 = phosphorylation of Stat3;sorafenib

pubmed

LDH-A promotes malignant progression via activation of epithelial-to-mesenchymal transition and conferring stemness in muscle-invasive bladder cancer.

Lactate dehydrogenase-A(LDH-A) is an important rate-limiting enzyme in the Warburg effect. Survival analysis indicated poor clinical outcomes in MIBC with high LDH-A expression. The results of in vitro experiment indicated that LDH-A promotes MIBC cells proliferation, invasion and migration. The positive relationship between LDH-A expression and CSC/EMT markers was confirmed both in invasive bladder cell line and in 136 MIBC specimens. Thus, we conclude that LDH-A may be a promising target for MIBC.

E-cadherin;Epithelial-to-mesenchymal transition;Histone deacetylases;Lactate dehydrogenase-A;Muscle-invasive bladder cancer;Oct4

pubmed

APPL1 acts as a protective factor against podocytes injury in high glucose environment.

APPL1, an intracellular adaptor protein, takes part in numerous metabolic reactions. Although APPL1 plays a key role in glucose metabolism via adiponectin pathway and has been proved associated with type 2 diabetes, little is known about its role in diabetic nephropathy. To explore the role of APPL1 in diabetic nephropathy, we upregulated the expression of APPL1 in cultured mouse podocytes by adenovirus infection and tested the effects of APPL1 overexpression in podocytes treated with high glucose. Here, a mouse podocyte cell line (generated from H-2Kb-tsA58 immortmouse) was cultured and divided into four groups: Group 1 (normal glucose, NG), Group 2 (high glucose, HG), Group 3 (HG and infected with control adenovirus) and Group 4 (HG and infected with Ad-APPL1). Cell vitality of Group 4 is significantly higher than Group 2, but notably lower than Group 1 (P<0.01). The apoptosis rate of Group 4 was much lower (P<0.01) than Group 2 and Group 3. A decrease in phase G0/G1 and an increase in phase S was observed in Group 4 compared with Group 2 (P<0.01). These data suggested the protective role of APPL1 overexpression in high glucose condition. Moreover, the levels of Nephrin, AMPK and p-AMPK were decreased by high-glucose treatment, but increased by APPL1 overexpression. In conclusion, in the experimental high glucose condition, APPL1 acts as a protective factor against podocytes injury through regulating AMPK signaling, and may be a new therapy target for diabetic nephropathy.

AMPK;APPL1;high glucose;podocytes

pubmed

Zinc Accumulation and Tolerance in Solanum nigrum are Plant Growth Dependent.

Zinc tolerance, accumulation, and organic acid production by Solanum nigrum, a known Zn accumulator, was studied during pre- and post-flowering stages of development. The plants, when challenged with Zn concentrations lethal to plantlets, showed an increase in tolerance from pre-flowering to post-flowering, which was accompanied by a reduction of Zn translocation to the aerial plant parts. Treatment with Zn induced a differential response in organic acids according to the plant organ and developmental stage. In the roots, where Zn concentrations were similar in pre- and post-flowering plants, a general decrease in organic acid in pre-flowering roots contrasted with the increase observed in post-flowering plants. In the stems, Zn induced a generalized increase in organic acids at both growth stages while in the leaves, a slight increase in malic and shikimic was observed in pre-flowering plants and only shikimic acid levels were significantly increased in post-flowering plants. This work shows that Zn accumulation and tolerance in S. nigrum vary during plant development--an observation that may be important to improve the efficiency of phytoremediation approaches. Furthermore, the data suggest the involvement of specific organic acids in this response.

Solanum nigrum;organic acids;phytoremediation;plant development/growth phase;zinc accumulation

pubmed

Real-Time Visualization of Platelet Interaction With Micro Structured Surfaces.

Improving the hemocompatibility of artificial implants by micro structuring their surfaces has shown promising results, but the mechanisms which lead to this improvement are not yet understood. Therefore, we built a test setup for real-time visualization of platelet interaction with a plain and two micro structured surfaces. The micro structures, defined by the distance of the plain surface area between the structures, were chosen to be 3 and 30 μm, representing a positive and a negative effect on the hemocompatibility. The main part of the test setup was a flow chamber containing films of low density polyethylene (LDPE) with the differently structured surfaces. For different wall shear stresses, no considerable differences were observed in the platelet-surface interaction for all surface types. Whereas, major differences in flow behavior were observed when comparing the surfaces to each other. The platelets "rolled" along the smooth surface, being in constant contact with the surface material. Although the platelets "rolled" over the surface with small structures as well, they were only in contact with the tips of the structure and therefore had less surface contact with the foreign material. The increased distance and height of the structures of the last surface led to a trapping of platelets between the structures. This resulted in a longer contact time with the foreign material as well as a larger contact area, which both increase the risk of platelet activation, adhesion, and finally clotting. Our results showed the mechanisms which lead to these effects and thus revealed why micro structuring of surfaces impacts the hemocompatibility. Furthermore, we established a test setup which can be used for future investigations on the platelet-structure interactions.

Flow chamber;Hemocompatibility;Live cell imaging;Micro structured surfaces;Visualization of platelets

pubmed

Early-onset facioscapulohumeral muscular dystrophy type 1 with some atypical features.

Facioscapulohumeral muscular dystrophy cases with facial weakness before the age of 5 and signs of shoulder weakness by the age of 10 are defined as early onset. Contraction of the D4Z4 repeat on chromosome 4q35 is causally related to facioscapulohumeral muscular dystrophy type 1, and the residual size of the D4Z4 repeat shows a roughly inverse correlation with the severity of the disease. Contraction of the D4Z4 repeat on chromosome 4q35 is believed to induce a local change in chromatin structure and consequent transcriptional deregulation of 4qter genes. We present early-onset cases in the Polish population that amounted to 21% of our total population with facioscapulohumeral muscular dystrophy. More than 27% of them presented with severe phenotypes (wheelchair dependency). The residual D4Z4 repeat sizes ranged from 1 to 4 units. In addition, even within early-onset facioscapulohumeral muscular dystrophy type 1 phenotypes, some cases had uncommon features (head drop, early disabling contractures, progressive ptosis, and respiratory insufficiency and cardiomyopathy).

4q35 deletion;early-onset facioscapulohumeral muscular dystrophy;infantile facioscapulohumeral muscular dystrophy

pubmed

Maternal-pup interaction disturbances induce long-lasting changes in the newborn rat pulmonary vasculature.

The factors accounting for the pathological maintenance of a high pulmonary vascular (PV) resistance postnatally remain elusive, but neonatal stressors may play a role in this process. Cross-fostering in the immediate neonatal period is associated with adult-onset vascular and behavioral changes, likely triggered by early-in-life stressors. In hypothesizing that fostering newborn rats induces long-lasting PV changes, we evaluated them at 14 days of age during adulthood and compared the findings with animals raised by their biological mothers. Fostering resulted in reduced maternal-pup contact time when compared with control newborns. At 2 wk of age, fostered rats exhibited reduced pulmonary arterial endothelium-dependent relaxation secondary to downregulation of tissue endothelial nitric oxide synthase expression and tetrahydrobiopterin deficiency-induced uncoupling. These changes were associated with neonatal onset-increased ANG II receptor type 1 expression, PV remodeling, and right ventricular hypertrophy that persisted into adulthood. The pulmonary arteries of adult-fostered rats exhibited a higher contraction dose response to ANG II and thromboxane A2, the latter of which was abrogated by the oxidant scavenger Tempol. In conclusion, fostering-induced neonatal stress induces long-standing PV changes modulated via the renin-angiotensin system.

neonatal stressors;pulmonary vasomotor tone;renin angiotensin system

pubmed

Effect of lithium salts addition on the ionic liquid based extraction of essential oil from Farfarae Flos.

