Effect of insulin on glucose metabolism in the dog after portacaval transposition

The effect of insulin on hepatic glucose metabolism was studied by a multiple-catheter technique in unanesthetized dogs with Eck fistula and with portacaval transposition. With the latter preparation, blood entering and leaving the liver was sampled from peripherally inserted catheters. In the unanesthetized Eck-fistula animals, insulin infusion produced a decrease in the hepatic glucose output. In the dogs with portacaval transposition, a constant infusion of insulin was given alternately by systemic and by intraportal routes. There was no significant difference between the effects of insulin administered by the two routes. During insulin infusion, glucose concentration differences across the liver were reduced, hepatic plasma flow was transiently elevated, and hepatic glucose output was decreased. After discontinuance of insulin, there was a transient rise of hepatic glucose output to above control values. </jats:p

The Prostate Health Index adds predictive value to multi-parametric MRI in detecting significant prostate cancers in a repeat biopsy population

Both multi-parametric MRI (mpMRI) and the Prostate Health Index (PHI) have shown promise in predicting a positive biopsy in men with suspected prostate cancer. Here we investigated the value of combining both tests in men requiring a repeat biopsy. PHI scores were measured in men undergoing re-biopsy with an mpMRI image-guided transperineal approach (n = 279, 94 with negative mpMRIs). The PHI was assessed for ability to add value to mpMRI in predicting all or only significant cancers (Gleason ≥7). In this study adding PHI to mpMRI improved overall and significant cancer prediction (AUC 0.71 and 0.75) compared to mpMRI + PSA alone (AUC 0.64 and 0.69 respectively). At a threshold of ≥35, PHI + mpMRI demonstrated a NPV of 0.97 for excluding significant tumours. In mpMRI negative men, the PHI again improved prediction of significant cancers; AUC 0.76 vs 0.63 (mpMRI + PSA). Using a PHI≥35, only 1/21 significant cancers was missed and 31/73 (42%) men potentially spared a re-biopsy (NPV of 0.97, sensitivity 0.95). Decision curve analysis demonstrated clinically relevant utility of the PHI across threshold probabilities of 5-30%. In summary, the PHI adds predictive performance to image-guided detection of clinically significant cancers and has particular value in determining re-biopsy need in men with a negative mpMRI

Pii‐21

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109873/1/cptclpt2006159.pd

Changing geo-ecological functions of coral reefs in the Anthropocene

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record The ecology of many coral reefs has changed markedly over recent decades in response to various combinations of local and global stressors. These ecological changes have important implications for the abundance of taxa that regulate the production and erosion of skeletal carbonates, and thus for many of the geo-ecological functions that coral reefs provide, including reef framework production and sediment generation, the maintenance of reef habitat complexity and reef growth potential. These functional attributes underpin many of the ecosystem goods and services that reefs provide to society. Rapidly changing conditions of reefs in the Anthropocene are likely to significantly impact the capacity of reefs to sustain these geo-ecological functions. Although the Anthropocene footprint of disturbance will be expressed differently across ecoregions and habitats, the end point for many reefs may be broadly similar: (a) progressively shifting towards net neutral or negative carbonate budget states; (b) becoming structurally flatter; and (c) having lower vertical growth rates. It is also likely that a progressive depth-homogenisation will occur in terms of these processes. The Anthropocene is likely to be defined by an increasing disconnect between the ecological processes that drive carbonate production on the reef surface, and the net geological outcome of that production, that is, the accumulation of the underlying reef structure. Reef structures are thus likely to become increasingly relict or senescent features, which will reduce reef habitat complexity and sediment generation rates, and limit reef potential to accrete vertically at rates that can track rising sea levels. In the absence of pervasive stressors, recovery of degraded coral communities has been observed, resulting in high net-positive budgets being regained. However, the frequency and intensity of climate-driven bleaching events are predicted to increase over the next decades. This would increase the spatial footprint of disturbances and exacerbate the magnitude of the changes described here, limiting the capacity of many reefs to maintain their geo-ecological functions. The enforcement of effective marine protection or the benefits of geographic isolation or of favourable environmental conditions (“refugia” sites) may offer the hope of more optimistic futures in some locations. A plain language summary is available for this article.Royal Societ

A comparison of the hypoglycemic effect of insulin with systemic venous and portal venous administration

The hyperglycemic effect of insulin by prolonged intraportal and systemic infusion was measured in unanesthetized dogs with a modified portacaval transposition. There was no significant difference in response with the two routes of administration. The relation of these results to research directed to surgical therapy of diabetes is discussed. © 1963 W. B. Saunders Company

Evolution and oncological outcomes of a contemporary radical prostatectomy practice in a UK regional tertiary referral centre.

