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"text": "\n135177\nDifferences in human papillomavirus type distribution in high-grade cervical intraepithelial neoplasia and invasive cervical cancer in Europe.\n\nTjalma, WA\n\nFiander, A\n\nReich, O\n\nPowell, N\n\nNowakowski, AM\n\nKirschner, B\n\nKoiss, R\n\nO'Leary, J\n\nJoura, EA\n\nRosenlund, M\n\nColau, B\n\nSchledermann, D\n\nKukk, K\n\nDamaskou, V\n\nRepanti, M\n\nVladareanu, R\n\nKolomiets, L\n\nSavicheva, A\n\nShipitsyna, E\n\nOrdi, J\n\nMolijn, A\n\nQuint, W\n\nRaillard, A\n\nRosillon, D\n\nDe Souza, SC\n\nJenkins, D\n\nHoll, K\n\nHERACLES/SCALE Study Group\n\nBeiträge in Fachzeitschriften\nISI:000314069400012\n22752992.0\n10.1002/ijc.27713\nNone\nKnowledge of differences in human papillomavirus (HPV)-type prevalence between high-grade cervical intraepithelial neoplasia (HG-CIN) and invasive cervical cancer (ICC) is crucial for understanding the natural history of HPV-infected cervical lesions and the potential impact of HPV vaccination on cervical cancer prevention. More than 6, 00 women diagnosed with HG-CIN or ICC from 17 European countries were enrolled in two parallel cross-sectional studies (108288/108290). Centralised histopathology review and standardised HPV-DNA typing were applied to formalin-fixed paraffin-embedded cervical specimens dated 2001-2008. The pooled prevalence of individual HPV types was estimated using meta-analytic methods. A total of 3, 03 women were diagnosed with HG-CIN and a total of 3, 62 with ICC (median ages: 34 and 49 years, respectively), of which 98.5 and 91.8% were HPV-positive, respectively. The most common HPV types in women with HG-CIN were HPV16/33/31 (59.9/10.5/9.0%) and in ICC were HPV16/18/45 (63.3/15.2/5.3%). In squamous cell carcinomas, HPV16/18/33 were most frequent (66.2/10.8/5.3%), and in adenocarcinomas, HPV16/18/45 (54.2/40.4/8.3%). The prevalence of HPV16/18/45 was 1.1/3.5/2.5 times higher in ICC than in HG-CIN. The difference in age at diagnosis between CIN3 and squamous cervical cancer for HPV18 (9 years) was significantly less compared to HPV31/33/'other' (23/20/17 years), and for HPV45 (1 year) than HPV16/31/33/'other' (15/23/20/17 years). In Europe, HPV16 predominates in both HG-CIN and ICC, whereas HPV18/45 are associated with a low median age of ICC. HPV18/45 are more frequent in ICC than HG-CIN and associated with a high median age of HG-CIN, with a narrow age interval between HG-CIN and ICC detection. These findings support the need for primary prevention of HPV16/18/45-related cervical lesions.\n\nReich, Olaf\n\n\n"
},
{
"text": "\n142532\nSkin explant model of human graft-versus-host disease: prediction of clinical outcome and correlation with biological risk factors.\n\nWang, XN\n\nCollin, M\n\nSviland, L\n\nMarshall, S\n\nJackson, G\n\nSchulz, U\n\nHoller, E\n\nKarrer, S\n\nGreinix, H\n\nElahi, F\n\nHromadnikova, I\n\nDickinson, AM\n\nBeiträge in Fachzeitschriften\nISI:000235284900004\n16443513.0\n10.1016/j.bbmt.2005.09.018\nNone\nA human skin explant model has been used to predict the clinical outcome and to study the immunopathology of human graft-versus-host disease (GVHD). Whether the model gives the same predictive effect for GVHD in different hematopoietic stem cell transplantation (HSCT) settings has not been assessed. It is also unknown whether the skin explant result reflects the known biological risk factors for clinical GVHD. In this study, the skin explant model was used to detect graft-versus-host reactions (GVHR) in vitro for 225 eligible patient/donor pairs. The predicted skin GVHR grade was correlated with the outcome of clinical GVHD, as well as HLA matching status, sex mismatches, and patient age. In sibling HSCT under either myeloablative or reduced-intensity conditioning, a significant correlation was observed between the predicted skin GVHR and clinical GVHD (P < .001 and P = .033, respectively). In HSCT using unrelated donors, the involvement of T-cell depletion led to a sharp increase in false-positive GVHR results, and no correlation was observed between the predicted skin GVHR and clinical GVHD. The skin GVHR grade correlated significantly with the HLA matching status (HLA-matched sibling pairs, HLA-matched unrelated pairs, and HLA-unmatched unrelated pairs). Furthermore, HLA-matched sibling pairs with a female-to-male sex mismatch had a significantly higher overall skin GVHR grade and a higher ratio of high- versus low-grade skin GVHR than the sibling pairs with all other sex combinations. Patient age was not reflected in the skin explant result. In conclusion, the predictive value of the skin explant model for aGVHD varies depending on the clinical transplant protocols, such as the type of GVHD prophylaxis used. Nevertheless, the skin explant model remains a unique in vitro system that provides an in situ histopathologic readout for studying alloreactivity and human GVHD. The model has also the potential to aid the development of novel prophylaxis and treatment for GVHD.\n\nGreinix, Hildegard\n\n\n"
},
{
"text": "\n145300\nElo1p-dependent carboxy-terminal elongation of C14:1Delta(9) to C16:1Delta(11) fatty acids in Saccharomyces cerevisiae.\n\nSchneiter, R\n\nTatzer, V\n\nGogg, G\n\nLeitner, E\n\nKohlwein, SD\n\nBeiträge in Fachzeitschriften\nISI:000087602900008\n10850979.0\n10.1128/JB.182.13.3655-3660.2000\nPMC94535\nSaccharomyces cerevisiae medium-chain acyl elongase (ELO1) mutants have previously been isolated in screens for fatty acid synthetase (FAS) mutants that fail to grow on myristic acid (C14:0)-supplemented media. Here we report that wild-type cells cultivated in myristoleic acid (C14:1Delta(9))-supplemented media synthesized a novel unsaturated fatty acid that was identified as C16:1Delta(11) fatty acid by gas chromatography-mass spectroscopy. Synthesis of C16:1Delta(11) was dependent on a functional ELO1 gene, indicating that Elo1p catalyzes carboxy-terminal elongation of unsaturated fatty acids (alpha-elongation). In wild-type cells, the C16:1Delta(11) elongation product accounted for approximately 12% of the total fatty acids. This increased to 18% in cells that lacked a functional acyl chain desaturase (ole1Delta mutants) and hence were fully dependent on uptake and elongation of C14:1. The observation that ole1Delta mutant cells grew almost like wild type on medium supplemented