HTTP 200 OK
Allow: GET, HEAD, OPTIONS
Content-Type: application/json
Vary: Accept
{
"count": 127182,
"next": "https://api-test.medunigraz.at/v1/research/search/publication/?format=api&limit=20&offset=126800",
"previous": "https://api-test.medunigraz.at/v1/research/search/publication/?format=api&limit=20&offset=126760",
"results": [
{
"text": "\n147741\nEvidence from the very beginning: endoglandular trophoblasts penetrate and replace uterine glands in situ and in vitro.\n\nMoser, G\n\nWeiss, G\n\nGauster, M\n\nSundl, M\n\nHuppertz, B\n\nBeiträge in Fachzeitschriften\nISI:000368437300008\n26493408.0\n10.1093/humrep/dev266\nPMC4719185\nHow is histiotrophic nutrition of the embryo secured during the first trimester of pregnancy?\n Rather than specifically focusing on invasion into spiral arteries, extravillous trophoblasts also invade into uterine glands (endoglandular trophoblast) from the very beginning and open them toward the intervillous space.\n Extravillous trophoblasts can be found in close contact and within the lumen of uterine glands, sometimes replacing glandular epithelial cells.\n As well as extensive screening of specimens from first trimester placentation sites in situ we used a previously established three-dimensional co-culture in vitro model system of first trimester villous explants with non-invaded decidua parietalis.\n First trimester placentas were obtained from elective terminations of pregnancies (n = 48) at 5-11 weeks of gestational age. A subset was processed for confrontation co-culture (n = 31). Invaded decidua basalis was obtained from 20 placentas. All tissues were sectioned, subsequently immunostained and immunodoublestained with antibodies against keratin 7 (KRT7), major histocompatibility complex, class I, G (HLA-G), matrix metallopeptidase 9 (MMP9), von Willebrand factor (VWF) and the appropriate Immunoglobulin G (IgG) negative controls. Replacement of endothelial/epithelial cells by extravillous trophoblasts was quantified semi-quantitatively. Additionally, hematoxylin and eosin-stained archival specimens from early implantation sites were assessed.\n The earliest available specimen was from around Day 10 after conception; already at this stage trophoblasts had penetrated into uterine glands and had started to replace the epithelium of the glands. Endoglandular trophoblasts replaced uterine glands in vitro and in situ and could be found in the lumen of invaded glands. Quantitative analysis revealed significantly more replacement of epithelial cells in glands (63.8 ± 22.1%) compared with endothelial cells in vessels (26.4 ± 8.8%). Accumulated detached glandular epithelial cells could be repeatedly observed in the lumen of invaded glands. Additionally, in areas of trophoblast invasion the glandular epithelium seemed to be completely disintegrated compared with glandular epithelium in the non-invaded parts of the decidua. Whole tissue specimens were used in vitro and in situ instead of cell lines; these systems mostly maintain the context of the in vivo situation.\n This is a descriptive study supported by in vitro experiments. However, a histological section will always only be a snapshot and quantification from histological sections has its limitations.\n This study further strengthens the hypothesis of histiotrophic nutrition of the embryo prior to the establishment of the maternal blood flow toward the placenta. Invasion of uterine glands by endoglandular trophoblasts may have more impact on the outcome of early pregnancy than assumed up to now.\n © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.\n\nGauster, Martin\n\nHuppertz, Berthold\n\nMoser, Gerit\n\nSundl, Monika\n\n\n"
},
{
"text": "\n136187\nImmediate breast reconstruction - a review of indications, techniques and results\n\nFrey, M\n\nSchrogendorfer, K\n\nKropf, N\n\nKarle, B\n\nHaslik, W\n\nLammer, C\n\nBeiträge in Fachzeitschriften\nISI:000256864500006\nNone\n10.1007/s10353-007-0346-0\nNone\nBackground: It has only been during the last decade that immediate breast reconstruction has become accepted as an integrated part of the treatment concept of breast cancer in Austria. The involvement of the plastic surgeon in the planning of treatment at the time of the diagnosis of breast cancer is still far from standard. The aim of this review article is to make it more widely known that immediate breast reconstruction is a choice for the majority of women undergoing complete breast removal or greater disfiguring resections of the breast gland and does not have any negative influence on the oncological late outcome. Methods: On the basis of a review of the international literature and our own prospective studies on breast reconstruction, the actual indications and contraindications for immediate reconstruction are outlined. Having analysed patients of the Division of Plastic and Reconstructive Surgery at the Department of Surgery at the Medical University of Vienna for the last 15 years, the evolution of immediate breast reconstruction and of the methods applied is described. Special attention is paid to the biology and the course of the tumour disease, to the possible interference with adjuvant therapies, to the influence of age, and to the selection of the operative technique depending the individual situation. Results: All major studies of local recurrence rate and survival rate after immediate breast reconstruction have ruled out any negative effect on the oncological course. Therefore information on the possibility of immediate breast reconstruction has to be passed on to every breast cancer patient at the time of diagnosis. This information has to include the whole range of techniques offered by plastic surgeons for breast preserving surgery, from the local glandular mammaplasty, the reduction mammaplasty for tumor resections in bigger breasts, the partial reconstruction with a myocutaneous latissimus dorsi flap to the reconstruction with a breast implant. In the case of a mastectomy, usually as skin-sparing mastectomy, again the whole spectrum of reconstructive approaches has to be discussed with the patient from the very beginning: the Deep Inferior Epigastric Perforator Flap (DIEP - flap), the Transverse Rectus Abdominis Myocutaneous Flap (TRAM - flap), and the extended latissimus dorsi myocutaneous flap for autologous breast reconstruction, or with the involvement of a breast implant. The immediate breast reconstruction with autologous tissue has become the procedure of first choice, because the disadvantages of the use of implants in the case of necessary postoperative irradiation therapy can be avoided. Conclusions: Information on all reconstructive possibilities should be passed on by the plastic surgeon to the patient needing a resection of the whole or a greater part of the breast because of breast cancer at the time of diagnosis so as not to miss the chance of immediate reconstruction if preferred by the patient.\n\n\n"
},
{