In this study, an ionic liquids (ILs) based extraction approach has been successfully applied to the extraction of essential oil from Farfarae Flos, and the effect of lithium chloride was also investigated. The results indicated that the oil yields can be increased by the ILs, and the extraction time can be reduced significantly (from 4h to 2h), compared with the conventional water distillation. The addition of lithium chloride showed different effect according to the structures of ILs, and the oil yields may be related with the structure of cation, while the chemical compositions of essential oil may be related with the anion. The reduction of extraction time and remarkable higher efficiency (5.41-62.17% improved) by combination of lithium salt and proper ILs supports the suitability of the proposed approach.

Chemical composition;Essential oil;Farfarae Flos;Ionic liquids;Lithium salt;Oil yields

pubmed

Nociception-specific blink reflex: pharmacology in healthy volunteers.

The physiology and pharmacology of activation or perception of activation of pain-coding trigeminovascular afferents in humans is fundamental to understanding the biology of headache and developing new treatments. The blink reflex was elicited using a concentric electrode and recorded in four separate sessions, at baseline and two minutes after administration of ramped doses of diazepam (final dose 0.07 mg/kg), fentanyl (final dose 1.11 μg/kg), ketamine (final dose 0.084 mg/kg) and 0.9 % saline solution. The AUC (area under the curve, μV*ms) and the latency (ms) of the ipsi- and contralateral R2 component of the blink reflex were calculated by PC-based offline analysis. Immediately after each block of blink reflex recordings certain psychometric parameters were assessed. There was an effect due to DRUG on the ipsilateral (F 3,60 = 7.3, P < 0.001) AUC as well as on the contralateral (F 3,60 = 6.02, P < 0.001) AUC across the study. A significant decrement in comparison to placebo was observed only for diazepam, affecting the ipsilateral AUC. The scores of alertness, calmness, contentedness, reaction time and precision were not affected by the DRUG across the sessions. Previous studies suggest central, rather than peripheral changes in nociceptive trigeminal transmission in migraine. This study demonstrates a robust effect of benzodiazepine receptor modulation of the nociception specific blink reflex (nBR) without any μ-opiate or glutamate NMDA receptor component. The nociception specific blink reflex offers a reproducible, quantifiable method of assessment of trigeminal nociceptive system in humans that can be used to dissect pharmacology relevant to primary headache disorders.

Migraine;Nociception specific blink reflex (nBR);Pharmacology;Trigeminovascular system

pubmed

G-fibre cell wall development in willow stems during tension wood induction.

Willows (Salix spp.) are important as a potential feedstock for bioenergy and biofuels. Previous work suggested that reaction wood (RW) formation could be a desirable trait for biofuel production in willows as it is associated with increased glucose yields, but willow RW has not been characterized for cell wall components. Fasciclin-like arabinogalactan (FLA) proteins are highly up-regulated in RW of poplars and are considered to be involved in cell adhesion and cellulose biosynthesis. COBRA genes are involved in anisotropic cell expansion by modulating the orientation of cellulose microfibril deposition. This study determined the temporal and spatial deposition of non-cellulosic polysaccharides in cell walls of the tension wood (TW) component of willow RW and compared it with opposite wood (OW) and normal wood (NW) using specific antibodies and confocal laser scanning microscopy and transmission electron microscopy. In addition, the expression patterns of an FLA gene (SxFLA12) and a COBRA-like gene (SxCOBL4) were compared using RNA in situ hybridization. Deposition of the non-cellulosic polysaccharides (1-4)-β-D-galactan, mannan and de-esterified homogalacturonan was found to be highly associated with TW, often with the G-layer itself. Of particular interest was that the G-layer itself can be highly enriched in (1-4)-β-D-galactan, especially in G-fibres where the G-layer is still thickening, which contrasts with previous studies in poplar. Only xylan showed a similar distribution in TW, OW, and NW, being restricted to the secondary cell wall layers. SxFLA12 and SxCOBL4 transcripts were specifically expressed in developing TW, confirming their importance. A model of polysaccharides distribution in developing willow G-fibre cells is presented.

(1–4)-β-D-galactan;CCRC-M38;LM10;LM21;LM5;SxCOBL4;SxFLA12;TEM;fasciclin;gelatinous fibres;homogalacturonan;immunofluorescence;immunogold;in situ hybridization;mannan;reaction wood;tension wood;willow;xylan.

pubmed

Resveratrol, in its natural combination in whole grape, for health promotion and disease management.

The grape antioxidant resveratrol has been a topic of intense research for the past three decades. Resveratrol and other grape ingredients, as well as whole-grape products, have shown considerable promise in health promotion and disease management. Phytochemically, whole grape represents a natural combination of resveratrol and other phytonutrients, as it contains several catechins, anthocyanins, polyphenols, and flavonols. Thus, whole grape products or specific combinations of grape constituents provide us with the possibility of synergistic interactions leading to improved efficacy. Recent research has suggested that whole-grape products may help in maintaining heart health and protect against aging, aging-associated diseases, neurodegeneration, and some cancers. On the basis of available recent literature, the grape fruit or whole-grape products seem to be safer choices for better health and disease prevention. However, for advanced disease conditions, individual grape ingredients (such as resveratrol) or combinations of multiple ingredients, together with existing therapies, appear to be better approaches. Further clinical studies are needed to understand the benefits of grapes and their products in the prevention and management of specific diseases.

clinical trials;grape;resveratrol

pubmed

Elemental composition of two ecologically contrasting seamount fishes, the bluemouth (Helicolenus dactylopterus) and blackspot seabream (Pagellus bogaraveo).

Concentrations of V, Cr, Mn, Co, Ni, Cu, Zn, As, Se, Cd and Pb were determined in muscle, liver and gonads of two ecologically contrasting fishes, Helicolenus dactylopterus (benthic) and Pagellus bogaraveo (benthopelagic). Elevated concentrations of As, Se and Cd found in tissues of both species appear to mirror the contribution of volcanic activity to the natural inputs of elements to Azorean waters. Results showed different element accumulation between the two species. Whereas higher concentrations were found in the liver of P. bogaraveo, elevated values were observed in the muscle of H. dactylopterus. Differences in accumulation are most likely related to metabolic rates, diet specificities and habitat. Concentrations in gonads varied up to four orders of magnitude, being higher and more variable in P. bogaraveo than H. dactylopterus. Elevated values of Cd were detected in gonads of both species despite its non-essential role on metabolic functions, presumably related to elimination.

Bioaccumulation;Condor seamount;Deep sea;Helicolenus dactylopterus;Metals;Pagellus bogaraveo

pubmed

Reduced Port Thoracoscopic Surgery for Mediastinal and Pleural Disease: Experiences in a Single Institution.

