Neural mechanisms of anaphoric reference revealed by FMRI.
Pronouns are bound to their antecedents by matching syntactic and semantic information. The aim of this functional magnetic resonance imaging study was to localize syntactic and semantic information retrieval and integration during pronoun resolution. Especially we investigated their possible interaction with verbal working memory manipulated by distance between antecedent and pronoun. We disentangled biological and syntactic gender information using German sentences about persons (biological/syntactic gender) or things (syntactic gender) followed by congruent or incongruent pronouns. Increasing the distance between pronoun and antecedent resulted in a short and a long distance condition. Analysis revealed a language related network including inferior frontal regions bilaterally (integration), left anterior and posterior temporal regions (lexico-semantics and syntactic retrieval) and the anterior cingulate gyrus (conflict resolution) involved in pronoun resolution. Activities within the inferior frontal region were driven by Congruency (incongruent > congruent) and Distance (long > short). Temporal regions were sensitive to Distance and Congruency (but solely within long distant conditions). Furthermore, anterior temporal regions were sensitive to the antecedent type with an increased activity for person pronouns compared to thing pronouns. We suggest that activity modulations within these areas reflect the integration process of an appropriate antecedent which depends on the type of information that has to be retrieved (lexico-syntactic posterior temporal, lexico-semantics anterior temporal). It also depends on the overall syntactic and semantic complexity of long distant sentences. The results are interpreted in the context of the memory-unification-control model for sentence comprehension as proposed by Vosse and Kempen (2000), Hagoort (2005), and Snijders et al. (2009).


Histological and Histomorphometrical Evaluation of a New Implant Macrogeometry. A Sheep Study.
Decompression or healing chambers between the threads have been proposed to improve and accelerate the osseointegration process of dental implants. The aim of the present work was to test, in an in vivo sheep study, if healing chambers between the threads could produce a better osseointegration process. Thirty titanium implants (15 conventional design (control) and 15 implants with healing chambers (test)) were inserted in a random fashion in the tibia of 3 sheep. The animals were euthanized after 30 days of healing, and the retrieved specimens treated to obtain thin ground sections. Histological observations showed that the quantity of newly formed bone growing in an apical direction was lower in the control group (1095 µm) when compared to the Test group (1658 µm). This difference was statistically significant. Moreover, a layer of osteogenic matrix was present around the portion of implants immersed in the marrow spaces. This osteogenic tissue was thicker in the test group. In conclusion, the present study confirmed the very good results in implants with healing chambers that presented a higher percentage of new bone formation.


Acceptance of disability predicts quality of life in patients with epilepsy.
Acceptance of disability (AOD) is a key concept in rehabilitation psychology that enhances psychosocial adjustment of individuals with disability. However, the impact of AOD on well-being has never been examined for patients with epilepsy. The present study investigated whether AOD affects quality of life (QOL) in patients with epilepsy in the presence of other multiple aspects of epilepsy based on the biopsychosocial model. We retrospectively reviewed 151 consecutive patients with epilepsy (77 men, aged 18-74 years) who underwent comprehensive assessment including long-term video-EEG monitoring, neuroimaging studies, and neuropsychological and psychosocial assessment in our epilepsy monitoring unit. Data were obtained from medical records and self-reported questionnaires. The outcome variable was QOL. Predictive variables included demographic characteristics, seizure-related variables (i.e., duration of epilepsy, seizure frequency, and number of antiepileptic drugs), psychological factors (i.e., AOD, depression, and self-stigma), and social factors (i.e., social support and education level). Acceptance of disability was measured by the Adaptation of Disability Scale-Revised (ADS-R), which we translated into Japanese with the original author's approval, and examined its internal consistency reliability. Data were analyzed using four hierarchical multiple regression analysis models. The mean ADS-R score was 80 (range 45-115). The predictors accounted for 42% of the variance in QOL (R2 = 0.45, ΔR2 = 0.42, F[8, 141] = 14.47, p = 0.00). Higher AOD (p < 0.01), higher social support (p < 0.01), and lower depression scores (p = 0.02) were found to contribute significantly to higher overall QOL. The present study revealed AOD as an important psychological concept, in addition to social support and depression as previously reported, to improve the QOL of patients with epilepsy. Acceptance of disability should be incorporated in the intervention to increase QOL of patients with epilepsy.


Preventative Vaccines for Zika Virus Outbreak: Preliminary Evaluation.
Since it emerged in Brazil in May 2015, the mosquito-borne Zika virus (ZIKV) has raised global concern due to its association with a significant rise in the number of infants born with microcephaly and neurological disorders such as Guillain-Barré syndrome. We developed prototype subunit and adenoviral-based Zika vaccines encoding the extracellular portion of the ZIKV envelope gene (E) fused to the T4 fibritin foldon trimerization domain (Efl). The subunit vaccine was delivered intradermally through carboxymethyl cellulose microneedle array (MNA). The immunogenicity of these two vaccines, named Ad5.ZIKV-Efl and ZIKV-rEfl, was tested in C57BL/6 mice. Prime/boost immunization regimen was associated with induction of a ZIKV-specific antibody response, which provided neutralizing immunity. Moreover, protection was evaluated in seven-day-old pups after virulent ZIKV intraperitoneal challenge. Pups born to mice immunized with Ad5.ZIKV-Efl were all protected against lethal challenge infection without weight loss or neurological signs, while pups born to dams immunized with MNA-ZIKV-rEfl were partially protected (50%). No protection was seen in pups born to phosphate buffered saline-immunized mice. This study illustrates the preliminary efficacy of the E ZIKV antigen vaccination in controlling ZIKV infectivity, providing a promising candidate vaccine and antigen format for the prevention of Zika virus disease.


Second primary malignancies in retinoblastoma patients treated with intra-arterial chemotherapy: the first 10 years.
Survivors of retinoblastoma carry a lifetime risk of secondary malignancies. It is well established that external beam radiation increases this risk; however, the risk with ophthalmic artery chemosurgery (OAC) remains unknown. We report on 10 years of experience with OAC and the rate of second primary malignancy (SPM) development. This is a single-centre retrospective review approved by the Memorial Sloan Kettering Cancer Center Institutional Review Board of all patients who received OAC over a 10-year period, from May 2006 to November 2016. The second tumour incidence and survival in patients with germline disease (bilateral and unilateral with family history or confirmed germline mutation) was estimated using the Kaplan-Meier method. Patients who received external beam radiotherapy were excluded from analyses. Two hundred and thirty-three patients with heritable retinoblastoma who received OAC were analysed. Nineteen patients were excluded for having received external beam radiation. The Kaplan-Meier estimate of the likelihood for SPM development was 2.7% at 5 years (95% CI 0 to 25). All of the SPMs were pineoblastomas and all patients had bilateral disease in this cohort. In our 10-year experience, we have found that SPM development in patients with germline retinoblastoma treated with OAC alone is comparable to previously published rates. In the first 10 years, OAC did not increase the known incidence of SPMs. This cohort will continue to be followed to establish the rate of development with extended follow-up.


Therapeutic effects of systemic administration of chaperone αB-crystallin associated with binding proinflammatory plasma proteins.
The therapeutic benefit of the small heat shock protein αB-crystallin (HspB5) in animal models of multiple sclerosis and ischemia is proposed to arise from its increased capacity to bind proinflammatory proteins at the elevated temperatures within inflammatory foci. By mass spectral analysis, a common set of ∼70 ligands was precipitated by HspB5 from plasma from patients with multiple sclerosis, rheumatoid arthritis, and amyloidosis and mice with experimental allergic encephalomyelitis. These proteins were distinguished from other precipitated molecules because they were enriched in the precipitate as compared with their plasma concentrations, and they exhibited temperature-dependent binding. More than half of these ligands were acute phase proteins or members of the complement or coagulation cascades. Consistent with this proposal, plasma levels of HspB5 were increased in patients with multiple sclerosis as compared with normal individuals. The combination of the thermal sensitivity of the HspB5 combined with the high local concentration of these ligands at the site of inflammation is proposed to explain the paradox of how a protein believed to exhibit nonspecific binding can bind with some relative apparent selectivity to proinflammatory proteins and thereby modulate inflammation.


The chloroplast genomes of Bryopsis plumosa and Tydemania expeditiones (Bryopsidales, Chlorophyta): compact genomes and genes of bacterial origin.
Species of Bryopsidales form ecologically important components of seaweed communities worldwide. These siphonous macroalgae are composed of a single giant tubular cell containing millions of nuclei and chloroplasts, and harbor diverse bacterial communities. Little is known about the diversity of chloroplast genomes (cpDNAs) in this group, and about the possible consequences of intracellular bacteria on genome composition of the host. We present the complete cpDNAs of Bryopsis plumosa and Tydemania expeditiones, as well as a re-annotated cpDNA of B. hypnoides, which was shown to contain a higher number of genes than originally published. Chloroplast genomic data were also used to evaluate phylogenetic hypotheses in the Chlorophyta, such as monophyly of the Ulvophyceae (the class in which the order Bryopsidales is currently classified). Both DNAs are circular and lack a large inverted repeat. The cpDNA of B. plumosa is 106,859 bp long and contains 115 unique genes. A 13 kb region was identified with several freestanding open reading frames (ORFs) of putative bacterial origin, including a large ORF (>8 kb) closely related to bacterial rhs-family genes. The cpDNA of T. expeditiones is 105,200 bp long and contains 125 unique genes. As in B. plumosa, several regions were identified with ORFs of possible bacterial origin, including genes involved in mobile functions (transposases, integrases, phage/plasmid DNA primases), and ORFs showing close similarity with bacterial DNA methyltransferases. The cpDNA of B. hypnoides differs from that of B. plumosa mainly in the presence of long intergenic spacers, and a large tRNA region. Chloroplast phylogenomic analyses were largely inconclusive with respect to monophyly of the Ulvophyceae, and the relationship of the Bryopsidales within the Chlorophyta. The cpDNAs of B. plumosa and T. expeditiones are amongst the smallest and most gene dense chloroplast genomes in the core Chlorophyta. The presence of bacterial genes, including genes typically found in mobile elements, suggest that these have been acquired through horizontal gene transfer, which may have been facilitated by the occurrence of obligate intracellular bacteria in these siphonous algae.


