Vancomycin-resistant enterococci (VRE) screening and isolation in the general medicine ward: a cost-effectiveness analysis.
Vancomycin-resistant enterococci (VRE) are a serious antimicrobial resistant threat in the healthcare setting. We assessed the cost-effectiveness of VRE screening and isolation for patients at high-risk for colonisation on a general medicine ward compared to no VRE screening and isolation from the healthcare payer perspective. We developed a microsimulation model using local data and VRE literature, to simulate a 20-bed general medicine ward at a tertiary-care hospital with up to 1000 admissions, approximating 1 year. Primary outcomes were accrued over the patient's lifetime, discounted at 1.5%, and included expected health outcomes (VRE colonisations, VRE infections, VRE-related bacteremia, and deaths subsequent to VRE infection), quality-adjusted life years (QALYs), healthcare costs, and incremental cost-effectiveness ratio (ICER). Probabilistic sensitivity analysis (PSA) and scenario analyses were conducted to assess parameter uncertainty. In our base-case analysis, VRE screening and isolation prevented six healthcare-associated VRE colonisations per 1000 admissions (6/1000), 0.6/1000 VRE-related infections, 0.2/1000 VRE-related bacteremia, and 0.1/1000 deaths subsequent to VRE infection. VRE screening and isolation accrued 0.0142 incremental QALYs at an incremental cost of $112, affording an ICER of $7850 per QALY. VRE screening and isolation practice was more likely to be cost-effective (> 50%) at a cost-effectiveness threshold of $50,000/QALY. Stochasticity (randomness) had a significant impact on the cost-effectiveness. VRE screening and isolation can be cost-effective in majority of model simulations at commonly used cost-effectiveness thresholds, and is likely economically attractive in general medicine settings. Our findings strengthen the understanding of VRE prevention strategies and are of importance to hospital program planners and infection prevention and control.


Pharmaceutical advertising in emergency departments.
Promotion of prescription drugs represents a growing source of pharmaceutical marketing expenditures. This study was undertaken to identify the frequency of items containing pharmaceutical advertising in clinical emergency departments (EDs). In this observational study, emergency physician on-site investigators quantified a variety of items containing pharmaceutical advertising present at specified representative times and days, in clinical EDs. Measurements were obtained by 65 on-site investigators, representing 22 states. Most EDs in this study were community EDs (87% community and 14% university or university affiliate), and most were in urban settings (50% urban, 38% suburban, and 13% rural). Investigators measured 42 items per ED (mean = 42; median = 31; interquartile range of 14-55) containing pharmaceutical advertising in the clinical area. The most commonly observed items included pens (mean 15 per ED; median 10), product brochures (mean 5; median 3), stethoscope labels (mean 4; median 2), drug samples (mean 3; median 0), books (mean 3.4), mugs (mean 2.4), and published literature (mean 3.1). EDs with a policy restricting pharmaceutical representatives in the ED had significantly fewer items containing pharmaceutical advertising (median 7.5; 95% CI = 0 to 27) than EDs without such a policy (median 35; 95% CI = 27 to 47, p = 0.005, nonparametric Wilcoxon two-sample test). There were no differences in quantities of pharmaceutical advertising for EDs in community compared with university settings (p = 0.5), rural compared with urban settings (p = 0.3), or annual ED volumes (p = 0.9). Numerous items containing pharmaceutical advertising are frequently observed in EDs. Policies restricting pharmaceutical representatives in the ED are associated with reduced pharmaceutical advertising.


Zinc, insulin, and the liver: a ménage à trois.
Insulin and Zn2+ enjoy a multivalent relationship. Zn2+ binds insulin in pancreatic β cells to form crystalline aggregates in dense core vesicles (DCVs), which are released in response to physiological signals such as increased blood glucose. This transition metal is an essential cofactor in insulin-degrading enzyme and several key Zn2+ finger transcription factors that are required for β cell development and insulin gene expression. Studies are increasingly revealing that fluctuations in Zn2+ concentration can mediate signaling events, including dynamic roles that extend beyond that of a static structural or catalytic cofactor. In this issue of the JCI, Tamaki et al. propose an additional function for Zn2+ in relation to insulin: regulation of insulin clearance from the bloodstream.


Mild thyroid peroxidase deficiency caused by TPO mutations with residual activity: Correlation between clinical phenotypes and enzymatic activity.
Thyroid peroxidase (TPO) deficiency, caused by biallelic TPO mutations, is a well-established genetic form of congenital hypothyroidism (CH). More than 100 patients have been published, and the patients have been diagnosed mostly in the frame of newborn screening (NBS) programs. Correlation between clinical phenotypes and TPO activity remains unclear. Here, we report clinical and molecular findings of two unrelated TPO mutation-carrying mildly hypothyroid patients. The two patients were born at term after an uneventful pregnancy and delivery, and were NBS negative. They sought medical attention due to goiter at age 8 years. Evaluation of the thyroid showed mild elevation of serum TSH levels, normal or slightly low serum T4 levels, high serum T3 to T4 molar ratio, high serum thyroglobulin levels, and high thyroidal 123I uptake. We performed next-generation sequencing-based genetic screening, and found that one patient was compound heterozygous for two novel TPO mutations (p.Asp224del; c.820-2A>G), and the other was homozygous for a previously known mutation (p.Trp527Cys). In vitro functional analyses using HEK293 cells showed that the two amino acid-altering mutations (p.Asp224del and p.Trp527Cys) caused partial loss of the enzymatic activity. In conclusion, we report that TPO mutations with residual activity are associated with mild TPO deficiency, which is clinically characterized by marked goiter, mild TSH elevation, high serum T3 to T4 molar ratio, and high serum thyroglobulin levels. Our findings illuminate the hitherto under-recognized correlation between clinical phenotypes and residual enzymatic activity among patients with TPO deficiency.


Making family planning accessible in resource-poor settings.
It is imperative to make family planning more accessible in low resource settings. The poorest couples have the highest fertility, the lowest contraceptive use and the highest unmet need for contraception. It is also in the low resource settings where maternal and child mortality is the highest. Family planning can contribute to improvements in maternal and child health, especially in low resource settings where overall access to health services is limited. Four critical steps should be taken to increase access to family planning in resource-poor settings: (i) increase knowledge about the safety of family planning methods; (ii) ensure contraception is genuinely affordable to the poorest families; (iii) ensure supply of contraceptives by making family planning a permanent line item in healthcare system's budgets and (iv) take immediate action to remove barriers hindering access to family planning methods. In Africa, there are more women with an unmet need for family planning than women currently using modern methods. Making family planning accessible in low resource settings will help decrease the existing inequities in achieving desired fertility at individual and country level. In addition, it could help slow population growth within a human rights framework. The United Nations Population Division projections for the year 2050 vary between a high of 10.6 and a low of 7.4 billion. Given that most of the growth is expected to come from today's resource-poor settings, easy access to family planning could make a difference of billions in the world in 2050.


Green Photoluminescence of Perovskite CsPb(Br1-x I x )3 Nanocrystals for Wide Color Gamut Displays.
All-inorganic mixed-halide CsPb(Br1-x I x )3 perovskite nanocrystals (NCs) are excellent candidates for green-emitting phosphors in wide color gamut displays; however, a detailed investigation of their photoluminescence (PL) properties based on the halide composition has been missing. In this work, we report a fundamental investigation of the changes in the PL properties of CsPb(Br1-x I x )3 NCs. The PL color of the NCs, which were prepared by a hot-injection method, changed from green to red with increasing iodide composition (x). Almost ideal green emission close to the chromaticity coordinates of the green vertex of the BT.2020 standard was achieved by appropriately substituting iodide ions for bromide ions in monohalide CsPbBr3 NCs. However, the PL peak width of the mix-halide NCs at x ∼ 0.5 was 0.127 eV, which was broader than the 0.105 eV peak width of the monohalide CsPbBr3 NCs. This phenomenon should be due to the compositional inhomogeneity among the individual CsPb(Br1-x I x )3 NCs. On the other hand, the PL quantum yield (PLQY) for the monohalide CsPbBr3 NCs decreased from 70 to 25% as x increased to 0.5. This result may be attributed to lattice distortion by the difference in the ionic radii of bromide and iodide. Improvements in the compositional inhomogeneity and lattice distortion would enhance the color purity of the green emission and the PLQY, respectively, of the CsPb(Br1-x I x )3 NCs.


The Use of Extracorporeal Life Support in a Patient Suffering from Venlafaxine Intoxication. A Case Report.
Very few reports exist on serious cardiac complications associated with intake of serotonin-noradrenaline reuptake inhibitors. This paper describes and discusses the case of a patient who ingested a dose of 17.5 g venlafaxine. She developed a full serotonergic syndrome leading to multi-organ failure, including refractory cardiovascular shock, which was managed by early implantation of an extracorporeal life support (ECLS) system as a bridging strategy. This intervention was successful and resulted in full recovery of the patient.


An artificial intelligence approach to early predict non-ST-elevation myocardial infarction patients with chest pain.
Hospital admission rate for the patients with chest pain has already been increased worldwide but no existing risk score has been designed to stratify non-ST-elevation myocardial infarction (NSTEMI) from non-cardiogenic chest pain. Clinical diagnosis of chest pain in the emergency department is always highly subjective and variable. We, therefore, aimed to develop an artificial intelligence approach to predict stable NSTEMI that would give valuable insight to reduce misdiagnosis in the real clinical setting. A standard protocol was developed to collect data from chest pain patients who had visited the emergency department between December 2016 and February 2017. All the chest pain patients with aged <20 years were primarily included in this study. However, STEMI, previous history of ACS, and out-of-hospital cardiac arrest were excluded from our study. An artificial neural network (ANN) model was then developed to predict NSTEMI patients. The accuracy, sensitivity, specificity, and receiver operating characteristic curve was used to measure the performance of this model. A total of 268 chest pain patients were included in this study; of those, 47 (17.5%) was stable NSTEMI, and 221 (82.5%) was unstable angina patients. Serval risk factors such as cardiac risk factor, systolic blood pressure, hemoglobin, corrected QT interval (QTc), PR interval, glutamic-oxaloacetic transaminase, glutamic pyruvic transaminase and troponin were independently associated with stable NSTEMI. The area under the receiver operating characteristic (AUROC) and accuracy of ANN were 98.4, and 92.86. Additionally, the sensitivity, specificity, positive predictive value, and negative predictive value of the ANN model was 90.91, 93.33, 76.92, and 97.67 respectively. Our prediction model showed a higher accuracy to predict NSTEMI patients. This model has a potential application in disease detection, monitoring, and prognosis of chest pain at risk of AMI.