"text": "\n143525\nGenome-Wide Association Study for Circulating Tissue Plasminogen Activator Levels and Functional Follow-Up Implicates Endothelial STXBP5 and STX2.\n\nHuang, J\n\nHuffman, JE\n\nYamkauchi, M\n\nTrompet, S\n\nAsselbergs, FW\n\nSabater-Lleal, M\n\nTregouet, DA\n\nChen, WM\n\nSmith, NL\n\nKleber, ME\n\nShin, SY\n\nBecker, DM\n\nTang, WH\n\nDehghan, A\n\nJohnson, AD\n\nTruong, V\n\nFolkersen, L\n\nYang, Q\n\nOudot-Mellkah, T\n\nBuckley, BM\n\nMoore, JH\n\nWilliams, FMK\n\nCampbell, H\n\nSilbernagel, G\n\nVitart, V\n\nRudan, I\n\nTofler, GH\n\nNavis, GJ\n\nDeStefano, A\n\nWright, AF\n\nChen, MH\n\nde Craen, AJM\n\nWorrall, BB\n\nRudnicka, AR\n\nRumley, A\n\nBookman, EB\n\nPsaty, BM\n\nChen, F\n\nKeene, KL\n\nFranco, OH\n\nBohm, BO\n\nUitterlinden, AG\n\nCarter, AM\n\nJukema, JW\n\nSattar, N\n\nBis, JC\n\nIkram, MA\n\nSale, MM\n\nMcKnight, B\n\nFornage, M\n\nFord, I\n\nTaylor, K\n\nSlagboom, PE\n\nMcArdle, WL\n\nHsu, FC\n\nFranco-Cereceda, A\n\nGoodall, AH\n\nYanek, LR\n\nFurie, KL\n\nCushman, M\n\nHofman, A\n\nWitteman, JCM\n\nFolsom, AR\n\nBasu, S\n\nMatijevic, N\n\nvan Gilst, WH\n\nWilson, JF\n\nWestendorp, RGJ\n\nKathiresan, S\n\nReilly, MP\n\nTracy, RP\n\nPolasek, O\n\nWinkelmann, BR\n\nGrant, PJ\n\nHillege, HL\n\nCambien, F\n\nStott, DJ\n\nLowe, GD\n\nSpector, TD\n\nMeigs, JB\n\nMarz, W\n\nEriksson, P\n\nBecker, LC\n\nMorange, PE\n\nSoranzo, N\n\nWilliams, SM\n\nHayward, C\n\nvan der Harst, P\n\nHamsten, A\n\nLowenstein, CJ\n\nStrachan, DP\n\nO'Donnell, CJ\n\n\n\nBeiträge in Fachzeitschriften\nISI:000334373500021\n24578379.0\n10.1161/ATVBAHA.113.302088\nPMC4009733\nTissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for endogenous fibrinolysis. In some populations, elevated plasma levels of tPA have been associated with myocardial infarction and other cardiovascular diseases. We conducted a meta-analysis of genome-wide association studies to identify novel correlates of circulating levels of tPA.\n Fourteen cohort studies with tPA measures (N=26 929) contributed to the meta-analysis. Three loci were significantly associated with circulating tPA levels (P<5.0×10(-8)). The first locus is on 6q24.3, with the lead single nucleotide polymorphism (SNP; rs9399599; P=2.9×10(-14)) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739; P=1.3×10(-9)) is intronic to POLB and <200 kb away from the tPA encoding the gene PLAT. We identified a nonsynonymous SNP (rs2020921) in modest linkage disequilibrium with rs3136739 (r(2)=0.50) within exon 5 of PLAT (P=2.0×10(-8)). The third locus is on 12q24.33, with the lead SNP (rs7301826; P=1.0×10(-9)) within intron 7 of STX2. We further found evidence for the association of lead SNPs in STXBP5 and STX2 with expression levels of the respective transcripts. In in vitro cell studies, silencing STXBP5 decreased the release of tPA from vascular endothelial cells, whereas silencing STX2 increased the tPA release. Through an in silico lookup, we found no associations of the 3 lead SNPs with coronary artery disease or stroke.\n We identified 3 loci associated with circulating tPA levels, the PLAT region, STXBP5, and STX2. Our functional studies implicate a novel role for STXBP5 and STX2 in regulating tPA release.\n\nMärz, Winfried\n\nSilbernagel, Günther\n\n\n"
},
{
"text": "\n84812\nPrognostic value of renal vein and inferior vena cava involvement in renal cell carcinoma.\n\nWagner, B\n\nPatard, JJ\n\nMéjean, A\n\nBensalah, K\n\nVerhoest, G\n\nZigeuner, R\n\nFicarra, V\n\nTostain, J\n\nMulders, P\n\nChautard, D\n\nDescotes, JL\n\nde la Taille, A\n\nSalomon, L\n\nPrayer-Galetti, T\n\nCindolo, L\n\nValéri, A\n\nMeyer, N\n\nJacqmin, D\n\nLang, H\n\nBeiträge in Fachzeitschriften\nISI:000262775400027\n18692951.0\n10.1016/j.eururo.2008.07.053\nNone\nBackground: The prognostic significance of venous tumor thrombus extension in patients with renal cell carcinoma (RCC) is a matter of many controversies in the current literature. Objective: To evaluate the prognostic role of inferior vena cava (IVC) involvement in a large series of pT3b and pT3c RCCs. Design, setting, and participants: A total of 1192 patients from 13 European institutions underwent a radical nephrectomy for pT3b and pT3c RCC between 1982 and 2003. The patients were evaluated in a retrospective manner. Age, gender, clinical symptoms, Eastern Cooperative Oncology Group (ECOG) performance status, TNM stage, tumor size, adrenal invasion, perinephric fat invasion, histological type, and Fuhrman grade were reviewed. The log-rank and Cox uni- and multivariate regression analyses were used to evaluate prognostic factors for overall survival. Measurements: Overall survival and prognostic factors for overall survival in patients with RCC extending to the renal vein (RV) or to the IVC. Results and limitations: The median follow-up was 61.4 mo (56.3-66.5 mo). The. mean age was 63.2 yr. The mean tumor size was 8.9 cm. Group 1 (Gr 1) included 933 patients with a renal vein tumor thrombus (78.3%), Group 2 (Gr 2) included 196 patients with a subdiaphragmatic IVC tumor thrombus (16.4%), and Group 3 (Gr 3) included 63 patients with a supradiaphragmatic IVC tumor thrombus (5.3%). Median survival was 52 mo for Gr 1, 25.8 mo for Gr 2, and 18 mo for Gr 3. In univariate analysis, Gr 1 had a significantly better overall survival than Gr 2 (p < 0.001) and Gr 3 (p < 0.001). No significant difference in survival was noted between Gr 2 and Gr 3 (p = 0.613). Prognostic factors for overall survival in univariate analysis were clinical symptoms (p < 0.001), tumor size (p < 0.001), perinephric fat invasion (p < 0.001), Fuhrman grade (p < 0.001), histological type (p = 0.021), lymph node invasion (p < 0.001), and distant metastasis (p < 0.001). Independent prognostic factors in multivariate analysis were tumor size (p = 0.013), perinephric fat invasion (p = 0.003), lymph node invasion (p < 0.001), distant metastasis (p < 0.001), and IVC invasion (p = 0.008). Conclusions: The level of tumor thrombus in the IVC does not significantly affect long-term overall survival in patients with renal cell carcinoma. The overall survival was statistically different for patients with a tumor thrombus in the RV compared to those with IVC involvement. This has to be considered for the next revision of the TNM system, and the pT3b and pT3c stages have to be redesigned. (C) 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved.\n\nZigeuner, Richard\n\n\n"
},
{
"text": "\n66265\nHip and nonvertebral fracture prediction in nursing home patients: role of bone ultrasound and bone marker measurements.\n\nDobnig, H\n\nPiswanger-Sölkner, JC\n\nObermayer-Pietsch, B\n\nTiran, A\n\nStrele, A\n\nMaier, E\n\nMaritschnegg, P\n\nRiedmüller, G\n\nBrueck, C\n\nFahrleitner-Pammer, A\n\nBeiträge in Fachzeitschriften\nISI:000246221200020\n17311861.0\n10.1210/jc.2006-2079\nNone\nCONTEXT: Absolute fracture risk in nursing home patients is the highest among the communities studied. Screening for high-risk patients in such an environment is usually difficult. OBJECTIVE: The objective was to investigate whether quantitative bone ultrasound measurements and/or markers of bone turnover/metabolism help in predicting which patients will incur hip or nonvertebral fractures. DESIGN, SETTING, AND PARTICIPANTS: In this prospective study, mobile teams enrolled 1664 female patients from 95 nursing homes in Austria. MAIN OUTCOME MEASURES: Calcaneal stiffness (n = 1117), radial speed of sound (SOS) (n = 1332), and phalangeal SOS (n = 1498) measurements were performed at baseline. Serum samples (n = 960) were analyzed for serum calcium and phosphate, 25 hydroxyvitamin D, PTH, osteocalcin, C-terminal telopeptide crosslinks, and osteoprotegerin (OPG). Patients were prospectively followed for hip and other nonvertebral fractures for 2 yr. RESULTS: A total of 117 hip fractures and 269 nonvertebral fractures developed during a mean observation period of 2 yr. Prevalence of vitamin D deficiency and secondary hyperparathyroidism was high. A history of a past fracture was significantly associated with a hazard ratio (HR) of 1.47 (95% confidence interval, 1.01-2.15) and 1.65 (1.26-2.16) for the development of hip and nonvertebral fractures, respectively. Cox regression analysis revealed a multivariate adjusted elevation in both hip [HR 1.30 (1.12-1.43)] and nonvertebral [HR 1.14 (1.02-1.25)] fracture risk for each sd decrease in calcaneal stiffness. Patients in the lowest quartile for calcaneal stiffness Z-score had 2.5 and 1.2 times higher rates of hip and nonvertebral fractures when compared with patients in the highest quartile. Fracture rates were not statistically associated with baseline radial or phalangeal SOS measurements or with serum osteocalcin, C-terminal telopeptide crosslinks, and OPG concentrations. When adjusted for bone mass, higher serum OPG levels were associated with fewer hip as well as nonvertebral fractures [HR 0.85 (0.73-0.99) and 0.89 (0.80-0.99) per increment of 1]. Higher serum phosphate levels indicated an increased hip [HR 1.54 (1.07-2.21)] and nonvertebral fracture risk [HR 1.40 (1.10-1.78) per increase of 1 mg/dl]. Body mass index was protective of hip fractures [HR 0.94 (0.90-0.98) per increase of 1] as well as medication with acetylsalicylic acid [HR 0.59 (0.36-0.95) for hip and 0.72 (0.52-0.99) for nonvertebral fractures]. In contrast, current use of glucocorticoids [HR 5.65 (1.77-18.0)] and opiates [HR 1.85 (1.18-2.92)] exerted a negative effect on prospective hip fracture risk. CONCLUSION: Calcaneal stiffness measurements proved to be useful in predicting hip fractures and to a lesser extent nonvertebral fractures in nursing home residents. Radial and phalangeal bone ultrasound measurements and baseline markers of bone turnover, however, were not indicative of future fracture risk in this population.\n\nFahrleitner-Pammer, Astrid\n\nGroselj-Strele, Andrea\n\nObermayer-Pietsch, Barbara\n\nPiswanger-Solkner, Claudia\n\n\n"
},
{
"text": "\n147543\nPositive family history of colorectal cancer in a general practice setting [FRIDA.Frankfurt]: study protocol of a of a cross-sectional study.\n\nSiebenhofer, A\n\nPlath, J\n\nTaubenroth, M\n\nSinger, S\n\nHechtner, M\n\nDahlhaus, A\n\nRauck, S\n\nSchulz-Rothe, S\n\nKoné, I\n\nGerlach, FM\n\nBeiträge in Fachzeitschriften\nISI:000360110900001\n26314581.0\n10.1186/s12885-015-1600-7\nPMC4552264\nAlthough the risk of developing colorectal cancer (CRC) is 2-4 times higher in case of a positive family history, risk-adapted screening programs for family members related to CRC- patients do not exist in the German health care system. CRC screening recommendations for persons under 55 years of age that have a family predisposition have been published in several guidelines. The primary aim of this study is to determine the frequency of positive family history of CRC (1st degree relatives with CRC) among 40-54 year old persons in a general practitioner (GP) setting in Germany. Secondary aims are to detect the frequency of occurrence of colorectal neoplasms (CRC and advanced adenomas) in 1st degree relatives of CRC patients and to identify the variables (e.g. demographic, genetic, epigenetic and proteomic characteristics) that are associated with it. This study also explores whether evidence-based information contributes to informed decisions and how screening participation correlates with anxiety and (anticipated) regret.\n Prior to the beginning of the study, the GP team (GP and one health care assistant) in around 50 practices will be trained, and about 8, 50 persons that are registered with them will be asked to complete the "Network against colorectal cancer" questionnaire. The 10% who are expected to have a positive family history will then be invited to give their informed consent to participate in the study. All individuals with positive family history will be provided with evidence-based information and prevention strategies. We plan to examine each participant's family history of CRC in detail and to collect information on further variables (e.g. demographics) associated with increased risk. Additional stool and blood samples will be collected from study-participants who decide to undergo a colonoscopy (n ~ 350) and then analyzed at the German Cancer Research Center (DKFZ) Heidelberg to see whether further relevant variables are associated with an increased risk of CRC. One screening list and four questionnaires will be used to collect the data, and a detailed statistical analysis plan will be provided before the database is closed (expected to be June 30, 2015).\n It is anticipated that when persons with a family history of colorectal cancer have been provided with professional advice by the practice team, there will be an increase in the availability of valid information on the frequency of affected individuals and an increase in the number of persons making informed decisions. We also expect to identify further variables that are associated with colorectal cancer. This study therefore has translational relevance from lab to practice.\n German Clinical Trials Register DRKS00006277.\n\nSiebenhofer-Kroitzsch, Andrea\n\n\n"
},
{
"text": "\n187197\nInterdisciplinary Radical "En-Bloc" Resection of Ewing Sarcoma of the Chest Wall and Simultaneous Chest Wall Repair Achieves Excellent Long-Term Survival in Children and Adolescents.\n\nBasharkhah, A\n\nLackner, H\n\nKarastaneva, A\n\nBergovec, M\n\nSpendel, S\n\nCastellani, C\n\nSorantin, E\n\nBenesch, M\n\nLiegl-Atzwanger, B\n\nSmolle-Jüttner, FM\n\nUrban, C\n\nHöllwarth, M\n\nSinger, G\n\nTill, H\n\nBeiträge in Fachzeitschriften\nISI:000634102500001\n33791262.0\n10.3389/fped.2021.661025\nPMC8005523\nIntroduction: Ewing sarcomas of the chest wall, historically known as "Askin tumors" represent highly aggressive pediatric malignancies with a reported 5-year survival ranging only between 40 and 60% in most studies. Multimodal oncological treatment according to specific Ewing sarcoma protocols and radical "en-bloc" resection with simultaneous chest wall repair are key factors for long-term survival. However, the surgical complexity depends on tumor location and volume and potential infiltrations into lung, pericardium, diaphragm, esophagus, spine and major vessels. Thus, the question arises, which surgical specialties should join their comprehensive skills when approaching a child with Ewing sarcoma of the chest wall. Patients and Methods: All pediatric patients with Ewing sarcomas of the chest wall treated between 1990 and 2020 were analyzed focusing on complete resection, chest wall reconstruction, surgical complications according to Clavien-Dindo (CD) and survival. Patients received neo-adjuvant chemotherapy according to the respective Ewing sarcoma protocols. Depending on tumor location and organ infiltration, a multi-disciplinary surgical team was orchestrated to perform radical en-bloc resection and simultaneous chest wall repair. Results: Thirteen consecutive patients (seven boys and six girls) were included. Median age at presentation was 10.9 years (range 2.2-21 years). Neo-adjuvant chemotherapy (n = 13) and irradiation (n = 3) achieved significant reduction of the median tumor volume (305.6 vs. 44 ml, p < 0.05). En-bloc resection and simultaneous chest wall reconstruction was achieved without major complications despite multi-organ involvement. Postoperatively, one patient with infiltration of the costovertebral joint and laminectomy required surgical re-intervention (CD IIIb). 11/13 patients were treated with clear resections margins (R1 resection in one patient with infiltration of the costovertebral joint and marginal resection <1 mm in one child with multiple pulmonary metastases). All patients underwent postoperative chemotherapy; irradiation was performed in four children. Two deaths occurred 18 months and 7.5 years after diagnosis, respectively. Median follow-up for the remaining patients was 8.8 years (range: 0.9-30.7 years). The 5-year survival rate was 89% and the overall survival 85%. Conclusion: EWING specific oncological treatment and multi-disciplinary surgery performing radical en-bloc resections and simultaneous chest wall repair contribute to an improved survival of children with Ewing sarcoma of the chest wall.\n Copyright © 2021 Basharkhah, Lackner, Karastaneva, Bergovec, Spendel, Castellani, Sorantin, Benesch, Liegl-Atzwanger, Smolle-Jüttner, Urban, Höllwarth, Singer and Till.\n\nBasharkhah, Alireza\n\nBenesch, Martin\n\nBergovec, Marko\n\nCastellani, Christoph\n\nHöllwarth, Michael\n\nKarastaneva, Anna\n\nLackner, Herwig\n\nLiegl-Atzwanger, Bernadette\n\nSinger, Georg\n\nSmolle-Juettner, Freyja-Maria\n\nSorantin, Erich\n\nSpendel, Stephan\n\nTill, Holger\n\nUrban, Ernst-Christian\n\n\n"