Purification and serological characterization of the major envelope glycoprotein from AKR murine leukemia virus and its reactivity with autogenous immune sera from mice.
The major envelope glycoprotein (gp71) from AKR murine leukemia virus (MuLV) was purified and its serological reactivity with heterologous and autogenous immune mouse sera was examined. Homologous and interspecies competition radioimmunoassays using antisera to Rauscher-MulV gp69/71 or Friend-MuLV gp71 or antisera to feline leukemia virus to precipitate 125I-labeled gp71 from various MuLV showed that distinct differences exist between Rauscher- or Friend-MuLV and AKR-MuLV glycoproteins. Characteristically the AKR-MuLV gp71, in contrast to FLV or RLV gp71, does not compete fully in homologous or interspecies radioimmunoassays with iodinated Friend of Rauscher glycoproteins. Purified 125I-labeled AKR-MuLV gp71, in contrast to the Rauscher- or Friend-MuLV glycoproteins, reacts with normal (autogenous immune) mouse sera in direct radioimmune precipitation assays. Competition experiments further demonstrate that this is a predominant immunological reactivity of normal mouse sera which had previously been detected by radioimmune precipitation assay against intact virions.


Evolution of recurrent herpes simplex lesions. An immunohistologic study.
We performed immunoperoxidase stains on skin biopsies taken from nine patients with recurrent peripheral herpes simplex lesions at 12 h to 6 d after onset of signs of symptoms to phenotype the inflammatory infiltrate, to detect cells producing interferons alpha and gamma, and to locate herpes simplex virus antigen-containing cells. Viral glycoprotein antigen was located in the nuclei and cytoplasm of necrotic epidermal cells, often within vesicles, in biopsies taken between the first and third day. Histologically, biopsies of all stages showed intradermal focal perivascular and diffuse mononuclear inflammatory infiltrates. The cells constituting the infiltrates were predominantly T lymphocytes with lesser numbers of histiocytes; Leu 7+ (most natural killer/killer) cells and B cells were rare in the biopsy specimens. Leu 3a+ ("helper") T lymphocytes predominated in both subepidermal and perivascular regions of early lesions (12-24 h). Tissue helper/suppressor ratios ranged from 6.3 to 3.4 compared with 1.9-1.0 in blood. In later lesions (after 2 d), monocytes/macrophages were more prominent in tissue sections and the helper/suppressor ratios (2.3-2.5) more nearly approximated those of blood (1.6-2.7). The negative correlation of tissue ratios with time was significant (P less than or equal to 0.02). A large proportion of the infiltrated T lymphocytes expressed DR antigens. There was also diffuse strong DR expression on epidermal cells in five cases (all of two or more days). In six biopsies, scattered macrophages and small cells, presumably lymphocytes, demonstrated cytoplasmic or membrane staining for a substance which copurifies with interferon gamma. We identified such stained cells within vessels, suggesting that these cells circulate. Gamma interferon might have an important role within the herpetic lesions, possibly inducing macrophage activation and cytotoxic T lymphocytes and increasing DR expression on monocyte and epidermal cells.


Dual roles for the telomeric repeats in chromosomally integrated human herpesvirus-6.
Approximately 1 percent of healthy individuals carry human herpesvirus-6 within a host chromosome. This is referred to as chromosomally integrated herpesvirus-6 (CIHHV-6). In this study, we investigated the chromosomal integration site in six individuals harboring CIHHV-6B. Using FISH, we found that HHV-6B signals are consistently located at the telomeric region. The proximal endpoints of the integrated virus were mapped at one of two telomere-repeat-like sequences (TRSs) within the DR-R in all cases. In two cases, we isolated junction fragments between the viral TRS and human telomere repeats. The distal endpoints were mapped at the distal TRS in all cases. The size of the distal TRS was found to be ~5 kb which is sufficient to fulfill cellular telomeric functions. We conclude that the viral TRS in the DR regions fulfill dual functions for CIHHV-6: homology-mediated integration into the telomeric region of the chromosome and neo-telomere formation that is then stably transmitted.


High relaxivity Gd(III)-DNA gold nanostars: investigation of shape effects on proton relaxation.
Gadolinium(III) nanoconjugate contrast agents (CAs) have distinct advantages over their small-molecule counterparts in magnetic resonance imaging. In addition to increased Gd(III) payload, a significant improvement in proton relaxation efficiency, or relaxivity (r1), is often observed. In this work, we describe the synthesis and characterization of a nanoconjugate CA created by covalent attachment of Gd(III) to thiolated DNA (Gd(III)-DNA), followed by surface conjugation onto gold nanostars (DNA-Gd@stars). These conjugates exhibit remarkable r1 with values up to 98 mM(-1) s(-1). Additionally, DNA-Gd@stars show efficient Gd(III) delivery and biocompatibility in vitro and generate significant contrast enhancement when imaged at 7 T. Using nuclear magnetic relaxation dispersion analysis, we attribute the high performance of the DNA-Gd@stars to an increased contribution of second-sphere relaxivity compared to that of spherical CA equivalents (DNA-Gd@spheres). Importantly, the surface of the gold nanostar contains Gd(III)-DNA in regions of positive, negative, and neutral curvature. We hypothesize that the proton relaxation enhancement observed results from the presence of a unique hydrophilic environment produced by Gd(III)-DNA in these regions, which allows second-sphere water molecules to remain adjacent to Gd(III) ions for up to 10 times longer than diffusion. These results establish that particle shape and second-sphere relaxivity are important considerations in the design of Gd(III) nanoconjugate CAs.


Inadequate reporting of trials compromises the applicability of systematic reviews.
Uncertainty about the applicability of controlled trial findings is an increasing concern for clinicians and policy decision makers. This study aimed to determine whether information reported in studies included in systematic reviews was adequate enough to assess their applicability. We used the databases of four recently conducted systematic reviews on the comparative efficacy and safety of second-generation antidepressants, inhaled corticosteroids, Alzheimer's drugs, and targeted immune modulators. We developed and pilot-tested a questionnaire to assess the adequacy of reporting with respect to seven previously validated criteria of study design that distinguish explanatory from pragmatic studies. For each of the 137 included studies, two reviewers independently assessed the adequacy of reporting. Overall, only 12 percent of the included studies provided sufficient information to reliably distinguish explanatory from pragmatic studies. The areas with the greatest lack of reporting were the setting of the study, methods of adverse event assessment, and sample size considerations to determine a minimally important difference from a patient perspective. Substantial shortcomings in reporting exist in aspects of study design important to determine whether a study is applicable to specific populations of interest.


Technical Note: A feasibility study of using the flat panel detector on linac for the kV x-ray generator test.
To investigate the feasibility of using kV flat panel detector on linac for consistency evaluations of kV x-ray generator performance. An in-house designed aluminum (Al) array phantom with six 9 × 9 cm2 square regions having various thickness was proposed and used in this study. Through XML script-driven image acquisition, kV images with various acquisition settings were obtained using the kV flat panel detector. Utilizing pre-established baseline curves, the consistency of x-ray tube output characteristics, including tube voltage accuracy, exposure accuracy and exposure linearity was assessed through image quality assessment metrics including ROI mean intensity, ROI standard deviation (SD), and noise power spectrums (NPS). The robustness of this method was tested on two linacs for a 3-month period. With the proposed method, tube voltage accuracy can be verified through conscience check with a 2% tolerance and 2 kVp intervals for forty different kVp settings. The exposure accuracy can be tested with a 4% consistency tolerance for three mAs settings over forty kVp settings. The exposure linearity tested with 3 mAs settings achieved a coefficient of variation (CV) of 0.1. We proposed a novel approach that uses the kV flat panel detector available on linac for x-ray generator test. This approach eliminates the inefficiencies and variability associated with using third-party QA detectors while enabling an automated process.


Hospital-based bereavement services following the death of a child: a mixed study review.
There has been a breadth of research on the grief experience of parents following the death of a child. However, the role and impact of hospital-based bereaved services remain unclear. To identify services offered to bereaved families in perinatal, neonatal, and pediatric hospital settings and summarize the psychosocial impact of these services and published recommendations for best practice hospital-based bereavement care. Systematic review of qualitative, quantitative, and mixed method studies guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist and methodological quality appraised in accordance with the Mixed Method Appraisal Tool. MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health, and PsychINFO were searched to find studies describing hospital-based bereavement services/interventions for parents, siblings, and grandparents. In all, 14 qualitative, 6 quantitative, and 10 mixed method studies were identified. Nine descriptive articles were also included. Qualitatively, family members described feeling cared for and supported by staff, a reduction in sense of isolation, and improved coping and personal growth. Quantitatively, bereavement services have most effect for parents experiencing more complex mourning. It is recommended that bereavement services be theoretically driven and evidence based, offer continuity of care prior to and following the death of a child, and provide a range of interventions for the "whole family" and flexibility in service delivery. There is a role for transitional hospital-based services/interventions for families in the lead up to and following the death of a child. Further mixed method research is required to inform best practice bereavement care guidelines in the perinatal, neonatal, and pediatric hospital settings.


Antithrombotic and thrombolytic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
Since publication of the seventh American College of Chest Physicians (ACCP) supplement on antithrombotic and thrombolytic therapy, the results of clinical trials have provided important new information on the management of thromboembolic disorders, and the science of developing recommendations has advanced. In the accompanying supplement, we provide the new and updated recommendations and review several important changes that we have made in our guideline development process. We again made a conscious effort to increase the participation of female authors and contributors from outside North America, the latter reflecting the widespread use and dissemination of these guidelines internationally. The grading system for the recommendations was adopted in 2006 by the ACCP for all its guidelines, is similar to the increasingly widely used Grades of Recommendation, Assessment, Development, and Evaluation approach, and is described in detail in one of the introductory chapters. While most of the evidence on which recommendations are made remains low quality in fields of pediatric thrombosis, thrombosis in pregnancy, and thrombosis in valvular heart disease, rigorous studies in other fields have resulted in new and strong evidence-based recommendations for many indications.