with C14:1 indicated that uptake and elongation of unsaturated fatty acids were efficient. Interestingly, wild-type cells supplemented with either C14:1 or C16:1 fatty acids displayed dramatic alterations in their phospholipid composition, suggesting that the availability of acyl chains is a dominant determinant of the phospholipid class composition of cellular membranes. In particular, the relative content of the two major phospholipid classes, phosphatidylethanolamine and phosphatidylcholine, was strongly dependent on the chain length of the supplemented fatty acid. Moreover, analysis of the acyl chain composition of individual phospholipid classes in cells supplemented with C14:1 revealed that the relative degree of acyl chain saturation characteristic for each phospholipid class appeared to be conserved, despite the gross alteration in the cellular acyl chain pool. Comparison of the distribution of fatty acids that were taken up and elongated (C16:1Delta(11)) to those that were endogenously synthesized by fatty acid synthetase and then desaturated by Ole1p (C16:1Delta(9)) in individual phospholipid classes finally suggested the presence of two different pools of diacylglycerol species. These results will be discussed in terms of biosynthesis of different phospholipid classes via either the de novo or the Kennedy pathway.\n\nWinkler-Tatzer, Verena\n\n\n"
},
{
"text": "\n148795\nAre There Specific Indications for Laparoscopic Appendectomy? A Review and Critical Appraisal of the Literature.\n\nPopa, D\n\nSoltes, M\n\nUranues, S\n\nFingerhut, A\n\nBeiträge in Fachzeitschriften\nISI:000364766300006\n26575247.0\n10.1089/lap.2014.0624\nNone\nLaparoscopic appendectomy (LA) has proven to be a feasible alternative to open appendectomy (OA). However, as some of the purported advantages of LA (versus OA) are marginal, evidence is accumulating that appendectomy may not be necessary for uncomplicated appendicitis and there is concern about using laparoscopy for all patients with suspected acute appendicitis. In spite of widespread popularity and use, the literature reporting the indications is sparse and sometimes misleading (i.e., containing distorted deductions or conclusions, also called "spin"). This study aimed to determine subsets of patients for whom LA may present real advantages over OA and to analyze the validity of specific indications for LA (instead of OA).\n A systematic review and critical analysis of the literature were conducted.\n We analyzed 90 retrospective reviews, prospective studies, meta-analyses, and cohort and prospective randomized studies, presenting a total of approximately 390, 00 patients, concerning potentially specific advantages of LA in the elderly, the obese, during pregnancy, and complicated appendicitis, including diffuse peritonitis and ectopic appendices. Overall, LA was associated with (1) lower overall complication rates (and notably less decompensated comorbidities), mortality, and costs, as well as shorter duration of hospital stay, in the elderly, (2) decreased morbidity (notably parietal) in the obese, and (3) potential (diagnostic) advantages in pregnancy (even though LA is associated with a higher rate of fetal loss than in OA). In complicated or ectopic appendicitis, LA is feasible and safe and, if performed without conversion, should lead to less short- and long-term parietal morbidity. However, published data are very heterogeneous, there are few sound controlled trials, and conclusions found in the literature are often based on misleading deductions or a very low level of evidence.\n LA is a safe and effective method to treat acute appendicitis in specific settings such as the elderly and the obese, as well as in ectopic appendices, with potentially specific parietal advantages in these subsets of patients. Further randomized studies and robust meta-analyses are necessary before recommending LA for complicated appendicitis and peritonitis, as well as in pregnancy.\n\nUranüs, Selman\n\n\n"
},
{
"text": "\n151414\nImpacts to the chest of PMHSs - Influence of impact location and load distribution on chest response.\n\nHolmqvist, K\n\nSvensson, MY\n\nDavidsson, J\n\nGutsche, A\n\nTomasch, E\n\nDarok, M\n\nRavnik, D\n\nBeiträge in Fachzeitschriften\nISI:000368221900017\n26687541.0\n10.1016/j.aap.2015.11.035\nNone\nThe chest response of the human body has been studied for several load conditions, but is not well known in the case of steering wheel rim-to-chest impact in heavy goods vehicle frontal collisions. The aim of this study was to determine the response of the human chest in a set of simulated steering wheel impacts. PMHS tests were carried out and analysed. The steering wheel load pattern was represented by a rigid pendulum with a straight bar-shaped front. A crash test dummy chest calibration pendulum was utilised for comparison. In this study, a set of rigid bar impacts were directed at various heights of the chest, spanning approximately 120mm around the fourth intercostal space. The impact energy was set below a level estimated to cause rib fracture. The analysed results consist of responses, evaluated with respect to differences in the impacting shape and impact heights on compression and viscous criteria chest injury responses. The results showed that the bar impacts consistently produced lesser scaled chest compressions than the hub; the Middle bar responses were around 90% of the hub responses. A superior bar impact provided lesser chest compression; the average response was 86% of the Middle bar response. For inferior bar impacts, the chest compression response was 116% of the chest compression in the middle. The damping properties of the chest caused the compression to decrease in the high speed bar impacts to 88% of that in low speed impacts. From the analysis it could be concluded that the bar impact shape provides lower chest criteria responses compared to the hub. Further, the bar responses are dependent on the impact location of the chest. Inertial and viscous effects of the upper body affect the responses. The results can be used to assess the responses of human substitutes such as anthropomorphic test devices and finite element human body models, which will benefit the development process of heavy goods vehicle safety systems. \n Copyright © 2015 Elsevier Ltd. All rights reserved.\n\nDarok, Mario\n\n\n"
