Neuronal guidance molecule netrin-1 attenuates inflammatory cell trafficking during acute experimental colitis

Background: Inflammatory bowel diseases, encompassing Crohn’s disease and ulcerative colitis, are characterised by persistent leucocyte tissue infiltration leading to perpetuation of an inappropriate inflammatory cascade. The neuronal guidance molecule netrin-1 has recently been implicated in the orchestration of leucocyte trafficking during acute inflammation. We therefore hypothesised that netrin-1 could modulate leucocyte infiltration and disease activity in a model of inflammatory bowel disease. Design: DSS-colitis was performed in mice with partial genetic netrin-1 deficiency (Ntn-1+/- mice) or wild-type mice treated with exogenous netrin-1 via osmotic pump to examine the role of endogenous and therapeutically administered netrin-1. These studies were supported by in vitro models of transepithelial migration and intestinal epithelial barrier function. Results: Consistent with our hypothesis, we observed induction of netrin-1 during intestinal inflammation in vitro or in mice exposed to experimental colitis. Moreover, mice with partial netrin-1 deficiency demonstrated an exacerbated course of DSS-colitis compared to littermate controls, with enhanced weight loss and colonic shortening. Conversely, mice treated with exogenous mouse netrin-1 experienced attenuated disease severity. Importantly, permeability studies and quantitative assessment of apoptosis reveal that netrin-1 signalling events do not alter mucosal permeability or intestinal epithelial cell apoptosis. In vivo studies of leucocyte transmigration demonstrate suppression of neutrophil trafficking as a key function mediated by endogenous or exogenously administered netrin-1. Finally, genetic studies implicate the A2B adenosine receptor in netrin-1-mediated protection during DSS-colitis. Conclusions: The present study identifies a previously unrecognised role for netrin-1 in attenuating experimental colitis through limitation of neutrophil trafficking

Metal sorption on kaolinite

A key issue in performance assessment of low-level radioactive waste sites is predicting the transport and retardation of radionuclides through local soils under a variety of hydrologic and geochemical conditions. Improved transport codes should include a mechanistic model of radionuclide retardation. The authors have been investigating metal sorption (Cs{sup +}, Sr{sup 2+}, and Ba{sup 2+}) on a simple clay mineral (kaolinite) to better understand the geochemical interactions of common soil minerals with contaminated groundwaters. These studies include detailed characterizations of kaolinite surfaces, experimental adsorption measurements, surface complexation modeling, and theoretical simulations of cation sorption. The aluminol edge (010) site has been identified as the most likely site for metal sorption on kaolinite in natural solutions. Relative metal binding strengths decrease from Ba{sup 2+} to Sr{sup 2+} to Cs{sup +}, with some portion sorbed on both kaolinite edges and basal surfaces. Some Cs{sup +} also appears to be irreversibly sorbed on both sites. Molecular dynamics simulations suggest that Cs{sup +} is sorbed at aluminol (010) edge sites as an inner-sphere complex and weakly sorbed as an outer-sphere complex on (001) basal surfaces. These results provide the basis to understand and predict metal sorption onto kaolinite, and a framework to characterize sorption processes on more complex clay minerals

Improving patient-reported measures in oncology: A payer call to action

Despite rising interest in integrating the patient voice in value-based payment (VBP) models for oncology, barriers persist to implementing patient-reported measures (PRMs), including patient-reported performance measures (PR-PMs). This article describes the landscape of oncology PRMs and PR-PMs, identifies implementation barriers, and recommends solutions for public and private payers to accelerate the appropriate use of PRMs in oncology VBP programs. Our research used a multimethod approach that included a literature review, landscape scan, stakeholder interviews and survey, and a multistakeholder roundtable. The literature review and landscape scan found that limited oncology-specific PR-PMs are available and some are already used in VBP programs. Diverse stakeholder perspectives provided insight into filling current gaps in measurement and removing implementation barriers, such as limited relevance of existing PRMs and PR-PMs for oncology; methodological challenges; patient burden and survey fatigue; and provider burden from resource constraints, competing priorities, and insufficient incentives. Key recommendations include: (a) identify or develop meaningful measures that fill gaps, engaging patients throughout measure and program development and evaluation; (b) design programs that include scientifically sound measures standardized to reduce patient and provider burden while supporting care; and (c) engage providers using a stepwise approach that offers resources and incentives to support implementation

Coastal upwelling in the Rias Bajas, NW Spain: Contrasting the benthic regimes of the Rias de Arosa and de Muros

Nutrient-rich North Atlantic water upwells off the NW coast of Spain and intermittently intrudes into the rias, coastal embayments, by displacement during periods of offshore winds. High primary production associated with the upwelling supports an intensive raft culture of the edible mussel, Mytilus edulis. This culture is most intensive (ca. 2000 rafts) in the Ria de Arosa, and results in one of the highest protein yields per unit area on earth...