Tartrate-resistant acid phosphatase 5b is a useful serum marker for extensive bone metastasis in breast cancer patients.
Previous studies showed that serum tartrate-resistant acid phosphatase 5b (TRACP5b) activity was increased in 70% to 94% of breast cancer (BC) patients with bone metastasis (BM). This study aims to determine whether serum TRACP5b is useful for identifying limited or extensive BM in BC patients. Serum TRACP5b activity was measured in 168 BC patients, including 81 who were newly diagnosed with early BC, 20 with extraosseous metastasis, 24 with limited BM, and 43 with extensive BM. Serum TRACP5b activity was also measured monthly in 151 patients with early BC until they developed BM. Four hundred and twenty-seven (427) healthy women ages 18 to 90 served as control. One-way ANOVA was used to compare serum TRACP5b among groups. The sensitivity and specificity of serum TRACP5b as a marker for BM were estimated by receiver operator characteristic (ROC) curves. Serum TRACP5b increased with age in healthy women ( P < 0.0001). It was significantly elevated in patients with extensive BM compared with all other groups ( P < 0.0001). ROC analysis established a cutoff value of 4.026 units/L to identify patients with extensive BM with a specificity of 98% and a sensitivity of 93% (area under the curve = 0.9807; 95% CI = 0.9698-0.9915). Among the 151 patients with early BC, 6 developed limited BM and 2 developed extensive BM during the follow-up period. Serum TRACP5b remained below the cutoff value in patients with limited BM, but became significantly increased in those whose BM became extensive. Serum TRACP5b activity is a useful diagnostic marker for extensive BM in patients with BC.


Successful Aging among Elders Living in the Mani Continental Region vs. Insular Areas of the Mediterranean: the MEDIS Study.
To evaluate the role of geography i.e., continental vs. insular Mediterranean, on successful aging among older inhabitants. During 2005-2014, 2693 elderly (aged 65 to 100 years) individuals from 21 Mediterranean islands in Greece, Italy and Spain as well as Cyprus, Malta, and the rural region of Mani (southeast continental region of Greece keeping old-time traditions), were voluntarily recruited. Successful aging was evaluated using a validated index composed of 10 health-related socio-lifestyle and clinical characteristics. After accounting for age, sex, body mass index (BMI), physical activity, smoking habits, MedDietScore and access to health care services, the older inhabitants of islands were found to have a higher level of the successful aging index when compared to their counterparts in Mani (Beta=0.174, p<0.001); moreover, islanders exhibited slightly more years of "good" health (68.7 vs 68.4 years for Mani residents (p=0.99)). However, compared to the residents of Mani, islanders had 1.64 times higher odds (95%CI, 1.08-2.48) for having hypertension, 2.4-times higher odds (95%CI, 1.34-4.21) for having diabetes and 1.52 times higher odds (95%CI, 0.97-2.38) for having hypercholesterolemia. Engaging in physical activities and healthy dietary habits were the major determinants of healthy aging, among islanders as compared to their counterparts of continental Mani region. Elder residents of the continental Mani area enjoyed a better health status, whereas elder islanders had a higher level of successful aging; a finding which could be attributed to differences in lifestyle among elders.


Design Strategies for Alkaline Exchange Membrane-Electrode Assemblies: Optimization for Fuel Cells and Electrolyzers.
Production of hydrocarbon-based, alkaline exchange, membrane-electrode assemblies (MEA's) for fuel cells and electrolyzers is examined via catalyst-coated membrane (CCM) and gas-diffusion electrode (GDE) fabrication routes. The inability effectively to hot-press hydrocarbon-based ion-exchange polymers (ionomers) risks performance limitations due to poor interfacial contact, especially between GDE and membrane. The addition of an ionomeric interlayer is shown greatly to improve the intimacy of contact between GDE and membrane, as determined by ex situ through-plane MEA impedance measurements, indicated by a strong decrease in the frequency of the high-frequency zero phase angle of the complex impedance, and confirmed in situ with device performance tests. The best interfacial contact is achieved with CCM's, with the contact impedance decreasing, and device performance increasing, in the order GDE >> GDE+Interlayer > CCM. The GDE+interlayer fabrication approach is further examined with respect to hydrogen crossover and alkaline membrane electrolyzer cell performance. An interlayer strongly reduces the rate of hydrogen crossover without strongly decreasing electrolyzer performance, while crosslinking the ionomeric layer further reduces the crossover rate though also limiting device performance. The approach can be applied and built upon to improve the design and production of alkaline, and more generally, hydrocarbon-based MEA's and exchange membrane devices.


Non-steroidal anti-inflammatory drugs (NSAIDs) for axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis).
Axial spondyloarthritis (axSpA) comprises ankylosing spondylitis (radiographic axSpA) and non-radiographic (nr-)axSpA and is associated with psoriasis, uveitis and inflammatory bowel disease. Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended as first-line drug treatment. To determine the benefits and harms of NSAIDs in axSpA. We searched CENTRAL, MEDLINE and EMBASE to 18 June 2014. Randomised controlled trials (RCTs) or quasi-RCTs of NSAIDs versus placebo or any comparator in adults with axSpA and observational cohort studies studying the long term effect (≥ six months) of NSAIDs on radiographic progression or adverse events (AEs). The main comparions were traditional or COX-2 NSAIDs versus placebo. The major outcomes were pain, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Metrology Index (BASMI), radiographic progression, number of withdrawals due to AEs and number of serious AEs Two review authors independently selected trials for inclusion, assessed the risk of bias, extracted data and assessed the quality of evidence for major outcomes using GRADE. We included 39 studies (35 RCTs, two quasi-RCTs and two cohort studies); and 29 RCTs and two quasi-RCTs (n = 4356) in quantitative analyses for the comparisons: traditional NSAIDs versus placebo, cyclo-oxygenase-2 (COX-2) versus placebo, COX-2 versus traditional NSAIDs, NSAIDs versus NSAIDs, naproxen versus other NSAIDs, low versus high dose. Most trials were at unclear risk of selection bias (n = 29), although blinding of participants and personnel was adequate in 24 trials. Twenty-five trials had low risk of attrition bias and 29 trials had low risk of reporting bias. Risk of bias in both cohort studies was high for study participation, and low or unclear for all other criteria. No trials in the meta-analyses assessed patients with nr-axSpA.Traditional NSAIDs were more beneficial than placebo at six weeks. High quality evidence (four trials, N=850) indicates better pain relief with NSAIDs (pain in control group ranged from 57 to 64 on a 100mm visual analogue scale (VAS) and was 16.5 points lower in the NSAID group (95% confidence interval (CI) -20.8 to -12.2), lower scores indicate less pain, NNT 4 (3 to 6)); moderate quality evidence (one trial, n = 190) indicates improved disease activity with NSAIDs (BASDAI in control group was 54.7 on a 100-point scale and was 17.5 points lower in the NSAID group, 95% CI -23.1 to -11.8), lower scores indicate less disease activity, NNT 3 (2 to 4)); and high quality evidence (two trials, n = 356) indicates improved function with NSAIDs (BASFI in control group was 50.0 on a 100-point scale and was 9.1 points lower in the NSAID group (95% CI -13.0 to -5.1), lower scores indicate better functioning, NNT 5 (3 to 8)). High (five trials, n = 1165) and moderate (three trials, n = 671) quality evidence (downgraded due to potential imprecision) indicates that withdrawals due to AEs and number of serious AEs did not differ significantly between placebo (52/1000 and 2/1000) and NSAID (39/1000 and 3/1000) groups after 12 weeks (risk ratio (RR) 0.75, 95% CI 0.46 to 1.21; and RR 1.69, 95% CI 0.36 to 7.97, respectively). BASMI and radiographic progression were not reported.COX-2 NSAIDS were also more efficacious than placebo at six weeks. High quality evidence (two trials, n = 349) indicates better pain relief with COX-2 (pain in control group was 64 points and was 21.7 points lower in the COX-2 group (95% CI -35.9 to -7.4), NNT 3 (2 to 24)); moderate quality evidence (one trial, n = 193) indicates improved disease activity with COX-2 (BASDAI in control groups was 54.7 points and was 22 points lower in the COX-2 group (95% CI -27.4 to -16.6), NNT 2 (1 to 3)); and high quality evidence (two trials, n = 349) showed improved function with COX-2 (BASFI in control group was 50.0 points and was 13.4 points lower in the COX-2 group (95% CI -17.4 to -9.5), NNT 3 (2 to 4)). Low and moderate quality evidence (three trials, n = 669) (downgraded due to potential imprecision and heterogeneity) indicates that withdrawals due to AEs and number of serious AEs did not differ significantly between placebo (11/1000 and 2/1000) and COX-2 (24/1000 and 2/1000) groups after 12 weeks (RR 2.14, 95% CI 0.36 to 12.56; and RR 0.92, 95% CI 0.14 to 6.21, respectively). BASMI and radiographic progression were not reported.There were no significant differences in benefits (pain on VAS: MD -2.62, 95% CI -10.99 to 5.75; three trials, n = 669) or harms (withdrawals due to AEs: RR 1.04, 95% CI 0.60 to 1.82; four trials, n = 995) between NSAID classes. While indomethacin use resulted in significantly more AEs (RR 1.25, 95% CI 1.06 to 1.48; 11 studies, n = 1135), and neurological AEs (RR 2.34, 95% CI 1.32 to 4.14; nine trials, n = 963) than other NSAIDs, these findings were not robust to sensitivity analyses. We found no important differences in harms between naproxen and other NSAIDs (three trials, n = 646), although other NSAIDs appeared more effective for relieving pain (MD 6.80, 95% CI 3.72 to 9.88; two trials, n = 232). We found no clear dose-response effect on benefits or harms (five studies, n = 1136). Single studies suggest NSAIDs may be effective in retarding radiographic progression, especially in certain subgroups of patients, e.g. patients with high CRP, and that this may be best achieved by continuous rather than on-demand use of NSAIDs. High to moderate quality evidence indicates that both traditional and COX-2 NSAIDs are efficacious for treating axSpA, and moderate to low quality evidence indicates harms may not differ from placebo in the short term. Various NSAIDs are equally effective. Continuous NSAID use may reduce radiographic spinal progression, but this requires confirmation.


Two-quadrant area structure function analysis for optical surface characterization.
This paper describes the use of the area structure function (SF) for the specification and characterization of optical surfaces. A two-quadrant area SF is introduced because the one-quadrant area SF does not completely describe surfaces with certain asymmetries. Area SF calculations of simulation data and of a diamond turned surface are shown and compared to area power spectral density (PSD) and area autocorrelation function (ACF) representations. The direct relationship between SF, PSD, and ACF for a stationary surface does not apply to non-stationary surfaces typical of optics with figure errors.


