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"text": "\n2187\nRadiosurgery for epilepsy associated with cavernous malformation: retrospective study in 49 patients.\n\nRégis, J\n\nBartolomei, F\n\nKida, Y\n\nKobayashi, T\n\nVladyka, V\n\nLiscàk, R\n\nForster, D\n\nKemeny, A\n\nSchröttner, O\n\nPendl, G\n\nBeiträge in Fachzeitschriften\nISI:000090144400024\n11063101.0\n10.1097%2F00006123-200011000-00013\nNone\nOBJECTIVE: Microsurgical resection of a cavernous malformation (CM) with or without associated cortical resection can provide efficient treatment of drug-resistant associated epilepsy. To explore the potential alternative role of radiosurgery and to evaluate its safety and efficacy for this indication, we conducted a retrospective multicenter study. METHODS: We retrospectively reviewed the files of patients with long-lasting drug-resistant epilepsy, presumably caused by CM, who were treated by gamma knife (GK) surgery for the control of their epilepsy in five centers (Marseilles, Komaki City, Prague, Graz, and Sheffield). A satisfactory follow-up was available for 49 patients (mean follow-up period, 23.66 +/- 13 mo). The mean duration of epilepsy before the GK procedure was 7.5 (+/-9.3) years. The mean frequency of seizures was 6.9/month (+/-14). The mean marginal radiation dose was 19.17 Gy +/- 4.4 (range, 11.25-36). Among the 49 patients, 17 (35%) had a CM located in or involving a highly functional area. RESULTS: At the last follow-up examination, 26 patients (53%) were seizure-free (Engel's Class I), including 24 in Class IA (49%) and 2 patients with occasional auras (Class IB, 4%). A highly significant decrease in the number of seizures was achieved in 10 patients (Class IIB, 20%). The remaining 13 patients (26%) showed little or no improvement. The mediotemporal site was associated with a higher risk of failure. One patient bled during the observation period, and another experienced radiation-induced edema with transient aphasia. Postradiosurgery excision was performed in five patients, and a second radiosurgical treatment was carried out in one patient. CONCLUSION: This series is the first to specifically evaluate the capability of GK surgery to safely and efficiently treat epilepsy associated with CM. Seizure control can be reached when a good electroclinical correlation exists between CM location and epileptogenic zone. Although we do not recommend GK surgery for prevention of bleeding for a CM that has not bled previously, our findings suggest that GK surgery can be proposed for the treatment of epilepsy when the CM is located in a highly functional area.\n\n\n"
},
{
"text": "\n3724\nEffects of weight loss on leptin, sex hormones, and measures of adiposity in obese children.\n\nSudi, KM\n\nGallistl, S\n\nBorkenstein, MH\n\nPayerl, D\n\nAigner, R\n\nMöller, R\n\nTafeit, E\n\nBeiträge in Fachzeitschriften\nISI:000169301400019\n11444441.0\n10.1385%2FENDO%3A14%3A3%3A429\nNone\nAdipose tissue influences steroid conversion by paracrine and autocrine mechanisms. Leptin is secreted by adipocytes and influenced by sex hormones and adiposity. Short-term weight loss in the treatment of childhood obesity reduces leptin and adipose tissue. We therefore asked, Do alterations in sex hormones occur owing to weight loss? and can these alterations be explained by changes in fat mass or sc fat and are alterations in sex hormones directly related to the fall in leptin? Twenty obese boys and 40 obese girls were studied before and after 3 wk of low-calorie diet and physical activity. The weight loss program significantly lowered fat mass, abdominal fat distribution, sc fat (all p < 0.0001), leptin, insulin, and estradiol (all p < 0.0001) but not testosterone. Changes in leptin were related to changes in body mass and to changes in fat mass in boys. In girls, changes in leptin were related to changes in sc fatness and also to changes in insulin. In boys, the