Elevation of lymphocyte and hematopoietic stem cell numbers in mice transgenic for human granulocyte CSF.
Transgenic mice expressing human granulocyte colony stimulating factor (hG-CSF) were bred to establish an experimental model for studying the biologic function of hG-CSF. The mice produced approximately 1000 pg/ml of hG-CSF in sera and expressed hG-CSF mRNA in all of the tissues examined. Granulocytosis and elevation of hematopoietic precursor number were observed in hematopoietic tissues as expected, but lymphocytosis with 5-fold increase in peripheral blood and 2-fold increase in spleen was also evident. Hematopoietic stem cells capable of reconstituting lethally irradiated recipient mice were abundant in the circulation of these transgenic mice. No disadvantageous tissue damage was observed when various organs were analyzed. As shown in this study, G-CSF has a stimulating effect on lymphopoiesis when it is expressed in a certain condition. The lymphocytosis, as well as the high level of hematopoietic stem cell mobilization into circulation, indicates a wider range of potential G-CSF activity than expected. The mice transgenic for hG-CSF described herein will contribute greatly to the understanding of the regulatory mechanism in hematopoiesis.


Rapamycin inhibits vascular smooth muscle cell migration.
Abnormal vascular smooth muscle cell (SMC) proliferation and migration contribute to the development of restenosis after percutaneous transluminal coronary angioplasty and accelerated arteriopathy after cardiac transplantation. Previously, we reported that the macrolide antibiotic rapamycin, but not the related compound FK506, inhibits both human and rat aortic SMC proliferation in vitro by inhibiting cell cycle-dependent kinases and delaying phosphorylation of retinoblastoma protein (Marx, S.O., T. Jayaraman, L.O. Go, and A.R. Marks. 1995. Circ. Res. 362:801). In the present study the effects of rapamycin on SMC migration were assayed in vitro using a modified Boyden chamber and in vivo using a porcine aortic SMC explant model. Pretreatment with rapamycin (2 ng/ml) for 48 h inhibited PDGF-induced migration (PDGF BB homodimer; 20 ng/ml) in cultured rat and human SMC (n = 10; P < 0.0001), whereas FK506 had no significant effect on migration. Rapamycin administered orally (1 mg/kg per d for 7 d) significantly inhibited porcine aortic SMC migration compared with control (n = 15; P < 0.0001). Thus, in addition to being a potent immunosuppressant and antiproliferative, rapamycin also inhibits SMC migration.


Cumulative Effects of Psychologic Distress, Visceral Hypersensitivity, and Abnormal Transit on Patient-reported Outcomes in Irritable Bowel Syndrome.
Little is known about the link between pathophysiologic factors and symptoms of irritable bowel syndrome (IBS), or whether these factors have cumulative effects on patient-reported outcomes (PROs). We investigated whether pathophysiologic alterations associated with IBS have cumulative or independent effects on PROs. We performed a retrospective analysis of data from 3 cohorts of patients with IBS (n = 407; 74% female; mean age, 36 ± 12 years), based on Rome II or Rome III criteria, seen at a specialized unit for functional gastrointestinal disorders in Sweden from 2002 through 2014. All patients underwent assessments of colonic transit time (radiopaque markers); compliance, allodynia, and hyperalgesia (rectal barostat); anxiety and depression (Hospital Anxiety and Depression scale), as pathophysiologic factors. Dysfunction was defined by available normal values. PROs included IBS symptom severity, somatic symptom severity, and disease-specific quality of life. Allodynia was observed in 36% of patients, hyperalgesia in 22%, accelerated colonic transit in 18%, delayed transit in 7%, anxiety in 52%, and depression in 24%: each of these factors was associated with severity of at least 1 symptom of IBS. Rectal compliance was not associated with more severe symptoms of IBS. At least 3 pathophysiologic factors were present in 20% of patients, 2 in 30%, 1 in 31%, and none in 18%. With increasing number of pathophysiologic abnormalities, there was a gradual increase in IBS symptom severity (P < .0001) and somatic symptom severity (P < .0001), and a gradual reduction in quality of life (P < .0001). Visceral hypersensitivity, including allodynia and hyperalgesia, abnormal colonic transit, and psychologic factors are all associated with IBS symptoms. These factors have a cumulative effect on gastrointestinal and nongastrointestinal symptoms, as well as on quality of life, in patients with IBS and are therefore relevant treatment targets.


Dietary intake in edentulous subjects with good and poor quality complete dentures.
Previous studies in complete denture wearers evaluated the relationship between diet and measures of chewing, yet only isolated nutrient intake was considered. This limited information makes the assessment of overall diet quality and the planning of interventions difficult. This study investigated the relationship of complete denture quality to masticatory performance, perceived ability to chew, and diet quality as measured by the Healthy Eating Index (HEI), an overall diet quality index. The study population comprised 54 complete denture wearers. Data were obtained from clinical examinations, masticatory performance measurements, and 2 non-consecutive 24-hour dietary recalls. (Masticatory performance data were not collected for 9 subjects because of time constraints, patient fatigue, or patient refusal. Statistical analysis showed no significant effect of their absence on the reported findings.) Based on a composite rating scale, subjects were divided into 3 denture quality groups described as good, medium, and poor. The outcome variables were the HEI and its components, plus selected nutrient and non-nutrient intake. Explanatory variables were quality of complete dentures, masticatory performance, and reported chewing ability. Data were analyzed with Kruskal-Wallis tests, Mann-Whitney U-tests, and Fisher exact tests. Because a large number of dietary components were examined, results were considered significant at alpha=.01. Masticatory performance and perceived ability to chew were unrelated to diet quality. The good quality denture group had significantly better masticatory performance than the medium and poor quality groups, but the median HEI scores and dietary intakes were not significantly different among these 3 groups. Milk, vegetable, fruit, and grain intake scores were mainly responsible for the low overall HEI scores. In the population evaluated, complete denture quality, food comminution capacity, and perceived chewing ability were not related to diet quality. The majority of subjects had deficient diets regardless of the technical quality of their dentures.


Immunotherapy of patients with metastatic melanoma.
Malignant melanoma (MM) is the primary cause of skin cancer related death and the incidence is increasing in the past years. Advanced MM still has a poor prognosis, but in recent years, the development of immunotherapy has changed its poor prognosis. Immune checkpoints show the revolutionary treatment of metastatic melanoma. Ipilimumab and pembrolizumab, monoclonal antibodies against the CTLA-4 and PD-1 respectively, have been shown to prolong overall survival (OS) in patients with advanced melanoma. The combination immunotherapy seems to be superior to monotherapy. In this review, recently immunotherapy clinical trial results are presented. The combination of immunotherapy provides new options for the treatment of MM patients. However, further studies are necessary to answer such question as optimal treatment, combination of immunotherapies, crowd selection and risk balance in patients with melanoma.


Anti-Siglec-F antibody reduces allergen-induced eosinophilic inflammation and airway remodeling.
Siglec-F is a sialic acid-binding Ig superfamily receptor that is highly expressed on eosinophils. We have investigated whether administration of an anti-Siglec-F Ab to OVA-challenged wild-type mice would reduce levels of eosinophilic inflammation and levels of airway remodeling. Mice sensitized to OVA and challenged repetitively with OVA for 1 mo who were administered an anti-Siglec-F Ab had significantly reduced levels of peribronchial eosinophilic inflammation and significantly reduced levels of subepithelial fibrosis as assessed by either trichrome staining or lung collagen levels. The anti-Siglec-F Ab reduced the number of bone marrow, blood, and tissue eosinophils, suggesting that the anti-Siglec-F Ab was reducing the production of eosinophils. Administration of a F(ab')(2) fragment of an anti-Siglec-F Ab also significantly reduced levels of eosinophilic inflammation in the lung and blood. FACS analysis demonstrated increased numbers of apoptotic cells (annexin V(+)/CCR3(+) bronchoalveolar lavage and bone marrow cells) in anti-Siglec-F Ab-treated mice challenged with OVA. The anti-Siglec-F Ab significantly reduced the number of peribronchial major basic protein(+)/TGF-beta(+) cells, suggesting that reduced levels of eosinophil-derived TGF-beta in anti-Siglec-F Ab-treated mice contributed to reduced levels of peribronchial fibrosis. Administration of the anti-Siglec-F Ab modestly reduced levels of periodic acid-Schiff-positive mucus cells and the thickness of the smooth muscle layer. Overall, these studies suggest that administration of an anti-Siglec-F Ab can significantly reduce levels of allergen-induced eosinophilic airway inflammation and features of airway remodeling, in particular subepithelial fibrosis, by reducing the production of eosinophils and increasing the number of apoptotic eosinophils in lung and bone marrow.


Spanish health care cuts: penny wise and pound foolish?
The purpose of this paper is to convey the specific health care actions and policies undertaken by the Spanish government, as well as by regional governments, as a result of the economic crisis. Throughout the last two years we have witnessed a number of actions in areas such as human capital, activity and processes, outsourcing and investment that, poorly coordinated, have shaped the nature of financial cuts on public services. This paper discloses the size and magnitude of these actions, the main actors involved and the major consequences for the health sector, citizens and patients. We further argue that there are a number of factors which have been neglected in the discourse and in the actions undertaken. First, the crisis situation is not being used as an opportunity for major reforms in the health care system. Further, the lay public and professionals have remained as observers in the process, with little to no participation at any point. Moreover, there is a general perception that the solution to the Spanish situation is either the proposed health care cuts or an increase in cost sharing for services which neglects alternative and/or complementary measures. Finally, there is a complete absence of any scientific component in the discourse and in the policies proposed.


White-light spectral interferometry for surface plasmon resonance sensing applications.
A novel differential phase detecting surface plasmon resonance (SPR) sensor based on white-light spectral interferometry is presented. Our proposed scheme employs a white-light source for SPR excitation and measures the corresponding SPR phase change at the optimized coupling wavelength with fixed angle of incidence across the visible spectrum. Compared to existing laser based phase detecting schemes, this system offers optimal sensitivity and extended dynamic range of measurement without any compromise in phase detection resolution. Results obtained from sodium chloride solutions indicate that the detection limit is 2.6×10⁻⁷ RIU over a refractive index range of 10⁻² RIU, which is considerably wider than that achievable by existing laser based approach, thus making our scheme very attractive for practical SPR sensing applications.