DNA methylation in intron 1 of the frataxin gene is related to GAA repeat length and age of onset in Friedreich ataxia patients.
The most frequent mutation of Friedreich ataxia (FRDA) is the abnormal expansion of a GAA repeat located within the first intron of FXN gene. It is known that the length of GAA is directly correlated with disease severity. The effect of mutation is a severe reduction of mRNA. Recently, a link among aberrant CpG methylation, chromatin organisation and GAA repeat was proposed. In this study, using pyrosequencing technology, we have performed a quantitative analysis of the methylation status of five CpG sites located within the region upstream of GAA repeat, in 67 FRDA patients. We confirm previous observation about differences in the methylation degree between FRDA individuals and controls. We showed a direct correlation between CpG methylation and triplet expansion size. Significant differences were found for each CpG tested (ANOVA p<0.001). These differences were largest for CpG1 and CpG2: 84.45% and 76.80%, respectively, in FRDA patients compared to 19.65% and 23.34% in the controls. Most importantly, we found a strong inverse correlation between CpG2 methylation degree and age of onset (Spearman's rho = -0.550, p<0.001). Because epigenetic changes may cause or contribute to gene silencing, our data may have relevance for the therapeutic approach to FRDA. Since the analysis can be performed in peripheral blood leucocytes (PBL), evaluation of the methylation status of specific CpG sites in FRDA patients could be a convenient biomarker.


A special case of lower back pain in a 3-year-old girl.
We describe the case of a 3-year-old girl with a 15-day clinical history of lower back pain. We diagnosed a spondylodiscitis of vertebral bodies L5-S1 caused by Salmonella species group B that totally recovered with appropriate antibiotic therapy. Spondylodiscitis in children is a rare condition and Salmonella infection is one of the rarest aetiology. A high index of suspicion is needed for prompt diagnosis to ensure better long-term outcome. Microbiological diagnosis is essential for the appropriate choice of antibiotic treatment.


The development of hyperbaric oxygen therapy for skin rejuvenation and treatment of photoaging.
Hyperbaric oxygen therapy (HBOT), a therapy that have patients breath in pure oxygen in a pressurized chamber, has been long used as a treatment for conditions such as decompression sickness and carbon monoxide poisoning. Oxygen recently has been found to be an important component in skin rejuvenation, treatment of photoaging skin, and improvement in skin complexions. The interest in the use of HBOT for this purpose is continually growing and becoming more widespread. In addition to aging and genetic makeup, chronic UV radiation due to everyday exposure, especially UV-B, can greatly increase the rate of wrinkle formation through increasing skin angiogenesis and degradation of extracellular matrix molecules. The use of HBOT and hyperoxia conditions has been found to attenuate the formation of wrinkles from UV irradiation. It accomplishes the task by possibly inhibiting various processes and pathways involved such as the HIF1-α, VEGF, neutrophil infiltrations, and MMP-2 & MMP-9, which are directly involved with promoting skin angiogenesis in its active state. There are currently medical aesthetic clinics that are using oxygen therapy under high pressure applied directly to skin to reduce visible wrinkles but this procedure is not widespread yet due to more research that needs to be done on this topic. However, this treatment for wrinkles is definitely growing due to recent studies done showing the effectiveness of oxygen therapy on wrinkles. This review article will explore and summarize researches done on possible mechanisms dealing with the use of oxygen therapy for reduction of UVB-caused wrinkles, its side effects, and its possible future improvement and use in medicine.


Ophthalmic lesions in neonatal foals evaluated for nonophthalmic disease at referral hospitals.
To determine types and frequency of ophthalmic lesions detected in neonatal foals evaluated for nonophthalmic disease at 3 veterinary referral hospitals and to investigate associations between systemic and ophthalmic diseases in these foals. Prospective cross-sectional study. 70 foals < 30 days old. Complete ophthalmic examinations were performed. Signalment, clinical signs, mentation during ophthalmic examination, results of clinicopathologic tests, and diagnosis of systemic disease were recorded. Descriptive data analysis including a χ(2) test for associations was performed. Most foals (39/70 [55.7%]) with systemic disease had ≥ 1 ophthalmic lesion detected. Of the 39 foals with ophthalmic disease, 24 (61.5%) had potentially vision-threatening lesions. Clinically important abnormalities included conjunctival hyperemia or episcleral injection (30/70 [42.9%]), uveitis (18/70 [25.7%]), ulcerative keratitis (13/70 [18.6%]), nonulcerative keratitis (10/70 [14.3%]), entropion (8/70 [11.4%]), retinal hemorrhage (8/70 [11.4%]), and cataract (6/70 [8.6%]). Foals with sepsis were significantly more likely to have uveitis than were those without sepsis. Foals with sepsis and uveitis were also significantly less likely to survive to discharge than were foals that had sepsis without uveitis. Acquired ophthalmic disease (detected in 37/70 [52.9%] foals) was significantly more common than congenital ophthalmic disease (detected in 9/70 [12.9%]). Ophthalmic lesions were detected in 55.7% of neonatal foals with systemic disease. Acquired ophthalmic disease was more commonly detected than congenital ophthalmic disease. Foals with sepsis were more likely to have uveitis than were foals without sepsis. A complete ophthalmic examination is indicated in neonatal foals evaluated for systemic disease.


The top-ten in journal impact factor manipulation.
A considerable part of the scientific community is, at least to some degree, involved in the "impact factor game". Editors strive to increase their journals' impact factor (IF) in order to gain influence in the fields of basic and applied research and scientists seek to profit from the "added value" of publishing in top IF journals. In this article we point out the most common "tricks" of engineering and manipulating the IF undertaken by a portion of professionals of the scientific publishing industry. They attempt to increase the nominator or decrease the denominator of the IF equation by taking advantage of certain design flaws and disadvantages of the IF that permit a degree of artificial and arbitrary inflation. Some of these practices, if not scientifically unethical, are at least questionable and should be abandoned. Editors and publishers should strive for quality through fair and thoughtful selection of papers forwarded for peer review and editorial comments that enhance the quality and scientific accuracy of a manuscript.


The Roles of Glutamine in the Intestine and Its Implication in Intestinal Diseases.
Glutamine, the most abundant free amino acid in the human body, is a major substrate utilized by intestinal cells. The roles of glutamine in intestinal physiology and management of multiple intestinal diseases have been reported. In gut physiology, glutamine promotes enterocyte proliferation, regulates tight junction proteins, suppresses pro-inflammatory signaling pathways, and protects cells against apoptosis and cellular stresses during normal and pathologic conditions. As glutamine stores are depleted during severe metabolic stress including trauma, sepsis, and inflammatory bowel diseases, glutamine supplementation has been examined in patients to improve their clinical outcomes. In this review, we discuss the physiological roles of glutamine for intestinal health and its underlying mechanisms. In addition, we discuss the current evidence for the efficacy of glutamine supplementation in intestinal diseases.


Plasmon delocalization onset in finite sized nanostructures.
The transition from localized to delocalized plasmons (i.e. the transition from a situation where the decay length of a travelling surface plasma wave is greater than its propagation distance to a situation where it is smaller) and hence the onset of plasmon delocalization is studied in a single 2D silver nanoparticle of increasing length. A fourier analysis in the near-field of the nanoparticle is used as the main tool for analysis. This method, along with far-field scattering spectra simulations and the near-field profile directly above and along the length of the nanoparticle are used to investigate and clearly show the transition from localized to delocalized modes. In particular, it is found that for a finite sized rectangular nanoparticle, both the emerging odd and even delocalized modes are nothing but a superposition of many standing wave plasmon modes. As a consequence, even very short metal films can support delocalized plasmons that bounce back and forth along the film.


Hydrocarbon absorption coefficients at the 3.39-microm He-Ne laser transition.
In view of the application of light-extinction techniques for fuel-specie-concentration measurements in combustion systems, the vapor-absorption coefficient of several hydrocarbon species at the 3.39-microm He-Ne laser transition has been measured. The hydrocarbon species include paraffins, olefins, and aromatics. Result are included for total pressure over the range of approximately 200-650 Torr at 295 K with air as the buffer gas. Observations are made regarding the difference in the absorption coefficient within and between hydrocarbon classifications.


Assessing reliability, heritability and general cognitive ability in a battery of cognitive tasks for laboratory mice.
This report includes the first sibling study of mouse behavior, and presents evidence for a heritable general cognitive ability (g) factor influencing cognitive batteries. Data from a population of male and female outbred mice (n = 84), and a replication study of male sibling pairs (n = 167) are reported. Arenas employed were the T-maze, the Morris water maze, the puzzle box, the Hebb-Williams maze, object exploration, a water plus-maze, and a second food-puzzle arena. The results show a factor structure consistent with the presence of g in mice. Employing one score per arena, this factor accounts for 41% of the variance in the first study (or 36% after sex regression) and 23% in the second, where this factor also showed sibling correlations of 0.17-0.21, which translates into an upper-limit heritability estimate of around 40%. Reliabilities of many tasks are low and consequently set an even lower ceiling for inter-arena or sibling correlations. Nevertheless, the factor structure is seen to remain fairly robust across permutations of the battery composition and the current findings fit well with other recent studies.


DNA binding site sequence directs glucocorticoid receptor structure and activity.
Genes are not simply turned on or off, but instead their expression is fine-tuned to meet the needs of a cell. How genes are modulated so precisely is not well understood. The glucocorticoid receptor (GR) regulates target genes by associating with specific DNA binding sites, the sequences of which differ between genes. Traditionally, these binding sites have been viewed only as docking sites. Using structural, biochemical, and cell-based assays, we show that GR binding sequences, differing by as little as a single base pair, differentially affect GR conformation and regulatory activity. We therefore propose that DNA is a sequence-specific allosteric ligand of GR that tailors the activity of the receptor toward specific target genes.


Efficacy and safety of surgical decompression in patients with cervical spondylotic myelopathy: results of the AOSpine North America prospective multi-center study.
Cervical spondylotic myelopathy is the leading cause of spinal cord dysfunction worldwide. The objective of this study was to evaluate the impact of surgical decompression on functional, quality-of-life, and disability outcomes at one year after surgery in a large cohort of patients with this condition. Adult patients with symptomatic cervical spondylotic myelopathy and magnetic resonance imaging evidence of spinal cord compression were enrolled at twelve North American centers from 2005 to 2007. At enrollment, the myelopathy was categorized as mild (modified Japanese Orthopaedic Association [mJOA] score ≥ 15), moderate (mJOA = 12 to 14), or severe (mJOA < 12). Patients were followed prospectively for one year, at which point the outcomes of interest included the mJOA score, Nurick grade, Neck Disability Index (NDI), and Short Form-36 version 2 (SF-36v2). All outcomes at one year were compared with the preoperative values with use of univariate paired statistics. Outcomes were also compared among the severity classes with use of one-way analysis of variance. Finally, a multivariate analysis that adjusted for baseline differences among the severity groups was performed. Treatment-related complication data were collected and the overall complication rate was calculated. Eighty-five (30.6%) of the 278 enrolled patients had mild cervical spondylotic myelopathy, 110 (39.6%) had moderate disease, and 83 (29.9%) had severe disease preoperatively. One-year follow-up data were available for 222 (85.4%) of 260 patients. There was a significant improvement from baseline to one year postoperatively (p < 0.05) in the mJOA score, Nurick grade, NDI score, and all SF-36v2 health dimensions (including the mental and physical health composite scores) except general health. With the exception of the change in the mJOA, the degree of improvement did not depend on the severity of the preoperative symptoms. These results remained unchanged after adjusting for relevant confounders in the multivariate analysis. Fifty-two patients experienced complications (prevalence, 18.7%), with no significant differences among the severity groups. Surgical decompression for the treatment of cervical spondylotic myelopathy was associated with improvement in functional, disability-related, and quality-of-life outcomes at one year of follow-up for all disease severity categories. Furthermore, complication rates observed in the study were commensurate with those in previously reported cervical spondylotic myelopathy series.


