Polyanalgesic Consensus Conference--2012: recommendations on trialing for intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel.

INTRODUCTION: Trialing for intrathecal pump placement is an essential part of the decision-making process in placing a permanent device. In both the United States and the international community, the proper method for trialing is ill defined. METHODS: The Polyanalgesic Consensus Conference (PACC) is a group of well-published experienced practitioners who meet to update the state of care for intrathecal therapies on the basis of current knowledge in the literature and clinical experience. Anexhaustive search is performed to create a base of information that the panel considers when making recommendations for best clinical practices. This literature, coupled with clinical experience, is the basis for recommendations and for identification of gaps in the base of knowledge regarding trialing for intrathecal pump placement. RESULTS: The panel has made recommendations for the proper methods of trialing for long-term intrathecal drug delivery. CONCLUSION: The use of intrathecal drug delivery is an important part of the treatment algorithm for moderate to severe chronic pain. It has become common practice to perform a temporary neuroaxial infusion before permanent device implantation. On the basis of current knowledge, the PACC has developed recommendations to improve care. The need to update these recommendations will be very important as new literature is published.

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

Genome-wide association analysis identifies 20 loci that influence adult height.

Adult height is a model polygenic trait, but there has been limited success in identifying the genes underlying its normal variation. To identify genetic variants influencing adult human height, we used genome-wide association data from 13,665 individuals and genotyped 39 variants in an additional 16,482 samples. We identified 20 variants associated with adult height (P < 5 x 10(-7), with 10 reaching P < 1 x 10(-10)). Combined, the 20 SNPs explain approximately 3% of height variation, with a approximately 5 cm difference between the 6.2% of people with 17 or fewer 'tall' alleles compared to the 5.5% with 27 or more 'tall' alleles. The loci we identified implicate genes in Hedgehog signaling (IHH, HHIP, PTCH1), extracellular matrix (EFEMP1, ADAMTSL3, ACAN) and cancer (CDK6, HMGA2, DLEU7) pathways, and provide new insights into human growth and developmental processes. Finally, our results provide insights into the genetic architecture of a classic quantitative trait.

Blood pressure loci identified with a gene-centric array.

Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.

Blood pressure loci identified with a gene-centric array.

Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.

Genetic loci influencing kidney function and chronic kidney disease.

Using genome-wide association, we identify common variants at 2p12-p13, 6q26, 17q23 and 19q13 associated with serum creatinine, a marker of kidney function (P = 10(-10) to 10(-15)). Of these, rs10206899 (near NAT8, 2p12-p13) and rs4805834 (near SLC7A9, 19q13) were also associated with chronic kidney disease (P = 5.0 x 10(-5) and P = 3.6 x 10(-4), respectively). Our findings provide insight into metabolic, solute and drug-transport pathways underlying susceptibility to chronic kidney disease.

Lusignan

Le projet "Regeneration" dirigé par Daid Wallace propose une histoire littéraire de la seconde moitié du XIVe siècle sous forme d'itinéraires. Pour chaque lieu sont établis les liens entre l'histoire et la littérature.

Transhepatic ipsilateral right portal vein embolization extended to segment IV: improving hypertrophy and resection outcomes with spherical particles and coils.

PURPOSE: To analyze outcomes after right portal vein embolization extended to segment IV (right PVE + IV) before extended right hepatectomy, including liver hypertrophy, resection rates, and complications after embolization and resection, and to assess differences in outcomes with two different particulate embolic agents. MATERIALS AND METHODS: Between 1998 and 2004, transhepatic ipsilateral right PVE + IV with particles and coils was performed in 44 patients with malignant hepatobiliary disease, including metastases (n = 24), biliary cancer (n = 14), and hepatocellular carcinoma (n = 6). Right PVE + IV was considered if the future liver remnant (FLR; segments II/III with or without I) was less than 25% of the total estimated liver volume (TELV). Tris-acryl microspheres (100-700 microm; n = 21) or polyvinyl alcohol (PVA) particles (355-1,000 microm; n = 23) were administered in a stepwise fashion. Smaller particles were used to occlude distal branches, followed by larger particles to occlude proximal branches until near-complete stasis. Coils were then placed in secondary portal branches. Computed tomographic volumetry was performed before and 3-4 weeks after right PVE + IV to assess FLR hypertrophy. Liver volumes and postembolization and postoperative outcomes were measured. RESULTS: After right PVE + IV with PVA particles, FLR volume increased 45.5% +/- 40.9% and FLR/TELV ratio increased 6.9% +/- 5.6%. After right PVE + IV with tris-acryl microspheres, FLR volume increased 69.0% +/- 30.7% and FLR/TELV ratio increased 9.7% +/- 3.3%. Differences in FLR volume (P = .0011), FLR/TELV ratio (P = .027), and resection rates (P = .02) were statistically significant. Seventy-one percent of patients underwent extended right hepatectomy (86% after receiving tris-acryl microspheres, 57% after receiving PVA). Thirteen patients (29%) did not undergo resection (extrahepatic spread [n = 9], inadequate hypertrophy [n = 3], other reasons [n = 1]). No patient developed postembolization syndrome or progressive liver insufficiency after embolization or resection. One death after resection occurred as a result of sepsis and hemorrhage. Median hospital stays were 1 day after right PVE + IV and 7 days after resection. CONCLUSION: Transhepatic ipsilateral right PVE + IV with use of particles and coils is a safe, effective method for inducing contralateral hypertrophy before extended right hepatectomy. Embolization with small spherical particles provides improved hypertrophy and resection rates compared with larger, nonspherical particles.

