Morphine activates neuroinflammation in a manner parallel to endotoxin

Opioids create a neuroinflammatory response within the CNS, compromising opioid-induced analgesia and contributing to various unwanted actions. How this occurs is unknown but has been assumed to be via classic opioid receptors. Herein, we provide direct evidence that morphine creates neuroinflammation via the activation of an innate immune receptor and not via classic opioid receptors. We demonstrate that morphine binds to an accessory protein of Toll-like receptor 4 (TLR4), myeloid differentiation protein 2 (MD-2), thereby inducing TLR4 oligomerization and triggering proinflammation. Small-molecule inhibitors, RNA interference, and genetic knockout validate the TLR4/MD-2 complex as a feasible target for beneficially modifying morphine actions. Disrupting TLR4/MD-2 protein–protein association potentiated morphine analgesia in vivo and abolished morphine-induced proinflammation in vitro, the latter demonstrating that morphine-induced proinflammation only depends on TLR4, despite the presence of opioid receptors. These results provide an exciting, nonconventional avenue to improving the clinical efficacy of opioids.Xiaohui Wang, Lisa C. Loram, Khara Ramos, Armando J. de Jesus, Jacob Thomas, Kui Cheng, Anireddy Reddy, Andrew A. Somogyi, Mark R. Hutchinson, Linda R. Watkins and Hang Yi

A statistical approach for predicting grassland degradation in disturbance-driven landscapes

Maintaining a land base that supports safe and realistic training operations is a significant challenge for military land managers which can be informed by frequent monitoring of land condition in relation to management practices. This study explores the relationship between fire and trends in tallgrass prairie vegetation at military and non -military sites in the Kansas Flint Hills. The response variable was the longterm linear trend (2001-2010) of surface greenness measured by MODIS NDVI using BFAST time series trend analysis. Explanatory variables included fire regime (frequency and seasonality) and spatial strata based on existing management unit boundaries. Several non-spatial generalized linear models (GLM) were computed to explain trends by fire regime and/or stratification. Spatialized versions of the GLMs were also constructed. For non-spatial models at the military site, fire regime explained little (4%) of the observed surface greenness trend compared to strata alone (7% - 26%). The non-spatial and spatial models for the non -military site performed better for each explanatory variable and combination tested with fire regime. Existing stratifications contained much of the spatial structure in model residuals. Fire had only a marginal effect on surface greenness trends at the military site despite the use of burning as a grassland management tool. Interestingly, fire explained more of the trend at the nonmilitary site and models including strata improved explanatory power. Analysis of spatial model predictors based on management unit stratification suggested ways to reduce the number of strata while achieving similar performance and may benefit managers of other public areas lacking sound data regarding land usage

A security proof of continuous-variable QKD using three coherent states

We introduce a ternary quantum key distribution (QKD) protocol and asymptotic security proof based on three coherent states and homodyne detection. Previous work had considered the binary case of two coherent states and here we nontrivially extend this to three. Our motivation is to leverage the practical benefits of both discrete and continuous (Gaussian) encoding schemes creating a best-of-both-worlds approach; namely, the postprocessing of discrete encodings and the hardware benefits of continuous ones. We present a thorough and detailed security proof in the limit of infinite signal states which allows us to lower bound the secret key rate. We calculate this is in the context of collective eavesdropping attacks and reverse reconciliation postprocessing. Finally, we compare the ternary coherent state protocol to other well-known QKD schemes (and fundamental repeaterless limits) in terms of secret key rates and loss.Comment: Close to the published versio

Psoriatic disease and body composition : a systematic review and narrative synthesis