Glucose attenuates impairments in memory and CREB activation produced by an α4β2 but not an α7 nicotinic receptor antagonist.
Glucose improves memory for a variety of tasks when administered to rats and mice near the time of training. Prior work indicates glucose may enhance memory by increasing the synthesis and release of the neurotransmitter acetylcholine in the brain. To investigate if specific acetylcholine receptor subtypes may mediate some of the memory-enhancing actions of glucose, we examined the effects of subtype-specific nicotinic acetylcholine receptor antagonists on memory in Fischer-344 rats and also examined the ability of glucose to reverse drug-induced impairments. Pre-training peripheral injections of methyllycaconitine (MLA) or dihydro-beta-erythroidine (DHβE), which are specific α7 and α4β2 nicotinic receptor antagonists, respectively, dose-dependently impaired retention latencies in an inhibitory avoidance task when tested 7-days but not 1 h after training. Immediate post-training glucose injections attenuated the impairments, but were more effective in attenuating the DHβE-induced impairments. Likewise, peripheral or direct intrahippocampal injections of MLA or DHβE dose-dependently impaired spatial working memory scores on a spontaneous alternation task. Concurrent administration of glucose reversed DHβE- but not MLA-induced impairments. CREB phosphorylation downstream of cholinergic signaling was assessed 30 min after spontaneous alternation testing and intrahippocampal drug infusions. Both MLA and DHβE impaired hippocampal CREB phosphorylation; glucose reversed DHβE- but not MLA-induced deficits. The effectiveness of glucose in reversing DHβE- but not MLA-induced impairments in behavioral performance and CREB phosphorylation suggests that activation of α7 receptors may play an important role in memory enhancement by glucose.


Electrochemical strategies for C-H functionalization and C-N bond formation.
Conventional methods for carrying out carbon-hydrogen functionalization and carbon-nitrogen bond formation are typically conducted at elevated temperatures, and rely on expensive catalysts as well as the use of stoichiometric, and perhaps toxic, oxidants. In this regard, electrochemical synthesis has recently been recognized as a sustainable and scalable strategy for the construction of challenging carbon-carbon and carbon-heteroatom bonds. Here, electrosynthesis has proven to be an environmentally benign, highly effective and versatile platform for achieving a wide range of nonclassical bond disconnections via generation of radical intermediates under mild reaction conditions. This review provides an overview on the use of anodic electrochemical methods for expediting the development of carbon-hydrogen functionalization and carbon-nitrogen bond formation strategies. Emphasis is placed on methodology development and mechanistic insight and aims to provide inspiration for future synthetic applications in the field of electrosynthesis.


Progressive cerebellar, auditory, and esophageal dysfunction caused by targeted disruption of the frizzled-4 gene.
Wnt signaling has been implicated in the control of cell proliferation and in synapse formation during neural development, and these actions are presumed to be mediated by frizzled receptors. In this paper we report the phenotype of mice carrying a targeted deletion of the frizzled-4 (fz4) gene. fz4(-/-) mice exhibit three distinct defects: (1) progressive cerebellar degeneration associated with severe ataxia, (2) absence of a skeletal muscle sheath around the lower esophagus associated with progressive esophageal distension and dysfunction, and (3) progressive deafness caused by a defect in the peripheral auditory system unaccompanied by loss of hair cells or other auditory neurons. As assayed using a lacZ knock-in reporter, fz4 is widely expressed within the CNS. In particular, fz4 is expressed in cerebellar Purkinje cells, esophageal skeletal muscle, and cochlear inner hair cells, and the absence of Fz4 in these cells is presumed to account for the fz4(-/-) phenotype. In contrast to the early cell proliferation and patterning effects classically ascribed to Wnts, the auditory and cerebellar phenotypes of fz4(-/-) mice implicate Frizzled signaling in maintaining the viability and integrity of the nervous system in later life.


The dynamics of reading complex words: evidence from steady-state visual evoked potentials.
The present study used steady-state visual evoked potentials (SSVEPs) to examine the spatio-temporal dynamics of reading morphologically complex words and test the neurophysiological activation pattern elicited by stems and suffixes. Three different types of target words were presented to proficient readers in a delayed naming task: truly suffixed words (e.g., farmer), pseudo-suffixed words (e.g., corner), and non-suffixed words (e.g., cashew). Embedded stems and affixes were flickered at two different frequencies (18.75 Hz and 12.50 Hz, respectively). The stem data revealed an earlier SSVEP peak in the truly suffixed and pseudo-suffixed conditions compared to the non-suffixed condition, thus providing evidence for the form-based activation of embedded stems during reading. The suffix data also showed a dissociation in the SSVEP response between suffixes and non-suffixes with an additional activation boost for truly suffixed words. The observed differences are discussed in the context of current models of complex word recognition.


Reductive site-selective atypical C,Z-type/N2-C2 cleavage allows C-terminal protein amidation.
Biomolecule environments can enhance chemistries with the potential to mediate and modulate self-modification (e.g., self-cleavage). While these enhanced modes are found in certain biomolecules (e.g., RNA ribozymes), it is more rare in proteins. Targeted proteolytic cleavage is vital to physiology, biotechnology, and even emerging therapy. Yet, purely chemically induced methods for the site-selective cleavage of proteins remain scarce. Here, as a proof of principle, we designed and tested a system intended to combine protein-enhanced chemistry with tag modification to enable synthetic reductive protein chemistries promoted by diboron. This reductively driven, single-electron chemistry now enables an operationally simple, site-selective cleavage protocol for proteins directed to readily accessible dehydroalanine (Dha) residues as tags under aqueous conditions and in cell lysates. In this way, a mild, efficient, enzyme-free method now allows not only precise chemical proteolysis but also simultaneous use in the removal of affinity tags and/or protein-terminus editing to create altered N- and C-termini such as protein amidation (─CONH2).


Horizontal gene transfer of microbial cellulases into nematode genomes is associated with functional assimilation and gene turnover.
Natural acquisition of novel genes from other organisms by horizontal or lateral gene transfer is well established for microorganisms. There is now growing evidence that horizontal gene transfer also plays important roles in the evolution of eukaryotes. Genome-sequencing and EST projects of plant and animal associated nematodes such as Brugia, Meloidogyne, Bursaphelenchus and Pristionchus indicate horizontal gene transfer as a key adaptation towards parasitism and pathogenicity. However, little is known about the functional activity and evolutionary longevity of genes acquired by horizontal gene transfer and the mechanisms favoring such processes. We examine the transfer of cellulase genes to the free-living and beetle-associated nematode Pristionchus pacificus, for which detailed phylogenetic knowledge is available, to address predictions by evolutionary theory for successful gene transfer. We used transcriptomics in seven Pristionchus species and three other related diplogastrid nematodes with a well-defined phylogenetic framework to study the evolution of ancestral cellulase genes acquired by horizontal gene transfer. We performed intra-species, inter-species and inter-genic analysis by comparing the transcriptomes of these ten species and tested for cellulase activity in each species. Species with cellulase genes in their transcriptome always exhibited cellulase activity indicating functional integration into the host's genome and biology. The phylogenetic profile of cellulase genes was congruent with the species phylogeny demonstrating gene longevity. Cellulase genes show notable turnover with elevated birth and death rates. Comparison by sequencing of three selected cellulase genes in 24 natural isolates of Pristionchus pacificus suggests these high evolutionary dynamics to be associated with copy number variations and positive selection. We could demonstrate functional integration of acquired cellulase genes into the nematode's biology as predicted by theory. Thus, functional assimilation, remarkable gene turnover and selection might represent key features of horizontal gene transfer events in nematodes.


Applicability of cervical sagittal vertical axis, cervical lordosis, and T1 slope on pain and disability outcomes after anterior cervical discectomy and fusion in patients without deformity.
Understanding what influences pain and disability following anterior cervical discectomy and fusion (ACDF) in patients with degenerative cervical spine disease is critical. This study examines the timing of clinical improvement and identifies factors (including spinal alignment) associated with worse outcomes. Consecutive adult patients were enrolled in a prospective outcomes database from two academic centers participating in the Quality Outcomes Database from 2013 to 2016. Demographics, surgical details, radiographic data, arm and neck pain (visual analog scale [VAS] scores), and disability (Neck Disability Index [NDI] and EQ-5D scores) were reviewed. Multivariate analysis was used. A total of 186 patients were included, and 48.4% were male. Their mean age was 55.4 years, and 45.7% had myelopathy. Preoperative cervical sagittal vertical axis (cSVA), cervical lordosis (CL), and T1 slope values were 24.9 mm (range 0-55 mm), 10.4° (range -6.0° to 44°), and 28.3° (range 14.0°-51.0°), respectively. ACDF was performed at 1, 2, and 3 levels in 47.8%, 42.0%, and 10.2% of patients, respectively. Preoperative neck and arm VAS scores were 5.7 and 5.4, respectively. NDI and EQ-5D scores were 22.1 and 0.5, respectively. There was significant improvement in all outcomes at 3 months (p < 0.001) and 12 months (p < 0.001). At 3 months, neck VAS (3.0), arm VAS (2.2), NDI (12.7), and EQ-5D (0.7) scores were improved, and at 12 months, neck VAS (2.8), arm VAS (2.3), NDI (11.7), and EQ-5D (0.8) score improvements were sustained. Improvements occurred within the first 3-month period; there was no significant difference in outcomes between the 3-month and 12-month mark. There was no correlation among cSVA, CL, or T1 slope with any outcome endpoint. The most consistent independent preoperative factors associated with worse outcomes were high neck and arm VAS scores and a severe NDI result (p < 0.001). Similar findings were seen with worse NDI and EQ-5D scores (p < 0.001). A significant linear trend of worse NDI and EQ-5D scores at 3 and 12 months was associated with worse baseline scores. Of the 186 patients, 171 (91.9%) had 3-month follow-up data, and 162 (87.1%) had 12-month follow-up data. ACDF is effective in improving pain and disability, and improvement occurs within 3 months of surgery. cSVA, CL, and T1 slope do not appear to influence outcomes following ACDF surgery in the population with degenerative cervical disease. Therefore, in patients with relatively normal cervical parameters, augmenting alignment or lordosis is likely unnecessary. Worse preoperative pain and disability were independently associated with worse outcomes.