The purpose of this study was to present our current experience with reduced port thoracoscopic surgery (RPTS) for the treatment of mediastinal and pleural disease and thereafter discuss its indications and technical challenges. A total of 11 patients underwent surgery by the RPTS approach for the following conditions: thymoma (n = 2), bronchogenic cyst (n = 2), metastatic pleural tumor, thymic cyst, solitary fibrous tumor, pulmonary sequestration, pericardial cyst, neurinoma, and malignant lymphoma (n = 1). An Endo Relief forceps (Hope Denshi Co, Ltd, Chiba, Japan) was used for three of the surgical procedures. The elements of the data set consisted of gender, age, duration of operation, drain placement, hospital stay, mass location, and mass size. The median surgical time was 45 min (range, 40-78 min). There were no intraoperative complications and no need for a second surgery to open additional ports. The duration until chest tube removal was 1 day for all the cases. The median hospital stay was 4 days (range, 3-6 days). The median mass size was 2.2 cm (range, 1.2-4.2 cm). The median length of skin incision was 2.0 cm (range, 2.0-3.5 cm). In conclusion, RPTS for mediastinal and pleural disease may be a possible alternative approach to conventional multiportal video-assisted thoracoscopic surgery (VATS). Although it is technically plausible and feasible for selected cases, the issues of patient acceptability and cosmetic and oncological results remain to be determined in the future with randomized-controlled trials and long-term follow-up.

Mediastinal and pleural disease;Minimally invasive surgery;Reduced port surgery;Single-incision video-assisted thoracoscopic surgery

pubmed

The varying faces of IL-6: From cardiac protection to cardiac failure.

IL6 is a pleiotropic cytokine that is made in response to perturbations in homeostasis. IL6 becomes elevated in the acute response to host injury and can activate immune cells, direct immune cell trafficking, signal protective responses in local tissue, initial the acute phase response or initiate wound healing. In the short term this proinflammatory response is protective and limits host damage. It is when this acute response remains chronically activated that IL6 becomes pathogenic to the host. Chronically elevated IL6 levels lead to chronic inflammation and fibrotic disorders. The heart is a tissue where this temporal regulation of IL6 is very apparent. Studies from myocardial infarction show how short-term IL6 signaling can protect and preserve the heart tissue in response to acute damage, where long term IL6 signaling or an over-production of IL6R protein plays a causal role in cardiovascular disease. Thus, IL6 can be both protective and pathogenic, depending on the kinetics of the host response.

Heart failure;IL6;Myocarditis;Trans-signaling;gp130

pubmed

Evaluating the relationship between cannabis use and IQ in youth and young adults at clinical high risk of psychosis.

Among people with psychosis, those with a history of cannabis use show better cognitive performance than those who are cannabis naïve. It is unknown whether this pattern is present in youth at clinical high risk (CHR) of psychosis. We evaluated relationships between IQ and cannabis use while controlling for use of other substances known to impact cognition in 678 CHR and 263 healthy control (HC) participants. IQ was estimated using the Vocabulary and Block Design subtests of the Wechsler Abbreviated Scale of Intelligence. Drug and alcohol use severity and frequency were assessed with the Alcohol and Drug Use Scale, and we inquired participants' age at first use. CHR were further separated into early and late age at onset of cannabis use sub-groups, and low-, moderate- and high-frequency sub-groups. No significant differences in IQ emerged between CHR or HC cannabis users vs. non-users, or between use frequency groups. CHR late-onset users showed significantly higher IQ than CHR early-onset users. Age at onset of cannabis use was significantly and positively correlated with IQ in CHR only. Results suggest that age at onset of cannabis may be a more important factor for IQ than use current use or use frequency in CHR.

Age at onset;Alcohol;Cannabis;IQ;Prodrome;Schizophrenia

pubmed

Community and hospital acquired Clostridium difficile in South Australia - ribotyping of isolates and a comparison of laboratory detection methods.

A total of 274 samples were screened for toxigenic Clostridium difficile using a combination of several commercially available assays, and positive isolates ribotyped. A two-step algorithm assisted in demonstrating an increased prevalence of C. difficile infection in South Australia of 9·8%, most of which were ribotypes 014 and 052. A glutamate dehydrogenase assay followed by the detection of genes associated with toxin production was the most sensitive and specific algorithm for screening for toxigenic C. difficile. Rapid and accurate detection of toxigenic Clostridium difficile is important for the diagnosis of C. difficile colitis and the management of patients in healthcare institutions to minimize the spread of disease. A critical review of currently available commercial methods supports a recommendation for a 2-step algorithm that is relatively inexpensive and amenable to the routine pathology laboratory. It is anticipated that the detection of C. difficile will increase with improved detection methods, and the ribotype prevalence presented in this manuscript will be useful for any current and future source tracking purposes.

Clostridium difficile;glutamate dehydrogenase;infection control;molecular;ribotyping

pubmed

Evaluation of canine intervertebral disc degeneration in colour-coded computed tomography.

Canine intervertebral disc degeneration can lead to intervertebral disc disease. Mild degenerative changes in the structure of the canine intervertebral disc can be identified in magnetic resonance images, whereas these changes are not visible in computed tomographic images. Therefore, one aim of this study was to detect whether colour-coded computed tomography enhances the visibility of mild degenerative changes in the canine disc structure compared to non-contrast computed tomography. Furthermore, the study aimed to detect if intervertebral disc degeneration could be classified with a higher reliability in colour-coded images than in non-contrast images. Computed tomographic image studies of 144 canine intervertebral discs were coloured using three different lookup tables. Canine intervertebral disc degeneration was evaluated by three observers using a 5-grade classification system and compared to the evaluation of non-contrast CT and MRI images. A moderate to almost perfect intraobserver and a moderate to substantial interobserver agreement were found depending on the used colour code. On comparing non-contrast and colour-coded CT significant differences were found by one observer only. Significant differences in evaluation were found in grading intervertebral disc degeneration in MRI and colour-coded CT. Intervertebral disc degeneration could not be classified with a higher reliability on colour-coded images compared to non-contrast images. Furthermore, colour-coded CT did not enhance the visibility of mild degenerative changes in disc structure compared to non-contrast CT. However, the better intraobserver agreement and the subjective impression of the observers highlighted that the usage of colour encoded CT data sets with a wide range of tonal values of few primary and secondary colours may facilitate evaluation.

Canine;Classification;Colour;Comparison;Computed tomography;Dog;Intervertebral disc degeneration;Magnetic resonance imaging

pubmed

Non-thermal plasma-activated water inactivation of food-borne pathogen on fresh produce.

Non-thermal plasma has been widely considered to be an effective method for decontamination of foods. Recently, numerous studies report that plasma-activated water (PAW) also has outstanding antibacterial ability. This study presents the first report on the potential of PAW for the inactivation of Staphylococcus aureus (S. aureus) inoculated on strawberries. PAW treatments achieved a reduction of S. aureus ranging from 1.6 to 2.3 log at day-0 storage, while 1.7 to 3.4 log at day-4 storage. The inactivation efficiency depended on the plasma-activated time for PAW generation and PAW-treated time of strawberries inoculated with S. aureus. LIVE/DEAD staining and scanning electron microscopy results confirm that PAW could damage the bacterial cell wall. Moreover, optical emission spectra and oxidation reduction potential results demonstrate the inactivation is mainly attributed to oxidative stress induced by reactive oxygen species in PAW. In addition, no significant change was found in color, firmness and pH of the PAW treated strawberries. Thus, PAW can be a promising alternative to traditional sanitizers applied in the fresh produce industry.