Background Obesity is a leading comorbidity in psoriatic disease, including both psoriasis (PsO) and psoriatic arthritis (PsA), and is associated with adverse metabolic and cardiovascular (CV) outcomes. Anthropometric parameters, such as weight, body mass index (BMI) and waist-to-hip ratio, have been extensively reported in psoriatic disease. However, the associations of body composition and fat distribution with psoriasis have not yet been fully defined. Objectives To identify whether patients with psoriatic disease, including psoriatic arthritis, have altered body composition compared with the general population, and to review existing modalities for the assessment of body composition. Methods Electronic searches of the literature were conducted in PubMed, Medline (Ovid®), Embase (Ovid®), Cochrane Central Register of Controlled Trials (CENTRAL) and Google Scholar. Titles and abstracts were reviewed by two authors independently against a set of prespecified inclusion/exclusion criteria. The research question was answered with a systematic literature review and results were summarized narratively. Results Twenty-five full text articles met the inclusion criteria and were included in the final narrative analysis. The studies were of heterogeneous design and used a range of objective measures to assess body composition, including simple anthropometric measures, bioimpedance analysis (BIA), dual energy X-ray absorptiometry (DXA) and computed tomography (CT). Few studies met all the quality assessment criteria. Clinical heterogeneity prevented meta-analysis. Conclusions Patients with psoriatic disease reveal defined body composition changes that are independent of obesity and the customary metabolic syndrome, including higher overall body fat, visceral fat and sarcopenia. These findings emphasize that patients with psoriatic disease should be screened for abnormal adipose effects beyond their weight and body mass index (BMI). Our findings show that the last decade has seen an exciting expansion of research interest in the development and validation of new modalities for the assessment of body composition. There is no consensus on the optimal assessment method of body composition for this diverse group; hence there is a need for validation of existing modalities and standardization of assessment tools

Targeting endogenous proteins for degradation through the affinity-directed protein missile system

Targeted proteolysis of endogenous proteins is desirable as a research toolkit and in therapeutics. CRISPR/Cas9-mediated gene knockouts are irreversible and often not feasible for many genes. Similarly, RNA interference approaches necessitate prolonged treatments, can lead to incomplete knockdowns and are often associated with off-target effects. Targeted proteolysis can overcome these limitations. In this report, we describe an affinity-directed protein missile (AdPROM) system that harbours the von Hippel–Lindau (VHL) protein, the substrate receptor of the Cullin2 (CUL2) E3 ligase complex, tethered to polypeptide binders that selectively bind and recruit endogenous target proteins to the CUL2-E3 ligase complex for ubiquitination and proteasomal degradation. By using synthetic monobodies that selectively bind the protein tyrosine phosphatase SHP2 and a camelid-derived VHH nanobody that selectively binds the human ASC protein, we demonstrate highly efficient AdPROM-mediated degradation of endogenous SHP2 and ASC in human cell lines. We show that AdPROM-mediated loss of SHP2 in cells impacts SHP2 biology. This study demonstrates for the first time that small polypeptide binders that selectively recognize endogenous target proteins can be exploited for AdPROM-mediated destruction of the target proteins.</jats:p

Successful renal transplantation following prior bone marrow transplantation in pediatric patients

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72010/1/j.1399-3046.2004.00208.x.pd

Relative Sea-Level Change in the Northern Strait of Georgia, British Columbia

Twenty-four new radiocarbon dates from isolation basin cores, excavations and natural exposures, and an archeological site, constrain relative sea-level change since the last glaciation in the northern Strait of Georgia, British Columbia. Relative sea level fell rapidly from about 150 m elevation to 45 m elevation from 11 750 to 11 000 BP (13 750 to 13 000 cal BP), then its rate of fall slowed. The initial rapid emergence began soon after the transition from proximal to distal glaciomarine sedimentation, when the glacial front retreated from the Strait of Georgia and the Earth’s surface was unloaded. A sea-level lowstand a few metres below present-day sea level may have occurred in the early Holocene, but sea level was near its present level by 2000 BP. Sea-level change in the northern Strait of Georgia lagged the mid Strait of Georgia, 80 km to the south, by a few hundred years during initial emergence. The lowstand in the northern strait was later and probably shallower than in the mid strait. Isostatic depression inferred from the sea-level observations can be fit with two decaying exponential terms with characteristic decay times of 500 and 2600 years. The faster decay time corresponds to a shallow mantle viscosity of about 1019 Pa s, consistent with previous glacio-isostatic modelling. The present-day crustal uplift rate from the residual isostatic effects of the Cordilleran Ice Sheet is about 0.25 mm/a. Crustal uplift is not expected to significantly ameliorate projected sea-level rise in the mid and northern Strait of Georgia because present-day vertical crustal movements are inferred to be small.Vingt-quatre nouvelles dates au 14C provenant de carottes sédimentaires de bassins isolés, d’excavations, de coupes naturellement exposées et archéologiques permettent de cerner les changements du niveau marin relatif depuis la dernière glaciation dans la partie nord du détroit de Géorgie, en Colombie-Britannique. Le niveau marin relatif a rapidement passé de 150 m à 45 m d’altitude entre 11 750 et 11 000 ans BP (13 750-13 000 cal. BP), le taux d’abaissement ayant ralenti par la suite. L’émersion initiale rapide correspond à la fin de la sédimentation glaciomarine distale qui accompagnait le retrait du front glaciaire. Un bas niveau de quelques mètres sous le niveau actuel a pu s’instaurer durant l’Holocène inférieur, jusqu’en 2000 ans BP. Au début, le soulèvement isostatique a accusé un retard de quelques siècle sur celui de la zone du détroit à 80 km plus au sud. Le bas niveau de la partie nord du détroit est survenu plus tard et fut moins prononcé. Les données indiquent un enfoncement isostatique de type exponentiel avec des constantes de désintégration de 500 et de 2600 ans 14C. Le taux le plus rapide correspond à une viscosité du manteau terrestre d’environ 1019 Pa s, ce qui concorde avec les résultats de la modélisation glacio-isostatique. Le taux de soulèvement glacio-isostatique actuel résultant de l’inlandsis de la Cordillère s’établit à environ 0,25 mm/a. Ce taux ne peut contrer les effets du rehaussement du niveau marin prévu pour cette région en raison des faibles mouvements de la croûte terrestre qui y sont envisagés