},
{
"text": "\n91967\nGenetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data.\n\nVasan, RS\n\nGlazer, NL\n\nFelix, JF\n\nLieb, W\n\nWild, PS\n\nFelix, SB\n\nWatzinger, N\n\nLarson, MG\n\nSmith, NL\n\nDehghan, A\n\nGrosshennig, A\n\nSchillert, A\n\nTeumer, A\n\nSchmidt, R\n\nKathiresan, S\n\nLumley, T\n\nAulchenko, YS\n\nKönig, IR\n\nZeller, T\n\nHomuth, G\n\nStruchalin, M\n\nAragam, J\n\nBis, JC\n\nRivadeneira, F\n\nErdmann, J\n\nSchnabel, RB\n\nDörr, M\n\nZweiker, R\n\nLind, L\n\nRodeheffer, RJ\n\nGreiser, KH\n\nLevy, D\n\nHaritunians, T\n\nDeckers, JW\n\nStritzke, J\n\nLackner, KJ\n\nVölker, U\n\nIngelsson, E\n\nKullo, I\n\nHaerting, J\n\nO'Donnell, CJ\n\nHeckbert, SR\n\nStricker, BH\n\nZiegler, A\n\nReffelmann, T\n\nRedfield, MM\n\nWerdan, K\n\nMitchell, GF\n\nRice, K\n\nArnett, DK\n\nHofman, A\n\nGottdiener, JS\n\nUitterlinden, AG\n\nMeitinger, T\n\nBlettner, M\n\nFriedrich, N\n\nWang, TJ\n\nPsaty, BM\n\nvan Duijn, CM\n\nWichmann, HE\n\nMunzel, TF\n\nKroemer, HK\n\nBenjamin, EJ\n\nRotter, JI\n\nWitteman, JC\n\nSchunkert, H\n\nSchmidt, H\n\nVölzke, H\n\nBlankenberg, S\n\nBeiträge in Fachzeitschriften\nISI:000267696500026\n19584346.0\n10.1001/jama.2009.978-a\nPMC2975567\nCONTEXT: Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease. OBJECTIVE: To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples. DESIGN, SETTING, AND PARTICIPANTS: Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort. MAIN OUTCOME MEASURES: Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size. RESULTS: In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance). CONCLUSIONS: We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.\n\nSchmidt, Helena\n\nSchmidt, Reinhold\n\nWatzinger, Norbert\n\nZweiker, Robert\n\n\n"
},
{
"text": "\n149394\nSexual Dysfunction Related to Drugs: a Critical Review. Part V: α-Blocker and 5-ARI Drugs.\n\nLa Torre, A\n\nGiupponi, G\n\nDuffy, D\n\nConca, A\n\nCai, T\n\nScardigli, A\n\nBeiträge in Fachzeitschriften\nISI:000368945800002\n26569417.0\n10.1055/s-0035-1565100\nNone\nSexual dysfunction is a potential side effect of BPH (benign prostatic hyperplasia) and LUTS (lower urinary tract symptoms) drugs: this article is a critical review of the current literature. Many studies have been published on this topic. Methodological flaws limit the conclusions of these studies, mainly because of the lack of diagnostic criteria for ejaculatory and sexual desire dysfunction. Few of these studies are RCTs. The α-blocker (also called α1-adrenergic antagonist, alpha-adrenoceptor antagonist, alpha-blocker or AB) and 5-ARI (also called 5α-reductase inhibitor or testosterone-5-alpha reductase inhibitor) drugs can in particular cause erectile dysfunction, ejaculatory disorders and reduction of sexual desire. The sexual side effect profile of these drugs is different. Among the α-blockers, silodosin appears have the highest incidence of ejaculatory disorders. Persistent sexual side effects after discontinuation of finasteride has recently been reported, however further studies are needed to clarify the true incidence and the significance of this finding. It is desirable that future studies include validated tools to assess and diagnose sexual dysfunction induced by these medications, especially for ejaculation and sexual desire disorders. Only a small amount of research has intentionally set out to investigate sexual dysfunction caused by α-blocker and 5-ARI drugs: studies to specifically assess sexual dysfunction induced by these drugs are needed. Further studies are also needed to assess in the long term the role of combined therapy of phosphodiesterase type 5 inhibitors and α-blockers or 5-ARIs in treating LUTS/BPH.\n This study was conducted in 2014 using the paper and electronic resources of the library of the "Azienda Provinciale per i Servizi Sanitari (APSS)" in Trento, Italy (http://atoz.ebsco.com/Titles/2793). The library has access to a wide range of databases including DYNAMED, MEDLINE Full Text, CINAHL Plus Full Text, The Cochrane Library, Micromedex healthcare series, BMJ Clinical Evidence. The full list of available journals can be viewed at http://atoz.ebsco.com/Titles/2793, or at the APSS web site (http://www.apss.tn.it). In completing this review, a literature search was conducted using the key words "benign prostatic hyperplasia drugs", "lower urinary tract symptoms drugs", "α-blockers", "5-ARIs", "sexual dysfunction", "sexual side effects", "treatment-emergent sexual dysfunction", "phosphodiesterase type 5 (PDE5) inhibitors". All resulting listed articles were reviewed. Studies published between 2002 and December 2014 were included in the review. We included all studies that explicitly reported data on sexual dysfunction during treatment with α-blockers and 5-ARIs. We also reviewed studies that have evaluated the use of phosphodiesterase type 5 (PDE5) inhibitors in combination with these drugs. The purpose was to identify possible intervention strategies for sexual dysfunction related to these drugs.\n © Georg Thieme Verlag KG Stuttgart · New York.\n\n\n"
},
{
"text": "\n181865\nGenome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure.\n\nShah, S\n\nHenry, A\n\nRoselli, C\n\nLin, H\n\nSveinbjörnsson, G\n\nFatemifar, G\n\nHedman, ÅK\n\nWilk, JB\n\nMorley, MP\n\nChaffin, MD\n\nHelgadottir, A\n\nVerweij, N\n\nDehghan, A\n\nAlmgren, P\n\nAndersson, C\n\nAragam, KG\n\nÄrnlöv, J\n\nBackman, JD\n\nBiggs, ML\n\nBloom, HL\n\nBrandimarto, J\n\nBrown, MR\n\nBuckbinder, L\n\nCarey, DJ\n\nChasman, DI\n\nChen, X\n\nChen, X\n\nChung, J\n\nChutkow, W\n\nCook, JP\n\nDelgado, GE\n\nDenaxas, S\n\nDoney, AS\n\nDörr, M\n\nDudley, SC\n\nDunn, ME\n\nEngström, G\n\nEsko, T\n\nFelix, SB\n\nFinan, C\n\nFord, I\n\nGhanbari, M\n\nGhasemi, S\n\nGiedraitis, V\n\nGiulianini, F\n\nGottdiener, JS\n\nGross, S\n\nGuðbjartsson, DF\n\nGutmann, R\n\nHaggerty, CM\n\nvan der Harst, P\n\nHyde, CL\n\nIngelsson, E\n\nJukema, JW\n\nKavousi, M\n\nKhaw, KT\n\nKleber, ME\n\nKøber, L\n\nKoekemoer, A\n\nLangenberg, C\n\nLind, L\n\nLindgren, CM\n\nLondon, B\n\nLotta, LA\n\nLovering, RC\n\nLuan, J\n\nMagnusson, P\n\nMahajan, A\n\nMargulies, KB\n\nMärz, W\n\nMelander, O\n\nMordi, IR\n\nMorgan, T\n\nMorris, AD\n\nMorris, AP\n\nMorrison, AC\n\nNagle, MW\n\nNelson, CP\n\nNiessner, A\n\nNiiranen, T\n\nO'Donoghue, ML\n\nOwens, AT\n\nPalmer, CNA\n\nParry, HM\n\nPerola, M\n\nPortilla-Fernandez, E\n\nPsaty, BM\n\nRegeneron Genetics Center\n\nRice, KM\n\nRidker, PM\n\nRomaine, SPR\n\nRotter, JI\n\nSalo, P\n\nSalomaa, V\n\nvan Setten, J\n\nShalaby, AA\n\nSmelser, DT\n\nSmith, NL\n\nStender, S\n\nStott, DJ\n\nSvensson, P\n\nTammesoo, ML\n\nTaylor, KD\n\nTeder-Laving, M\n\nTeumer, A\n\nThorgeirsson, G\n\nThorsteinsdottir, U\n\nTorp-Pedersen, C\n\nTrompet, S\n\nTyl, B\n\nUitterlinden, AG\n\nVeluchamy, A\n\nVölker, U\n\nVoors, AA\n\nWang, X\n\nWareham, NJ\n\nWaterworth, D\n\nWeeke, PE\n\nWeiss, R\n\nWiggins, KL\n\nXing, H\n\nYerges-Armstrong, LM\n\nYu, B\n\nZannad, F\n\nZhao, JH\n\nHemingway, H\n\nSamani, NJ\n\nMcMurray, JJV\n\nYang, J\n\nVisscher, PM\n\nNewton-Cheh, C\n\nMalarstig, A\n\nHolm, H\n\nLubitz, SA\n\nSattar, N\n\nHolmes, MV\n\nCappola, TP\n\nAsselbergs, FW\n\nHingorani, AD\n\nKuchenbaecker, K\n\nEllinor, PT\n\nLang, CC\n\nStefansson, K\n\nSmith, JG\n\nVasan, RS\n\nSwerdlow, DI\n\nLumbers, RT\n\nBeiträge in Fachzeitschriften\nISI:000511898900014\n31919418.0\n10.1038/s41467-019-13690-5\nPMC6952380\nHeart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47, 09 cases and 930, 14 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.\n\nMärz, Winfried\n\n\n"