Inactivation;Non-thermal plasma-activated water;Reactive oxygen species;Staphylococcus aureus;Strawberries

pubmed

The role of AMP-activated protein kinase in the androgenic potentiation of cannabinoid-induced changes in energy homeostasis.

Orexigenic mediators can impact the hypothalamic feeding circuitry via the activation of AMP-dependent protein kinase (AMPK). Given that testosterone is an orexigenic hormone, we hypothesized that androgenic changes in energy balance are due to enhanced cannabinoid-induced inhibition of anorexigenic proopiomelanocortin (POMC) neurons via activation of AMPK. To this end, whole animal experiments were carried out in gonadectomized male guinea pigs treated subcutaneously with either testosterone propionate (TP; 400 μg) or its sesame oil vehicle (0.1 ml). TP-treated animals displayed increases in energy intake associated with increases in meal size. TP also increased several indices of energy expenditure as well as the p-AMPK/AMPK ratio in the arcuate nucleus (ARC) measured 2 and 24 h posttreatment. Subcutaneous administration of the CB1 receptor antagonist AM251 (3 mg/kg) rapidly blocked the hyperphagic effect of TP. This was mimicked largely upon third ventricular administration of AM251 (10 μg). Electrophysiological studies revealed that TP potentiated the ability of the cannabinoid receptor agonist WIN 55,212-2 to decrease the frequency of miniature excitatory postsynaptic currents in ARC neurons. TP also increased the basal frequency of miniature inhibitory postsynaptic currents. In addition, depolarization-induced suppression (DSE) is potentiated in cells from TP-treated animals and blocked by AM251. The AMPK inhibitor compound C attenuated DSE from TP-treated animals, whereas the AMPK activator metformin enhanced DSE from vehicle-treated animals. These effects occurred in a sizable number of identified POMC neurons. Collectively, these results indicate that the androgen-induced increases in energy intake are mediated via an AMPK-dependent augmentation in endocannabinoid tone onto POMC neurons.

AMP-activated protein kinase;cannabinoid;energy balance;proopiomelanocortin;testosterone

pubmed

Establishing the Framework for Tissue Engineered Heart Pumps.

Development of a natural alternative to cardiac assist devices (CADs) will pave the way to a heart failure therapy which overcomes the disadvantages of current mechanical devices. This work provides the framework for fabrication of a tissue engineered heart pump (TEHP). Artificial heart muscle (AHM) was first fabricated by culturing 4 million rat neonatal cardiac cells on the surface of a fibrin gel. To form a TEHP, AHM was wrapped around an acellular goat carotid artery (GCA) and a chitosan hollow cylinder (CHC) scaffold with either the cardiac cells directly contacting the construct periphery or separated by the fibrin gel. Histology revealed the presence of cardiac cell layer cohesion and adhesion to the fibrin gel scaffold, acellular GCA, and synthesized CHC. Expression of myocytes markers, connexin43 and α-actinin, was also noted. Biopotential measurements revealed the presence of ~2.5 Hz rhythmic propagation of action potential throughout the TEHP. Degradation of the fibrin gel scaffold of the AHM via endogenous proteases may be used as a means of delivering the cardiac cells to cylindrical scaffolds. Further development of the TEHP model by use of multi-stimulus bioreactors may lead to the application of bioengineered CADs.

Cardiac assist devices;Cardiac pumps;Cell culture;Heart failure;Tissue engineering

pubmed

Radical SAM-Mediated Methylation of Ribosomal RNA.

While RNA methylation occurs in all kingdoms of life, the type and the distribution of different methylated species varies substantially among archaea, bacteria, and eukaryotes. The most prevalent type of RNA methylation is methylation of nucleobases. However, despite recent advances in our knowledge of these marks, the biological roles of such modifications are still incompletely understood (Machnicka et al., 2013; Motorin & Helm, 2011; Sergeeva et al., 2014; Sergiev et al., 2011). A number of mechanisms have evolved to enable RNA methylation, which are tuned to the electronic demands of the substrate. Herein, we provide an overview of methods for expression, purification, and activity analysis of a specific type of RNA methylating enzymes, radical SAM methylsynthases. These enzymes modify the amidine carbon atoms of an adenosine, A2503, in bacterial 23S rRNA. The activities of these enzymes have only been recently reconstituted (Yan et al., 2010), which can be attributed to the complex anaerobic catalysis that they perform. As the substrate A2503 is located at the nascent peptide exit tunnel of the bacterial ribosome, methylations catalyzed by these enzymes have profound impact on the biology of the host strain. RlmN, an endogenous protein found in all bacteria, methylates the C2 amidine carbon and contributes to the translational fidelity (Benitez-Paez et al., 2012; Ramu et al., 2011; Vazquez-Laslop, Ramu, Klepacki, Kannan, & Mankin, 2010). Cfr, found in pathogenic species, methylates the C8 amidine carbon, a modification that confers resistance to various classes of antibiotics (Giessing et al., 2009; Long et al., 2006; Smith & Mankin, 2008). Interestingly, C2 methylated adenosine was recently detected in a subset of tRNAs, raising the question of the physiological role of this modification (Benitez-Paez et al., 2012). With an increase in available whole genome sequences, the development of methods to identify target substrates of RNA methylating enzymes (Khoddami & Cairns, 2013; Meyer et al., 2012; Tim, Katharina, & Matthias, 2010), as well as advances in the characterization of their activities, we anticipate the coming years will unravel novel aspects of mechanisms of the RNA methylation and deepen insight into the function of the resulting modification.

2-Methyladenosine;8-Methyladenosine;Cfr;Radical SAM methylation;Ribosomal RNA;RlmN

pubmed

Optimizing Sedation Management to Promote Early Mobilization for Critically Ill Children.

Achieving successful early mobilization for the intubated, critically ill child is dependent on optimizing sedation and analgesia. Finding the fine balance between oversedation and undersedation can be challenging. The ideal is for a child to be lucid and interactive during the daytime and demonstrate normal circadian rhythm for sleep with rest at night. Being alert during the day facilitates active participation in therapy including potential ambulation, while decreasing the risk of delirium during mechanical ventilation. An active state during the day with frequent mobilization promotes restorative sleep at night, which brings with it multiple benefits for healing and recovery. Indeed, this ideal may not be physiologically feasible given a child's critical illness and trajectory, but defining it as the "gold standard" for early mobilization provides a consistent goal for the pediatric intensive care unit (PICU) hospitalization. As such, goal-directed, patient-specific sedation plans are integral to creating a culture of mobility in the PICU. We review currently available sedation strategies for mechanically ventilated children for successful implementation of early mobilization in the PICU, as well as pharmacologic considerations for specific classes of sedative-analgesics.

analgesia;delirium;early mobilization;intensive care units;mechanical ventilation;pediatric;rehabilitation;sedation;sleep

pubmed

Spatial and vertical distribution of metals in sediment cores from Río Espíritu Santo estuary, Puerto Rico, United States.