},
{
"text": "\n155996\nAccuracy of estimation of graft size for living-related liver transplantation: first results of a semi-automated interactive software for CT-volumetry.\n\nMokry, T\n\nBellemann, N\n\nMüller, D\n\nLorenzo Bermejo, J\n\nKlauß, M\n\nStampfl, U\n\nRadeleff, B\n\nSchemmer, P\n\nKauczor, HU\n\nSommer, CM\n\nBeiträge in Fachzeitschriften\nISI:000345204100046\n25330198.0\n10.1371/journal.pone.0110201\nPMC4201494\nTo evaluate accuracy of estimated graft size for living-related liver transplantation using a semi-automated interactive software for CT-volumetry.\n Sixteen donors for living-related liver transplantation (11 male; mean age: 38.2±9.6 years) underwent contrast-enhanced CT prior to graft removal. CT-volumetry was performed using a semi-automated interactive software (P), and compared with a manual commercial software (TR). For P, liver volumes were provided either with or without vessels. For TR, liver volumes were provided always with vessels. Intraoperative weight served as reference standard. Major study goals included analyses of volumes using absolute numbers, linear regression analyses and inter-observer agreements. Minor study goals included the description of the software workflow: degree of manual correction, speed for completion, and overall intuitiveness using five-point Likert scales: 1--markedly lower/faster/higher for P compared with TR, 2--slightly lower/faster/higher for P compared with TR, 3--identical for P and TR, 4--slightly lower/faster/higher for TR compared with P, and 5--markedly lower/faster/higher for TR compared with P.\n Liver segments II/III, II-IV and V-VIII served in 6, 3, and 7 donors as transplanted liver segments. Volumes were 642.9±368.8 ml for TR with vessels, 623.8±349.1 ml for P with vessels, and 605.2±345.8 ml for P without vessels (P<0.01). Regression equations between intraoperative weights and volumes were y = 0.94x+30.1 (R2 = 0.92; P<0.001) for TR with vessels, y = 1.00x+12.0 (R2 = 0.92; P<0.001) for P with vessels, and y = 1.01x+28.0 (R2 = 0.92; P<0.001) for P without vessels. Inter-observer agreement showed a bias of 1.8 ml for TR with vessels, 5.4 ml for P with vessels, and 4.6 ml for P without vessels. For the degree of manual correction, speed for completion and overall intuitiveness, scale values were 2.6±0.8, 2.4±0.5 and 2.\n CT-volumetry performed with P can predict accurately graft size for living-related liver transplantation while improving workflow compared with TR.\n\nSchemmer, Peter\n\n\n"
},
{
"text": "\n166081\nClinical and neuropsychological outcome in 33 patients with biotinidase deficiency ascertained by nationwide newborn screening and family studies in Austria.\n\nMöslinger, D\n\nStöckler-Ipsiroglu, S\n\nScheibenreiter, S\n\nTiefenthaler, M\n\nMühl, A\n\nSeidl, R\n\nStrobl, W\n\nPlecko, B\n\nSuormala, T\n\nBaumgartner, ER\n\nBeiträge in Fachzeitschriften\nNone\n11388594.0\nNone\nNone\nNewborn screening for biotinidase deficiency (BD) provides prevention of neurological sequelae in patients with low residual enzyme activity by early treatment with oral biotin substitution. Screening 1.1 million newborns in Austria and consecutive family studies led to the identification of 21 patients with profound BD (residual activity <10%) (incidence: 1:59, 00) and to 12 patients with partial BD (residual activity 10%-30%) (incidence 1:89, 00). Application of an HPLC assay using the natural substrate biocytin allowed exact quantification of extremely low residual biotinidase activities and thus subdivision of patients with profound BD into a group with a residual activity 0%-1% of normal activity (n = 5) and >1%-<10% (n = 16) respectively. Evaluation of clinical and neuropsychological outcome showed that only patients with a biotinidase activity < 1% (n = 3/5) exhibited characteristic clinical symptoms within the first weeks of life, while five patients with a residual activity of 1.2%-4.6% did not develop clinical symptoms even when not treated until 3.5 21 years. In all patients with residual activity <10% and biotin substitution within the first weeks of life, neuropsychological outcome was normal, while abnormal in three out of five patients tested for IQ and treated after the age of 3.5 years. In five out of nine patients with poor compliance or delayed or no treatment, visual and brainstem auditory evoked potentials were measured and were within age-related normal values. All patients with partial BD available for follow-up remained clinically and neuropsychologically asymptomatic without treatment at ages 2.5 10 years.\n The incidence of biotinidase deficiency in Austria is comparable to other European countries. Subdivision of the group of patients with profound biotinidase deficiency suggests that only patients with residual activities < 1% are prone to develop clinical symptoms early in life, while patients with residual activities >1% may remain asymptomatic even without treatment, as do patients with partial deficiency. Moderate mental retardation might represent a possible manifestation of cerebral dysfunction in patients with profound biotinidase deficiency.\n\nPlecko, Barbara\n\n\n"
},
{
"text": "\n172256\nNovel stereotactic body radiation therapy (SBRT)-based partial tumor irradiation targeting hypoxic segment of bulky tumors (SBRT-PATHY): improvement of the radiotherapy outcome by exploiting the bystander and abscopal effects.\n\nTubin, S\n\nPopper, HH\n\nBrcic, L\n\nBeiträge in Fachzeitschriften\nISI:000457225800002\n30696472.0\n10.1186/s13014-019-1227-y\nPMC6352381\nDespite the advances in oncology, patients with bulky tumors have worse prognosis and often receive only palliative treatments. Bulky disease represents an important challenging obstacle for all currently available radical treatment options including conventional radiotherapy. The purpose of this study was to assess a retrospective outcome on the use of a newly developed unconventional stereotactic body radiation therapy (SBRT) for PArtial Tumor irradiation of unresectable bulky tumors targeting exclusively their HYpoxic segment (SBRT-PATHY) that exploits the non-targeted effects of radiotherapy: bystander effects (local) and the abscopal effects (distant).