},
{
"text": "\n4505\nTissue counter analysis of histologic sections of melanoma: influence of mask size and shape, feature selection, statistical methods and tissue preparation.\n\nSmolle, J\n\nGerger, A\n\nWeger, W\n\nKutzner, H\n\nTronnier, M\n\nBeiträge in Fachzeitschriften\nISI:000178790300002\n12446955.0\n10.1155/2002/141295\nPMC4618008\nBACKGROUND: Tissue counter analysis is an image analysis tool designed for the detection of structures in complex images at the macroscopic or microscopic scale. As a basic principle, small square or circular measuring masks are randomly placed across the image and image analysis parameters are obtained for each mask. Based on learning sets, statistical classification procedures are generated which facilitate an automated classification of new data sets. OBJECTIVE: To evaluate the influence of the size and shape of the measuring masks as well as the importance of feature selection, statistical procedures and technical preparation of slides on the performance of tissue counter analysis in microscopic images. As main quality measure of the final classification procedure, the percentage of elements that were correctly classified was used. STUDY DESIGN: HE-stained slides of 25 primary cutaneous melanomas were evaluated by tissue counter analysis for the recognition of melanoma elements (section area occupied by tumour cells) in contrast to other tissue elements and background elements. Circular and square measuring masks, various subsets of image analysis features and classification and regression trees compared with linear discriminant analysis as statistical alternatives were used. The percentage of elements that were correctly classified by the various classification procedures was assessed. In order to evaluate the applicability to slides obtained from different laboratories, the best procedure was automatically applied in a test set of another 50 cases of primary melanoma derived from the same laboratory as the learning set and two test sets of 20 cases each derived from two different laboratories, and the measurements of melanoma area in these cases were compared with conventional assessment of vertical tumour thickness. RESULTS: Square measuring masks were slightly superior to circular masks, and larger masks (64 or 128 pixels in diameter) were superior to smaller masks (8 to 32 pixels in diameter). As far as the subsets of image analysis features were concerned, colour features were superior to densitometric and Haralick texture features. Statistical moments of the grey level distribution were of least significance. CART (classification and regression tree) analysis turned out to be superior to linear discriminant analysis. In the best setting, 95% of melanoma tissue elements were correctly recognized. Automated measurement of melanoma area in the independent test sets yielded a correlation of r=0.846 with vertical tumour thickness (p<0.001), similar to the relationship reported for manual measurements. The test sets obtained from different laboratories yielded comparable results. CONCLUSIONS: Large, square measuring masks, colour features and CART analysis provide a useful setting for the automated measurement of melanoma tissue in tissue counter analysis, which can also be used for slides derived from different laboratories.\n\nGerger, Armin\n\nSmolle, Josef\n\nWeger, Wolfgang\n\n\n"
},
{
"text": "\n158464\nThe genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.\n\nRedin, C\n\nBrand, H\n\nCollins, RL\n\nKammin, T\n\nMitchell, E\n\nHodge, JC\n\nHanscom, C\n\nPillalamarri, V\n\nSeabra, CM\n\nAbbott, MA\n\nAbdul-Rahman, OA\n\nAberg, E\n\nAdley, R\n\nAlcaraz-Estrada, SL\n\nAlkuraya, FS\n\nAn, Y\n\nAnderson, MA\n\nAntolik, C\n\nAnyane-Yeboa, K\n\nAtkin, JF\n\nBartell, T\n\nBernstein, JA\n\nBeyer, E\n\nBlumenthal, I\n\nBongers, EM\n\nBrilstra, EH\n\nBrown, CW\n\nBrüggenwirth, HT\n\nCallewaert, B\n\nChiang, C\n\nCorning, K\n\nCox, H\n\nCuppen, E\n\nCurrall, BB\n\nCushing, T\n\nDavid, D\n\nDeardorff, MA\n\nDheedene, A\n\nD'Hooghe, M\n\nde Vries, BB\n\nEarl, DL\n\nFerguson, HL\n\nFisher, H\n\nFitzPatrick, DR\n\nGerrol, P\n\nGiachino, D\n\nGlessner, JT\n\nGliem, T\n\nGrady, M\n\nGraham, BH\n\nGriffis, C\n\nGripp, KW\n\nGropman, AL\n\nHanson-Kahn, A\n\nHarris, DJ\n\nHayden, MA\n\nHill, R\n\nHochstenbach, R\n\nHoffman, JD\n\nHopkin, RJ\n\nHubshman, MW\n\nInnes, AM\n\nIrons, M\n\nIrving, M\n\nJacobsen, JC\n\nJanssens, S\n\nJewett, T\n\nJohnson, JP\n\nJongmans, MC\n\nKahler, SG\n\nKoolen, DA\n\nKorzelius, J\n\nKroisel, PM\n\nLacassie, Y\n\nLawless, W\n\nLemyre, E\n\nLeppig, K\n\nLevin, AV\n\nLi, H\n\nLi, H\n\nLiao, EC\n\nLim, C\n\nLose, EJ\n\nLucente, D\n\nMacera, MJ\n\nManavalan, P\n\nMandrile, G\n\nMarcelis, CL\n\nMargolin, L\n\nMason, T\n\nMasser-Frye, D\n\nMcClellan, MW\n\nMendoza, CJ\n\nMenten, B\n\nMiddelkamp, S\n\nMikami, LR\n\nMoe, E\n\nMohammed, S\n\nMononen, T\n\nMortenson, ME\n\nMoya, G\n\nNieuwint, AW\n\nOrdulu, Z\n\nParkash, S\n\nPauker, SP\n\nPereira, S\n\nPerrin, D\n\nPhelan, K\n\nAguilar, RE\n\nPoddighe, PJ\n\nPregno, G\n\nRaskin, S\n\nReis, L\n\nRhead, W\n\nRita, D\n\nRenkens, I\n\nRoelens, F\n\nRuliera, J\n\nRump, P\n\nSchilit, SL\n\nShaheen, R\n\nSparkes, R\n\nSpiegel, E\n\nStevens, B\n\nStone, MR\n\nTagoe, J\n\nThakuria, JV\n\nvan Bon, BW\n\nvan de Kamp, J\n\nvan Der Burgt, I\n\nvan Essen, T\n\nvan Ravenswaaij-Arts, CM\n\nvan Roosmalen, MJ\n\nVergult, S\n\nVolker-Touw, CM\n\nWarburton, DP\n\nWaterman, MJ\n\nWiley, S\n\nWilson, A\n\nYerena-de Vega, MC\n\nZori, RT\n\nLevy, B\n\nBrunner, HG\n\nde Leeuw, N\n\nKloosterman, WP\n\nThorland, EC\n\nMorton, CC\n\nGusella, JF\n\nTalkowski, ME\n\nBeiträge in Fachzeitschriften\nISI:000390976600009\n27841880.0\n10.1038/ng.3720\nPMC5307971\nDespite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology.\n\nKroisel, Peter\n\n\n"
},
{