The concentration and distribution of Cd, Cr, Cu, Fe, Mn, Ni, Pb, and Zn were investigated in three sediment cores representing 100-150years of accumulation in upriver, midriver, and estuarine environments in Río Espíritu Santo (RES), Puerto Rico. Grain-size distribution, organic matter and carbonate content were determined to assess their influence on metal concentrations. Minimum biotoxicity levels of Ni and Cu were exceeded in the upriver and midriver sites, while the minimum biotoxicity level of Cu was exceeded in the estuarine location. Pb concentration decreased by ~35% in the upper portion of the midriver and estuarine cores compared to downcore concentrations as a consequence of leaded gasoline regulation. Enrichment Factors and Geoaccumulation Indices were calculated for each metal revealing high levels of Cu in all three cores, likely from an igneous source. Our results provide a baseline for metal contamination in an area facing further land use change.

Caribbean;Estuary;Metals;Pollution;Puerto Rico;Sediment

pubmed

Nanoscale Single-Element Color Filters.

Visible-light filters constructed from nanostructured materials typically consist of a metallic grating and rely on the excitation of surface plasmon polaritons (SPPs). In order to operate at full efficiency, the number of grating elements needs to be maximized such that light can couple more efficiently to the SPPs through improved diffraction. Such conditions impose a limitation on the compactness of the filter since a larger number of grating elements represents a larger effective size. For emerging applications involving nanoscale transmitters or receivers, a device that can filter localized excitations is highly anticipated but is challenging to realize through grating-type filters. In this work, we present the design of an optical filter operating with a single element, marking a departure from diffractive plasmonic coupling. Our device consists of a ZnO nanorod enclosed by two layers of Ag film. For diffraction-limited light focused on the nanorod, narrow passbands can be realized and tuned via variation of the nanorod diameter across the visible spectrum. The spectral and spatial filtering originates from scattering cancellation localized at the nanorod due to the cavity and nanorod exhibiting opposite effective dipole moments. This ability to realize high-performance optical filtering at the ultimate size introduces intriguing possibilities for nanoscale near-field communication or ultrahigh resolution imaging pixels.

ZnO;color filter;nanoscale filter;optical filter

pubmed

Emotion regulation in adolescents with mental health problems.

Current literature points to a clear and consistent association between poor emotion control and psychopathology in adolescence, a critical developmental period during which most adult mental health problems emerge. However, nearly all of the studies in this literature have assessed emotion regulation in nonclinical cohorts, or indexed this construct using only self-report methodology. The present study compared adolescents with a mental illness (n = 41) to demographically matched controls (n = 45) on an experimental task that required them to either suppress or amplify their emotion expressive behavior in response to images that were either negative or positive in affective valence. Clinical participants (like controls) showed evidence of being able to regulate their behavioral expression of emotion, indicating that the presence of mental health problems in adolescence does not prevent a basic level of control being exercised over the emotions that are expressed to others. However, the capacity to amplify expressive behavior was reduced, particularly for negative emotions. In addition, poorer emotion regulation in the clinical group was associated with reduced quality of life. These data indicate that specific aspects of emotion expressive behavior are disrupted in adolescents with mental illness and are discussed in the context of theoretical models that regard emotion dysregulation as a core, transdiagnostic feature of mental illness.

Emotion regulation;adolescence;expressive behavior;psychopathology;transdiagnostic model

pubmed

Education Intervention "Caregivers Like Me" for Latino Family Caregivers Improved Attitudes Toward Professional Assistance at End-of-life Care.

This study explores the ability of a culturally sensitive and case-based education intervention, Caregivers Like Me, to improve knowledge and attitudes regarding end-of-life (EOL) resources among Latino caregivers. A multicentered, cross-sectional study of Latino communities from different geographical regions and cultural backgrounds. An educational intervention was administered to family caregivers of Latino elders using a case-based video "telenovela" and pretest-posttest questionnaires. Participants (N = 145) were mostly females (79%) with mean age of 56 ± 15 years. They reported active learning from intervention (91%) and high satisfaction (92%) with educational experience. Both caregiver stress self-awareness and willingness to accept professional help improved significantly from pretest to posttest. A culturally sensitive educational intervention increased Latino caregivers' self-awareness about caregiver stress and the need to consider professional assistance for EOL care.

Latino;culture;education intervention;end of life;family caregivers;hospice;palliative;pretest–posttest

pubmed

From osmotic second virial coefficient (B22 ) to phase behavior of a monoclonal antibody.

Antibodies are complex macromolecules and their phase behavior as well as interactions within different solvents and precipitants are still not understood. To shed some light into the processes on a molecular dimension, the occurring self-interactions between antibody molecules were analyzed by means of the osmotic second virial coefficient (B22 ). The determined B22 follows qualitatively the phenomenological Hofmeister series describing the aggregation probability of antibodies for the various solvent compositions. However, a direct correlation between crystallization probability and B22 in form of a crystallization slot does not seem to be feasible for antibodies since the phase behavior is strongly dependent on their anisotropy. Kinetic parameters have to be taken into account due to the molecular size and complexity of the molecules. This is confirmed by a comparison of experimental data with a theoretical phase diagram. On the other hand the solubility is thermodynamically driven and therefore the B22 could be used to establish a universal solubility line for the monoclonal antibody mAb04c and different solvent compositions by using thermodynamic models.

monoclonal antibody;phase behavior;phase diagram;protein interactions;static light scattering

pubmed

Anti-inflammatory effect of Impatiens textori Miq. extract via inhibition of NLRP3 inflammasome activation in in vitro and in vivo experimental models.

Impatiens textori Miq. (I. textori, Balsaminaceae) is a traditional medicinal herb used for centuries to treat several inflammatory related skin infections and allergic disorders in Asian countries. In this study, we elucidated the effects of whole plant extracts of I. textori on inflammasome activation using in vitro and in vivo models. LPS-stimulated murine bone marrow macrophages were used to study the regulatory effect of I. textori extract (IT) on inflammasome activation. ATP, nigericin and MSU were used as danger-associated molecules to activate the NLRP3 inflammasome. An LPS-induced acute lung injury (ALI) mouse model was used to study the in vivo effect of IT on inflammasome activation. IT treated at 25, 50, and 100μg/mL concentrations suppressed interleukin-1β secretion through the attenuation of NLRP3 inflammasome activation (p<0.001 at 100μg/mL) leading to the decreased amount of ASC oligomerization and caspase-1 maturation. For the in vivo model, IT inhibited the NLRP3 expression and cell recruitment at the lung tissue in the ALI mouse model. IT exhibited potent anti-inflammatory effects via the attenuation of NLRP3 inflammasome activation supporting the traditional claims and may provide a valuable therapeutic strategy in treating various inflammation-related disorders.

ALI;Anti-inflammasome;Danger-associated molecules;IL-1β;NLRP3

pubmed

Aloe vera gel facilitates re-epithelialization of corneal alkali burn in normal and diabetic rats.