Receptive and expressive English language assessments used for young children: a scoping review protocol.
The majority of a child's language development occurs in the first 5 years of life when brain development is most rapid. There are significant long-term benefits to supporting all children's language and literacy development such as maximizing their developmental potential (i.e., cognitive, linguistic, social-emotional), when children are experiencing a critical period of development (i.e., early childhood to 9 years of age). A variety of people play a significant role in supporting children's language development, including parents, guardians, family members, educators, and/or speech-language pathologists. Speech-language pathologists and educators are the professionals who predominantly support children's language development in order for them to become effective communicators and lay the foundation for later developing literacy skills (i.e., reading and writing skills). Therefore, these professionals need formal and informal assessments that provide them information on a child's understanding and/or use of the increasingly complex aspects of language in order to identify and support the receptive and expressive language learning needs of diverse children during their early learning experiences (i.e., aged 1.5 to 9 years). However, evidence on what methods and tools are being used is lacking. The authors will carry out a scoping review of the literature to identify studies and map the receptive and expressive English language assessment methods and tools that have been published and used since 1980. Arksey and O'Malley's (2005) six-stage approach to conducting a scoping review was drawn upon to design the protocol for this investigation: (1) identifying the research question; (2) identifying relevant studies; (3) study selection; (4) charting the data; (5) collating, summarizing, and reporting the results; and (6) consultation. This information will help these professionals identify and select appropriate assessment methods or tools that can be used to support development and/or identify areas of delay or difficulty and plan, implement, and monitor the progress of interventions supporting the development of receptive and expressive language skills in individuals with diverse language needs (e.g., typically developing children, children with language delays and disorders, children learning English as a second or additional language, Indigenous children who may be speaking dialects of English). Researchers plan to evaluate the effectiveness of the assessment methods or tools identified in the scoping review as an extension of this study.


Mass spectrometric immunoassay and MRM as targeted MS-based quantitative approaches in biomarker development: potential applications to cardiovascular disease and diabetes.
Type 2 diabetes mellitus (T2DM) is an important risk factor for cardiovascular disease (CVD)--the leading cause of death in the United States. Yet not all subjects with T2DM are at equal risk for CVD complications; the challenge lies in identifying those at greatest risk. Therapies directed toward treating conventional risk factors have failed to significantly reduce this residual risk in T2DM patients. Thus newer targets and markers are needed for the development and testing of novel therapies. Herein we review two complementary MS-based approaches--mass spectrometric immunoassay (MSIA) and MS/MS as MRM--for the analysis of plasma proteins and PTMs of relevance to T2DM and CVD. Together, these complementary approaches allow for high-throughput monitoring of many PTMs and the absolute quantification of proteins near the low picomolar range. In this review article, we discuss the clinical relevance of the high density lipoprotein (HDL) proteome and Apolipoprotein A-I PTMs to T2DM and CVD as well as provide illustrative MSIA and MRM data on HDL proteins from T2DM patients to provide examples of how these MS approaches can be applied to gain new insight regarding cardiovascular risk factors. Also discussed are the reproducibility, interpretation, and limitations of each technique with an emphasis on their capacities to facilitate the translation of new biomarkers into clinical practice.


Evapotranspiration and water yield of a pine-broadleaf forest are not altered by long-term atmospheric [CO2 ] enrichment under native or enhanced soil fertility.
Changes in evapotranspiration (ET) from terrestrial ecosystems affect their water yield (WY), with considerable ecological and economic consequences. Increases in surface runoff observed over the past century have been attributed to increasing atmospheric CO2 concentrations resulting in reduced ET by terrestrial ecosystems. Here, we evaluate the water balance of a Pinus taeda (L.) forest with a broadleaf component that was exposed to atmospheric [CO2 ] enrichment (ECO2 ; +200 ppm) for over 17 years and fertilization for 6 years, monitored with hundreds of environmental and sap flux sensors on a half-hourly basis. These measurements were synthesized using a one-dimensional Richard's equation model to evaluate treatment differences in transpiration (T), evaporation (E), ET, and WY. We found that ECO2 did not create significant differences in stand T, ET, or WY under either native or enhanced soil fertility, despite a 20% and 13% increase in leaf area index, respectively. While T, ET, and WY responded to fertilization, this response was weak (<3% of mean annual precipitation). Likewise, while E responded to ECO2 in the first 7 years of the study, this effect was of negligible magnitude (<1% mean annual precipitation). Given the global range of conifers similar to P. taeda, our results imply that recent observations of increased global streamflow cannot be attributed to decreases in ET across all ecosystems, demonstrating a great need for model-data synthesis activities to incorporate our current understanding of terrestrial vegetation in global water cycle models.


Targeting transporters: promoting blood-brain barrier repair in response to oxidative stress injury.
The blood-brain barrier (BBB) is a physical and biochemical barrier that precisely regulates the ability of endogenous and exogenous substances to accumulate within brain tissue. It possesses structural and biochemical features (i.e., tight junction and adherens junction protein complexes, influx and efflux transporters) that work in concert to control solute permeation. Oxidative stress, a critical component of several diseases including cerebral hypoxia/ischemia and peripheral inflammatory pain, can cause considerable injury to the BBB and lead to significant CNS pathology. This suggests a critical need for novel therapeutic approaches that can protect the BBB in diseases with an oxidative stress component. Recent studies have identified molecular targets (i.e., putative membrane transporters, intracellular signaling systems) that can be exploited for optimization of endothelial drug delivery or for control of transport of endogenous substrates such as the antioxidant glutathione (GSH). In particular, targeting transporters offers a unique approach to protect BBB integrity by promoting repair of cell-cell interactions at the level of the brain microvascular endothelium. This review summarizes current knowledge in this area and emphasizes those targets that present considerable opportunity for providing BBB protection and/or promoting BBB repair in the setting of oxidative stress. This article is part of a Special Issue entitled SI: Cell Interactions In Stroke.


Application of a theoretical model to evaluate COPD disease management.
Disease management programmes are heterogeneous in nature and often lack a theoretical basis. An evaluation model has been developed in which theoretically driven inquiries link disease management interventions to outcomes. The aim of this study is to methodically evaluate the impact of a disease management programme for patients with chronic obstructive pulmonary disease (COPD) on process, intermediate and final outcomes of care in a general practice setting. A quasi-experimental research was performed with 12-months follow-up of 189 COPD patients in primary care in the Netherlands. The programme included patient education, protocolised assessment and treatment of COPD, structural follow-up and coordination by practice nurses at 3, 6 and 12 months. Data on intermediate outcomes (knowledge, psychosocial mediators, self-efficacy and behaviour) and final outcomes (dyspnoea, quality of life, measured by the CRQ and CCQ, and patient experiences) were obtained from questionnaires and electronic registries. Implementation of the programme was associated with significant improvements in dyspnoea (p < 0.001) and patient experiences (p < 0.001). No significant improvement was found in mean quality of life scores. Improvements were found in several intermediate outcomes, including investment beliefs (p < 0.05), disease-specific knowledge (p < 0.01; p < 0.001) and medication compliance (p < 0.01). Overall, process improvement was established. The model showed associations between significantly improved intermediate outcomes and improvements in quality of life and dyspnoea. The application of a theory-driven model enhances the design and evaluation of disease management programmes aimed at improving health outcomes. This study supports the notion that a theoretical approach strengthens the evaluation designs of complex interventions. Moreover, it provides prudent evidence that the implementation of COPD disease management programmes can positively influence outcomes of care.


Did the breakout of laurentia turn gondwanaland inside-out?
Comparative geology suggests that the continents adjacent to northern, western, southern, and eastern Laurentia in the Late Proterozoic were Siberia, Australia-Antarctica, southern Africa, and Amazonia-Baltica, respectively. Late Proterozoic fragmentation of the supercontinent centered on Laurentia would then have been followed by rapid fan-like collapse of the (present) southern continents and eventual consolidation of East and West Gondwanaland. In this scenario, a pole of rotation near the Weddell Sea would explain the observed dominance of wrench tectonics in (present) east-west trending Pan-African mobile belts and subduction-accretion tectonics in north-south trending belts. In the process of fragmentation, rifts originating in the interior of the Late Proterozoic supercontinent became the external margins of Paleozoic Gondwanaland; exterior margins of the Late Proterozoic supercontinent became landlocked within the interior of Gondwanaland.


Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response.
Genetic factors contribute to the phenotype of drug response. We systematically analyzed all available pharmacogenetic data from Medline databases (1970-2003) on the impact that genetic polymorphisms have on positive and adverse reactions to antidepressants and antipsychotics. Additionally, dose adjustments that would compensate for genetically caused differences in blood concentrations were calculated. To study pharmacokinetic effects, data for 36 antidepressants were screened. We found that for 20 of those, data on polymorphic CYP2D6 or CYP2C19 were found and that in 14 drugs such genetic variation would require at least doubling of the dose in extensive metabolizers in comparison to poor metabolizers. Data for 38 antipsychotics were examined: for 13 of those CYP2D6 and CYP2C19 genotype was of relevance. To study the effects of genetic variability on pharmacodynamic pathways, we reviewed 80 clinical studies on polymorphisms in candidate genes, but those did not for the most part reveal significant associations between neurotransmitter receptor and transporter genotypes and therapy response or adverse drug reactions. In addition associations found in one study could not be replicated in other studies. For this reason, it is not yet possible to translate pharmacogenetic parameters fully into therapeutic recommendations. At present, antidepressant and antipsychotic drug responses can best be explained as the combinatorial outcome of complex systems that interact at multiple levels. In spite of these limitations, combinations of polymorphisms in pharmacokinetic and pharmacodynamic pathways of relevance might contribute to identify genotypes associated with best and worst responders and they may also identify susceptibility to adverse drug reactions.