\n Twenty-three patients with bulky tumors received partial bulky irradiation in order to induce the local non-targeted effect of radiation (bystander effect). The hypoxic tumor segment, called the bystander tumor volume (BTV), was defined using PET and contrast-enhanced CT, as a hypovascularized-hypometabolic junctional zone between the central necrotic and peripheral hypervascularized-hypermetabolic tumor segment. Based on tumor site and volume, the BTV was irradiated with 1-3 fractions of 10-12 Gy prescribed to 70% isodose-line. The pathologic lymph nodes and metastases were not irradiated in order to assess the distant non-targeted effects of radiation (abscopal effect). No patient received any systemic therapy.\n At the time of analysis, with median follow-up of 9.4 months (range: 4-20), 87% of patients remained progression-free. The bystander and abscopal response rates were 96 and 52%, respectively. Median shrinkage of partially irradiated bulky tumor expressing intensity of the bystander effect was 70% (range 30-100%), whereas for the non-irradiated metastases (intensity of the abscopal effect), it was 50% (range 30-100%). No patient experienced acute or late toxicity of any grade.\n SBRT-PATHY showed very inspiring results on exploitation of the radiation-hypoxia-induced non-targeted effects that need to be confirmed through our ongoing prospective trial. Present study has been retrospectively registered by the local ethic committee under study number A 26/18.\n\nBrcic, Luka\n\nPopper, Helmuth\n\n\n"
},
{
"text": "\n179285\nThe Prognostic Impact of Primary Tumor Site Differs According to the KRAS Mutational Status: A Study By the International Genetic Consortium for Colorectal Liver Metastasis.\n\nMargonis, GA\n\nAmini, N\n\nBuettner, S\n\nKim, Y\n\nWang, J\n\nAndreatos, N\n\nWagner, D\n\nSasaki, K\n\nBeer, A\n\nKamphues, C\n\nMorioka, D\n\nLøes, IM\n\nImai, K\n\nHe, J\n\nPawlik, TM\n\nKaczirek, K\n\nPoultsides, G\n\nLønning, PE\n\nBurkhart, R\n\nEndo, I\n\nBaba, H\n\nMischinger, HJ\n\nAucejo, FN\n\nKreis, ME\n\nWolfgang, CL\n\nWeiss, MJ\n\nBeiträge in Fachzeitschriften\nNone\n31389831.0\n10.1097/SLA.0000000000003504\nNone\nTo examine the prognostic impact of tumor laterality in colon cancer liver metastases (CLM) after stratifying by Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutational status.\n Although some studies have demonstrated that patients with CLM from a right sided (RS) primary cancer fare worse, others have found equivocal outcomes of patients with CLM with RS versus left-sided (LS) primary tumors. Importantly, recent evidence from unresectable metastatic CRC suggests that tumor laterality impacts prognosis only in those with wild-type tumors.\n Patients with rectal or transverse colon tumors and those with unknown KRAS mutational status were excluded from analysis. The prognostic impact of RS versus LS primary CRC was determined after stratifying by KRAS mutational status.\n 277 patients had a RS (38.6%) and 441 (61.4%) had a LS tumor. Approximately one-third of tumors (28.1%) harbored KRAS mutations. In the entire cohort, RS was associated with worse 5-year overall survival (OS) compared with LS (39.4% vs 50.8%, P = 0.03) and remained significantly associated with worse OS in the multivariable analysis (hazard ratio 1.45, P = 0.04). In wild-type patients, a worse 5-year OS associated with a RS tumor was evident in univariable analysis (43.7% vs 55.5%, P = 0.02) and persisted in multivariable analysis (hazard ratio 1.49, P = 0.01). In contrast, among patients with KRAS mutated tumors, tumor laterality had no impact on 5-year OS, even in the univariable analysis (32.8% vs 34.0%, P = 0.38).\n This study demonstrated, for the first time, that the prognostic impact of primary tumor side differs according to KRAS mutational status. RS tumors were associated with worse survival only in patients with wild-type tumors.\n Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.\n\nMischinger, Hans-Joerg\n\nWagner, Doris\n\n\n"
},
{
"text": "\n187206\nProphylactic Antibiotic Regimens In Tumor Surgery (PARITY): a multi-center randomized controlled study comparing alternative antibiotic regimens in patients undergoing tumor resections with endoprosthetic replacements-a statistical analysis plan.\n\nSchneider, P\n\nHeels-Ansdell, D\n\nThabane, L\n\nGhert, M\n\nPARITY Investigators\n\nBeiträge in Fachzeitschriften\nISI:000632931400001\n33752752.0\n10.1186/s13063-021-05147-2\nPMC7983267\nLimb salvage with endoprosthetic reconstruction is the current standard practice for the surgical management of lower extremity bone tumors in skeletally mature patients and typically includes tumor resection followed by the functional limb reconstruction with modular metallic and polyethylene endoprosthetic implants. However, owing to the complexity and length of these procedures, as well as the immunocompromised nature of patients treated with chemotherapy, the risk of surgical site infection (SSI) is high. The primary research objective of the Prophylactic Antibiotic Regimens In Tumor Surgery (PARITY) trial is to assess whether a 5-day regimen of post-operative antibiotics decreases the risk of SSI at 1 year post-operatively compared to a 1-day regimen. This article describes the statistical analysis plan for the PARITY trial.\n The PARITY trial is an ongoing multi-center, blinded parallel two-arm randomized controlled trial (RCT) of 600 participants who have been diagnosed with a primary bone tumor, a soft tissue sarcoma that has invaded the bone or oligometastatic bone disease of the femur or tibia that requires surgical resection and endoprosthetic reconstruction. This article describes the overall analysis principles, including how participants will be included in each analysis, the presentation of results, adjustments for covariates, the primary and secondary outcomes, and their respective analyses. Additionally, we will present the planned sensitivity and sub-group analyses.\n Our prior work has demonstrated (1) high rates of SSI after the treatment of lower extremity tumors by surgical excision and endoprosthetic reconstruction, (2) highly varied opinion and practice among orthopedic oncologists with respect to prophylactic antibiotic regimens, (3) an absence of applicable RCT evidence, (4) extensive support from international investigators to participate in a RCT, and (5) the feasibility of conducting a definitive RCT to evaluate a 5-day regimen of post-operative antibiotics in comparison with a 1-day regimen.\n ClinicalTrials.gov NCT01479283 . Registered on 24 November 2011.\n\nBergovec, Marko\n\nLeithner, Andreas\n\n\n"