reduction in sc fat was positively correlated to changes in testosterone (r = 0.54; p < 0.01) and inversely related to the fall in estradiol (r = -0.41; p < 0.05). In girls, changes in testosterone (r = 0.33; p < 0.05) and in estradiol (r = 0.40; p < 0.01) were related to changes in insulin. Stepwise regression showed that initial leptin was the best determinant for the fall in leptin (adjusted R2 = 0.87; p < 0.0001). The results show that alterations in sex hormones are related to changes in certain fat depots in boys whereas in girls changes in insulin might participate in changes in sex hormones. A greater fall in leptin owing to short-term weight loss is not associated with greater alterations in sex hormones and initial leptin is the best determinant to explain the variability in changes in leptin. The possibility of sex differences in changes in sex hormones secondary to the reduction in fatness warrants further study.\n\nAigner, Reingard\n\nBorkenstein, Helmuth Martin\n\nGallistl, Siegfried\n\nPayerl, Doris\n\nTafeit, Erwin\n\n\n"
},
{
"text": "\n4847\nRole of prolactin receptor and CD25 in protection of circulating T lymphocytes from apoptosis in patients with breast cancer.\n\nBauernhofer, T\n\nKuss, I\n\nFriebe-Hoffmann, U\n\nBaum, AS\n\nDworacki, G\n\nVonderhaar, BK\n\nWhiteside, TL\n\nBeiträge in Fachzeitschriften\nISI:000182891200025\n12698200.0\n10.1038/sj.bjc.6600860\nPMC2747567\nProlactin (PRL) has been reported to inhibit apoptosis in various cell types and to serve as a cofactor in the upregulation of CD25 on T cells during activation. We investigated a possible relation between prolactin receptor (PRL-R) or IL-2 receptor alpha (IL-2Ralpha, CD25) expression on circulating T lymphocytes and their apoptosis in patients with breast cancer. Peripheral blood mononuclear cells obtained from 25 patients, 25 normal controls (NC) and three cord blood samples were evaluated for Annexin V binding and expression of CD95, CD25, and PRL-R on CD3(+) T cells by multicolour flow cytometry. Plasma levels of PRL, sCD95L, and sIL-2R were determined in patients and controls and related to T-cell apoptosis. The ability of PRL to protect T cells from apoptosis induced by various agents was also studied. Expression of PRL-R on the surface of T cells was comparable in patients with breast cancer and NC, but PRL plasma levels in patients were significantly lower (P<0.05). In patients, 18+/-11% (mean+/-s.d.) of CD3(+) cells bound Annexin V, compared to 9+/-6% in NC (P<0.0004). Percentages of CD3(+)Fas(+) and CD3(+)CD25(+) cells were higher in the peripheral circulation of patients than NC (P<0.0001 and <0.04, respectively). Levels of sFasL were lowest in plasma of the patients with the highest proportions of CD3(+)Fas(+) T cells. Most T cells undergoing apoptosis were CD3(+)CD25(-) in patients, and the proportion of CD3(+)CD25(-) Annexin V(+) cells was significantly increased in patients compared to NC (P<0.006). Ex vivo PRL protected T cells from starvation-induced or anti-CD3Ab-induced but not from Fas/FasL-dependent apoptosis. These results indicate that expression of CD25 but not of PRL-R on the surface of activated T lymphocytes appears to be involved in modulating Fas/Fas - ligand interactions, which are, in part, responsible for apoptosis of T lymphocytes and excessive turnover of immune cells in the circulation of patients with breast cancer.\n\nBauernhofer, Thomas\n\n\n"
},
{