Sumoylation of poly(ADP-ribose) polymerase 1 inhibits its acetylation and restrains transcriptional coactivator function.
Poly(ADP-ribose) polymerase 1 (PARP1) is a chromatin-associated nuclear protein and functions as a molecular stress sensor. At the cellular level, PARP1 has been implicated in a wide range of processes, such as maintenance of genome stability, cell death, and transcription. PARP1 functions as a transcriptional coactivator of nuclear factor kappaB (NF-kappaB) and hypoxia inducible factor 1 (HIF1). In proteomic studies, PARP1 was found to be modified by small ubiquitin-like modifiers (SUMOs). Here, we characterize PARP1 as a substrate for modification by SUMO1 and SUMO3, both in vitro and in vivo. PARP1 is sumoylated at the single lysine residue K486 within its automodification domain. Interestingly, modification of PARP1 with SUMO does not affect its ADP-ribosylation activity but completely abrogates p300-mediated acetylation of PARP1, revealing an intriguing crosstalk of sumoylation and acetylation on PARP1. Genetic complementation of PARP1-depleted cells with wild-type and sumoylation-deficient PARP1 revealed that SUMO modification of PARP1 restrains its transcriptional coactivator function and subsequently reduces gene expression of distinct PARP1-regulated target genes.


Sounding the Alarm: Health in the Anthropocene.
There is growing scientific and public recognition that human actions, directly and indirectly, have profoundly changed the Earth system, in a still accelerating process, increasingly called the "Anthropocene". Planetary transformation, including of the atmosphere, climate, ecosystems and biodiversity, has enormous implications for human health, many of which are deeply disturbing, especially in low-income settings. A few health consequences of the Anthropocene have been partially recognized, including within environmental epidemiology, but their long-term consequences remain poorly understood and greatly under-rated. For example Syria could be a "sentinel" population, giving a glimpse to a much wider dystopian future. Health-Earth is a research network, co-founded in 2014, which seeks, with other groups, to catalyse a powerful curative response by the wider health community. This paper builds on a symposium presented by Health-Earth members at the 2015 conference of the International Society for Environmental Epidemiology. It reviews and synthesizes parts of the large literature relevant to the interaction between the changing Earth system and human health. It concludes that this topic should be prominent within future environmental epidemiology and public health. Created by our species, these challenges may be soluble, but solutions require far more understanding and resources than are currently being made available.


Discovery of genomic intervals that underlie nematode responses to benzimidazoles.
Parasitic nematodes impose a debilitating health and economic burden across much of the world. Nematode resistance to anthelmintic drugs threatens parasite control efforts in both human and veterinary medicine. Despite this threat, the genetic landscape of potential resistance mechanisms to these critical drugs remains largely unexplored. Here, we exploit natural variation in the model nematodes Caenorhabditis elegans and Caenorhabditis briggsae to discover quantitative trait loci (QTL) that control sensitivity to benzimidazoles widely used in human and animal medicine. High-throughput phenotyping of albendazole, fenbendazole, mebendazole, and thiabendazole responses in panels of recombinant lines led to the discovery of over 15 QTL in C. elegans and four QTL in C. briggsae associated with divergent responses to these anthelmintics. Many of these QTL are conserved across benzimidazole derivatives, but others show drug and dose specificity. We used near-isogenic lines to recapitulate and narrow the C. elegans albendazole QTL of largest effect and identified candidate variants correlated with the resistance phenotype. These QTL do not overlap with known benzimidazole target resistance genes from parasitic nematodes and present specific new leads for the discovery of novel mechanisms of nematode benzimidazole resistance. Analyses of orthologous genes reveal conservation of candidate benzimidazole resistance genes in medically important parasitic nematodes. These data provide a basis for extending these approaches to other anthelmintic drug classes and a pathway towards validating new markers for anthelmintic resistance that can be deployed to improve parasite disease control.


Serum adiponectin, resistin, and circulating soluble receptor for advanced glycation end products in colectomy patients.
Surgical trauma and associated complications are frequently related to physiological stress during colectomy. This study evaluated the response of adiponectin, resistin, and circulating soluble receptor for advanced glycation end products (sRAGE) in colectomy patients with or without an enhanced recovery protocol. Serum samples were collected from 44 colectomy patients at 3 timframes. The surgical procedures were laparoscopic (LAP), hand-assisted laparoscopic (HALS), or open colectomy (OPEN). Adiponectin, resistin, and sRAGE levels were determined by ELISA. Repeated measures ANOVA was applied and P values < 0.05 were considered significant. A total of 132 (44 × 3) sera were used for analysis. Levels of adiponectin was significantly decreased between PREOP and POD3 (P < 0.001). Conversely, concentrations of resistin significantly increased from PREOP to POD1 and returned to baseline value by POD3 (P < 0.001). Serum sRAGE levels were significantly higher in LAP in comparison with HALS (P = 0.004) and OPEN (P < 0.001). sRAGE levels were significantly higher in sera of patients that underwent ERP (P < 0.001). Serum adiponectin, resistin, and sRAGE have the potential to develop into a panel of stress markers. Higher sRAGE levels in sera of LAP and ERP patients may be indicative of a protective and syngeristic role for colectomy recovery.


Osseointegration and biocompatibility of different metal implants--a comparative experimental investigation in sheep.
In the present study, 4 different metallic implant materials, either partly coated or polished, were tested for their osseointegration and biocompatibility in a pelvic implantation model in sheep. Materials to be evaluated were: Cobalt-Chrome (CC), Cobalt-Chrome/Titanium coating (CCTC), Cobalt-Chrome/Zirconium/Titanium coating (CCZTC), Pure Titanium Standard (PTST), Steel, TAN Standard (TANST) and TAN new finish (TANNEW). Surgery was performed on 7 sheep, with 18 implants per sheep, for a total of 63 implants. After 8 weeks, the specimens were harvested and evaluated macroscopically, radiologically, biomechanically (removal torque), histomorphometrically and histologically. Cobalt-Chrome screws showed significantly (p = 0.031) lower removal torque values than pure titanium screws and also a tendency towards lower values compared to the other materials, except for steel. Steel screws showed no significant differences, in comparison to cobalt-chrome and TANST, however also a trend towards lower torque values than the remaining materials. The results of the fluorescence sections agreed with those of the biomechanical test. Histomorphometrically, there were no significant differences of bone area between the groups. The BIC (bone-to-implant-contact), used for the assessment of the osseointegration, was significantly lower for cobalt-chrome, compared to steel (p = 0.001). Steel again showed a lower ratio (p = 0.0001) compared to the other materials. This study demonstrated that cobalt-chrome and steel show less osseointegration than the other metals and metal-alloys. However, osseointegration of cobalt-chrome was improved by zirconium and/or titanium based coatings (CCTC, TANST, TAN, TANNEW) being similar as pure titanium in their osseointegrative behavior.


A route to de novo domestication of wild allotetraploid rice.
Cultivated rice varieties are all diploid, and polyploidization of rice has long been desired because of its advantages in genome buffering, vigorousness, and environmental robustness. However, a workable route remains elusive. Here, we describe a practical strategy, namely de novo domestication of wild allotetraploid rice. By screening allotetraploid wild rice inventory, we identified one genotype of Oryza alta (CCDD), polyploid rice 1 (PPR1), and established two important resources for its de novo domestication: (1) an efficient tissue culture, transformation, and genome editing system and (2) a high-quality genome assembly discriminated into two subgenomes of 12 chromosomes apiece. With these resources, we show that six agronomically important traits could be rapidly improved by editing O. alta homologs of the genes controlling these traits in diploid rice. Our results demonstrate the possibility that de novo domesticated allotetraploid rice can be developed into a new staple cereal to strengthen world food security.


Phorbol dibutyrate contractions in rabbit aorta: calcium dependence and sensitivity to nitrovasodilators and 8-BR-cyclic GMP.
Phorbol esters activate protein kinase C and induce contraction in vascular smooth muscle. The role of Ca and the sensitivity of this response to nitrovasodilators were evaluated in rabbit aortic rings. Phorbol dibutyrate (PDB) (0.01-10 microM) elicited a concentration-dependent contraction of rabbit aortic rings. Responses to PDB in a salt solution (SS) containing 2.54 mM CaCl2 were not significantly different from those in SS containing 0 Ca and 2 mM ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid. Contractions to PDB (1 microM) in zero Ca SS were not reduced by depletion of the norepinephrine-sensitive pool of intracellular Ca. The Ca entry blockers verapamil (100 microM) and nifedipine (100 microM) did not affect PDB (1 microM) responses. Nitroprusside (0.1-10 microM) and nitroglycerin (0.1-10 microM) inhibited PDB contractions in both normal SS and Ca-free SS. 8-Br-cyclic GMP (100 microM) also inhibited PDB responses. Effects of PDB on 45Ca fluxes were evaluated in separate experiments. PDB (1 and 10 microM) elicited contraction, but no change in 45Ca uptake or efflux. In contrast KCl (80 mM) and norepinephrine (10 microM) elicited an increase in both influx and efflux, reflecting a rise in cytosolic Ca. The data suggest that PDB-induced contractions in rabbit aorta are independent of extracellular Ca and are not associated with a rise in cytosolic Ca as detected by calcium flux studies.(ABSTRACT TRUNCATED AT 250 WORDS)


The potential for strategies using micronutrients and heterocyclic drugs to treat invasive gliomas.
Local invasion of neoplastic cells into the surrounding brain is perhaps the most important aspect of the biology of gliomas that precludes successful therapy. Despite significant advances in neuro-imaging, neurosurgery and radiotherapy, the median survival for patients with a malignant glioma is still less than one year. With the increasing knowledge of the biology of brain tumours, derived from cellular and molecular studies, new methods of treatment are being developed with some success. Approaches studied already include anti-invasive, pro-apoptotic and anti-angiogenesis strategies and clinical trials are imminent. In this article we review two new approaches to the management of gliomas: nutraceutical intervention and heterocyclic drugs. The first approach uses a combination of naturally occurring agents, including citrus flavonoids, chokeberry extract, red grape seed extract, lycopene, selenium and red clover extract. These agents can either trigger apoptosis or affect the pathways underlying diffuse invasion. The second approach involves the use of a heterocyclic drug, clomipramine, which selectively triggers apoptosis in neoplastic cells but not in normal glia. The article refers to the results of recent studies performed in our laboratory which suggest that these new approaches can be translated into benefit to patients.