Core Outcomes and Common Data Elements in Chronic Subdural Hematoma: A Systematic Review of the Literature Focusing on Reported Outcomes.

The plethora of studies in chronic subdural hematoma (CSDH) has not resulted in the development of an evidence-based treatment strategy, largely due to heterogeneous outcome measures that preclude cross-study comparisons and guideline development. This study aimed to identify and quantify the heterogeneity of outcome measures reported in the CSDH literature and to build a case for the development of a consensus-based core outcome set. This systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and was registered with the PROSPERO international prospective register of systematic reviews (CRD42014007266). All full-text English language studies with >10 patients (prospective) or >100 patients (retrospective) published after 1990 examining clinical outcomes in CSDH were eligible for inclusion. One hundred two eligible studies were found. There were 14 (13.7%) randomized controlled trials, one single arm trial (1.0%), 25 (24.5%) cohort comparison studies, and 62 (60.8%) prospective or retrospective cohort studies. Outcome domains reported by the studies included mortality (63.8% of included studies), recurrence (94.1%), complications (48.0%), functional outcomes (40.2%), and radiological (38.2%) outcomes. There was significant heterogeneity in the definitions of the outcome measures, as evidenced by the seven different definitions of the term "recurrence," with no definition given in 19 studies. The time-points of assessment for all the outcome domains varied greatly from inpatient/hospital discharge to 18 months. This study establishes and quantifies the heterogeneity of outcome measure reporting in CSDH and builds the case for the development of a robust consensus-based core outcome set for future studies to adhere to as part of the Core Outcomes and Common Data Elements in CSDH (CODE-CSDH) project.PJH is supported by a National Institute for Health Research (NIHR) Research Professorship and the NIHR Cambridge Biomedical Research Centre

Impact of previous hepatitis B infection on the clinical outcomes from chronic hepatitis C? A population-level analysis

Chronic coinfection with hepatitis C virus (HCV) and hepatitis B virus (HBV) is associated with adverse liver outcomes. The clinical impact of previous HBV infection on liver disease in HCV infection is unknown. We aimed at determining any association of previous HBV infection with liver outcomes using antibodies to the hepatitis B core antigen (HBcAb) positivity as a marker of exposure. The Scottish Hepatitis C Clinical Database containing data for all patients attending HCV clinics in participating health boards was linked to the HBV diagnostic registry and mortality data from Information Services Division, Scotland. Survival analyses with competing risks were constructed for time from the first appointment to decompensated cirrhosis, hepatocellular carcinoma (HCC) and liver‐related mortality. Records of 8513 chronic HCV patients were included in the analyses (87 HBcAb positive and HBV surface antigen [HBsAg] positive, 1577 HBcAb positive and HBsAg negative, and 6849 HBcAb negative). Multivariate cause‐specific proportional hazards models showed previous HBV infection (HBcAb positive and HBsAg negative) significantly increased the risks of decompensated cirrhosis (hazard ratio [HR]: 1.29, 95% CI: 1.01‐1.65) and HCC (HR: 1.64, 95% CI: 1.09‐2.49), but not liver‐related death (HR: 1.02, 95% CI: 0.80‐1.30). This is the largest study to date showing an association between previous HBV infection and certain adverse liver outcomes in HCV infection. Our analyses add significantly to evidence which suggests that HBV infection adversely affects liver health despite apparent clearance. This has important implications for HBV vaccination policy and indications for prioritization of HCV therapy