},
{
"text": "\n4280\nEffect of sildenafil on oesophageal motor function in healthy subjects and patients with oesophageal motor disorders.\n\nEherer, AJ\n\nSchwetz, I\n\nHammer, HF\n\nPetnehazy, T\n\nScheidl, SJ\n\nWeber, K\n\nKrejs, GJ\n\nBeiträge in Fachzeitschriften\nISI:000175812200007\n12010875.0\n10.1136/gut.50.6.758\nPMC1773249\nSildenafil blocks phosphodiesterase type 5 which degrades nitric oxide (NO) stimulated 3'5'-cyclic monophosphate (cGMP), thereby relaxing smooth muscle cells in various organs. We used sildenafil as a tool to investigate the role of the NO-cGMP pathway in the oesophagus of healthy volunteers and patients with hypercontractile oesophageal motility disorders.\n Six healthy male volunteers participated in a randomised double blind study on two separate days before and one hour after oral intake of either sildenafil 50 mg or placebo. Oesophageal manometry was performed to determine vector volume of the lower oesophageal sphincter (LOS) and pressure amplitudes of the oesophageal body. Four of the volunteers underwent 12 hour ambulatory oesophageal manometry on two separate days, once with sildenafil 50 mg and once with placebo. An activity index for spontaneous swallowing was calculated for every hour of the study. Eleven patients with hypercontractile oesophageal motility disorders took part in an open study of the effect of 50 mg sildenafil on manometric features of their disorder and on the clinical response to sildenafil taken as required.\n In healthy subjects, sildenafil significantly reduced LOS pressure vector volume and pressure amplitudes in the distal half of the oesophageal body. In three of four subjects the inhibitory effect of sildenafil lasted at least eight hours. In nine of 11 patients, manometric improvement after sildenafil was observed but only four had an improvement in oesophageal symptoms with sildenafil taken as required. Two of these four patients however experienced side effects and did not want to continue treatment.\n Sildenafil lowers LOS pressure and propulsive forces in the body of the oesophagus of healthy subjects as well as in patients with nutcracker oesophagus, hypertensive LOS, and achalasia. The effect of sildenafil on the oesophageal body may last for up to eight hours in healthy volunteers. A subset of patients with hypertensive LOS or nutcracker oesophagus may benefit from sildenafil but side effects are a limiting factor.\n\nEherer, Andreas\n\nHammer, Heinz\n\nKrejs, Günter Josef\n\nScheidl, Stefan\n\nWeber, Kurt\n\nZollner-Schwetz, Ines\n\n\n"
},
{
"text": "\n66917\nA controlled trial of recombinant human granulocyte-macrophage colony-stimulating factor after total body irradiation, high-dose chemotherapy, and autologous bone marrow transplantation for acute lymphoblastic leukemia or malignant lymphoma.\n\nLink, H\n\nBoogaerts, MA\n\nCarella, AM\n\nFerrant, A\n\nGadner, H\n\nGorin, NC\n\nHarabacz, I\n\nHarousseau, JL\n\nHervé, P\n\nHolldack, J\n\nLinkesch, W\n\net al.\n\nBeiträge in Fachzeitschriften\nISI:A1992JW43600005\n1421390.0\nNone\nNone\nInfections during granulocytopenia are major complications of autologous bone marrow transplantation (ABMT). Since recombinant human granulocyte-macrophage colony-stimulating factor (rhuGM-CSF) has proved to accelerate bone marrow recovery after cytostatic chemotherapy, we studied its effects on hematopoietic regeneration and on infectious complications after total body irradiation (TBI) and high-dose chemotherapy followed by ABMT. Eighty-one patients with acute lymphoblastic leukemia (ALL) in complete remission (CR) or with non-Hodgkin's lymphoma (NHL) in CR or partial remission were randomized in a double-blind, placebo-controlled trial. They received either rhuGM-CSF 250 micrograms/m2 (Escherichia coli-derived) daily by continuous infusion after ABMT, or placebo. Treatment was continued until the neutrophil counts reached greater than 500/microL for 1 week. The maximum treatment duration was 30 days. Thirty-nine patients in the rhuGM-CSF group and 40 patients in the placebo group were evaluable. The median time needed to reach a neutrophil count of 500/microL was 15 days with rhuGM-CSF and 28 days with placebo (P = .0001). Bacterial infections occurred in 14 (35.9%) of the patients with rhuGM-CSF and in 25 (62.5%) of the patients given the placebo (P = .024). Nine of the 14 bacterial infections in the rhuGM-CSF group and 20 of the 25 infections in the placebo group were diagnosed within the first 10 days after ABMT. Capillary leakage and a reversible fluid retention were seen in five of the rhuGM-CSF-treated patients. Patients treated with rhuGM-CSF had lower serum protein and albumin levels than patients in the placebo group. There was no statistically relevant difference in overall survival between the two groups (P = .47). Relapse occurred in 14 (34%) patients with rhuGM-CSF and in 18 (45%) patients with placebo. We conclude that continuous infusion of rhuGM-CSF after ABMT accelerates the regeneration of granulocytes and reduces the number of bacterial infections.\n\n\n"
},
{
"text": "\n107279\nInhibition of TNFalpha in vivo prevents hyperoxia-mediated activation of caspase 3 in type II cells\n\nGuthmann, F\n\nWissel, H\n\nSchachtrup, C\n\nTolle, A\n\nRudiger, M\n\nSpener, F\n\nRustow, B\n\nBeiträge in Fachzeitschriften\nISI:000227573100001\n15663790.0\n10.1186/1465-9921-6-10\nPMC548140\nBACKGROUND: The mechanisms during the initial phase of oxygen toxicity leading to pulmonary tissue damage are incompletely known. Increase of tumour necrosis factor alpha (TNFalpha) represents one of the first pulmonary responses to hyperoxia. We hypothesised that, in the initial phase of hyperoxia, TNFalpha activates the caspase cascade in type II pneumocytes (TIIcells). METHODS: Lung sections or freshly isolated TIIcells of control and hyperoxic treated rats (48 hrs) were used for the determination of TNFalpha (ELISA), TNF-receptor 1 (Western blot) and activity of caspases 8, 3, and 9 (colorimetrically). NF-kappaB activation was determined by EMSA, by increase of the p65 subunit in the nuclear fraction, and by immunocytochemistry using a monoclonal anti-NF-kappaB-antibody which selectively stained