OBJECTIVE: To investigate the clinical and pathological trends, over a 10-year period, in robot-assisted laparoscopic prostatectomy (RALP) in a UK regional tertiary referral centre. PATIENTS AND METHODS: In all, 1 500 consecutive patients underwent RALP between October 2005 and January 2015. Prospective data were collected on clinicopathological details at presentation as well as surgical outcomes and compared over time. RESULTS: The median (range) age of patients throughout the period was 62 (35-78) years. The proportion of preoperative high-grade cases (Gleason score 8-10) rose from 4.6% in 2005-2008 to 18.2% in 2013-2015 (P < 0.001). In the same periods the proportion of clinical stage T3 cases operated on rose from 2.4% to 11.4% (P < 0.001). The median prostate-specific antigen (PSA) level at diagnosis did not alter significantly. Overall, 11.6% of men in 2005-2008 were classified preoperatively as high-risk by National Institute for Health and Care Excellence criteria, compared with 33.6% in 2013-2015 (P < 0.001). The corresponding proportions for low-risk cases were 48.6% and 17.3%, respectively. Final surgical pathology showed an increase in tumour stage, Gleason grade, and nodal status over time. The proportion of pT3 cases rose from 43.2% in 2005-2008 to 55.5% in 2013-2015 (P < 0.001), Gleason score 9-10 tumours increased from 1.8% to 9.1% (P < 0.001) and positive nodal status increased from 1.6% to 12.9% (P < 0.001) between the same periods. Despite this, positive surgical margin rates showed a downward trend in all pT groups across the different eras (P = 0.72). CONCLUSION: This study suggests that the patient profile for RALP in our unit is changing, with increasing proportions of higher stage and more advanced disease being referred and operated on. However, surgical margin outcomes have remained good.This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1111/bju.1351

Extreme spatial heterogeneity in carbonate accretion potential on a Caribbean fringing reef linked to local human disturbance gradients

This is the final version. Available on open access from Wiley via the DOI in this recordThe capacity of coral reefs to maintain their structurally complex frameworks and to retain the potential for vertical accretion is vitally important to the persistence of their ecological functioning and the ecosystem services they sustain. However, datasets to support detailed along-coast assessments of framework production rates and accretion potential do not presently exist. Here we estimate, based on gross bioaccretion and bioerosion measures, the carbonate budgets and resultant maximum accretion potential (RAPmax) of the shallow reef zone of leeward Bonaire – between 5 to 12 m depth – at unique fine spatial resolution along this coast (115 sites). Whilst the fringing reef of Bonaire is often reported to be in a better ecological condition than most sites throughout the wider Caribbean region, our data show that the carbonate budgets of the reefs and derived RAPmax rates varied3 considerably across this ~58 km long fringing reef complex. Some areas, in particular the marine reserves, were indeed still dominated by structurally complex coral communities with high net carbonate production (> 10 kg CaCO3 m-2 year-1 35 ), high live coral cover and complex structural topography. The majority of the studied sites, however, were defined by relatively low budget states (< 2 kg CaCO3 m-2 year-1 36 ) or were in a state of net erosion. These data highlight the marked spatial heterogeneity that can occur in budgets states, and thus in reef accretion potential, even between quite closely spaced areas of individual reef complexes. This heterogeneity is linked strongly to the degree of localized land-based impacts along the coast, and resultant differences in the abundance of reef framework building coral species. The major impact of this variability is that those sections of reef defined by low-accretion potential will have limited capacity to maintain their structural integrity and to keep pace with current projections of climate change induced sea-level rise (SLR), thus posing a threat to reef functioning, biodiversity and trophic cascades. Since many Caribbean reefs are more severely degraded than those found around Bonaire, it is to be expected that the findings presented here are rather the rule than the exception, but the study also highlights the need for similar high spatial resolution (along-coast) assessments of budget states and accretion potential to meaningfully explore increasing coastal risk at the country level. The findings also more generally underline the significance of reducing local anthropogenic disturbance and restoring framework-building coral assemblages. Appropriately focussed local preservation efforts may aid in averting future large-scale submergence of Caribbean coral reefs and will constrain the social and economic implications associated with the loss of reef goods and services.Ministry of Economic AffairsWageningen UniversityRoyal Netherlands Institute for Sea Researc

Integration of copy number and transcriptomics provides risk stratification in prostate cancer: A discovery and validation cohort study.