To investigate the efficacy of topical applied aloe vera (AV) and to facilitate the repair of the standardized alkaline corneal ulcer in normal and diabetic rats. The corneal alkali-burn injury model was established unilaterally in Wistar rats by filter paper saturated with 0.01 M NaOH contacting the eyes for 45 seconds. Rats were divided into four groups: normal control (NC), normal AV (NAV), diabetic control (DC), and diabetic AV (DAV). NAV and DAV groups were treated with AV gel eye drops four times daily, and NC and DC groups were treated with normal saline for 3 days. Corneal epithelial wound closure and degree of edema were recorded using slit lamp and optical coherence tomography at 0, 24, 48, and 72 hours postwounding. Histological examination was conducted to evaluate the degree of inflammation and the healing effect. Corneal epithelial wound healing was better in the NAV group than in the NC group, and it was significantly higher in the DAV group than in the DC group (P<0.05). In comparison to the DC group, DAV treated with AV demonstrated a marked reduction in edema at 48 and 72 hours. Histologically, corneal re-epithelialization was complete and higher in DAV group than that in DC group; moreover, the inflammatory cells were increased in DC group than DAV group (P<0.05). This study demonstrated the efficacy of AV for enhanced corneal re-epithelialization, as well as reduced inflammatory response after alkali burn in rats; therefore, it could be useful as a therapy for diabetic keratopathy.

aloe vera;cornea;diabetes;epithelium;wound healing

pubmed

Potential for Co-Infection of a Mosquito-Specific Flavivirus, Nhumirim Virus, to Block West Nile Virus Transmission in Mosquitoes.

Nhumirim virus (NHUV) is an insect-specific virus that phylogenetically affiliates with dual-host mosquito-borne flaviviruses. Previous in vitro co-infection experiments demonstrated prior or concurrent infection of Aedes albopictus C6/36 mosquito cells with NHUV resulted in a 10,000-fold reduction in viral production of West Nile virus (WNV). This interference between WNV and NHUV was observed herein in an additional Ae. albopictus mosquito cell line, C7-10. A WNV 2K peptide (V9M) mutant capable of superinfection with a pre-established WNV infection demonstrated a comparable level of interference from NHUV as the parental WNV strain in C6/36 and C7-10 cells. Culex quinquefasciatus and Culex pipiens mosquitoes intrathoracically inoculated with NHUV and WNV, or solely with WNV as a control, were allowed to extrinsically incubate the viruses up to nine and 14 days, respectively, and transmissibility and replication of WNV was determined. The proportion of Cx. quinquefasciatus mosquitoes capable of transmitting WNV was significantly lower for the WNV/NHUV group than the WNV control at seven and nine days post inoculation (dpi), while no differences were observed in the Cx. pipiens inoculation group. By dpi nine, a 40% reduction in transmissibility in mosquitoes from the dual inoculation group was observed compared to the WNV-only control. These data indicate the potential that infection of some Culex spp. vectors with NHUV could serve as a barrier for efficient transmissibility of flaviviruses associated with human disease.

barrier;inhibition;mosquito;superinfection exclusion;transmission

pubmed

Research and Evaluations of the Health Aspects of Disasters, Part III: Framework for the Temporal Phases of Disasters.

Each of the elements described in the Conceptual Framework for disasters has a temporal designation; each has a beginning and end time. The Temporal Framework defines these elements as phases that are based on characteristics rather than on absolute times. The six temporal phases include the: (1) Pre-event; (2) Event; (3) Structural Damage; (4) Functional Damage (changes in levels of functions of the Societal Systems); (5) Relief; and (6) Recovery phases. Development is not a phase of a disaster. The use of the Temporal Framework in studying and reporting disasters allows comparisons to be made between similar phases of different disasters, regardless of the hazard involved and/or the community impacted. For research and evaluation purposes, assessments, plans, and interventions must be described in relation to the appropriate temporal phase.

damage;disaster;epidemiology;level of function;pre-event;recovery;relief;temporal phases

pubmed

Marine neustonic microplastics around the southeastern coast of Korea.

We investigated floating debris around the mouth of the Nakdong River in the Southeastern Sea of Korea using a Manta trawl (330-μm mesh) and hand-net (50 μm) before (May) and after (July) the rainy season in 2012. Microplastic (<2 mm) was present at all of the stations, whereas Styrofoam (2-5 mm) peaked only at a few stations far from the Nakdong River mouth in July. The dominant types were fibers (polyester), hard plastic (polyethylene), paint particles (alkyd), and Styrofoam (expanded polystyrene). The average abundances of fibers and hard plastic (<2 mm) in the trawl were significantly higher in July than in May (p<0.005, p<0.05, respectively), while two orders of magnitude more microplastics (<2 mm) were collected with the hand-net than with the trawl. Fibers and hard plastic by trawl were significantly compared temporally, and the hand-net proved the missed microplastics (50-330 μm) when trawl used.

A Manta trawl net;A hand-net;Floating debris;Microplastics;Nakdong River mouth;Rainy season

pubmed

Fish hematology and associated disorders.

Fish health is a growing concern as pets, education, and aquaculture evolves. For the veterinary staff, fish handling, diagnostics, medicine, and surgery may require specialized training and equipment in comparison with terrestrial and arboreal animals, simply because of their aquatic nature and diversity. Fish hematology is one diagnostic tool that may not require additional equipment, may be inexpensive, and provide useful information in guiding treatment options. Challenges involving hematology may include handling and restraint, venipuncture, evaluation, and interpretation. In this article, strategies for these challenges are discussed for teleost (bony fish) and elasmobranch (cartilaginous fish) fish types.

Blood cells;Elasmobranch;Erythrocytes;Fish;Hematology;Leukocytes;Teleost;Thrombocytes

pubmed

What caused the changes in the usage of Atractylodis Macrocephalae Rhizoma from ancient to current times?

Ancient Chinese medicine treatises on Atractylodis Macrocephalae Rhizoma (AMR), the rhizome of Atractylodes macrocephala Koidz, indicated that it possessed an expectorant effect. However, in modern times, it is commonly used as a tocolytic agent. In this study, the components of AMR that are responsible for its expectorant and tocolytic effects were evaluated in order to clarify the differences in its application between ancient and modern times. A decoction of AMR was separated into five fractions, namely, volatile oil (VO), petroleum ether (PE), alcohol eluate from macroporous resin (AE), water eluate from macroporous resin (WE), and polysaccharides (PS), using various separation methods. The expectorant experiment indicated that the VO fraction, which mainly contains atractylone, produced an obvious expectorant effect. The experiment that assessed the irritability of uterine smooth muscle (USM) showed that the PE, which is mainly composed of atractylenolides, and the PS, which is mainly composed of inulin-type polysaccharides, were the active fractions for tocolysis, but the VO fraction had the opposite action. These data suggested that volatile oils are the key components responsible for the usage change of AMR in both ancient and current usage.

Atractylodes macrocephala Koidz;Atractylodis Macrocephala Rhizoma;Expectorant;Tocolysis;Traditional medicine;Volatile oil

pubmed

An approach to monitor food and nutrition from "factory to fork".