Adapalene/Benzoyl Peroxide Gel 0.3%/2.5%: A Safe and Effective Acne Therapy in All Skin Phototypes.

BACKGROUND: Acne affects individuals of all races and ethnicities; however, lighter and darker skin phototypes face different treatment challenges that may affect treatment response and tolerability. This analysis investigated possible differences in the efficacy and safety of the fixed dose combination of 0.3% adapalene with 2.5% benzoyl peroxide (A/BPO gel 0.3%/2.5%) in subjects with Fitzpatrick Skin Types (FST) I-VI.

METHODS: This was a post-hoc analysis of a Phase 3, multicenter, randomized, double-blind, parallel-group study of moderate to severe acne in subjects with FST I-VI. Subjects received A/BPO gel 0.3%/2.5%, A/BPO gel 0.1%/2.5% (benchmark), or vehicle, once daily for 12 weeks. Efficacy measurements included success rate (IGA of Clear or Almost Clear), change in inflammatory and noninflammatory lesions from baseline to week 12, safety, and tolerability. The intent to treat (ITT) and safety populations were analyzed. Demographics and disposition were analyzed with descriptive statistics; categorical variables by frequency and percentage; and continuous variables with means, medians, minimum, maximum, and standard deviations.

RESULTS: The A/BPO gel 0.3%/2.5% treatment group included 128 subjects with FST I-III, and 89 subjects with FST IV-VI. At week 12, A/BPO gel 0.3%/2.5% was safe, tolerable, and significantly superior to vehicle for all FST and severity groups in inflammatory and noninflammatory lesion reduction (P less than equal to .05). Compared to baseline, 32% of subjects with FST I-III were clear or almost clear, compared to 7% in the vehicle group (P=.001). In FST IV-VI, 28% of subjects were clear or almost clear, compared to 15% for vehicle (P=NS). In all treatment groups and skin phototypes, week 12 tolerability scores were similar to baseline scores, and tolerability scores for most subjects of all skin phototypes were "none" or "mild" for all measures.

SUMMARY: We report that the fixed dose combination of A/BPO gel 0.3%/2.5% is efficacious and safe in patients with FST I-VI with moderate and severe inflammatory acne.

Clinicaltrials.gov registry: NCT01880320

J Drugs Dermatol. 2017;16(6):574-581.
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Subject-specific, multiscale simulation of electrophysiology: a software pipeline for image-based models and application examples.
Many simulation studies in biomedicine are based on a similar sequence of processing steps, starting from images and running through geometric model generation, assignment of tissue properties, numerical simulation and visualization of the results--a process known as image-based geometric modelling and simulation. We present an overview of software systems for implementing such a sequence both within highly integrated problem-solving environments and in the form of loosely integrated pipelines. Loose integration in this case indicates that individual programs function largely independently but communicate through files of a common format and support simple scripting, so as to automate multiple executions wherever possible. We then describe three specific applications of such pipelines to translational biomedical research in electrophysiology.


'Motor cognition' - what is it and is the cerebellum involved?
Motor cognition encompasses how we understand our own movement, and how movement helps us to understand the world. Here, the role of the cerebellum is discussed in two processes that could be considered aspects of motor cognition: predicting movement outcomes and understanding the meaning of movements. Recent behavioral, anatomical, and neurophysiological findings related to these processes are discussed. There are data to support a cerebellar role in predicting movement outcomes, which could be used both for motor control and for distinguishing sensory inputs due to our own movements from external influences. The data for a cerebellar role in understanding the meaning of movement are mixed, although anatomical findings suggest that it probably has some influence that bears further study.


Polymorphisms in the phosphate and tensin homolog gene are not associated with late-onset Alzheimer's disease.
The varepsilon4 allele of the APOE locus is the only confirmed risk factor for late-onset Alzheimer's disease (LOAD). The phosphate and tensin homolog (PTEN) gene is both a biological and positional candidate gene for LOAD. Eight polymorphisms spanning this gene were selected from dbSNP and genotyped in pooled DNA samples of both cases and controls. No evidence for association with LOAD was obtained in this study although further investigation revealed low levels of linkage disequlibrium (LD) between the genotyped SNPs. Our results suggest that it is unlikely that genetic variation within the PTEN gene contributes to risk of LOAD.


The case for addressing gender and power in sexuality and HIV education: a comprehensive review of evaluation studies.
Curriculum-based sexuality and HIV education is a mainstay of interventions to prevent STIs, HIV and unintended pregnancy among young people. Evidence links traditional gender norms, unequal power in sexual relationships and intimate partner violence with negative sexual and reproductive health outcomes. However, little attention has been paid to analyzing whether addressing gender and power in sexuality education curricula is associated with better outcomes. To explore whether the inclusion of content on gender and power matters for program efficacy, electronic and hand searches were conducted to identify rigorous sexuality and HIV education evaluations from developed and developing countries published between 1990 and 2012. Intervention and study design characteristics of the included interventions were disaggregated by whether they addressed issues of gender and power. Of the 22 interventions that met the inclusion criteria, 10 addressed gender or power, and 12 did not. The programs that addressed gender or power were five times as likely to be effective as those that did not; fully 80% of them were associated with a significantly lower rate of STIs or unintended pregnancy. In contrast, among the programs that did not address gender or power, only 17% had such an association. Addressing gender and power should be considered a key characteristic of effective sexuality and HIV education programs.


What are we tracking: a unified approach of tracking and recognition.
Tracking is essentially a matching problem. While traditional tracking methods mostly focus on low-level image correspondences between frames, we argue that high-level semantic correspondences are indispensable to make tracking more reliable. Based on that, a unified approach of low-level object tracking and high-level recognition is proposed for single object tracking, in which the target category is actively recognized during tracking. High-level offline models corresponding to the recognized category are then adaptively selected and combined with low-level online tracking models so as to achieve better tracking performance. Extensive experimental results show that our approach outperforms state-of-the-art online models in many challenging tracking scenarios such as drastic view change, scale change, background clutter, and morphable objects.


The Anguilla spp. migration problem: 40 million years of evolution and two millennia of speculation.
Anguillid eels Anguilla spp. evolved between 20 and 40 million years ago and possess a number of remarkable migratory traits that have fascinated scientists for millennia. Despite centuries of effort, the spawning areas and migrations are known only for a few species. Even for these species, information on migratory behaviour is remarkably sketchy. The latest knowledge on the requirements for successful migration and field data on the migrations of adults and larvae are presented, how experiments on swimming efficiency have progressed the understanding of migration are highlighted and the challenges of swimming at depth considered. The decline of Anguilla spp. across the world is an ongoing concern for fisheries and environmental managers. New developments in the knowledge of eel migration will, in addition to solving a centuries old mystery, probably help to identify how this decline might be halted or even reversed.


In vivo inhibition of neuronal activity in the rat ventromedial prefrontal cortex by midbrain-raphe nuclei: role of 5-HT1A receptors.
The ventral part of the medial prefrontal cortex (mPFC) plays an important role in mood and cognition. This study examined the effect of the 5-HT in this region by measuring the electrophysiological response of ventral mPFC neurones to electrical stimulation of the dorsal and median raphe nuclei (DRN and MRN), which are the source of the 5-HT input. DRN or MRN stimulation evoked a consistent, short-latency, post-stimulus inhibition in the majority of ventral mPFC neurones tested (DRN: 44/73 neurones; MRN: 24/31 neurones). Some neurones responded to DRN or MRN stimulation with antidromic spikes indicating that they were mPFC-raphe projection neurones. Both DRN- and MRN-evoked inhibitions were attenuated by systemic administration of the 5-HT1A antagonist WAY 100635 (0.1 mg/kg i.v.). DRN-evoked inhibition was also attenuated by iontophoretic application of WAY 100635 and by systemic administration of the 5-HT1A antagonist, NAD-299 (4 mg/kg i.v.) but not the 5-HT2 antagonist ketanserin (4 mg/kg, i.v.). These data suggest that DRN and MRN 5-HT neurones inhibit neurones in the ventral mPFC via activation of 5-HT1A receptors. Some of these mPFC neurones may be part of a 5-HT1A receptor-controlled postsynaptic feedback loop to the DRN and MRN.


Generalized reduced rank latent factor regression for high dimensional tensor fields, and neuroimaging-genetic applications.
We propose a generalized reduced rank latent factor regression model (GRRLF) for the analysis of tensor field responses and high dimensional covariates. The model is motivated by the need from imaging-genetic studies to identify genetic variants that are associated with brain imaging phenotypes, often in the form of high dimensional tensor fields. GRRLF identifies from the structure in the data the effective dimensionality of the data, and then jointly performs dimension reduction of the covariates, dynamic identification of latent factors, and nonparametric estimation of both covariate and latent response fields. After accounting for the latent and covariate effects, GRLLF performs a nonparametric test on the remaining factor of interest. GRRLF provides a better factorization of the signals compared with common solutions, and is less susceptible to overfitting because it exploits the effective dimensionality. The generality and the flexibility of GRRLF also allow various statistical models to be handled in a unified framework and solutions can be efficiently computed. Within the field of neuroimaging, it improves the sensitivity for weak signals and is a promising alternative to existing approaches. The operation of the framework is demonstrated with both synthetic datasets and a real-world neuroimaging example in which the effects of a set of genes on the structure of the brain at the voxel level were measured, and the results compared favorably with those from existing approaches.