"text": "\n182797\nEffect of novel short-arm human centrifugation induced gravitational gradients upon cardiovascular responses, cerebral perfusion and g-tolerance.\n\nLaing, C\n\nGreen, DA\n\nMulder, E\n\nHinghofer-Szalkay, H\n\nBlaber, AP\n\nRittweger, J\n\nGoswami, N\n\nBeiträge in Fachzeitschriften\nISI:000560922100001\n32715482.0\n10.1113/JP273615\nPMC7589294\nAim of this study was to determine the effect of rotational axis position (RAP and thus g-gradient) during short-arm human centrifugation (SAHC) upon cardiovascular responses, cerebral perfusion and g-tolerance. In 10 male and 10 female participants, 10-min passive SAHC runs were performed with the RAP above (P1), or at the apex of the head (P2), or at heart-level (P3), with foot-level Gz at 1.0 g, 1.7 g and 2.4 g. We hypothesized that movement of the RAP from (the conventional position) above the head towards the heart may reduce central hypovolemia, limit cardiovascular responses, aid cerebral perfusion, and thus promote g-tolerance. Moving the RAP footward towards the heart decreased the cerebral tissue saturation index, calf circumference and heart rate responses to SAHC, thereby promoting g-tolerance. Our results also suggest that RAP, and thus g-gradient warrants further investigation as it may support use as a holistic spaceflight countermeasure.\n Artificial gravity (AG) through short-arm human centrifugation (SAHC) has been proposed as a holistic spaceflight countermeasure. Movement of the rotational axis position (RAP) from above the head towards the heart may reduce central hypovolemia, aid cerebral perfusion, and thus promote g-tolerance. This study determined the effect of RAP upon cardiovascular responses, peripheral blood displacement (i.e. central hypovolemia), cerebral perfusion and g-tolerance, and their inter-relationships. Twenty (10 male) healthy participants (26.2 ± 4.0 yr) underwent nine (following a familiarisation run) randomised 10-minute passive SAHC runs with RAP set above the head (P1), at the apex of the head (P2), or at heart-level (P3) with foot-level Gz at 1.0 g, 1.7 g and 2.4 g. Cerebral tissue saturation index (cTSI, cerebral perfusion surrogate), calf circumference (CC, central hypovolemia), heart rate (HR) and digital heart-level mean arterial blood pressure (MAP) were continuously recorded, in addition to incidence of pre-syncopal symptoms (PSS). ΔCC and ΔHR increases were attenuated from P1 to P3 (ΔCC: 5.46 ± 0.54 mm to 2.23 ± 0.42 mm; ΔHR: 50 ± 4 bpm to 8 ± 2 bpm, P < 0.05). In addition, ΔcTSI decrements were also attenuated (ΔcTSI: -2.85 ± 0.48% to -0.95 ± 0.34%, P < 0.05) and PSS incidence lower in P3 vs. P1 (P < 0.05). A positive linear relationship was observed between ΔCC and ΔHR with increasing +Gz, and a negative relationship between ΔCC and ΔcTSI, both independent of RAP. Our data suggests that movement of RAP towards the heart (reduced g-gradient), independent of foot-level Gz, leads to improved g-tolerance. Further investigations are required to assess effect of differential baroreceptor feedback (i.e. aortic - carotid g-gradient). This article is protected by copyright. All rights reserved.\n This article is protected by copyright. All rights reserved.\n\nGoswami, Nandu\n\nHinghofer-Szalkay, Helmut\n\n\n"
},
{
"text": "\n126144\nCausal Relationship between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts.\n\nVimaleswaran, KS\n\nBerry, DJ\n\nLu, C\n\nTikkanen, E\n\nPilz, S\n\nHiraki, LT\n\nCooper, JD\n\nDastani, Z\n\nLi, R\n\nHouston, DK\n\nWood, AR\n\nMichaëlsson, K\n\nVandenput, L\n\nZgaga, L\n\nYerges-Armstrong, LM\n\nMcCarthy, MI\n\nDupuis, J\n\nKaakinen, M\n\nKleber, ME\n\nJameson, K\n\nArden, N\n\nRaitakari, O\n\nViikari, J\n\nLohman, KK\n\nFerrucci, L\n\nMelhus, H\n\nIngelsson, E\n\nByberg, L\n\nLind, L\n\nLorentzon, M\n\nSalomaa, V\n\nCampbell, H\n\nDunlop, M\n\nMitchell, BD\n\nHerzig, KH\n\nPouta, A\n\nHartikainen, AL\n\nGenetic Investigation of Anthropometric Traits (GIANT) consortium\n\nStreeten, EA\n\nTheodoratou, E\n\nJula, A\n\nWareham, NJ\n\nOhlsson, C\n\nFrayling, TM\n\nKritchevsky, SB\n\nSpector, TD\n\nRichards, JB\n\nLehtimäki, T\n\nOuwehand, WH\n\nKraft, P\n\nCooper, C\n\nMärz, W\n\nPower, C\n\nLoos, RJ\n\nWang, TJ\n\nJärvelin, MR\n\nWhittaker, JC\n\nHingorani, AD\n\nHyppönen, E\n\nBeiträge in Fachzeitschriften\nISI:000315592800005\n23393431.0\n10.1371/journal.pmed.1001383\nPMC3564800\nBackground: Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH) D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis.\nMethods and Findings: We used information from 21 adult cohorts (up to 42, 24 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH) D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123, 64). Each 1 kg/m(2) higher BMI was associated with 1.15% lower 25(OH) D (p = 6.52x10(-27)). The BMI allele score was associated both with BMI (p = 6.30x10(-62)) and 25(OH) D (20.06% [95% CI -0.10 to -0.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH) D (p ANDlt;= 8.07x10(-57) for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH) D concentrations (IV ratio: -4.2 [95% CI -7.1 to -1.3], p = 0.005). No association was seen for genetically instrumented 25(OH) D with BMI, a finding that was confirmed using data from the GIANT consortium (p ANDgt;= 0.57 for both vitamin D scores).\nConclusions: On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH) D, while any effects of lower 25(OH) D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency.\n\nMärz, Winfried\n\nPilz, Stefan\n\n\n"
},
{
"text": "\n127077\nEarly signs of toxicity and "subtoxic" conditions in infant monitoring. Bupivacaine plasma levels following caudal anesthesia].\n\nBreschan, C\n\nHellstrand, E\n\nLikar, R\n\nLönnquist, PA\n\nBeiträge in Fachzeitschriften\nISI:000073540400003\n9615845.0\n10.1007/s001010050559\nNone\nIn order to evaluate whether caudal bupivacaine 3.1 mg/kg is associated with early central nervous system toxicity in awake infants, a clinical trial was performed. Methods: After obtaining Local Ethical Committee approval and informed parental consent, seven awake infants (postconceptual age: 36-52 wks; weight: 2.2-4.7 kg) received a caudal block with bupivacaine 3.1 mg/kg with epinephrine 5 ug/ml in the left lateral position. Before performance of the caudal block a five minute EEG registration was performed, immediately followed by an assessment of the patient's clinical status based on a scoring system of following parameters: level of consciousness; muscular tone in upper extremities, tested by flexion and extension of the elbows; and the quality of the patient's cry in response to a skin pinch. Twenty minutes after the caudal block another EEG was performed and another assessment of the clinical status of the patient. After completion of the clinical assessment blood samples were collected for determination of plasma bupivacaine, lbumin and alpha-1 acid glycoprotein concentrations. Results:ln six of seven infants the EEG pat tern from the first to the second recording showed a shift of the general frequency spectrum towards a lower range. In two of these patients (No. 3 and 4) signs of pharmacologically induced antiepileptic effects (disappereance of sharp waves) were observed. Patients No. 2 and 6 showed signs of increased muscular activity and of suspect epileptic activity. Bupivacaine plasma concentrations ranged from 0.56-1.62 ug/ml, lpha-l acid glycoprotein levels from 0.33-0.76 g/l and albumin levels from 25-38 g/l. Discussion: In a few patients this systemic effect was clinically also associated with what is usually classified as early central nervous system toxicity. As a result of these findings the study was stopped prematurely, due to safety reasons. The low plasma levels of bupivacaine associated with side effects in this study may have two possible explanations. First, our patients did not receive any sedative drugs or anaesthetics that could have masked symptoms or have increased the threshold for systemic effects. Second, as can be expected in this age group plasma levels of alpha-1 acidglycoprotein were low. Thus, the lower plasma concentrations of total bupivacaine observed in the present study might have been associated with a similar unbound, free concentration of bupivacaine as it is seen in older children and adults at total plasma levels of 2-4 ug/ml and at alpha-1 acidglycoprotein levels within the normal adult range. We conclude that Bupivacaine at 3 mg/kg is associated with systemic side effects in infants receiving awake caudal anaesthesia. Therefore we recommend to aim at a dose of not larger than 2 mg/kg in caudal blocks if no premedication or other sedative drugs are given simultaneously.\n\nBreschan, Christian\n\n\n"
},
{