'Dusky Sally': La femme esclave entre histoire et fiction

Au travers d'une étude parallèle de deux femmes esclaves - l'une figure historique, l'autre personnage de fiction - et de la façon dont elles ont été inscrites dans, et surtout hors du récit historique et littéraire américain, cet essai vise d'une part à interroger les biais et les limitations de l'historiographie traditionnelle américaine dans sa représentation de l'esclave, et d'autre part à évaluer le rôle de la littérature dans la critique et la « re-vision » du discours historique. Le roman de Gloria Naylor Mama Day (1988) offre ainsi un détour intéressant pour mettre en lumière les processus discursifs, épistémologiques et idéologiques qui ont permis et perpétué l'absence de femmes comme Sally Hemings, esclave et maîtresse supposée de Thomas Jefferson, dans l'Histoire américaine.Through a parallel discussion of two slave women - the first a historical figure, the second a fiction character - and of the way they have been inscribed in, and indeed out of, the historical and fictional narrative of America's past, this essay aims both to interrogate the biases and limitations of traditional American historiography in its representation of slaves and to evaluate the role of literature in the critique and "re-vision" of historical discourse. Gloria Naylor's novel Mama Day (1988) thus provides an interesting detour to cast light on the discursive, epistemological and ideological processes that have permitted and perpetuated the absence from American History of women like Sally Hemings, Thomas Jefferson's slave and supposed mistress.

The Paediatric Rheumatology International Trials Organisation provisional criteria for the evaluation of response to therapy in juvenile dermatomyositis.

OBJECTIVE: To develop a provisional definition for the evaluation of response to therapy in juvenile dermatomyositis (DM) based on the Paediatric Rheumatology International Trials Organisation juvenile DM core set of variables. METHODS: Thirty-seven experienced pediatric rheumatologists from 27 countries achieved consensus on 128 difficult patient profiles as clinically improved or not improved using a stepwise approach (patient's rating, statistical analysis, definition selection). Using the physicians' consensus ratings as the "gold standard measure," chi-square, sensitivity, specificity, false-positive and-negative rates, area under the receiver operating characteristic curve, and kappa agreement for candidate definitions of improvement were calculated. Definitions with kappa values >0.8 were multiplied by the face validity score to select the top definitions. RESULTS: The top definition of improvement was at least 20% improvement from baseline in 3 of 6 core set variables with no more than 1 of the remaining worsening by more than 30%, which cannot be muscle strength. The second-highest scoring definition was at least 20% improvement from baseline in 3 of 6 core set variables with no more than 2 of the remaining worsening by more than 25%, which cannot be muscle strength (definition P1 selected by the International Myositis Assessment and Clinical Studies group). The third is similar to the second with the maximum amount of worsening set to 30%. This indicates convergent validity of the process. CONCLUSION: We propose a provisional data-driven definition of improvement that reflects well the consensus rating of experienced clinicians, which incorporates clinically meaningful change in core set variables in a composite end point for the evaluation of global response to therapy in juvenile DM.

Splenic arterial interventions: anatomy, indications, technical considerations, and potential complications.

Splenic arterial interventions are increasingly performed to treat various clinical conditions, including abdominal trauma, hypersplenism, splenic arterial aneurysm, portal hypertension, and splenic neoplasm. When clinically appropriate, these procedures may provide an alternative to open surgery. They may help to salvage splenic function in patients with posttraumatic injuries or hypersplenism and to improve hematologic parameters in those who otherwise would be unable to undergo high-dose chemotherapy or immunosuppressive therapy. Splenic arterial interventions also may be performed to exclude splenic artery aneurysms from the parent vessel lumen and prevent aneurysm rupture; to reduce portal pressure and prevent sequelae in patients with portal hypertension; to treat splenic artery steal syndrome and improve liver perfusion in liver transplant recipients; and to administer targeted treatment to areas of neoplastic disease in the splenic parenchyma. As the use of splenic arterial interventions increases in interventional radiology practice, clinicians must be familiar with the splenic vascular anatomy, the indications and contraindications for performing interventional procedures, the technical considerations involved, and the potential use of other interventional procedures, such as radiofrequency ablation, in combination with splenic arterial interventions. Familiarity with the complications that can result from these interventional procedures, including abscess formation and pancreatitis, also is important.

Proto-South-East Asia as a trigger of early angiosperm diversification

Darwin described as an 'abominable mystery' the abrupt origin of angiosperms in the mid-Cretaceous and the high diversification rates in their early history. The father of evolutionary theory could not fathom this rapid diversification and rather invoked that 'there was during long ages a small isolated continent in the S. hemisphere, which served as the birthplace of the higher plants'. In this essay, we comment on the spatial origin of angiosperms, but focus primarily on understanding the abiotic factors that promoted the early diversification of angiosperms by reviewing palaeobotanical, palaeogeographical, phylogenetics and biogeographical evidence. We argue that islands located in the region today occupied by South-East Asia played a major role in angiosperm diversification during the Late Jurassic and Early Cretaceous.