A potential synbiotic product improves the lipid profile of diabetic rats.
Previous studies showed that intake of yacon or some lactic acid bacteria was able to inhibit the development of diabetes mellitus, by reducing glucose and associated symptoms, for example, the lipid profile. The purpose of this study was to assess the consumption influence of a potential symbiotic product of soybean and yacon extract and fermented Enterococcus faecium CRL 183 and Lactobacillus helveticus ssp jugurti 416 in reducing blood glucose and lipid levels in an animal model. Diabetes mellitus was chemically induced by intraperitoneal administration of streptozotocin (50 mg/kg body weight). The rats were divided into four groups (n=10): GI - non-diabetic animals that received only a standard chow diet (negative control), GII - diabetic animals that received only chow diet (positive control), GIII - diabetic animals that received the chow diet + 1 mL/kg body weight/day of soybean and yacon unfermented product, GIV - diabetic rats that received the chow diet + 1 mL/kg body weight/day of soybean and yacon fermented product. There was a seven-week treatment period and the following parameters were evaluated: animal body weight, food and water intake, blood glucose, enzyme activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), triglycerides levels, total cholesterol, HDL-C, non-HDL-C. Cell viability of the fermented product was checked weekly for a seven-week period. The product average viable population was 10(8)-10(9) CFU/mL, by ensuring both the rods and cocci regular intake. No difference was observed between the water and feed intake and body weight of groups that received unfermented and fermented products and the untreated diabetic group. The same was observed for the blood glucose and AST and ALT activities, while some improvement was observed for a lipid profile, represented by reduction of triglycerides level by 15.07% and 33.50% in groups III and IV, respectively, and an increase of 23.70% in HDL-C level for group IV. The results showed that the ingestion of a potential symbiotic product was neither able to promote improvement in some of the disease symptoms, nor reduce blood glucose. However, a positive effect on triglycerides levels and HDL-cholesterol was observed in the groups that received the unfermented product containing yacon extract and the fermented product with Enterococcus faecium CRL 183, as well as Lactobacillus helveticus ssp jugurti 416 and yacon extract (symbiotic product).


Differential effects of lead and zinc on inhibitory avoidance learning in mice.
We studied the effects of chronic intoxication with the heavy metals lead (Pb2+) and zinc (Zn2+) on memory formation in mice. Animals were intoxicated through drinking water during the pre- and postnatal periods and then tested in the step-through inhibitory avoidance memory task. Chronic postnatal intoxication with Pb2+ did not change the step-through latency values recorded during the 4 weeks of the test (ANOVA, P>0.05). In contrast, mice intoxicated during the prenatal period showed significantly reduced latency values when compared to the control group (day 1: q = 4.62, P<0.05; day 7: q = 4.42, P<0.05; day 14: q = 5.65, P<0.05; day 21: q = 3.96, P<0.05, and day 28: q = 6.09, P<0.05). Although chronic postnatal intoxication with Zn2+ did not alter a memory retention test performed 24 h after training, we noticed a gradual decrease in latency at subsequent 4-week intervals (F = 3.07, P<0.05), an effect that was not observed in the control or in the Pb2+-treated groups. These results suggest an impairment of memory formation by Pb2+ when the animals are exposed during the critical period of neurogenesis, while Zn2+ appears to facilitate learning extinction.


Modulation of adipose tissue expression of murine matrix metalloproteinases and their tissue inhibitors with obesity.
The potential role of the matrix metalloproteinase (MMP) system in the pathophysiology of the adipose tissue was investigated in a mouse model of nutritionally induced obesity. mRNA levels of 16 MMPs and 4 tissue inhibitors of MMPs (TIMPs) were measured by semiquantitative RT-PCR in adipose tissue isolated from mice maintained for 15 weeks on a standard or high-fat diet. In mice on standard diet, with the exception of MMP-8, all MMP and TIMP transcripts were detected in both gonadal and subcutaneous depots. In obese mice, the expression of MMP-3, -11, -12, -13, and -14 and TIMP-1 mRNAs was upregulated, whereas that of MMP-7, -9, -16, and -24 and TIMP-4 was downregulated. Most MMP and TIMP mRNAs were expressed at higher levels in stromal-vascular cells than in mature adipocytes. Analysis of adipose tissue by in situ fluorescent zymography revealed MMP-dependent proteolytic activities, demonstrating the presence of active MMPs in the intact tissue. In vitro conversion of adipogenic 3T3-F442A cells into mature adipocytes was associated with substantial modulations of MMP and TIMP expression. Moreover, this in vitro adipogenesis was reduced in the presence of a synthetic MMP inhibitor. Thus, the adipose tissue expresses a large array of MMPs and TIMPs, which modulate adipocyte differentiation.


Blood levels of organochlorine residues and risk of breast cancer.
Organochlorines such as DDT [2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane] and PCBs (polychlorinated biphenyls), which have been used extensively as insecticides and as fluid insulators of electrical components, respectively, are known to be persistent environmental contaminants and animal carcinogens. These agents have been found in human tissue due to their inefficient metabolism and their solubility in lipids, which lead to lifelong sequestration in adipose tissue. Their association with human cancer occurrence, however, has been explored only marginally, with most studies having 20 or fewer cases. This blinded study was designed to determine whether exposure to PCBs and to DDE [1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene], the major metabolite of DDT, is associated with breast cancer risk in women. We analyzed sera from the stored blood specimens of 14,290 participants enrolled between 1985 and 1991 in the New York University Women's Health Study, a prospective cohort study of hormones, diet, and cancer. Cohort members who developed breast cancer were included as case patients in our nested case-control study. DDE and PCBs were measured by gas chromatography in the sera of 58 women with a diagnosis of breast cancer 1-6 months after they entered the cohort and in 171 matched control subjects from the same study population who did not develop cancer. Mean levels of DDE and PCBs were higher for breast cancer case patients than for control subjects, but paired differences were statistically significant only for DDE (P = .031). After adjustment for first-degree family history of breast cancer, lifetime lactation, and age at first full-term pregnancy, conditional logistic regression analysis showed a fourfold increase in relative risk of breast cancer for an elevation of serum DDE concentrations from 2.0 ng/mL (10th percentile) to 19.1 ng/mL (90th percentile). For PCBs, the relative risk for a change in serum levels from 3.9 ng/mL (10th percentile) to 10.6 ng/mL (90th percentile) was less than twofold, a nonsignificant association that was further reduced after adjustment for DDE. In this population of New York City women, breast cancer was strongly associated with DDE in serum but not with PCBs. These findings suggest that environmental chemical contamination with organochlorine residues may be an important etiologic factor in breast cancer. Given the widespread dissemination of organochlorine insecticides in the environment and the food chain, the implications are far-reaching for public health intervention worldwide.


MRS reveals additional hexose N-acetyl resonances in the brain of a mouse model for Sandhoff disease.
Sandhoff disease, one of several related lysosomal storage disorders, results from the build up of N-acetyl-containing glycosphingolipids in the brain and is caused by mutations in the genes encoding the hexosaminidase beta-subunit. Affected individuals undergo progressive neurodegeneration in response to the glycosphingolipid storage. (1)H magnetic resonance spectra of perchloric acid extracts of Sandhoff mouse brain exhibited several resonances ca 2.07 ppm that were not present in the corresponding spectra from extracts of wild-type mouse brain. High-performance liquid chromatography and mass spectrometry of the Sandhoff extracts post-MRS identified the presence of N-acetylhexosamine-containing oligosaccharides, which are the likely cause of the additional MRS resonances. MRS of intact brain tissue with magic angle spinning also showed additional resonances at ca 2.07 ppm in the Sandhoff case. These resonances appeared to increase with disease progression and probably arise, for the most part, from the stored glycosphingolipids, which are absent in the aqueous extracts. Hence in vivo MRS may be a useful tool for detecting early-stage Sandhoff disease and response to treatment.


Can a health advocate for homeless families reduce workload for the primary healthcare team? A controlled trial.
The objective of the present study was to determine whether provision of health advocacy for homeless patients would reduce the burden of care for a primary healthcare team. The impact of a health advocacy intervention was assessed in a quasi-experimental, three-armed controlled trial. Homeless patients registering at an inner-city health centre were allocated in alternating periods to health advocacy (with or without outreach registration) or 'usual care' over a total intake period of 3 years. The client group were homeless people in hostels or other temporary accommodation in the Liverpool 8 area of the UK. The majority of participants (n = 400) were women (76%) in their twenties (mean age = 26.6 years). Most (63%) were temporarily housed at either one of the women's refuges or Liverpool City Council family hostels, and all were registered with an inner-city health centre. Data on health service utilisation over a 3-month period was collected for all clients recruited to the study and direct health service costs were measured. Homeless adults who were proactively registered by the health advocate on outreach visits to hostels made significantly less use of health centre resources whilst having more contact with the health advocate than patients who registered at the health centre at a time of need. There was no reduction in health centre workload when the offer of health advocacy was made after registration at the health centre. The additional costs of providing health advocacy were offset by a reduction in demand for health-centre-based care. The results demonstrate that health advocacy can alter the pattern of help-seeking by temporarily homeless adults. The intervention was cost-neutral. The short-term health service workload associated with symptomatic homeless patients requiring medication was not reduced, but outreach health advocacy was used successfully to address psycho-social issues and reduce the workload for primary care staff.


Risk factors for serious prescription opioid-related toxicity or overdose among Veterans Health Administration patients.
Prescription opioid use and deaths related to serious toxicity, including overdose, have increased dramatically in the United States since 1999. However, factors associated with serious opioid-related respiratory or central nervous system (CNS) depression or overdose in medical users are not well characterized. The objective of this study was to examine the factors associated with serious toxicity in medical users of prescription opioids. Retrospective, nested, case-control analysis of Veterans Health Administration (VHA) medical, pharmacy, and health care resource utilization administrative data. Patients dispensed an opioid by VHA between October 1, 2010 and September 30, 2012 (N=8,987). Cases (N=817) experienced life-threatening opioid-related respiratory/CNS depression or overdose. Ten controls were randomly assigned to each case (N=8,170). Logistic regression was used to examine associations with the outcome. The strongest associations were maximum prescribed daily morphine equivalent dose (MED)≥ 100 mg (odds ratio [OR]=4.1, 95% confidence interval [CI], 2.6-6.5), history of opioid dependence (OR=3.9, 95% CI, 2.6-5.8), and hospitalization during the 6 months before the serious toxicity or overdose event (OR=2.9, 95% CI, 2.3-3.6). Liver disease, extended-release or long-acting opioids, and daily MED of 20 mg or more were also significantly associated. Substantial risk for serious opioid-related toxicity and overdose exists at even relatively low maximum prescribed daily MED, especially in patients already vulnerable due to underlying demographic factors, comorbid conditions, and concomitant use of CNS depressant medications or substances. Screening patients for risk, providing education, and coprescribing naloxone for those at elevated risk may be effective at reducing serious opioid-related respiratory/CNS depression and overdose in medical users of prescription opioids.