the activated, nuclear form of NF-kappa B. Apoptotic markers in lung tissue sections (TUNEL) and in TIIcells (cell death detection ELISA, Bax, Bcl-2, mitochondrial membrane potential, and late and early apoptotic cells) were measured using commercially available kits. RESULTS: In vivo, hyperoxia activated NF-kappaB and increased the expression of TNFalpha, TNF-receptor 1 and the activity of caspase 8 and 3 in freshly isolated TIIcells. Intratracheal application of anti-TNFalpha antibodies prevented the increase of TNFRI and of caspase 3 activity. Under hyperoxia, there was neither a significant change of cytosolic cytochrome C or of caspase 9 activity, nor an increase in apoptosis of TIIcells. Hyperoxia-induced activation of caspase 3 gradually decreased over two days of normoxia without increasing apoptosis. Therefore, activation of caspase 3 is a temporary effect in sublethal hyperoxia and did not mark the "point of no return" in TIIcells. CONCLUSION: In the initiation phase of pulmonary oxygen toxicity, an increase of TNFalpha and its receptor TNFR1 leads to the activation of caspase 8 and 3 in TIIcells. Together with the hyperoxic induced increase of Bax and the decrease of the mitochondrial membrane potential, activation of caspase 3 can be seen as sensitisation for apoptosis. Eliminating the TNFalpha effect in vivo by anti-TNFalpha antibodies prevents the pro-apoptotic sensitisation of TIIcells.\n\n\n"
},
{
"text": "\n154290\nPotentiation of anticancer effect of valproic acid, an antiepileptic agent with histone deacetylase inhibitory activity, by the cyclin-dependent kinase inhibitor P276-00 in human non-small-cell lung cancer cell lines.\n\nShirsath, N\n\nRathos, M\n\nChaudhari, U\n\nSivaramakrishnan, H\n\nJoshi, K\n\nBeiträge in Fachzeitschriften\nISI:000327365500005\n24051085.0\n10.1016/j.lungcan.2013.08.010\nNone\nP276-00 is a novel cyclin-dependent kinase (CDK) inhibitor is in Phase II clinical trials. Valproic acid (VPA), an antiepileptic agent has been associated with anticancer activity, through the inhibition of histone deacetylase I. Here we investigate the effect of the combination of VPA and P276-00, in non-small-cell lung cancer (NSCLC) cell lines.\n Cell growth inhibition was studied using the Propidium iodide (PI) assay. Cell cycle analysis and recovery were detected by flow cytometry. The expression levels of various proteins were detected by western blot. Inhibition of colony formation in H460 was checked in vitro. In vivo efficacy was studied in H460 xenograft model.\n The combination of P276-00 and VPA showed synergistic effect on p53+ and p53- NSCLC cell lines in antiproliferative assay at both constant and non-constant ratio with marked decrease in colony forming potential. Flow cytometric analysis confirmed a significant time dependent increase in apoptosis with 64% apoptotic population at 96 h compared to VPA (1%) and P276-00 (28%) alone (p < 0.0001). Incubation of the cells after treatment, in fresh medium without drugs, led to the recovery of cells treated with P276-00 alone but not the cells treated with the combination of both the drugs. The combination treatment up-regulated tumor suppressor proteins like p53, p21 and p27 along with down-regulation of proliferation and survival proteins viz. cyclin D1 and Bcl-2. This was also associated with the upregulation of the pro-apoptotic protein Bax and significant accumulation of hyperacetylated histones in the combination treatment. Interestingly, VPA in combination with P276-00 was much more effective as an antitumor agent than alone, in the H460 xenograft tumor model in SCID mice.\n This study indicates that the combination of HDAC inhibitor VPA with CDK inhibitor P276-00 is promising novel molecularly targeted therapeutic approach for NSCLC treatment.\n Copyright © 2013. Published by Elsevier Ireland Ltd.\n\n\n"
},
{
"text": "\n154409\nFractional flow reserve-guided PCI for stable coronary artery disease.\n\nDe Bruyne, B\n\nFearon, WF\n\nPijls, NH\n\nBarbato, E\n\nTonino, P\n\nPiroth, Z\n\nJagic, N\n\nMobius-Winckler, S\n\nRioufol, G\n\nWitt, N\n\nKala, P\n\nMacCarthy, P\n\nEngström, T\n\nOldroyd, K\n\nMavromatis, K\n\nManoharan, G\n\nVerlee, P\n\nFrobert, O\n\nCurzen, N\n\nJohnson, JB\n\nLimacher, A\n\nNüesch, E\n\nJüni, P\n\nFAME 2 Trial Investigators\n\nBeiträge in Fachzeitschriften\nISI:000342079700008\n25176289.0\n10.1056/NEJMoa1408758\nNone\nWe hypothesized that in patients with stable coronary artery disease and stenosis, percutaneous coronary intervention (PCI) performed on the basis of the fractional flow reserve (FFR) would be superior to medical therapy.\n In 1220 patients with stable coronary artery disease, we assessed the FFR in all stenoses that were visible on angiography. Patients who had at least one stenosis with an FFR of 0.80 or less were randomly assigned to undergo FFR-guided PCI plus medical therapy or to receive medical therapy alone. Patients in whom all stenoses had an FFR of more than 0.80 received medical therapy alone and were included in a registry. The primary end point was a composite of death from any cause, nonfatal myocardial infarction, or urgent revascularization within 2 years.\n The rate of the primary end point was significantly lower in the PCI group than in the medical-therapy group (8.1% vs. 19.5%; hazard ratio, 0.39; 95% confidence interval [CI], 0.26 to 0.57; P<0.001). This reduction was driven by a lower rate of urgent revascularization in the PCI group (4.0% vs. 16.3%; hazard ratio, 0.23; 95% CI, 0.14 to 0.38; P<0.001), with no significant between-group differences in the rates of death and myocardial infarction. Urgent revascularizations that were triggered by myocardial infarction or ischemic changes on electrocardiography were less frequent in the PCI group (3.4% vs. 7.0%, P=0.01). In a landmark analysis, the rate of death or myocardial infarction from 8 days to 2 years was lower in the PCI group than in the medical-therapy group (4.6% vs. 8.0%, P=0.04). Among registry patients, the rate of the primary end point was 9.0% at 2 years.\n In patients with stable coronary artery disease, FFR-guided PCI, as compared with medical therapy alone, improved the outcome. Patients without ischemia had a favorable outcome with medical therapy alone. (Funded by St. Jude Medical; FAME 2 ClinicalTrials.gov number, NCT01132495.).\n\nToth-Gayor, Gabor\n\n\n"