"text": "\n184718\nFailure on voxilaprevir, velpatasvir, sofosbuvir and efficacy of rescue therapy.\n\nDietz, J\n\nDi Maio, VC\n\nde Salazar, A\n\nMerino, D\n\nVermehren, J\n\nPaolucci, S\n\nKremer, AE\n\nLara, M\n\nPardo, MR\n\nZoller, H\n\nDegasperi, E\n\nPeiffer, KH\n\nSighinolfi, L\n\nTéllez, F\n\nGraf, C\n\nGhisetti, V\n\nSchreiber, J\n\nFernández-Fuertes, E\n\nBoglione, L\n\nMuñoz-Medina, L\n\nStauber, R\n\nGennari, W\n\nFigueruela, B\n\nSantos, J\n\nLampertico, P\n\nZeuzem, S\n\nCeccherini-Silberstein, F\n\nGarcía, F\n\nSarrazin, C\n\nHCV Virology Italian Resistance Network (VIRONET-C) collaborators\n\nSpanish GEHEP-004 Collaborators\n\nMembers of the German HCV resistance study group\n\nBeiträge in Fachzeitschriften\nISI:000632039100006\n33220331.0\n10.1016/j.jhep.2020.11.017\nNone\nThere are limited data on patients with chronic HCV infection in whom combination voxilaprevir (VOX), velpatasvir (VEL), sofosbuvir (SOF) retreatment fails. Thus, we aimed to assess treatment failure and rescue treatment options in these patients.\n Samples from 40 patients with HCV genotypes (GT) 1-4 in whom VOX/VEL/SOF retreatment failed were collected within the European Resistance Study Group. Population-based resistance analyses were conducted and clinical parameters and retreatment efficacies were evaluated retrospectively in 22 patients.\n Most VOX/VEL/SOF failure patients were infected with HCV GT3a (n = 18, 45%) or GT1a (n = 11, 28%) and had cirrhosis (n = 28, 70%). Previous treatments included an NS3-inhibitor (30%), an NS5A-inhibitor (100%) and SOF (85%). Baseline RAS data from a subgroup of patients before VOX/VEL/SOF retreatment (78%) showed few NS3 RASs apart from Q80K in GT1a (40%), typical NS5A RAS patterns in most patients (74%) and no S282T in NS5B. Sequencing after VOX/VEL/SOF failure was available in 98% of patients and showed only minor changes for NS3 and NS5A RASs. In 22 patients, rescue treatment was initiated with glecaprevir, pibrentasvir alone (n = 2) or with SOF±ribavirin (n = 15), VOX/VEL/SOF±ribavirin (n = 4) or VEL/SOF and ribavirin (n = 1) for 12 to 24 weeks. Sustained virologic response was achieved in 17/21 (81%) patients with a final treatment outcome. Of these, 2 GT3a-infected patients had virologic failure after rescue treatment with VEL/SOF or glecaprevir/pibrentasvir+SOF+ribavirin, and 2 patients with cirrhosis died during treatment or before reaching SVR12.\n VOX/VEL/SOF failure was mainly observed in HCV GT3- and GT1a-infected patients with cirrhosis and was not associated with specific RAS patterns within NS3, NS5A or NS5B target regions. Rescue treatment with multiple targeted therapies was effective in most patients.\n The advent of direct-acting antivirals has enabled the effective cure of chronic hepatitis C in most patients. However, treatment failure occurs in some patients, who are often retreated with a combination regimen called VOX/VEL/SOF, which is associated with very high rates of cure. However, VOX/VEL/SOF retreatment also fails in some patients. Herein, we analysed samples from patients in whom VOX/VEL/SOF retreatment failed and we assessed the efficacy of different rescue therapies, showing that rescue treatment is effective in most patients (81%).\n Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.\n\nStauber, Rudolf\n\n\n"
},
{
"text": "\n166125\nEpilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome.\n\nMills, PB\n\nCamuzeaux, SS\n\nFootitt, EJ\n\nMills, KA\n\nGissen, P\n\nFisher, L\n\nDas, KB\n\nVaradkar, SM\n\nZuberi, S\n\nMcWilliam, R\n\nStödberg, T\n\nPlecko, B\n\nBaumgartner, MR\n\nMaier, O\n\nCalvert, S\n\nRiney, K\n\nWolf, NI\n\nLivingston, JH\n\nBala, P\n\nMorel, CF\n\nFeillet, F\n\nRaimondi, F\n\nDel Giudice, E\n\nChong, WK\n\nPitt, M\n\nClayton, PT\n\nBeiträge in Fachzeitschriften\nISI:000336252800015\n24645144.0\n10.1093/brain/awu051\nPMC3999720\nThe first described patients with pyridox(am)ine 5'-phosphate oxidase deficiency all had neonatal onset seizures that did not respond to treatment with pyridoxine but responded to treatment with pyridoxal 5'-phosphate. Our data suggest, however, that the clinical spectrum of pyridox(am)ine 5'-phosphate oxidase deficiency is much broader than has been reported in the literature. Sequencing of the PNPO gene was undertaken for a cohort of 82 individuals who had shown a reduction in frequency and severity of seizures in response to pyridoxine or pyridoxal 5'-phosphate. Novel sequence changes were studied using a new cell-free expression system and a mass spectrometry-based assay for pyridoxamine phosphate oxidase. Three groups of patients with PNPO mutations that had reduced enzyme activity were identified: (i) patients with neonatal onset seizures responding to pyridoxal 5'-phosphate (n = 6); (ii) a patient with infantile spasms (onset 5 months) responsive to pyridoxal 5'-phosphate (n = 1); and (iii) patients with seizures starting under 3 months of age responding to pyridoxine (n = 8). Data suggest that certain genotypes (R225H/C and D33V) are more likely to result in seizures that to respond to treatment with pyridoxine. Other mutations seem to be associated with infertility, miscarriage and prematurity. However, the situation is clearly complex with the same combination of mutations being seen in patients who responded and did not respond to pyridoxine. It is possible that pyridoxine responsiveness in PNPO deficiency is affected by prematurity and age at the time of the therapeutic trial. Other additional factors that are likely to influence treatment response and outcome include riboflavin status and how well the foetus has been supplied with vitamin B6 by the mother. For some patients there was a worsening of symptoms on changing from pyridoxine to pyridoxal 5'-phosphate. Many of the mutations in PNPO affected residues involved in binding flavin mononucleotide or pyridoxal 5'-phosphate and many of them showed residual enzyme activity. One sequence change (R116Q), predicted to affect flavin mononucleotide binding and binding of the two PNPO dimers, and with high residual activity was found in Groups (ii) and (iii). This sequence change has been reported in the 1000 Genomes project suggesting it could be a polymorphism but alternatively it could be a common mutation, perhaps responsible for the susceptibility locus for genetic generalized epilepsy on 17q21.32 (close to rs72823592). We believe the reduction in PNPO activity and B6-responsive epilepsy in the patients reported here indicates that it contributes to the pathogenesis of epilepsy.\n\nPlecko, Barbara\n\n\n"
},
{