Accurate, adequate, and timely food and nutrition information is necessary in order to monitor changes in the US food supply and assess their impact on individual dietary intake. Our aim was to develop an approach that links time-specific purchase and consumption data to provide updated, market representative nutrient information. We utilized household purchase data (Nielsen Homescan, 2007-2008), self-reported dietary intake data (What We Eat in America [WWEIA], 2007-2008), and two sources of nutrition composition data. This Factory to Fork Crosswalk approach connected each of the items reported to have been obtained from stores from the 2007-2008 cycle of the WWEIA dietary intake survey to corresponding food and beverage products that were purchased by US households during the equivalent time period. Using nutrition composition information and purchase data, an alternate Crosswalk-based nutrient profile for each WWEIA intake code was created weighted by purchase volume of all corresponding items. Mean intakes of daily calories, total sugars, sodium, and saturated fat were estimated. Differences were observed in the mean daily calories, sodium, and total sugars reported consumed from beverages, yogurts, and cheeses, depending on whether the Food and Nutrient Database for Dietary Studies 4.1 or the alternate nutrient profiles were used. The Crosswalk approach augments national nutrition surveys with commercial food and beverage purchases and nutrient databases to capture changes in the US food supply from factory to fork. The Crosswalk provides a comprehensive and representative measurement of the types, amounts, prices, locations and nutrient composition of consumer packaged goods foods and beverages consumed in the United States. This system has potential to be a major step forward in understanding the consumer packaged goods sector of the US food system and the impacts of the changing food environment on human health.

Dietary intake;Food composition;Nutrient profile;Nutrition assessment;United States

pubmed

Influence of diet in the accumulation of organochlorine compounds in herons breeding in remote riverine environments.

The composition of organochlorine compounds (OCs), pentachlorobenzene (PeCB), hexachlorobenzene (HCB), hexachlorocyclohexanes (HCHs), DDTs and polychlorobiphenyls (PCBs), has been analyzed in eggs from cattle egret (Bubulcus ibis) and little egret (Egretta garzetta), two species of herons (family Ardeidae), nesting at the same remote riverine environment (Aiguabarreig, Ebro River). These two species were selected to evaluate the importance of diet in the accumulation of OCs. Cattle egret essentially feeds on dry grassy habitats and follow cattle or other large animals whereas little egret feeds on fish, amphibians and crustaceans captured in shallow waters. The δ(15)N and δ(13)C isotopic composition of the sampled eggs was studied and the results were consistent with these species feeding habits. In both species, the compounds accumulated the most were the less volatile and more lipophilic, e.g. PCB congeners of higher chlorination, DDT and metabolites. The distinct foraging species preferences were reflected in significant higher concentrations in little egret than cattle egret of all pollutant groups analysed. These differences were statistically significant for DDTs and PCBs (p < 0.015 and p < 0.047, respectively), e.g. the p,p'-DDE and PCB concentrations were 6 and 4.5 times higher, respectively, in the former than the latter. This strong contrast indicates that in remote environments aquatic riverine ecosystems are more efficient OC reservoirs than the terrestrial ecosystem.

Diet;Egrets;Herons;Organochlorine compounds;Riverine systems;Stable isotope composition

pubmed

Integrated system for temperature-controlled fast protein liquid chromatography. II. Optimized adsorbents and 'single column continuous operation'.

Continued advance of a new temperature-controlled chromatography system, comprising a column filled with thermoresponsive stationary phase and a travelling cooling zone reactor (TCZR), is described. Nine copolymer grafted thermoresponsive cation exchangers (thermoCEX) with different balances of thermoresponsive (N-isopropylacrylamide), hydrophobic (N-tert-butylacrylamide) and negatively charged (acrylic acid) units were fashioned from three cross-linked agarose media differing in particle size and pore dimensions. Marked differences in grafted copolymer composition on finished supports were sourced to base matrix hydrophobicity. In batch binding tests with lactoferrin, maximum binding capacity (qmax) increased strongly as a function of charge introduced, but became increasingly independent of temperature, as the ability of the tethered copolymer networks to switch between extended and collapsed states was lost. ThermoCEX formed from Sepharose CL-6B (A2), Superose 6 Prep Grade (B2) and Superose 12 Prep Grade (C1) under identical conditions displayed the best combination of thermoresponsiveness (qmax,50°C/qmax,10°C ratios of 3.3, 2.2 and 2.8 for supports 'A2', 'B2' and 'C1' respectively) and lactoferrin binding capacity (qmax,50°C∼56, 29 and 45mg/g for supports 'A2', 'B2' and 'C1' respectively), and were selected for TCZR chromatography. With the cooling zone in its parked position, thermoCEX filled columns were saturated with lactoferrin at a binding temperature of 35°C, washed with equilibration buffer, before initiating the first of 8 or 12 consecutive movements of the cooling zone along the column at 0.1mm/s. A reduction in particle diameter (A2→B2) enhanced lactoferrin desorption, while one in pore diameter (B2→C1) had the opposite effect. In subsequent TCZR experiments conducted with thermoCEX 'B2' columns continuously fed with lactoferrin or 'lactoferrin+bovine serum albumin' whilst simultaneously moving the cooling zone, lactoferrin was intermittently concentrated at regular intervals within the exiting flow as sharp uniformly sized peaks. Halving the lactoferrin feed concentration to 0.5mg/mL, slowed acquisition of steady state, but increased the average peak concentration factor from 7.9 to 9.2. Finally, continuous TCZR mediated separation of lactoferrin from bovine serum albumin was successfully demonstrated. While the latter's presence did not affect the time to reach steady state, the average lactoferrin mass per peak and concentration factor both fell (respectively from 30.7 to 21.4mg and 7.9 to 6.3), and lactoferrin loss in the flowthrough between elution peaks increased (from 2.6 to 12.2mg). Fouling of the thermoCEX matrix by lipids conveyed into the feed by serum albumin is tentatively proposed as responsible for the observed drops in lactoferrin binding and recovery.

Copolymer modified agarose adsorbents;Ion exchange adsorption;Lower critical solution temperature (LCST);N-Isopropylacrylamide;Smart polymers;Travelling cooling zone reactor

pubmed

The American Dental Association Caries Classification System for clinical practice: a report of the American Dental Association Council on Scientific Affairs.

The caries lesion, the most commonly observed sign of dental caries disease, is the cumulative result of an imbalance in the dynamic demineralization and remineralization process that causes a net mineral loss over time. A classification system to categorize the location, site of origin, extent, and when possible, activity level of caries lesions consistently over time is necessary to determine which clinical treatments and therapeutic interventions are appropriate to control and treat these lesions. In 2008, the American Dental Association (ADA) convened a group of experts to develop an easy-to-implement caries classification system. The ADA Council on Scientific Affairs subsequently compiled information from these discussions to create the ADA Caries Classification System (CCS) presented in this article. The ADA CCS offers clinicians the capability to capture the spectrum of caries disease presentations ranging from clinically unaffected (sound) tooth structure to noncavitated initial lesions to extensively cavitated advanced lesions. The ADA CCS supports a broad range of clinical management options necessary to treat both noncavitated and cavitated caries lesions. The ADA CCS is available for implementation in clinical practice to evaluate its usability, reliability, and validity. Feedback from clinical practitioners and researchers will allow system improvement. Use of the ADA CCS will offer standardized data that can be used to improve the scientific rationale for the treatment of all stages of caries disease.