BACKGROUND: Understanding the heterogeneous genotypes and phenotypes of prostate cancer is fundamental to improving the way we treat this disease. As yet, there are no validated descriptions of prostate cancer subgroups derived from integrated genomics linked with clinical outcome. METHODS: In a study of 482 tumour, benign and germline samples from 259 men with primary prostate cancer, we used integrative analysis of copy number alterations (CNA) and array transcriptomics to identify genomic loci that affect expression levels of mRNA in an expression quantitative trait loci (eQTL) approach, to stratify patients into subgroups that we then associated with future clinical behaviour, and compared with either CNA or transcriptomics alone. FINDINGS: We identified five separate patient subgroups with distinct genomic alterations and expression profiles based on 100 discriminating genes in our separate discovery and validation sets of 125 and 103 men. These subgroups were able to consistently predict biochemical relapse (p = 0.0017 and p = 0.016 respectively) and were further validated in a third cohort with long-term follow-up (p = 0.027). We show the relative contributions of gene expression and copy number data on phenotype, and demonstrate the improved power gained from integrative analyses. We confirm alterations in six genes previously associated with prostate cancer (MAP3K7, MELK, RCBTB2, ELAC2, TPD52, ZBTB4), and also identify 94 genes not previously linked to prostate cancer progression that would not have been detected using either transcript or copy number data alone. We confirm a number of previously published molecular changes associated with high risk disease, including MYC amplification, and NKX3-1, RB1 and PTEN deletions, as well as over-expression of PCA3 and AMACR, and loss of MSMB in tumour tissue. A subset of the 100 genes outperforms established clinical predictors of poor prognosis (PSA, Gleason score), as well as previously published gene signatures (p = 0.0001). We further show how our molecular profiles can be used for the early detection of aggressive cases in a clinical setting, and inform treatment decisions. INTERPRETATION: For the first time in prostate cancer this study demonstrates the importance of integrated genomic analyses incorporating both benign and tumour tissue data in identifying molecular alterations leading to the generation of robust gene sets that are predictive of clinical outcome in independent patient cohorts.Cambridge work was funded by a CRUK programme grant awarded to DEN; Swedish work and tissue collections were funded by grants from the Linne Centre for Breast and Prostate Cancer (CRISP, grant 70867901), Karolinska Institutet, the Swedish Research Council (K2010-70X-20430-04-3), and the Swedish Cancer Society (11-0287).This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.ebiom.2015.07.01

Integration of copy number and transcriptomics provides risk stratification in prostate cancer : a discovery and validation cohort study

Study data are deposited in NCBI GEO (unique identifier number GSE70770).Background : Understanding the heterogeneous genotypes and phenotypes of prostate cancer is fundamental to improving the way we treat this disease. As yet, there are no validated descriptions of prostate cancer subgroups derived from integrated genomics linked with clinical outcome. Methods : In a study of 482 tumour, benign and germline samples from 259 men with primary prostate cancer, we used integrative analysis of copy number alterations (CNA) and array transcriptomics to identify genomic loci that affect expression levels of mRNA in an expression quantitative trait loci (eQTL) approach, to stratify patients into subgroups that we then associated with future clinical behaviour, and compared with either CNA or transcriptomics alone. Findings : We identified five separate patient subgroups with distinct genomic alterations and expression profiles based on 100 discriminating genes in our separate discovery and validation sets of 125 and 103 men. These subgroups were able to consistently predict biochemical relapse (p = 0.0017 and p = 0.016 respectively) and were further validated in a third cohort with long-term follow-up (p = 0.027). We show the relative contributions of gene expression and copy number data on phenotype, and demonstrate the improved power gained from integrative analyses. We confirm alterations in six genes previously associated with prostate cancer ( MAP3K7, MELK, RCBTB2, ELAC2, TPD52, ZBTB4), and also identify 94 genes not previously linked to prostate cancer progression that would not have been detected using either transcript or copy number data alone. We confirm a number of previously published molecular changes associated with high risk disease, including MYC amplification, and NKX3-1, RB1 and PTEN deletions, as well as over-expression of PCA3 and AMACR, and loss of MSMB in tumour tissue. A subset of the 100 genes outperforms established clinical predictors of poor prognosis (PSA, Gleason score), as well as previously published gene signatures (p = 0.0001). We further show how our molecular profiles can be used for the early detection of aggressive cases in a clinical setting, and inform treatment decisions. Interpretation : For the first time in prostate cancer this study demonstrates the importance of integrated genomic analyses incorporating both benign and tumour tissue data in identifying molecular alterations leading to the generation of robust gene sets that are predictive of clinical outcome in independent patient cohorts.Publisher PDFPeer reviewe

Avoiding Coral Reef Functional Collapse Requires Local and Global Action

oral reefs face multiple anthropogenic threats, from pollution and overfishing to the dual effects of greenhouse gas emissions: rising sea temperature and ocean acidification [1]. While the abundance of coral has declined in recent decades [2, 3], the implications for humanity are difficult to quantify because they depend on ecosystem function rather than the corals themselves. Most reef functions and ecosystem services are founded on the ability of reefs to maintain their three-dimensional structure through net carbonate accumulation [4]. Coral growth only constitutes part of a reef's carbonate budget; bioerosion processes are influential in determining the balance between net structural growth and disintegration [5, 6]. Here, we combine ecological models with carbonate budgets and drive the dynamics of Caribbean reefs with the latest generation of climate models. Budget reconstructions using documented ecological perturbations drive shallow (6-10 m) Caribbean forereefs toward an increasingly fragile carbonate balance. We then projected carbonate budgets toward 2080 and contrasted the benefits of local conservation and global action on climate change. Local management of fisheries (specifically, no-take marine reserves) and the watershed can delay reef loss by at least a decade under "business-as-usual" rises in greenhouse gas emissions. However, local action must be combined with a low-carbon economy to prevent degradation of reef structures and associated ecosystem services