Analysis of the responses of myenteric neurons in the small intestine to chemical stimulation of the mucosa.
Responses of myenteric AH and S neurons to local application of chemicals to the mucosa of the guinea pig small intestine were obtained using conventional intracellular recording techniques. Preparations were dissected to reveal the myenteric plexus over one-half of the circumference of the gut with intact mucosa on the the half. Neurons were impaled within the exposed one-half, whereas potential stimulants, in buffered saline, were transiently applied to the mucosa, 1-1.5 mm circumferential from the impalement. The stimulants elicited action potentials (AP) in AH neurons that did not arise from synaptic activity. AH neurons also responded with slow excitatory postsynaptic potentials (EPSP). S neurons were activated synaptically, via fast and slow EPSP, but not nonsynaptically. Mucosal application of solutions of a low pH (3-5) or a high pH (9-11) were both effective stimulants. Solutions of a neutral pH, which was also a control for mild mechanical stimulation, were usually ineffective. Both a short-chain fatty acid, acetate (pH 7.2), and 5-hydroxytryptamine elicited responses in each neuronal type. We conclude that myenteric AH neurons of the guinea pig distal ileum are primary afferent neurons that respond to a variety of mucosally applied chemical stimuli with burst of AP. In addition, the physiologically evoked transmission of slow EPSP to AH neurons suggests that primary afferent neurons interconnect in a self-reinforcing network. S neurons are second or higher order neurons in the reflex pathways.


Women's perception of the benefits of mammography screening: population-based survey in four countries.
Screening programmes are often actively promoted to achieve high coverage, which may result in unrealistic expectations. We examined women's understanding of the likely benefits of mammography screening. Telephone survey of random samples of the female population aged > or =15 years in the US, UK, Italy, and Switzerland using three closed questions on the expected benefits of mammography screening. A total of 5964 women were contacted and 4140 women (69%) participated. Misconceptions were widespread: a majority of women believed that screening prevents or reduces the risk of contracting breast cancer (68%), that screening at least halves breast cancer mortality (62%), and that 10 years of regular screening will prevent 10 or more breast cancer deaths per 1000 women (75%). In multivariate analysis higher number of correct answers was positively associated with higher educational status (odds ratio [OR] = 1.44, 95% CI: 1.25, 1.66) and negatively with having had a mammography in the last 2 years (OR = 0.86, 95% CI: 0.73, 1.01). Compared with US women (reference group) and Swiss women (OR = 0.98, 95% CI: 0.82, 1.18) respondents in Italy (OR = 0.61, 95% CI: 0.50, 0.74) and the UK (OR = 0.73, 95% CI: 0.60, 0.88) gave fewer correct answers. In the US and three European countries a high proportion of women overestimated the benefits that can be expected from screening mammography. This finding raises doubts on informed consent procedures within breast cancer screening programmes.


Baseline levels of influenza-specific CD4 memory T-cells affect T-cell responses to influenza vaccines.
Factors affecting immune responses to influenza vaccines have not been studied systematically. We hypothesized that T-cell and antibody responses to the vaccines are functions of pre-existing host immunity against influenza antigens. During the 2004 and 2005 influenza seasons, we have collected data on cellular and humoral immune reactivity to influenza virus in blood samples collected before and after immunization with inactivated or live attenuated influenza vaccines in healthy children and adults. We first used cross-validated lasso regression on the 2004 dataset to identify a group of candidate baseline correlates with T-cell and antibody responses to vaccines, defined as fold-increase in influenza-specific T-cells and serum HAI titer after vaccination. The following baseline parameters were examined: percentages of influenza-reactive IFN-gamma(+) cells in T and NK cell subsets, percentages of influenza-specific memory B-cells, HAI titer, age, and type of vaccine. The candidate baseline correlates were then tested with the independent 2005 dataset. Baseline percentage of influenza-specific IFN-gamma(+) CD4 T-cells was identified as a significant correlate of CD4 and CD8 T-cell responses, with lower baseline levels associated with larger T-cell responses. Baseline HAI titer and vaccine type were identified as significant correlates for HAI response, with lower baseline levels and the inactivated vaccine associated with larger HAI responses. Previously we reported that baseline levels of CD56(dim) NK reactivity against influenza virus inversely correlated with the immediate T-cell response to vaccination, and that NK reactivity induced by influenza virus depended on IL-2 produced by influenza-specific memory T-cells. Taken together these results suggest a novel mechanism for the homeostasis of virus-specific T-cells, which involves interaction between memory helper T-cells, CD56(dim) NK and DC. These results demonstrate that assessment of baseline biomarkers may predict immunologic outcome of influenza vaccination and may reveal some of the mechanisms responsible for variable immune responses following vaccination and natural infection.


Seroprevalence of anti-tetanus antibodies in mothers and cord blood and associated factors in health-care settings in Lao People's Democratic Republic.
Maternal neonatal tetanus (MNT) was eliminated from Lao People's Democratic Republic (PDR) in 2014. WHO recommends 80% coverage of 2 or more tetanus vaccinations (TT2+) in pregnancy to maintain MNT control. Vaccination coverage in Lao PDR varies among regions although the reasons are not clear. 185 pregnant women giving birth in three district hospitals in Savannakhet province, Lao PDR were recruited. A questionnaire was administered to determine factors associated with seroprotection and blood was taken from mother and cord blood to be tested for anti-tetanus antibodies by ELISA. 77% of mothers and 79% of newborns had sufficiently protective antibody titres (>0.5 IU/ml) against tetanus. Only 70% of the mothers received one dose of TT vaccination during antenatal care (ANC) consultation and 45% received the recommended two injections. Although most of the vaccination took place during ANC 1 and 2, many were missed at these time-points. Anti-tetanus seroprotection in the mothers was associated with maternal age, number of ANC visits, number of TT vaccinations during and before pregnancy and gestational age. Seroprevalence of anti-tetanus antibodies in mothers and newborns was intermediate but TT2+ coverage was low in healthcare settings in Lao PDR. TT2+ coverage during ANC is likely to be significantly lower in settings with less robust ANC practices. Missed opportunities to vaccinate in ANC 1 and 2 suggest a need to promote vaccine awareness and vaccination at first ANC visit. A booster dose of TT containing vaccine should be considered for children aged between 4 and 7 years old.


Turning liabilities into resources: informal village doctors and tuberculosis control in Bangladesh.
In 1998, the Damien Foundation Bangladesh invited semi-qualified, private "gram dakter" (Bangla for "village doctors") to participate in tuberculosis (TB) programmes in a population of 26 million people in rural Bangladesh. The organization trained 12 525 village doctors to not only refer suspected TB cases for free diagnosis but also to provide directly observed treatment (DOT) free of charge. Source of referral and place of DOT was recorded as part of the standardized TB recording and reporting system, which enabled us to quantify the contribution of village doctors to case detection rates and also allowed disaggregated cohort analysis of treatment outcome. During 2002 and 2003, 11% of all TB cases with positive sputum smears in the study area had been referred by village doctors; the rate of positive tests in patients referred by village doctors was 14.4%. 18 792 patients received DOT from village doctors, accounting for between 20% and 45% of patients on treatment during the 1998-2003 period. The treatment success rate was about 90% throughout the period. Urine samples taken during random checks of treatment compliance were positive for isoniazid in 98% of patients treated by village doctors. Within the framework of Public-Private Mix DOTS, services provided by semi-qualified private health care providers are a feasible and effective way to improve access to affordable high quality TB treatment in poor rural populations. The large informal health workforce that exists in resource poor countries can be used to achieve public health goals. Involvement of village doctors in TB control has now become national policy in Bangladesh.


New Predictive Parameters of Bell's Palsy: Neutrophil to Lymphocyte Ratio and Platelet to Lymphocyte Ratio.
Bell's palsy is the most frequent cause of unilateral facial paralysis. Inflammation is thought to play an important role in the pathogenesis of Bell's palsy. Neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) are simple and inexpensive tests which are indicative of inflammation and can be calculated by all physicians. The aim of this study was to reveal correlations of Bell's palsy and degree of paralysis with NLR and PLR. Case-control study. The retrospective study was performed January 2010 and December 2013. Ninety-nine patients diagnosed as Bell's palsy were included in the Bell's palsy group and ninety-nine healthy individuals with the same demographic characteristics as the Bell's palsy group were included in the control group. As a result of analyses, NLR and PLR were calculated. The mean NLR was 4.37 in the Bell's palsy group and 1.89 in the control group with a statistically significant difference (p<0.001). The mean PLR was 137.5 in the Bell's palsy group and 113.75 in the control group with a statistically significant difference (p=0.008). No statistically significant relation was detected between the degree of facial paralysis and NLR and PLR. The NLR and the PLR were significantly higher in patients with Bell's palsy. This is the first study to reveal a relation between Bell's palsy and PLR. NLR and PLR can be used as auxiliary parameters in the diagnosis of Bell's palsy.


Hydroa vacciniforme: a distinctive form of Epstein-Barr virus-associated T-cell lymphoproliferative disorders.
Hydroa vacciniforme (HV) is a cutaneous subset of Epstein-Barr virus (EBV)-associated T/NK lymphoproliferative disorders (LPDs). Our previous case series study clearly showed a clinical spectrum of EBV-associated T/NK LPDs including HV, hypersensitivity to mosquito bites (HMB), chronic active EBV infection (CAEBV), and hemophagocytic lymphohistiocytosis (HLH). Patients with HV are divided into two groups: a benign subtype designated "classic HV" (cHV) and more serious systemic HV (sHV), also called "HV-like LPD" in the 2017 World Health Organization (WHO) classification. Patients with cHV usually have an increased number of EBV-infected γδT cells and patients with sHV without HMB are further classified into two groups: γδT-cell- and αβT-cell-dominant types. Patients with HMB, with or without HV-like eruptions, have an increased number of EBV-infected NK cells in the blood. Patients with cHV and γδT-cell-dominant sHV show a favourable prognosis, but the other subtypes such as αβT-cell-dominant sHV and HMB have a poor prognosis with mortality rates of 11.5 and 3.51 per 100 person-years, respectively. In addition to the clinical subtypes and the dominant lymphocyte subsets, the poor prognostic indicators include onset age over nine years and expression of the reactivation marker, BZLF1 mRNA. No prognostic correlation has been reported for anti-EBV antibody titres or EBV DNA load. The clinical subtypes and their prognostic factors should be considered for therapeutic interventions.