"text": "\n3162\nBasaloid neoplasms in nevus sebaceus.\n\nKaddu, S\n\nSchaeppi, H\n\nKerl, H\n\nSoyer, HP\n\nBeiträge in Fachzeitschriften\nISI:000088199000001\n10917159.0\n10.1034/j.1600-0560.2000.027007327.x\nNone\nBackground: Nevus sebaceus (NS) (organoider nevus) may frequently be associated with the development of a number of benign and malignant neoplasms among which basaloid neoplasms are the most common. Histopathologic criteria for diagnosis and classification of basaloid proliferations arising in NS are still debated. Most previous investigators have considered them to represent mainly basal cell carcinomas (BCCs). On the contrary, a number of recent authors have proposed that most basaloid neoplasms in NS exhibit predominantly morphologic features implying benignancy, thus representing trichobalstomas (TBs). In this study, we attempted to characterize better the histopathologic features of basaloid neoplasms in NS in a large series based on current morphologic criteria.Methods: Three-hundred and sixteen cases of NS seen over 19 years were consecutively sampled and reviewed for basaloid neoplasms. Twenty-four cases of basaloid neoplasms in NS were identified and categorized based on current histopathologic criteria either as TB or BCC. For comparison of histopathologic features, 37 solitary TB were also studied.Results: Following histopathologic analysis, 22 cases were categorized as TB (91.6%, 10 males, 12 females; mean age 40.8 years, range 19-78 years) and 2 cases as BCC (8.4%, 1 male, 1 female; 32 years and 40 years). Clinical features in both groups were generally similar. The lesions presented exclusively on the head and neck as skin colored to pigmented papules or nodules within NS (scalp in 19 TB cases and 1 BCC case; face in 2 TB cases and 1 BCC case; neck in 1 TB case). Histopathologically, TB in NS were characterized by smooth-bordered basaloid aggregations with either a nodular and/or a superficial pattern, abundant fibrous stroma with focal clefts within the stroma, and prominent features of limited follicular differentiation (rudimentary follicular germs in concert with papillae). In contrast, BCC in NS showed basaloid aggregations that vary markedly in size and shape, scant fibrous stroma, focal mucinous clefts between basaloid aggregations and surrounding stroma, and lack of prominent rudimentary follicular germs in concert with papillae. Remarkably, sections in a few cases of TB showed features occasionally found in BCCs but presently widely considered to be unspecific (e.g., ulceration, cystic degeneration, and focal clefts between basaloid aggregations and surrounding stroma). Two cases of TB in NS were associated with a sebaceoma and 1 case with a desmoplastic trichilemmoma. Follow-up data in 14 TB cases and 2 BCC: cases (mean follow-up 28.8 months; range 1 to 160 months) revealed no local recurrences or distant metastases.Conclusion: Our study confirms that the vast majority of the basaloid neoplasms arising in NS show clear-cut morphologic criteria for TB, whereas only a few cases display histopathologic features consistent with BCC. In a minority of cases, basaloid neoplasms with overall morphologic features of TB may present problems in diagnosis when they exhibit a few histopathologic features traditionally associated with BCC or when they occur in combination with other adnexal neoplasms.\n\nKaddu, Steven\n\nKerl, Helmut\n\n\n"
},
{
"text": "\n183826\nEssential versus accessory aspects of cell death: recommendations of the NCCD 2015.\n\nGalluzzi, L\n\nBravo-San Pedro, JM\n\nVitale, I\n\nAaronson, SA\n\nAbrams, JM\n\nAdam, D\n\nAlnemri, ES\n\nAltucci, L\n\nAndrews, D\n\nAnnicchiarico-Petruzzelli, M\n\nBaehrecke, EH\n\nBazan, NG\n\nBertrand, MJ\n\nBianchi, K\n\nBlagosklonny, MV\n\nBlomgren, K\n\nBorner, C\n\nBredesen, DE\n\nBrenner, C\n\nCampanella, M\n\nCandi, E\n\nCecconi, F\n\nChan, FK\n\nChandel, NS\n\nCheng, EH\n\nChipuk, JE\n\nCidlowski, JA\n\nCiechanover, A\n\nDawson, TM\n\nDawson, VL\n\nDe Laurenzi, V\n\nDe Maria, R\n\nDebatin, KM\n\nDi Daniele, N\n\nDixit, VM\n\nDynlacht, BD\n\nEl-Deiry, WS\n\nFimia, GM\n\nFlavell, RA\n\nFulda, S\n\nGarrido, C\n\nGougeon, ML\n\nGreen, DR\n\nGronemeyer, H\n\nHajnoczky, G\n\nHardwick, JM\n\nHengartner, MO\n\nIchijo, H\n\nJoseph, B\n\nJost, PJ\n\nKaufmann, T\n\nKepp, O\n\nKlionsky, DJ\n\nKnight, RA\n\nKumar, S\n\nLemasters, JJ\n\nLevine, B\n\nLinkermann, A\n\nLipton, SA\n\nLockshin, RA\n\nLópez-Otín, C\n\nLugli, E\n\nMadeo, F\n\nMalorni, W\n\nMarine, JC\n\nMartin, SJ\n\nMartinou, JC\n\nMedema, JP\n\nMeier, P\n\nMelino, S\n\nMizushima, N\n\nMoll, U\n\nMuñoz-Pinedo, C\n\nNuñez, G\n\nOberst, A\n\nPanaretakis, T\n\nPenninger, JM\n\nPeter, ME\n\nPiacentini, M\n\nPinton, P\n\nPrehn, JH\n\nPuthalakath, H\n\nRabinovich, GA\n\nRavichandran, KS\n\nRizzuto, R\n\nRodrigues, CM\n\nRubinsztein, DC\n\nRudel, T\n\nShi, Y\n\nSimon, HU\n\nStockwell, BR\n\nSzabadkai, G\n\nTait, SW\n\nTang, HL\n\nTavernarakis, N\n\nTsujimoto, Y\n\nVanden Berghe, T\n\nVandenabeele, P\n\nVillunger, A\n\nWagner, EF\n\nWalczak, H\n\nWhite, E\n\nWood, WG\n\nYuan, J\n\nZakeri, Z\n\nZhivotovsky, B\n\nMelino, G\n\nKroemer, G\n\nBeiträge in Fachzeitschriften\nISI:000347841600008\n25236395.0\n10.1038/cdd.2014.137\nPMC4262782\nCells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as 'accidental cell death' (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. 'Regulated cell death' (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.\n\nJost, Philipp\n\n\n"
},
{
"text": "\n187616\nAccuracy of the Hospital Anxiety and Depression Scale Depression subscale (HADS-D) to screen for major depression: systematic review and individual participant data meta-analysis.\n\nWu, Y\n\nLevis, B\n\nSun, Y\n\nHe, C\n\nKrishnan, A\n\nNeupane, D\n\nBhandari, PM\n\nNegeri, Z\n\nBenedetti, A\n\nThombs, BD\n\nDEPRESsion Screening Data (DEPRESSD) HADS Group\n\nBeiträge in Fachzeitschriften\nNone\n33972268.0\n10.1136/bmj.n972\nNone\nTo evaluate the accuracy of the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D) to screen for major depression among people with physical health problems.\n Systematic review and individual participant data meta-analysis.\n Medline, Medline In-Process and Other Non-Indexed Citations, PsycInfo, and Web of Science (from inception to 25 October 2018).\n Eligible datasets included HADS-D scores and major depression status based on a validated diagnostic interview. Primary study data and study level data extracted from primary reports were combined. For HADS-D cut-off thresholds of 5-15, a bivariate random effects meta-analysis was used to estimate pooled sensitivity and specificity, separately, in studies that used semi-structured diagnostic interviews (eg, Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders), fully structured interviews (eg, Composite International Diagnostic Interview), and the Mini International Neuropsychiatric Interview. One stage meta-regression was used to examine whether accuracy was associated with reference standard categories and the characteristics of participants. Sensitivity analyses were done to assess whether including published results from studies that did not provide raw data influenced the results.\n Individual participant data were obtained from 101 of 168 eligible studies (60%; 25 574 participants (72% of eligible participants), 2549 with major depression). Combined sensitivity and specificity was maximised at a cut-off value of seven or higher for semi-structured interviews, fully structured interviews, and the Mini International Neuropsychiatric Interview. Among studies with a semi-structured interview (57 studies, 10 664 participants, 1048 with major depression), sensitivity and specificity were 0.82 (95% confidence interval 0.76 to 0.87) and 0.78 (0.74 to 0.81) for a cut-off value of seven or higher, 0.74 (0.68 to 0.79) and 0.84 (0.81 to 0.87) for a cut-off value of eight or higher, and 0.44 (0.38 to 0.51) and 0.95 (0.93 to 0.96) for a cut-off value of 11 or higher. Accuracy was similar across reference standards and subgroups and when published results from studies that did not contribute data were included.\n When screening for major depression, a HADS-D cut-off value of seven or higher maximised combined sensitivity and specificity. A cut-off value of eight or higher generated similar combined sensitivity and specificity but was less sensitive and more specific. To identify medically ill patients with depression with the HADS-D, lower cut-off values could be used to avoid false negatives and higher cut-off values to reduce false positives and identify people with higher symptom levels.\n PROSPERO CRD42015016761.\n © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.\n\nJenewein, Josef\n\n\n"
}
]
}