},
{
"text": "\n175250\nMinimal invasive plating of distal radius fractures. A safe procedure?\n\nNeubauer, T\n\nPlecko, M\n\nGrechenig, S\n\nHartmann, A\n\nOrtmaier, R\n\nHitzl, W\n\nFeigl, G\n\nBeiträge in Fachzeitschriften\nISI:000481724600024\n31108191.0\n10.1016/j.aanat.2019.05.001\nNone\nMinimal invasive plate osteosynthesis (MIPO) with preservation of the pronator quadratus (PQ) muscle represents a new technique for stabilization of distal radius fractures. However, the complex anatomy of the distal radius metaphysis requires implants with features that address all morphologic specifics of this area to avoid complications, which are still reported with this technique. It was the aim of our anatomic investigation to evaluate the feasibility of plate insertion via a minimal transverse approach as well as the risk of soft- tissues compromise with the use of an implant, which is only partially adapted to the characteristics of distal radius metaphysis.\n Twenty forearm specimens, conservated with Thiels method, have been used for this study. The majority (n = 19/20) of implants (2.4 mm small fragment juxta-articular locking compression/ LCP T-plate -5-hole; Depuy - Synthes®, Solothurn, Switzerland) could be inserted easily and all were seated proximal to the so called "watershed line" (n = 20/20).\n In a total of 8/20 specimens close contacts or potential compromise to neighboring soft- tissues was seen: perforation of the PQ muscle by the plate occurred in 2/20 specimens and was related to an extreme muscle morphology. In 7/20 specimens close contacts between the T-plate and other soft tissues were observed, which were exclusively located at the radial edge of the distal transverse bar. They affected the brachio-radialis tendon (elevation: 2/20, side-to-side contact: 3/20, overriding: 1/20) and the radial artery (elevation: 4/20, side-to-side contact: 2/20, overriding: 1/20). No significant differences of morphologic types of PQ muscle and the difficulty of plate insertion, adjustment on the bone, PQ muscle damage and contact to neighboring soft-tissues could be evaluated.\n Insertion of volar radius plates through a MIPO approach can be easily accomplished without detachment and damage to the PQ muscle even with grossly adapted implants. However, perfectly pre-shaped plates which are adapted to all anatomic aspects of the distal radius metaphysis are required to achieve optimal contact with the metaphyseal bone and to avoid potential complications.\n Copyright © 2019 Elsevier GmbH. All rights reserved.\n\nPlecko, Michael\n\n\n"
},
{
"text": "\n179209\nA Randomized Pilot Trial to Evaluate the Bioavailability of Natural versus Synthetic Vitamin B Complexes in Healthy Humans and Their Effects on Homocysteine, Oxidative Stress, and Antioxidant Levels.\n\nLindschinger, M\n\nTatzber, F\n\nSchimetta, W\n\nSchmid, I\n\nLindschinger, B\n\nCvirn, G\n\nStanger, O\n\nLamont, E\n\nWonisch, W\n\nBeiträge in Fachzeitschriften\nISI:000504263700003\n31915511.0\n10.1155/2019/6082613\nPMC6930747\nThe vitamin B complex comprises 8 different water-soluble constituents that humans must sequester from the diet. This pilot study compared natural versus synthetic vitamin B complexes for their bioavailability, accumulation, and their impact on antioxidants, homocysteine levels, and oxidative stress. We conducted a double-blind randomized clinical trial with thirty healthy participants. They were randomly assigned to group N (natural) and group S (synthetic). Vitamin B was ingested daily for 6 weeks in the range of about 2.5 times above the recommended daily allowance. Blood samples were taken at baseline, 1.5 h, 4 h, 7 h (diurnal), 6 w (discontinuation of supplements), and 8 w (washout). Blood levels of thiamine (B1), riboflavin (B2), pyridoxine (B6), folic acid (B9), cobalamin (B12), homocysteine, total antioxidants, peroxidase activity, polyphenols, and total peroxides were determined. Compared to initial values, serum levels of each B vitamin increased at the end of the supplementation period: i.e., B1 (+23% N; +27% S), B2 (+14% N; +13% S), B6 (+101% N; +101% S), B9 (+86% N; +153% S), and B12 (+16% N) (p < 0.05). Homocysteine (-13% N) decreased, while peroxidase activity (+41% S) and antioxidant capacity increased (+26% N). Short-term effects were already observed after 1.5 h for B9 (+238% N; +246% S) and after 4 h for vitamin B2 (+7% N; +8% S), B6 (+59% N; +51% S), and peroxidase activity (+58% N; +58% S). During the washout period, serum levels of B vitamins decreased except for thiamine and peroxidase activity, which increased further. This clinical pilot study revealed comparable bioavailability for both natural and synthetic B vitamins but did not show statistically noticeable differences between groups despite some favourable tendencies within the natural vitamin group, i.e., sustained effects for cobalamin and endogenous peroxidase activity and a decrease in homocysteine and oxidative stress levels.\n Copyright © 2019 Meinrad Lindschinger et al.\n\nCvirn, Gerhard\n\nTatzber, Franz\n\nWonisch, Willibald\n\n\n"
},
{
"text": "\n181371\nOutcome measurement in functional neurological disorder: a systematic review and recommendations.\n\nPick, S\n\nAnderson, DG\n\nAsadi-Pooya, AA\n\nAybek, S\n\nBaslet, G\n\nBloem, BR\n\nBradley-Westguard, A\n\nBrown, RJ\n\nCarson, AJ\n\nChalder, T\n\nDamianova, M\n\nDavid, AS\n\nEdwards, MJ\n\nEpstein, SA\n\nEspay, AJ\n\nGarcin, B\n\nGoldstein, LH\n\nHallett, M\n\nJankovic, J\n\nJoyce, EM\n\nKanaan, RA\n\nKeynejad, RC\n\nKozlowska, K\n\nLaFaver, K\n\nLaFrance, WC\n\nLang, AE\n\nLehn, A\n\nLidstone, S\n\nMaurer, CW\n\nMildon, B\n\nMorgante, F\n\nMyers, L\n\nNicholson, C\n\nNielsen, G\n\nPerez, DL\n\nPopkirov, S\n\nReuber, M\n\nRommelfanger, KS\n\nSchwingenshuh, P\n\nSerranova, T\n\nShotbolt, P\n\nStebbins, GT\n\nStone, J\n\nTijssen, MA\n\nTinazzi, M\n\nNicholson, TR\n\nBeiträge in Fachzeitschriften\nISI:000539061900013\n32111637.0\n10.1136/jnnp-2019-322180\nPMC7279198\nWe aimed to identify existing outcome measures for functional neurological disorder (FND), to inform the development of recommendations and to guide future research on FND outcomes.