Assessment of Antibiotic Treatment of Cellulitis and Erysipelas: A Systematic Review and Meta-analysis.
The optimum antibiotic treatment for cellulitis and erysipelas lacks consensus. The available trial data do not demonstrate the superiority of any agent, and data are limited on the most appropriate route of administration or duration of therapy. To assess the efficacy and safety of antibiotic therapy for non-surgically acquired cellulitis. The following databases were searched to June 28, 2016: Cochrane Central Register of Controlled Trials (2016, issue 5), Medline (from 1946), Embase (from 1974), and Latin American and Caribbean Health Sciences Information System (LILACS) (from 1982). In addition, 5 trials databases and the reference lists of included studies were searched. Further searches of PubMed and Google Scholar were undertaken from June 28, 2016, to December 31, 2018. Randomized clinical trials comparing different antibiotics, routes of administration, and treatment durations were included. For data collection and analysis, the standard methodological procedures of the Cochrane Collaboration were used. For dichotomous outcomes, the risk ratio and its 95% CI were calculated. A summary of findings table was created for the primary end points, adopting the GRADE approach to assess the quality of the evidence. The primary outcome was the proportion of patients cured, improved, recovered, or symptom-free or symptom-reduced at the end of treatment, as reported by the trial. The secondary outcome was any adverse event. A total of 43 studies with a total of 5999 evaluable participants, whose age ranged from 1 month to 96 years, were included. Cellulitis was the primary diagnosis in only 15 studies (35%), and in other studies the median (interquartile range) proportion of patients with cellulitis was 29.7% (22.9%-50.3%). Overall, no evidence was found to support the superiority of any 1 antibiotic over another, and antibiotics with activity against methicillin-resistant Staphylococcus aureus did not add an advantage. Use of intravenous antibiotics over oral antibiotics and treatment duration of longer than 5 days were not supported by evidence. In this systematic review and meta-analysis, only low-quality evidence was found for the most appropriate agent, route of administration, and duration of treatment for patients with cellulitis; future trials need to use a standardized set of outcomes, including severity scoring, dosing, and duration of therapy.


Food allergy: a practical update from the gastroenterological viewpoint.
To present an up-to-date and critical review regarding food allergies, focusing mainly on treatment and prevention. Review of published literature searched on MEDLINE database; those data which were the most up-to-date and representative were selected (2000-2006). The search included the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the American Academy of Pediatrics (AAP). The prevalence of allergic diseases has increased over the last decades, and food allergy seems to be part of this increase. Food allergy is much more common in pediatrics and has a significant medical, financial and social impact on young children and their families. Treatment and prevention of food allergy is a major challenge for public health, scientific and medical communities. There is a lot of misinformation and the medical management of this condition is still discussable. We present and discuss the guidelines regarding criteria for the prevention of food allergy and atopic diseases published by the Nutrition Committees of ESPGHAN jointly with the European Society for Pediatric Allergy and Clinical Immunology (ESPACI) and AAP. The overdiagnosis of food allergy is quite prevalent. There is a need for standardization of definitions and diagnostic procedures. The primary goal of therapy should be to first establish effective means of preventing food allergies. There is a need for accurate diagnostic methods to confirm or rule out the diagnosis. Patients need appropriate treatment by eliminating foods that cause symptoms, while avoiding the nutritional side effects and the cost of inappropriate diets.


Double-blind comparison of the antiemetic effects of nabilone and prochlorperazine on chemotherapy-induced emesis.
The antiemetic effect of oral nabilone, a synthetic cannabinoid, given at a dose of 2 mg every 12 hours was compared to oral slow-release capsules of prochlorperazine given at a dose of 10 mg every 12 hours by a double-blind crossover method in 37 patients receiving cancer chemotherapy. Patients received one of the following as the primary emetic stimulus: high-dose cis-dichlorodiammineplatinum(II) (DDP), low-dose DDP, mechlorethamine, streptozotocin, actinomycin D, or DTIC. Although results varied according to strength of emetic stimulus received, both nabilone and prochlorperazine appeared to produce antiemetic effects. Eighteen of the 37 patients achieved a complete or partial elimination of symptoms: seven with nabilone alone, three with prochlorperazine alone, and eight with each drug. Nabilone appeared to be the more effective antiemetic for patients who received chemotherapy agents other than high dose DDP; it was equivalent to prochlorperazine for those who did receive high-dose DDP. Side effects from prochlorperazine were limited to mild drowsiness occurring among 35% of the patients. The side effects from nabilone were drowsiness and dizziness which occurred frequently and were dose-limiting in 25% of patients.


How common is ecological speciation in plant-feeding insects? A 'Higher' Nematinae perspective.
Ecological speciation is a process in which a transiently resource-polymorphic species divides into two specialized sister lineages as a result of divergent selection pressures caused by the use of multiple niches or environments. Ecology-based speciation has been studied intensively in plant-feeding insects, in which both sympatric and allopatric shifts onto novel host plants could speed up diversification. However, while numerous examples of species pairs likely to have originated by resource shifts have been found, the overall importance of ecological speciation in relation to other, non-ecological speciation modes remains unknown. Here, we apply phylogenetic information on sawflies belonging to the 'Higher' Nematinae (Hymenoptera: Tenthredinidae) to infer the frequency of niche shifts in relation to speciation events. Phylogenetic trees reconstructed on the basis of DNA sequence data show that the diversification of higher nematines has involved frequent shifts in larval feeding habits and in the use of plant taxa. However, the inferred number of resource shifts is considerably lower than the number of past speciation events, indicating that the majority of divergences have occurred by non-ecological allopatric speciation; based on a time-corrected analysis of sister species, we estimate that a maximum of c. 20% of lineage splits have been triggered by a change in resource use. In addition, we find that postspeciational changes in geographic distributions have led to broad sympatry in many species having identical host-plant ranges. Our analysis indicates that the importance of niche shifts for the diversification of herbivorous insects is at present implicitly and explicitly overestimated. In the case of the Higher Nematinae, employing a time correction for sister-species comparisons lowered the proportion of apparent ecology-based speciation events from c. 50-60% to around 20%, but such corrections are still lacking in other herbivore groups. The observed convergent but asynchronous shifting among dominant northern plant taxa in many higher-nematine clades, in combination with the broad overlaps in the geographic distributions of numerous nematine species occupying near-identical niches, indicates that host-plant shifts and herbivore community assembly are largely unconstrained by direct or indirect competition among species. More phylogeny-based studies on connections between niche diversification and speciation are needed across many insect taxa, especially in groups that exhibit few host shifts in relation to speciation.


CO2 laser and/or fluoride enamel treatment against in situ/ex vivo erosive challenge.
This in situ/ex vivo study investigated the effect of CO2 laser irradiation and acidulated phosphate fluoride gel (APF) application, separately and in combination, on enamel resistance to erosion. During 2 experimental 5-day crossover phases, 8 volunteers wore intraoral appliances containing bovine enamel blocks which were submitted to four groups: 1st phase - control, untreated and CO2 laser irradiation, 2nd phase - fluoride application and fluoride application before CO2 laser irradiation. Laser irradiation was performed at 10.6 µm wavelength, 5 µs pulse duration and 50 Hz frequency, with average power input and output of 2.3 W and 2.0 W, respectively (28.6 J/cm2). APF gel (1.23%F, pH 3.5) was applied on enamel surface with a microbrush and left on for 4 minutes. Then, the enamel blocks were fixed at the intraoral appliance level. The erosion was performed extraorally 4 times daily for 5 min in 150 mL of cola drink. Enamel loss was measured profilometrically after treatment and after the in situ phase. The data were tested using one-way Repeated Measures Anova and Tukey's test (p<0.05). CO2 laser alone (2.00±0.39 µm) did not show any significantly preventive effect against enamel erosion when compared with the control group (2.41±1.20 µm). Fluoride treated enamel, associated (1.50±0.30 µm) or not (1.47±0.63 µm) with laser irradiation, significantly differed from the control. The APF application decreased enamel wear; however, CO2 laser irradiation did not enhance fluoride ability to reduce enamel wear.


Duodenal and faecal microbiota of celiac children: molecular, phenotype and metabolome characterization.
Epidemiology of celiac disease (CD) is increasing. CD mainly presents in early childhood with small intestinal villous atrophy and signs of malabsorption. Compared to healthy individuals, CD patients seemed to be characterized by higher numbers of Gram-negative bacteria and lower numbers Gram-positive bacteria. This study aimed at investigating the microbiota and metabolome of 19 celiac disease children under gluten-free diet (treated celiac disease, T-CD) and 15 non-celiac children (HC). PCR-denaturing gradient gel electrophoresis (DGGE) analyses by universal and group-specific primers were carried out in duodenal biopsies and faecal samples. Based on the number of PCR-DGGE bands, the diversity of Eubacteria was the higher in duodenal biopsies of T-CD than HC children. Bifidobacteria were only found in faecal samples. With a few exceptions, PCR-DGGE profiles of faecal samples for Lactobacillus and Bifidobacteria differed between T-CD and HC. As shown by culture-dependent methods, the levels of Lactobacillus, Enterococcus and Bifidobacteria were confirmed to be significantly higher (P = 0.028; P = 0.019; and P = 0.023, respectively) in fecal samples of HC than in T-CD children. On the contrary, cell counts (CFU/ml) of presumptive Bacteroides, Staphylococcus, Salmonella, Shighella and Klebsiella were significantly higher (P = 0.014) in T-CD compared to HC children. Enterococcus faecium and Lactobacillus plantarum were the species most diffusely identified. This latter species was also found in all duodenal biopsies of T-CD and HC children. Other bacterial species were identified only in T-CD or HC faecal samples. As shown by Randomly Amplified Polymorphic DNA-PCR analysis, the percentage of strains identified as lactobacilli significantly (P = 0.011) differed between T-CD (ca. 26.5%) and HC (ca. 34.6%) groups. The metabolome of T-CD and HC children was studied using faecal and urine samples which were analyzed by gas-chromatography mass spectrometry-solid-phase microextraction and 1H-Nuclear Magnetic Resonance. As shown by Canonical Discriminant Analysis of Principal Coordinates, the levels of volatile organic compounds and free amino acids in faecal and/or urine samples were markedly affected by CD. As shown by the parallel microbiology and metabolome approach, the gluten-free diet lasting at least two years did not completely restore the microbiota and, consequently, the metabolome of CD children. Some molecules (e.g., ethyl-acetate and octyl-acetate, some short chain fatty acids and free amino acids, and glutamine) seems to be metabolic signatures of CD.