"text": "\n4932\nSerum osteoprotegerin is a major determinant of bone density development and prevalent vertebral fracture status following cardiac transplantation.\n\nFahrleitner, A\n\nPrenner, G\n\nLeb, G\n\nTscheliessnigg, KH\n\nPiswanger-Sölkner, C\n\nObermayer-Pietsch, B\n\nPortugaller, HR\n\nBerghold, A\n\nDobnig, H\n\nBeiträge in Fachzeitschriften\nISI:000184082700013\n12584041.0\n10.1016%2FS8756-3282%2802%2900926-2\nNone\nOsteoprotegerin (OPG) is an antiresorptive cytokine and a key regulator of osteoclastogenesis and activity. Since OPG is downregulated by glucocorticoids and cyclosporine A in vitro we examined whether immunosuppressive therapy would play a role in the development of transplantation osteoporosis. We enrolled 57 cardiac transplant recipients (median time since transplantation, 3.2 years (1.1-11.5 years)) in this cross-sectional study. Standardized spinal X-rays as well as hip bone density measurements were performed in all patients. Serum OPG was determined using a commercially available ELISA. Vertebral fractures were present in 56% of the patients. Bone densities of all femoral neck subregions were correlated to serum OPG concentrations (r values between 0.40 and 0.48, all P < 0.005). Multiple regression analysis revealed OPG levels to be independently correlated to femoral neck Z scores (r = 0.49, P = 0.002). After adjustment for age, BMI, neck Z score, renal function, and months since transplantation, serum OPG was the only significant predictor of prevalent vertebral fractures (P = 0.001). In a separate 6-month prospective study of 14 heart transplant recipients receiving calcium and vitamin D serum OPG levels fell by 41% (P = 0.0004) after 3 months and 47% (P = 0.0001) after 6 months following cardiac transplantation. Bone loss at the lumbar spine and femoral neck after 6 months was correlated to the decrease in serum OPG at 6 months (r = 0.82, P < 0.0001, and r = 0.60, P = 0.02, respectively) as well as 3 months after cardiac transplantation (r = 0.65, P = 0.01, and r = 0.69, P = 0.006, respectively). Serum OPG alone accounted for 67% of the variance of lumbar spine bone density changes over the first 6 months posttransplantation. We conclude that serum OPG levels decline consistently in all patients following initiation of immunosuppressive therapy and are independently correlated with changes in bone density. We hypothesize that OPG plays a major role in the development of transplantation osteoporosis.\n\nBerghold, Andrea\n\nFahrleitner-Pammer, Astrid\n\nObermayer-Pietsch, Barbara\n\nPiswanger-Solkner, Claudia\n\nPortugaller, Rupert\n\nPrenner, Günther\n\n\n"
},
{
"text": "\n69408\nMechanisms of postsystolic thickening in ischemic myocardium: mathematical modelling and comparison with experimental ischemic substrates.\n\nClaus, P\n\nWeidemann, F\n\nDommke, C\n\nBito, V\n\nHeinzel, FR\n\nD'hooge, J\n\nSipido, KR\n\nSutherland, GR\n\nBijnens, B\n\nBeiträge in Fachzeitschriften\nISI:000252114600013\n17673356.0\n10.1016/j.ultrasmedbio.2007.06.003\nNone\nIn the setting of regional ischemia, the "at-risk" myocardium exhibits a flow-related reduction in systolic thickening with a concomitant development of abnormal thickening after aortic valve closure (postsystolic thickening [PST]). With the introduction of high time-resolution ultrasonic-based strain/strain-rate imaging, this short lived phenomenon can be measured accurately in the clinical setting. The mechanisms underlying this ischemia-related PST are poorly understood and both active and passive etiologies have been proposed. This study aims at elucidating the potential mechanisms behind PST in the intact heart. A theoretical model, describing active force development, elasticity and segment interaction has been developed to simulate radial deformation during systole and iso-volumetric relaxation. Simulation results have been compared with experimental deformation curves obtained from postero-basal segments of a pig model undergoing varying controlled ischemic challenges. Three forms of regional ischemia could be simulated by varying the model parameters of the ischemic segments: (i) chronic regional hypo-perfusion (reduced and prolonged active force development; preserved elasticity); (ii) acute short-lived ischemia-temporary vessel occlusion (no active force development; preserved elasticity); and (iii) chronic myocardial infarction (no active force development; decreased