\n A systematic review was conducted to identify existing FND-specific outcome measures and the most common measurement domains and measures in previous treatment studies. Searches of Embase, MEDLINE and PsycINFO were conducted between January 1965 and June 2019. The findings were discussed during two international meetings of the FND-Core Outcome Measures group.\n Five FND-specific measures were identified-three clinician-rated and two patient-rated-but their measurement properties have not been rigorously evaluated. No single measure was identified for use across the range of FND symptoms in adults. Across randomised controlled trials (k=40) and observational treatment studies (k=40), outcome measures most often assessed core FND symptom change. Other domains measured commonly were additional physical and psychological symptoms, life impact (ie, quality of life, disability and general functioning) and health economics/cost-utility (eg, healthcare resource use and quality-adjusted life years).\n There are few well-validated FND-specific outcome measures. Thus, at present, we recommend that existing outcome measures, known to be reliable, valid and responsive in FND or closely related populations, are used to capture key outcome domains. Increased consistency in outcome measurement will facilitate comparison of treatment effects across FND symptom types and treatment modalities. Future work needs to more rigorously validate outcome measures used in this population.\n © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.\n\nSchwingenschuh, Petra\n\n\n"
},
{
"text": "\n2344\nSevere hypertriglyceridemia, reduced high density lipoprotein, and neonatal death in lipoprotein lipase knockout mice. Mild hypertriglyceridemia with impaired very low density lipoprotein clearance in heterozygotes.\n\nWeinstock, PH\n\nBisgaier, CL\n\nAalto-Setälä, K\n\nRadner, H\n\nRamakrishnan, R\n\nLevak-Frank, S\n\nEssenburg, AD\n\nZechner, R\n\nBreslow, JL\n\nBeiträge in Fachzeitschriften\nISI:A1995TK25700004\n8675619.0\n10.1172/JCI118319\nPMC185959\nLipoprotein lipase (LPL)-deficient mice have been created by gene targeting in embryonic stem cells. At birth, homozygous knockout pups have threefold higher triglycerides and sevenfold higher VLDL cholesterol levels than controls. When permitted to suckle, LPL-deficient mice become pale, then cyanotic, and finally die at approximately 18 h of age. Before death, triglyceride levels are severely elevated (15, 87 +/- 3, 05 vs 188 +/- 71 mg/dl in controls). Capillaries in tissues of homozygous knockout mice are engorged with chylomicrons. This is especially significant in the lung where marginated chylomicrons prevent red cell contact with the endothelium, a phenomenon which is presumably the cause of cyanosis and death in these mice. Homozygous knockout mice also have diminished adipose tissue stores as well as decreased intracellular fat droplets. By crossbreeding with transgenic mice expressing human LPL driven by a muscle-specific promoter, mouse lines were generated that express LPL exclusively in muscle but not in any other tissue. This tissue-specific LPL expression rescued the LPL knockout mice and normalized their lipoprotein pattern. This supports the contention that hypertriglyceridemia caused the death of these mice and that LPL expression in a single tissue was sufficient for rescue. Heterozygous LPL knockout mice survive to adulthood and have mild hypertriglyceridemia, with 1.5-2-fold elevated triglyceride levels compared with controls in both the fed and fasted states on chow, Western-type, or 10% sucrose diets. In vivo turnover studies revealed that heterozygous knockout mice had impaired VLDL clearance (fractional catabolic rate) but no increase in transport rate. In summary, total LPL deficiency in the mouse prevents triglyceride removal from plasma, causing death in the neonatal period, and expression of LPL in a single tissue alleviates this problem. Furthermore, half-normal levels of LPL cause a decrease in VLDL fractional catabolic rate and mild hypertriglyceridemia, implying that partial LPL deficiency has physiological consequences.\n\nLevak, Sanja\n\n\n"
},
{
"text": "\n81723\nThe mallet finger in children and adolescents\n\nSchmidt, B\n\nWeinberg, A\n\nFriedrich, H\n\nBeiträge in Fachzeitschriften\nISI:000257511400002\n18548355.0\n10.1055/s-2007-965475\nNone\nThe "mallet finger" in childhood and adolescence differs from the "mallet finger" in adults because of an open or gradually closing epiphysial plate. Thus, our results of conservative and operative treatment were evaluated particularly in consideration of an open growth plate. We analysed retrospectively the data of all patients who suffered a lesion at the extensor tendon insertion between 1996 and 2005 and were treated at our hospital. The coding was done according to age, sex, localisation, typing by Doyle, therapy and functional outcome. The typing by Doyle was extended through dividing type IV A into A1 (=Aitken I) and A2 (=Aitken II). Depending on extension deficits, the results were evaluated as very good (0 degrees ), medium (<15 degrees) and bad (>15 degrees). 76 patients, 45 boys and 31 girls aged 1 to 17 years (average age: 11.3) were studied. In consideration of the modified typing by Doyle, following distribution arose: type I (n=16), type II (n=14), type III (n=0), type IV A1 (n=17), type IV A2 (n=6), type IV B (n=21) and type IV C (n=2). A total of 50 patients was treated conservatively. Out of 26 operatively treated patients, 4 could be classified as type I, 12 as type II, 1 as type IV A1, 2 as type IV A2, 5 as type IV B, and 2 as type IV C. In 81.5 % of all patients no functional extension deficit was seen at the end of treatment; in patients treated conservatively, the percentage rate was 94 %. 6 patients, who were treated primarily operatively, showed poor functional outcome. 2 of these developed a suture track infection, in 2 cases chondral and osseous damage in the joint existed additionally, in one patient there was a comminuted fracture and in one patient a technical operative problem. Even in adolescence, conservative treatment of types I, IV A1 and A2, as well as IV B injuries is promising. A prerequisite is a consequent splint treatment and strict regular lateral X-ray control of the fracture fragment. At the beginning of treatment, we favour a plaster finger splint at an intrinsic plus position with hyperextension in the DIP joint.\n\nSchmidt, Barbara\n\nWeinberg, Annelie-Martina\n\n\n"
}
]
}