Caries classification system;caries activity;caries extent;caries lesion classification;caries location;caries management

pubmed

Decorin as a multivalent therapeutic agent against cancer.

Decorin is a prototypical small leucine-rich proteoglycan that epitomizes the multifunctional nature of this critical gene family. Soluble decorin engages multiple receptor tyrosine kinases within the target-rich environment of the tumor stroma and tumor parenchyma. Upon receptor binding, decorin initiates signaling pathways within endothelial cells downstream of VEGFR2 that ultimately culminate in a Peg3/Beclin 1/LC3-dependent autophagic program. Concomitant with autophagic induction, decorin blunts capillary morphogenesis and endothelial cell migration, thereby significantly compromising tumor angiogenesis. In parallel within the tumor proper, decorin binds multiple RTKs with high affinity, including Met, for a multitude of oncosuppressive functions including growth inhibition, tumor cell mitophagy, and angiostasis. Decorin is also pro-inflammatory by modulating macrophage function and cytokine secretion. Decorin suppresses tumorigenic growth, angiogenesis, and prevents metastatic lesions in a variety of in vitro and in vivo tumor models. Therefore, decorin would be an ideal therapeutic candidate for combating solid malignancies.

Angiogenesis;Autophagy;Endothelial cells;Mitophagy;Receptor tyrosine kinases;Small leucine-rich proteoglycan

pubmed

Effect of platelet-derived growth factor-B on renal cell carcinoma growth and progression.

Platelet-derived growth factor-B (PDGF-B) expression promotes the proliferation of mural cells surrounding the blood vessels during angiogenesis. The effect of PDGF-B involved in angiogenesis on tumor growth and progression in clear cell renal cell carcinoma (ccRCC) is unknown. We examined the expression of PDGF-B and its receptor PDGFR-β in 174 patients with ccRCC by microarray analysis. Cancer-specific survival was estimated using the Kaplan-Meier method. PDGF-B-transfected and mock-transfected ACHN cells were implanted into mice to induce tumor formation and tumor growth, respectively, and progression in mice models was assessed using immunohistochemistry and histomorphology. The role of PDGF-B during angiogenesis in vitro was evaluated by flow cytometry analysis, cell migration, and tube formation assay. High expression of PDGF-B was associated with significantly decreased risk of cancer-specific mortality (P ≤ 0.001). The data indicated significant inhibition of tumor growth (P ≤ 0.05) and a reduction in proliferating tumor cells (P = 0.019) in vivo. PDGF-B also inhibits tumor metastasis and invasion events in tumor-bearing mice models. In vitro studies revealed that the tube formation capability of vascular smooth muscle cells (VSMCs), which are believed to be the precursors to pericytes in vivo, significantly induced by PDGF-B. The PDGF-B overexpression also results in a tendency to reside in S and G2/M phases of the cell cycle (P = 0.001) and increasing migration capability of VSMCs (P ≤ 0.001). Our results demonstrated that PDGF-B, which increased VSMCs proliferation and migration capability during angiogenesis, limited tumor growth and progression in ccRCC. Therefore, PDGF-B may be a novel and promising prognostic marker.

Angiogenesis;Clear cell renal cell carcinoma;Metastasis;Platelet-derived growth factor-B;Progression

pubmed

Mental health disorders in home care elders: An integrative review.

Home care is the fastest growing U.S. health care sector, serving a predominance of highly vulnerable elderly patients. Mental health disorders (MHDs) are a major health concern in this population, however, current knowledge regarding their occurrence and associated correlates is inadequate. To address this gap, this integrative review examined existing findings regarding the prevalence and correlates of MHDs in home care elders. A search of six electronic databases and a hand search produced a final group of 36 articles for review. Poor data representativeness and methodological limitations impacted the quality of these studies, as reflected in an extremely wide range of prevalence estimates for these disorders (12% - 62%). A number of recommendations are made with respect to future research in this area. These include conducting multi-site investigations and the use of consistent and clear protocols for identification of MHDs in home care elders, a growing and significantly under-served population.

Geriatric psychiatry;Home care services

pubmed

Quality of life and coping strategies among immigrant women living with pain in Denmark: a qualitative study.

To examine quality of life and coping strategies among immigrant women living with chronic pain. Qualitative content analysis based on in-depth semistructured interviews. A clinic specifically targeting immigrants at a larger university hospital in Copenhagen, Denmark. Non-western female immigrant patients suffering from chronic pain (n=13). Experiences of the impact of chronic pain on quality of life. Chronic pain was perceived to have an extensive, adverse effect on all aspects of quality of life, including physical health, mental well-being and social relations. This included the ability to maintain activities of daily living and the ability to work. Chronic pain was further experienced as a cause of emotional distress, depression and altered personalities, which all had great consequences on women's social interactions, causing change and loss of social relations. A variety of coping strategies were used to cope with the pain, manage its consequences, and restore a level of health that would enable women to function and fulfil social roles. Many participants coped with the pain by altering everyday life, keeping daily activities to a minimum and taking pain-killing drugs, offering temporary relief. Seeking healthcare was another coping strategy used as an active means to assert agency and as a temporary distraction from pain. However, accessing healthcare also involved a risk of disagreement and disappointments. Chronic pain had a severe negative impact on quality of life and necessitated alterations in everyday life and active health-seeking strategies. Implications for practice imply a need for a more holistic approach to immigrant women with chronic pain, including a family-centred approach. Further research is needed to explore similarities or differences in and between populations with diverse ethnic, socioeconomic and psychosocial backgrounds, and to assess how ethnicity and culture might influence the experiences of chronic pain.

PAIN MANAGEMENT;PUBLIC HEALTH;QUALITATIVE RESEARCH;SOCIAL MEDICINE

pubmed

Can apparent resting state connectivity arise from systemic fluctuations?

It is widely accepted that the fluctuations in resting state blood oxygenation level dependent (BOLD) functional MRI (fMRI) reflect baseline neuronal activation through neurovascular coupling; this data is used to infer functional connectivity in the human brain during rest. Consistent activation patterns, i.e., resting state networks (RSN) are seen across groups, conditions, and even species. In this study, we show that some of these patterns can also be generated from the dynamic, systemic, non-neuronal physiological low frequency oscillations (sLFOs) in the BOLD signal alone. We have previously used multimodal imaging to demonstrate the wide presence of the same sLFOs in the brain (BOLD) and periphery with different time delays. This study shows that these sLFOs from BOLD signals alone can give rise to stable spatial patterns, which can be detected during resting state analyses. We generated synthetic resting state data for 11 subjects based only on subject-specific, dynamic sLFO information obtained from resting state data using concurrent peripheral optical imaging or a novel recursive procedure. We compared the results obtained by performing a group independent component analysis (ICA) on this synthetic data (i.e., the result from simulation) to the results obtained from analysis of the real data. ICA detected most of the eight well-known RSNs, including visual, motor, and default mode networks (DMNs), in both the real and the synthetic data sets. These findings suggest that RSNs may reflect, to some extent, vascular anatomy associated with systemic fluctuations, rather than neuronal connectivity.

BOLD fMRI;cerebral blood flow;resting state networks;slow oscillations;systemic oscillations

pubmed