No evidence for higher risk of cancer in patients with multiple sclerosis taking cladribine.
To compare the cancer risk of cladribine and other disease-modifying drugs (DMDs) in trials of people with relapsing multiple sclerosis (pwRMS). Meta-analysis of phase III trials of licensed DMDs for pwRMS and a phase III trial of cladribine (CLARITY). Cancer rates were compared using Fisher exact test. Eleven trials were included. Investigated treatments included cladribine, dimethyl fumarate, fingolimod, teriflunomide, natalizumab, alemtuzumab, and glatiramer acetate. The cancer rate in the CLARITY treatment group (0.34%) was not increased compared to all other treatment groups, whether including placebo-controlled trials only (0.6%, p = 0.4631) or all trials, i.e., including those with an active comparator arm (0.67%, p = 0.3669). No cancer was reported in the CLARITY placebo group, whereas the combined cancer rate of all other placebo groups was 1.19% (p = 0.0159). The cancer rate of zero in the CLARITY placebo group was also lower than that in the phase III trial of cladribine in people with clinically isolated syndrome (ORACLE MS, 2.91%, p = 0.0012). In fact, no difference was detected between cancer rates in the treatment groups of CLARITY (0.34%) and ORACLE MS (0.49%) (p = 0.6546). Our study does not support an increased cancer risk from cladribine in the doses used in CLARITY and ORACLE MS, which previously contributed to refusal of market authorization of cladribine in Europe. Longer-term follow-up is required to assess the safety profile of cladribine, as well as currently licensed DMDs, to definitively assess cancer risk.


Relationship between medical well baby visits and first dental examinations for young children in Medicaid.
We examined the relationship between preventive well baby visits (WBVs) and the timing of first dental examinations for young Medicaid-enrolled children. The study focused on children born in 2000 and enrolled continuously in the Iowa Medicaid Program from birth to age 41 months (n = 6322). The main predictor variables were number and timing of WBVs. The outcome variable was timing of first dental examination. We used survival analysis to evaluate these relationships. Children with more WBVs between ages 1 and 2 years and ages 2 and 3 years were 2.96 and 1.25 times as likely, respectively, to have earlier first dental examinations as children with fewer WBVs. The number of WBVs before age 1 year and the timing of the WBVs were not significantly related to the outcome. The number of WBVs from ages 1 to 3 years was significantly related to earlier first dental examinations, whereas the number of WBVs before age 1 year and the timing of WBVs were not. Future interventions and policies should actively promote first dental examinations by age 12 months at WBVs that take place during the first year of life.


Diurnal fluctuations in HPA and neuropeptide Y-ergic systems underlie differences in vulnerability to traumatic stress responses at different zeitgeber times.
The hypothalamic-pituitary-adrenal (HPA) axis displays a characteristic circadian pattern of corticosterone release, with higher levels at the onset of the active phase and lower levels at the onset of the inactive phase. As corticosterone levels modify the response to stress and influence the susceptibility to and/or severity of stress-related sequelae, we examined the effects of an acute psychological trauma applied at different zeitgeber times (ZTs) on behavioral stress responses. Rats were exposed to stress either at the onset of the inactive-(light) phase (ZT=0) or at the onset of the active-(dark) phase (ZT=12). Their behavior in the elevated plus-maze and acoustic startle response paradigms were assessed 7 days post exposure for retrospective classification into behavioral response groups. Serum corticosterone levels and the dexamethasone suppression test were used to assess the stress response and feedback inhibition of the HPA axis. Immunoreactivity for neuropeptide Y (NPY) and NPY-Y1 receptor (Y1R) in the paraventricular (PVN) and arcuate (ARC) hypothalamic nuclei, hippocampus, and basolateral amygdala were measured. The behavioral effects of NPY/Y1R antagonist microinfused into the PVN 30 min before stress exposure during the inactive or active phase, respectively, were evaluated. PVN immunoreactivity for NPY and Y1R was measured 1 day after the behavioral tests. The time of day of the traumatic exposure markedly affected the pattern of the behavioral stress response and the prevalence of rats showing an extreme behavioral response. Rats exposed to the stressor at the onset of their inactive phase displayed a more traumatic behavioral response, faster post-exposure corticosterone decay, and a more pronounced stress-induced decline in NPY and Y1R expression in the PVN and arcuate hypothalamic nuclei. Blocking PVN Y1R before stress applied in the active phase, or administering NPY to the PVN before stress applied in the inactive phase, had a resounding behavioral effect. The time at which stress occurred significantly affected the behavioral stress response. Diurnal variations in HPA and NPY/Y1R significantly affect the behavioral response, conferring more resilience at the onset of the active phase and more vulnerability at the onset of the inactive phase, implying that NPY has a significant role in conferring resilience to stress-related psychopathology.


Carbon nanotube functionalization as a route to enhancing the electrical and mechanical properties of Cu-CNT composites.
Copper-CNT (carbon nanotube) composite materials are promising alternatives to conventional conductors in applications ranging from interconnects in microelectronics to electrical cabling in aircraft and vehicles. Unfortunately, exploiting the full potential of these composites is difficult due to the poor Cu-CNT electro-mechanical interface. We demonstrate through large-scale ab initio calculations and sonication experiments that this problem can be addressed by CNT surface modification. Our calculations show that covalent functionalization of CNTs below 6.7 at% significantly improves Cu-CNT wetting and the mechanical properties of the composite. Oxidative pre-treatment of CNTs enhances the Young's modulus of the composite by nearly a factor 3 above that of pure Cu, whereas amination slightly improves the electrical current density with respect to the unmodified Cu-CNT system in the high bias regime. However, only nitrogen doping can effectively improve both the mechanical and electrical properties of the composite. As the experiments show, consistent with the calculations, substitutional doping with nitrogen effectively improves adhesion of the CNT to the Cu matrix. We also predict an improvement in the mechanical properties for the composite containing doped double-wall CNTs. Moreover, the calculations indicate that the presence of nitrogen dopants almost doubles locally the transmission through the nanotube and reduces the back scattering in the Cu matrix around the CNT. The computed electrical conductance of N-doped Cu-CNT "carpets" exceeds that of an undoped system by ∼160%.


The effect of verapamil on the pharmacokinetics of adriamycin.
The concurrent administration of adriamycin (intravenous) and verapamil (oral) is of considerable interest because of experimental data suggesting that resistance to adriamycin may be overcome by this means. The potential for a pharmacokinetic interaction between the two drugs has therefore been investigated in five patients with small cell lung cancer treated with combination chemotherapy comprising adriamycin, VP16, vincristine and cyclophosphamide. The data indicate that a significant interaction takes place. Adriamycin peak levels, terminal half-life and the volume of distribution at steady state are higher, whereas plasma drug clearance and the volume of the central compartment are lower with co-administration of verapamil. There was no evidence of enhanced drug toxicity in this study; however, the data should be considered in the interpretation of clinical trials in which adriamycin and verapamil are used together, both in terms of toxicity and tumour response.


The brain-pituitary-gonad axis in male teleosts, with special emphasis on flatfish (Pleuronectiformes).
The key component regulating vertebrate puberty and sexual maturation is the endocrine system primarily effectuated along the brain-pituitary-gonad (BPG) axis. By far most investigations on the teleost BPG axis have been performed on salmonids, carps, catfish and eels. Accordingly, earlier reviews on the BPG axis in teleosts have focused on these species, and mainly on females (e.g. 'Fish Physiology, vol. IXA. Reproduction (1983) pp. 97'; 'Proceedings of the Fourth International Symposium on the Reproductive Physiology of Fish. FishSymp91, Sheffield, UK, 1991, pp. 2'; 'Curr. Top. Dev. Biol. 30 (1995) pp. 103'; 'Rev. Fish Biol. Fish. 7 (1997) pp. 173'; 'Proceedings of the Sixth International Symposium on the Reproductive Physiology of Fish. John Grieg A/S, Bergen, Norway, 2000, pp. 211'). However, in recent years new data have emerged on the BPG axis in flatfish, especially at the level of the brain and pituitary. The evolutionarily advanced flatfishes are important model species both from an evolutionary point of view and also because many are candidates for aquaculture. The scope of this paper is to review the present status on the male teleost BPG axis, with an emphasis on flatfish. In doing so, we will first discuss the present understanding of the individual constituents of the axis in the best studied teleost models, and thereafter discuss available data on flatfish. Of the three constituents of the BPG axis, we will focus especially on the pituitary and gonadotropins. In addition to reviewing recent information on flatfish, we present some entirely new information on the phylogeny and molecular structure of teleost gonadotropins.


Limitations of rituximab/IVIg desensitization protocol in kidney transplantation; is this better than a tincture of time?
A plasmapheresis-free protocol for desensitization of donor kidney transplant candidates with high Calculated Panel Reactive Antibody (CPRA) was initiated at our center. The protocol was adopted from previously published work by Vo, Jordan et al. Five patients with CPRA of 94 ± 18%, awaiting kidney transplant from living or deceased donors received rituximab (1 g × 2 doses) and intravenous immunoglobulin (IVIG 2 g/kg × 2 doses) without plasmapheresis. Levels of donor specific antibodies (DSA) and T/B cell crossmatches were followed using solid phase flow cytometry. Three out of 5 patients were sensitized only to Class II HLA antigens. All patients had very high levels of alloantibodies before initiation of the treatment. All of the candidates initially demonstrated reduced levels of HLA antibody, but statistical significance was only obtained in one patient Class II antibody and in another only for Class I. Depletion was transient with observed antibody rebound. Rituximab effectively depleted CD20 cells in peripheral blood. None of the patients were transplanted due to persistently high levels of antibody and strong positive flow cytometry crossmatches. Under this protocol, reduction of HLA antibodies in patients with high levels was insufficient. Highly allo-sensitized patients with a CPRA above 85% may not benefit from a combination of rituximab-IVIG alone. The previously published protocol does not help all patients achieve an acceptable crossmatch. An individualized approach to the treatment of highly sensitized patients is still required.