Potential effects of oilseed rape expressing oryzacystatin-1 (OC-1) and of purified insecticidal proteins on larvae of the solitary bee Osmia bicornis

Despite their importance as pollinators in crops and wild plants, solitary bees have not previously been included in non-target testing of insect-resistant transgenic crop plants. Larvae of many solitary bees feed almost exclusively on pollen and thus could be highly exposed to transgene products expressed in the pollen. The potential effects of pollen from oilseed rape expressing the cysteine protease inhibitor oryzacystatin-1 (OC-1) were investigated on larvae of the solitary bee Osmia bicornis (= O. rufa). Furthermore, recombinant OC-1 (rOC-1), the Bt toxin Cry1Ab and the snowdrop lectin Galanthus nivalis agglutinin (GNA) were evaluated for effects on the life history parameters of this important pollinator. Pollen provisions from transgenic OC-1 oilseed rape did not affect overall development. Similarly, high doses of rOC-1 and Cry1Ab as well as a low dose of GNA failed to cause any significant effects. However, a high dose of GNA (0.1%) in the larval diet resulted in significantly increased development time and reduced efficiency in conversion of pollen food into larval body weight. Our results suggest that OC-1 and Cry1Ab expressing transgenic crops would pose a negligible risk for O. bicornis larvae, whereas GNA expressing plants could cause detrimental effects, but only if bees were exposed to high levels of the protein. The described bioassay with bee brood is not only suitable for early tier non-target tests of transgenic plants, but also has broader applicability to other crop protection products

A systematic review of the evidence for single stage and two stage revision of infected knee replacement

BACKGROUND: Periprosthetic infection about the knee is a devastating complication that may affect between 1% and 5% of knee replacement. With over 79 000 knee replacements being implanted each year in the UK, periprosthetic infection (PJI) is set to become an important burden of disease and cost to the healthcare economy. One of the important controversies in treatment of PJI is whether a single stage revision operation is superior to a two-stage procedure. This study sought to systematically evaluate the published evidence to determine which technique had lowest reinfection rates. METHODS: A systematic review of the literature was undertaken using the MEDLINE and EMBASE databases with the aim to identify existing studies that present the outcomes of each surgical technique. Reinfection rate was the primary outcome measure. Studies of specific subsets of patients such as resistant organisms were excluded. RESULTS: 63 studies were identified that met the inclusion criteria. The majority of which (58) were reports of two-stage revision. Reinfection rated varied between 0% and 41% in two-stage studies, and 0% and 11% in single stage studies. No clinical trials were identified and the majority of studies were observational studies. CONCLUSIONS: Evidence for both one-stage and two-stage revision is largely of low quality. The evidence basis for two-stage revision is significantly larger, and further work into direct comparison between the two techniques should be undertaken as a priority

RNASeq analysis of differentiated keratinocytes reveals a massive response to late events during human papillomavirus type 16 infection, including loss of epithelial barrier function.

The human papillomavirus (HPV) replication cycle is tightly linked to epithelial cell differentiation. To examine HPV-associated changes in the keratinocyte transcriptome, RNAs isolated from undifferentiated and differentiated cell populations of normal, spontaneously immortalised, keratinocytes (NIKS), and NIKS stably transfected with HPV16 episomal genomes (NIKS16), were compared using RNASeq. HPV16 infection altered expression of 2862 cellular genes. Next, to elucidate the role of keratinocyte gene expression in late events during the viral life cycle, RNASeq was carried out on triplicate differentiated populations of NIKS (uninfected) and NIKS16 (infected). Of the top 966 genes altered (>log2 = 1.8, 3.5-fold change) 670 genes were downregulated and 296 genes were up-regulated. HPV down-regulated many genes involved in epithelial barrier function that involves structural resistance to the environment and immunity to infectious agents. For example, HPV infection repressed expression of the differentiated keratinocyte-specific pattern recognition receptor TLR7, the Langerhans cell chemoattractant, CCL20, and proinflammatory cytokines, IL1A and IL1B. However, IRF1, IFNκ and viral restriction factors (IFIT1, 2, 3, 5, OASL, CD74, RTP4) were up-regulated. HPV infection abrogated gene expression associated with the physical epithelial barrier, including keratinocyte cytoskeleton, intercellular junctions and cell adhesion. qPCR and western blotting confirmed changes in expression of seven of the most significantly altered mRNAs. Expression of three genes showed statistically significant changes during cervical disease progression in clinical samples. Taken together, the data indicate that HPV infection manipulates the differentiating keratinocyte transcriptome to create an environment conducive to productive viral replication and egress.IMPORTANCE Human papillomavirus (HPV) genome amplification and capsid formation takes place in differentiated keratinocytes. The viral life cycle is intimately associated with host cell differentiation. Deep sequencing (RNASeq) of RNA from undifferentiated and differentiated uninfected and HPV16-positive keratinocytes showed that almost 3000 genes were differentially expressed in keratinocyte due to HPV16 infection. Strikingly, the epithelial barrier function of differentiated keratinocytes, comprising keratinocyte immune function and cellular structure, was found to be disrupted. These data provide new insights into virus-host interaction crucial for production of infectious virus and reveal that HPV infection remodels keratinocytes for completion of the virus replication cycle