Acid microenvironment promotes cell survival of human bone sarcoma through the activation of cIAP proteins and NF-κB pathway.
Extracellular acidification is a very common cause of stress in tumor microenvironment and of Darwinian pressure. In acid areas of the tumor, most cancer cells are-albeit slowly proliferating-more resistant to cell death than those in well-perfused regions. Tumor acidosis can directly regulate the expression of pro-survival proteins since a low extracellular pH activates the caspase-dependent cell death machinery. This mechanism has never been explored in bone sarcomas. We cultured osteosarcoma and Ewing sarcoma cells under low pH (pH 6.5), and we performed deep-sequencing and protein analysis. Both in in vitro and in vivo models, acidification activity enhanced tumor cells survival. However, we did not observe any change in ERK1 phosphorylation. On the contrary, both at the mRNA and protein level, we found a significant induction of TRAF adaptor proteins and of cIAP proteins (BIRC2 and/or BIRC3). As a consequence, the downstream nuclear transcription factor kappa B (NF-κB) survival pathway was increased. Furthermore, the treatment with the cIAP inhibitor LCL161 reverted the protection from apoptosis under low pH. In vitro results were confirmed both in Ewing sarcoma xenograft and in osteosarcoma patients, since the analysis of tumor tissues demonstrated that the levels of expression of TRAF1 or NF-κB1 significantly correlate with the level of expression of the vacuolar ATPase (V-ATPase), the most important proton pump in eukaryotes. Moreover, in the tissue sections of xenograft model, the nuclear translocation of RelB, a key subunit of the NF-κB transcriptional complex, localized in the tumor region that also corresponded to the acid microenvironment associated with the highest levels of expression of LAMP2 and V-ATPase, in the internal area of the tumor, as revealed by immunohistochemistry. Our data confirm that tumor acid microenvironment activates a stress-regulated switch to promote cell survival of bone sarcoma, and support the hypothesis that this mechanism is mediated by the recruitment of TRAF/cIAP complexes. Altogether, these results suggest that TRAF/cIAP can be considered as a target for anti-cancer therapies.


β-Arrestin 2 knockout mice exhibit sensitized dopamine release and increased reward in response to a low dose of alcohol.
The rewarding effects of alcohol have been attributed to interactions between opioid and dopaminergic system within the mesolimbic reward pathway. We have previously shown that ablation of β-arrestin 2 (Arrb2), a crucial regulator of μ-opioid receptor function, attenuates alcohol-induced hyperlocomotion and c-fos activation in the nucleus accumbens. Here, we further investigated the role of Arrb2 in modulating alcohol-induced dopamine (DA) release and conditioned place preference (CPP). We also assessed the functional importance of Arrb2 for μ-opioid receptor surface expression and signaling following an acute alcohol challenge. Alcohol-evoked (0.375, 0.75, and 1.5 g/kg intraperitoneally) DA release was measured by in vivo microdialysis in the shell of nucleus accumbens. Reward was assessed by the CPP paradigm. Receptor function was assessed by μ-receptor binding and [(35)S]GTP-γ-S autoradiography. In Arrb2 knockout mice accumbal DA levels reach maximum response at a lower dose compared to wild-type (wt) animals. In line with these results, Arrb2 knockout mice display increased CPP for alcohol as compared to wt mice. Finally, Arrb2 mutant mice display increased μ-opioid receptor signaling in the ventral and dorsal striatum and amygdala in response to a low dose of alcohol, indicating impaired desensitization mechanisms in these mice. Our results show that Arrb2 modulates the response to low doses of alcohol on various levels including μ-opioid receptor signaling, DA release, and reward. They also reveal a clear dissociation between the effects of Arrb2 on psychomotor and reward behaviors.


Muscle ring finger-3 protects against diabetic cardiomyopathy induced by a high fat diet.
The pathogenesis of diabetic cardiomyopathy (DCM) involves the enhanced activation of peroxisome proliferator activating receptor (PPAR) transcription factors, including the most prominent isoform in the heart, PPARα. In cancer cells and adipocytes, post-translational modification of PPARs have been identified, including ligand-dependent degradation of PPARs by specific ubiquitin ligases. However, the regulation of PPARs in cardiomyocytes and heart have not previously been identified. We recently identified that muscle ring finger-1 (MuRF1) and MuRF2 differentially inhibit PPAR activities by mono-ubiquitination, leading to the hypothesis that MuRF3 may regulate PPAR activity in vivo to regulate DCM. MuRF3-/- mice were challenged with 26 weeks 60% high fat diet to induce insulin resistance and DCM. Conscious echocardiography, blood glucose, tissue triglyceride, glycogen levels, immunoblot analysis of intracellular signaling, heart and skeletal muscle morphometrics, and PPARα, PPARβ, and PPARγ1 activities were assayed. MuRF3-/- mice exhibited a premature systolic heart failure by 6 weeks high fat diet (vs. 12 weeks in MuRF3+/+). MuRF3-/- mice weighed significantly less than sibling-matched wildtype mice after 26 weeks HFD. These differences may be largely due to resistance to fat accumulation, as MRI analysis revealed MuRF3-/- mice had significantly less fat mass, but not lean body mass. In vitro ubiquitination assays identified MuRF3 mono-ubiquitinated PPARα and PPARγ1, but not PPARβ. These findings suggest that MuRF3 helps stabilize cardiac PPARα and PPARγ1 in vivo to support resistance to the development of DCM. MuRF3 also plays an unexpected role in regulating fat storage despite being found only in striated muscle.


The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus.
Retinoic acid is a vitamin A derivative with striking effects on development and cell differentiation. Several nuclear retinoic acid receptors (RARs), acting as ligand-inducible transcription factors, have been characterized and indirect evidence suggests that they have distinct roles. One of the most intriguing properties of retinoic acid is its ability to induce in vivo differentiation of acute promyelocytic leukaemia (APL) cells into mature granulocytes, leading to morphological complete remissions. Because the RAR alpha gene maps to chromosome 17q21 (ref. 14), close to the t(15;17) (q21-q11-22) translocation specifically associated with APL, we analysed RAR alpha gene structure and expression in APL cells. We report here that, in one APL-derived cell line, the RAR alpha gene has been translocated to a locus, myl, on chromosome 15, resulting in the synthesis of a myl/RAR alpha fusion messenger RNA. Using two probes located on either side of the cloned breakpoint, we have found genomic rearrangements of one or other locus in six patients out of eight, demonstrating that the RAR alpha and/or myl genes are frequently rearranged in APL and the breakpoints are clustered. These findings strongly implicate retinoic acid receptor alpha in leukaemogenesis.


Addition of cyclophosphamide to antiretroviral therapy does not diminish the cellular reservoir in HIV-infected persons.
The chronically HIV-infected cellular reservoir in lymphoid tissue (LT) represents a formidable obstacle to the long-term success of antiretroviral therapy. Cytoreductive chemotherapy with cyclophosphamide (CTX) reduces cells in LT, and we hypothesized that coadministration of antiretroviral therapy with CTX may diminish the cellular reservoir over time. Ten antiretroviral treatment-naive subjects were recruited, and they received stavudine, lamivudine and nelfinavir (antiretroviral therapy, ART) until 2 consecutive plasma HIV RNA levels measured < 50 copies/ml (step 1). Five subjects then received ART alone, whereas five subjects received ART plus three escalating doses of CTX (step 2). Viral DNA was measured in LT obtained by excisional lymph node biopsy and peripheral blood mononuclear cells (PBMCs), using quantitative polymerase chain reaction at three time points in both groups (before steps 1 and 2, and after CTX). Viral DNA declined in both groups after the initiation of ART alone in step 1. During step 2 both groups experienced a modest decline compared with step 1. However, no significant differences were observed in viral DNA in LT or PBMCs between the ART alone and the ART plus CTX groups. Suppression of plasma HIV RNA levels < 50 copies/ml was not maintained in the ART plus CTX group, perhaps because of inadequate medication adherence. The group receiving ART plus CTX had lower CD4(+) lymphocyte counts and absolute total lymphocytes compared with the ART alone group. We conclude that the addition of CTX to ART did not diminish the cellular reservoir in HIV-infected persons.


A social rank explanation of how money influences health.
Financial resources are a potent determinant of health, yet it remains unclear why this is the case. We aimed to identify whether the frequently observed association between absolute levels of monetary resources and health may occur because money acts an indirect proxy for a person's social rank. To address this question we examined over 230,000 observations on 40,400 adults drawn from two representative national panel studies; the British Household Panel Survey and the English Longitudinal Study of Ageing. We identified each person's absolute income/wealth and their objective ranked position of income/wealth within a social reference-group. Absolute and rank income/wealth variables were then used to predict a series of self-reported and objectively recorded health outcomes in cross-sectional and longitudinal analyses. As anticipated, those with higher levels of absolute income/wealth were found to have better health than others, after adjustment for age, gender, education, marital status, and labor force status. When evaluated simultaneously the ranked position of income/wealth but not absolute income/wealth predicted all health outcomes examined including: objective measures of allostatic load and obesity, the presence of long-standing illness, and ratings of health, physical functioning, role limitations, and pain. The health benefits of high rank were consistent in cross-sectional and longitudinal analyses and did not depend on the reference-group used to rank participants. This is the first study to demonstrate that social position rather than material conditions may explain the impact of money on human health.


Inhibitory FcγRIIb (CD32b) becomes activated by therapeutic mAb in both cis and trans and drives internalization according to antibody specificity.
A major feature that distinguishes type I from type II anti-CD20 monoclonal antibodies (mAbs) and reduces their therapeutic efficacy is the tendency to internalize from the cell surface. We have shown previously that the extent of internalization correlates with the capacity of type I mAb to simultaneously engage both CD20 and the inhibitory Fcγ receptor, FcγRIIb, in a bipolar configuration. Here, we investigated whether mAbs directed at other B-cell surface receptors also engaged FcγRIIb and whether this interaction promoted internalization. Most mAbs engaged and activated FcγRIIb, with the strength of activation related to the level of mAb bound to the cell surface. However, engagement did not affect internalization of most mAb-ligated receptors, either in cell lines or primary chronic lymphocytic leukemia cells with the exception of CD19 and CD38. Furthermore, at high cell concentrations/density both cis and trans interactions between cell-surface bound mAb and FcγRIIb were evident, but trans interactions did not inhibit type I anti-CD20 mAb-mediated internalization. These data identify that FcγRIIb is engaged by many mAbs in both cis and trans configurations, triggering its activation, but that internalization via FcγRIIb occurs for only a select subset. These findings have implications when designing new antibody-based therapeutics.


A new pliopithecid genus (primates: Pliopithecoidea) from Castell de Barberà (Vallès-Penedès Basin, Catalonia, Spain).
Barberapithecus huerzeleri gen. et sp. nov. (Primates, Pliopithecidae) is erected on the basis of material from Castell de Barberà (Middle to Late Miocene, ca. 11.2-10.5 Ma), in the Vallès-Penedès Basin (Catalonia, Spain), including: 15 teeth (representing most of the permanent dentition) from a single female individual (holotype); an isolated P/3 (paratype); and a male C1/ (referred to the hypodigm). Previously, this material had been only partially figured and described, being attributed to Pliopithecus or to a new taxon with possible crouzeliine affinities. The erection of a new genus is justified by several autapomorphic features, such as markedly buccolingually compressed and mesiodistally elongated C1/, extremely buccolingually compressed, and mesiodistally oriented C/1 main cusp, P/4 with a large trigonid subequal to the talonid, very large distal foveae on the M/1 and especially the M/2, and lower molars with a quadrangular central fovea and a mesially situated entoconid. These features are associated with a set of crouzeliine synapomorphies, such as buccolingually compressed and peripheralized cusps, well-developed crests, large and well-defined occlusal foveae, upper molars with long preprotocrista, short hypoparacrista, somewhat distally situated protocone and short distal fovea, distinct P/3 metaconid, well-developed P/4 premetacristid, and relatively narrow lower molars with a reduced entoconid. Although more primitive, Barberapithecus resembles Anapithecus in some derived features. Both taxa are included into a new tribe (Anapithecini), together with other crouzeliines except Plesiopliopithecus (tribe Crouzeliini). The retention of primitive, pliopithecine-like features in Barberapithecus suggests that anapithecins might have evolved from a Pliopithecus ancestor, so that as currently conceived the Crouzeliinae might be polyphyletic.


Alcohol consumption and sport: a cross-sectional study of alcohol management practices associated with at-risk alcohol consumption at community football clubs.
Excessive alcohol consumption is responsible for considerable harm from chronic disease and injury. Within most developed countries, members of sporting clubs participate in at-risk alcohol consumption at levels above that of communities generally. There has been limited research investigating the predictors of at-risk alcohol consumption in sporting settings, particularly at the non-elite level. The purpose of this study was to examine the association between the alcohol management practices and characteristics of community football clubs and at-risk alcohol consumption by club members. A cross sectional survey of community football club management representatives and members was conducted. Logistic regression analysis (adjusting for clustering by club) was used to determine the association between the alcohol management practices (including alcohol management policy, alcohol-related sponsorship, availability of low- and non-alcoholic drinks, and alcohol-related promotions, awards and prizes) and characteristics (football code, size and location) of sporting clubs and at-risk alcohol consumption by club members. Members of clubs that served alcohol to intoxicated people [OR: 2.23 (95% CI: 1.26-3.93)], conducted 'happy hour' promotions [OR: 2.84 (95% CI: 1.84-4.38)] or provided alcohol-only awards and prizes [OR: 1.80 (95% CI: 1.16-2.80)] were at significantly greater odds of consuming alcohol at risky levels than members of clubs that did not have such alcohol management practices. At-risk alcohol consumption was also more likely among members of clubs with less than 150 players compared with larger clubs [OR:1.45 (95% CI: 1.02-2.05)] and amongst members of particular football codes. The findings of this study suggest a need and opportunity for the implementation of alcohol harm reduction strategies targeting specific alcohol management practices at community football clubs.


Polyphenols as Modulator of Oxidative Stress in Cancer Disease: New Therapeutic Strategies.
Cancer onset and progression have been linked to oxidative stress by increasing DNA mutations or inducing DNA damage, genome instability, and cell proliferation and therefore antioxidant agents could interfere with carcinogenesis. It is well known that conventional radio-/chemotherapies influence tumour outcome through ROS modulation. Since these antitumour treatments have important side effects, the challenge is to develop new anticancer therapeutic strategies more effective and less toxic for patients. To this purpose, many natural polyphenols have emerged as very promising anticancer bioactive compounds. Beside their well-known antioxidant activities, several polyphenols target epigenetic processes involved in cancer development through the modulation of oxidative stress. An alternative strategy to the cytotoxic treatment is an approach leading to cytostasis through the induction of therapy-induced senescence. Many anticancer polyphenols cause cellular growth arrest through the induction of a ROS-dependent premature senescence and are considered promising antitumour therapeutic tools. Furthermore, one of the most innovative and interesting topics is the evaluation of efficacy of prooxidant therapies on cancer stem cells (CSCs). Several ROS inducers-polyphenols can impact CSCs metabolisms and self-renewal related pathways. Natural polyphenol roles, mainly in chemoprevention and cancer therapies, are described and discussed in the light of the current literature data.


Circuit quantum electrodynamics with a spin qubit.
Electron spins trapped in quantum dots have been proposed as basic building blocks of a future quantum processor. Although fast, 180-picosecond, two-quantum-bit (two-qubit) operations can be realized using nearest-neighbour exchange coupling, a scalable, spin-based quantum computing architecture will almost certainly require long-range qubit interactions. Circuit quantum electrodynamics (cQED) allows spatially separated superconducting qubits to interact via a superconducting microwave cavity that acts as a 'quantum bus', making possible two-qubit entanglement and the implementation of simple quantum algorithms. Here we combine the cQED architecture with spin qubits by coupling an indium arsenide nanowire double quantum dot to a superconducting cavity. The architecture allows us to achieve a charge-cavity coupling rate of about 30 megahertz, consistent with coupling rates obtained in gallium arsenide quantum dots. Furthermore, the strong spin-orbit interaction of indium arsenide allows us to drive spin rotations electrically with a local gate electrode, and the charge-cavity interaction provides a measurement of the resulting spin dynamics. Our results demonstrate how the cQED architecture can be used as a sensitive probe of single-spin physics and that a spin-cavity coupling rate of about one megahertz is feasible, presenting the possibility of long-range spin coupling via superconducting microwave cavities.


Catalytic selective mono- and difluoroalkylation using fluorinated silyl enol ethers.
The judicious incorporation of a fluoroalkyl moiety often brings about beneficial effects on the properties of bioactive molecules. Consequently, efficient methods for selective fluoroalkylation are much sought after in drug discovery. Despite significant achievements in trifluoromethylation, selective mono- and difluoroalkylation is still undeveloped. Catalytic functionalization of fluorinated silyl enol ethers (FSEEs) emerges as a fruitful approach for the diversity-oriented synthesis of value-added α-mono or difluoroalkylated ketones. In this feature article, we detail our efforts in developing catalytic selective mono- and difluoroalkylation reactions using FSEEs. Specifically, we highlight our findings such as activating FSEEs by amines for catalytic enantioselective synthesis, taking advantage of the often observed high activity of FSEEs over the non-fluorinated analogues for reaction development, and the influence of C-FH-X interactions on reactivity and selectivity.


Auditory Lexical Decisions in Developmental Language Disorder: A Meta-Analysis of Behavioral Studies.
Despite the apparent primacy of syntactic deficits, children with developmental language disorder (DLD) often also evidence lexical impairments. In particular, it has been argued that this population have difficulty forming lexical representations that are detailed enough to support effective spoken word processing. In order to better understand this deficit, a meta-analysis of studies testing children with DLD in the auditory lexical decision task was conducted. The objective was to provide summary effect size estimates for accuracy and response time measures for comparisons to age- and language-matched control groups. Two thousand three hundred seventy-two records were initially identified through electronic searches and expert consultation, with this cohort reduced to 9 through duplicate removal and the application of eligibility and quality criteria. The final study cohort included 499 children aged 3;8-11;4 (years;months). Multivariate analysis suggests that children with DLD were significantly less accurate in the auditory lexical decision task than age-matched controls. For the response time estimate, however, confidence intervals for the same group comparison crossed 0, suggesting no reliable difference between groups. Confidence intervals also crossed 0 for language-matched control estimates for both accuracy and response time, suggesting no reliable difference between groups on either measure. Results broadly support the hypothesis that children with DLD have difficulty in forming detailed lexical representations relative to age- though not language-matched peers. However, further work is required to determine the performance profiles of potential subgroups and the impact of manipulating different lexical characteristics, such as the position and degree of nonword error, phonotactic probability, and semantic network size.


Electric-field-modulated light scattering near a morphological resonance of a trapped aerosol particle.
We describe electric-field-induced fluctuations in the elastic scattering near optical resonances of a spherical aerosol particle trapped at the null point of an electrodynamic levitator. The particle is apparently driven into a quadrupolar distortion by the electromechanical stress at its surface. Our results coupled with recent theory indicate that the effect is principally due to a modulation in the frequencies of individual optical resonances, that a coherent distortion smaller than one part in 10(5) ( approximately 0.1 nm) is detected, and that the effect may be used for a continuous probe of surface tension and bulk viscosity.


The operative treatment of Crohn's enteritis complicated by ileosigmoid fistula.
An ileosigmoid fistula complicating Crohn's disease of the small bowel has been considered a perplexing entity, but in practice does not pose a serious operative problem. The presence of such a fistula does not signify that the sigmoid colon is a primary site of Crohn's disease. The operative treatment of this entity is simple and usually does not require resection of the sigmoid colon. Rather the sigmoid colon defect may easily be treated by simple closure, or by minimal partial resection and closure. Temporary diversion of the fecal stream is occasionally indicated because of local inflammation. Forty-four of the 48 patients treated in this manner had successful resolution of their problem. Four patients were found to have primary Crohn's disease of the colon and required further treatments in addition to closure of the fistula.


FishPathogens.eu/vhsv: a user-friendly viral haemorrhagic septicaemia virus isolate and sequence database.
A database has been created, http://www.FishPathogens.eu, with the aim of providing a single repository for collating important information on significant pathogens of aquaculture, relevant to their control and management. This database will be developed, maintained and managed as part of the European Community Reference Laboratory for Fish Diseases function. This concept has been initially developed for viral haemorrhagic septicaemia virus and will be extended in future to include information on other significant aquaculture pathogens. Information included for each isolate comprises sequence, geographical origin, host origin and useful key literature. Various search mechanisms make it easy to find specific groups of isolates. Search results can be presented in several different ways including table-based, map-based and graph-based outputs. When retrieving sequences, the user is given freedom to obtain data from any selected part of the genome of interest. The output of the sequence search can be readily retrieved as a FASTA file ready to be imported into a sequence alignment tool of choice, facilitating further molecular epidemiological study.