Adora2b Adenosine Receptor Engagement Enhances Regulatory T Cell Abundance during Endotoxin-Induced Pulmonary Inflammation

Anti-inflammatory signals play an essential role in constraining the magnitude of an inflammatory response. Extracellular adenosine is a critical tissue-protective factor, limiting the extent of inflammation. Given the potent anti-inflammatory effects of extracellular adenosine, we sought to investigate how extracellular adenosine regulates T cell activation and differentiation. Adenosine receptor activation by a pan adenosine-receptor agonist enhanced the abundance of murine regulatory T cells (Tregs), a cell type critical in constraining inflammation. Gene expression studies in both naïve CD4 T cells and Tregs revealed that these cells expressed multiple adenosine receptors. Based on recent studies implicating the Adora2b in endogenous anti-inflammatory responses during acute inflammation, we used a pharmacologic approach to specifically activate Adora2b. Indeed, these studies revealed robust enhancement of Treg differentiation in wild-type mice, but not in Adora2b−/− T cells. Finally, when we subjected Adora2b-deficient mice to endotoxin-induced pulmonary inflammation, we found that these mice experienced more severe inflammation, characterized by increased cell recruitment and increased fluid leakage into the airways. Notably, Adora2b-deficient mice failed to induce Tregs after endotoxin-induced inflammation and instead had an enhanced recruitment of pro-inflammatory effector T cells. In total, these data indicate that the Adora2b adenosine receptor serves a potent anti-inflammatory role, functioning at least in part through the enhancement of Tregs, to limit inflammation

Abordagem da artroplastia total do joelho no Brasil: estudo transversal

CONTEXT AND OBJECTIVE: Total knee arthroplasty (TKA) has evolved particularly since the 1970s, with improvements in implants and surgical instruments, and has thus become an effective intervention for treating knee arthrosis. Many studies have presented rates of satisfactory clinical and radiological results greater than 90%, from follow-ups of over ten years. Nevertheless, despite scientific evidence showing the efficacy of TKA, the approaches taken present controversies in certain respects. The objective of this study was to evaluate how the Brazilian orthopedists deal with TKA, with investigation of the main aspects of this procedure. DESIGN AND SETTING: Cross-sectional survey conducted during the 39th Brazilian Congress of Orthopedics and Traumatology, in São Paulo, Brazil, in November 2007. METHODS: We applied a questionnaire to orthopedists registered at the congress. The questionnaire was randomly distributed and participation was voluntary; 858 completed questionnaires were included in the analysis. RESULTS: Most of the Brazilian orthopedists were members of SBOT and worked in the southeastern region. They used imported cemented implants through an anterior access route centered on the patella, with replacement of the joint surface of the patella and preservation of the posterior cruciate ligament. They did not have experience with simultaneous bilateral TKA. Postoperatively, they used antibiotics and suction drains for 48 hours. There was no consensus regarding prophylaxis for venous thromboembolism or the frequency of the main complications. CONCLUSION: The majority of Brazilian orthopedists work in the southeastern region of the country and agree about the main aspects of the approaches towards TKA.CONTEXTO E OBJETIVO: A artroplastia total do joelho (ATJ) evoluiu sobremaneira desde os anos 70, com melhora dos implantes e do instrumental cirúrgico, tornando-se uma intervenção efetiva para o tratamento da artrose do joelho. Muitos estudos apresentam resultados clínicos e radiológicos satisfatórios superiores a 90% no acompanhamento acima de 10 anos. Apesar das evidências científicas sobre sua eficácia da ATJ, a sua abordagem apresenta controvérsias em alguns aspectos. O objetivo do estudo foi avaliar como o ortopedista brasileiro aborda a ATJ e os principais aspectos técnicos na realização deste procedimento. TIPO DE ESTUDO E LOCAL: Estudo transversal, realizado durante o 39º Congresso Brasileiro de Ortopedia e Traumatologia em São Paulo, Brasil, em novembro de 2007. MÉTODOS: Aplicamos um questionário aos ortopedistas inscritos no congresso. A distribuição foi aleatória com adesão voluntária. Foram incluídos 858 questionários para análise. RESULTADOS: A maioria dos Ortopedistas Brasileiros são membros da SBOT e atua na região sudeste. Usam o implante importado, cimentado, por via de acesso anterior centrada na patela, com substituição da superfície articular da patela e preservação do ligamento cruzado posterior e não tem experiência com a artroplastia total bilateral simultânea. No pós-operatório utilizam antibióticos e dreno de sucção por 48 horas. Não houve consenso quanto à profilaxia para tromboembolismo venoso e frequência das principais complicações. CONCLUSÃO: A maioria dos ortopedistas brasileiros trabalha na região sudeste e concorda quanto aos principais aspectos da abordagem da ATJ.Universidade Federal de São Paulo (UNIFESP) Department of Orthopedics and TraumatologyUniversidade Federal de São Paulo (UNIFESP) Department of Orthopedics and Traumatology Orthopedist and Head of the Knee GroupUNIFESP, Department of Orthopedics and TraumatologyUNIFESP, Department of Orthopedics and Traumatology Orthopedist and Head of the Knee GroupSciEL