elasticity). For all ischemic substrates, the simulated curves closely correlate to the deformation measured in the corresponding porcine models without the need for active force development during the occurrence of PST. This suggests that segment interaction is the key determinant in the development of PST. Thus, in all instances, at the time of its manifestation, ischemia-related PST could be explained in a unified way as a passive phenomenon that was the result of elastic segment interaction. Its occurrence originates from the end-systolic inhomogeneous state where neighboring segments have a different wall thickness. The occurrence of these differences at end-systole depends on the presence of regional differences within the ventricle in the magnitude and duration of the developed contraction force during the first part of systole, the elasticity of the ischemic segment and the left-ventricular pressure.\n\n\n"
},
{
"text": "\n90192\nStress Doppler echocardiography in relatives of patients with idiopathic and familial pulmonary arterial hypertension: results of a multicenter European analysis of pulmonary artery pressure response to exercise and hypoxia.\n\nGrunig, E\n\nWeissmann, S\n\nEhlken, N\n\nFijalkowska, A\n\nFischer, C\n\nFourme, T\n\nGalie, N\n\nGhofrani, A\n\nHarrison, RE\n\nHuez, S\n\nHumbert, M\n\nJanssen, B\n\nKober, J\n\nKoehler, R\n\nMachado, RD\n\nMereles, D\n\nNaeije, R\n\nOlschewski, H\n\nProvencher, S\n\nReichenberger, F\n\nRetailleau, K\n\nRocchi, G\n\nSimonneau, G\n\nTorbicki, A\n\nTrembath, R\n\nSeeger, W\n\nBeiträge in Fachzeitschriften\nISI:000264928800009\n19307479.0\n10.1161/CIRCULATIONAHA.108.800938\nNone\nBackground-This large, prospective, multicentric study was performed to analyze the distribution of tricuspid regurgitation velocity (TRV) values during exercise and hypoxia in relatives of patients with idiopathic and familial pulmonary arterial hypertension (PAH) and in healthy control subjects. We tested the hypothesis that relatives of idiopathic/familial PAH patients display an enhanced frequency of hypertensive TRV response to stress and that this response is associated with mutations in the bone morphogenetic protein receptor II (BMPR2) gene. Methods and Results-TRV was estimated by Doppler echocardiography during supine bicycle exercise in normoxia and during 120 minutes of normobaric hypoxia (FIO(2) = 12%; approximate to 4500 m) in 291 relatives of 109 PAH patients and in 191 age-matched control subjects. Mean maximal TRVs were significantly higher in PAH relatives during both exercise and hypoxia. During exercise, 10% of control subjects but 31.6% of relatives (P < 0.0001) exceeded the 90% quantile of mean maximal TRV seen in control subjects. Hypoxia revealed hypertensive TRV in 26% of relatives (P = 0.0029). Among control subjects, TRV at rest was not related to age, sex, body mass index, systemic blood pressure, smoking status, or heart rate. Within kindreds identified as harboring deleterious mutations of the BMPR2 gene, a hypertensive TRV response occurred significantly more often compared with those without detected mutations. Conclusions-Pulmonary hypertensive response to exercise and hypoxia in idiopathic/familial PAH relatives appears as a genetic trait with familial clustering, being correlated to but not caused by a BMPR2 mutation. The suitability of this trait to predict manifest PAH development should be addressed in long-term follow-up studies. (Circulation. 2009; 119: 1747-1757.)\n\nOlschewski, Horst\n\n\n"
},
{
"text": "\n117932\nMonocytes do not make mast cells when cultured in the presence of SCF. Characterization of the circulating mast cell progenitor as a c-kit+, CD34+, Ly-, CD14-, CD17-, colony-forming cell.\n\nAgis, H\n\nWillheim, M\n\nSperr, WR\n\nWilfing, A\n\nKrömer, E\n\nKabrna, E\n\nSpanblöchl, E\n\nStrobl, H\n\nGeissler, K\n\nSpittler, A\n\nBoltz-Nitulescu, G\n\nMajdic, O\n\nLechner, K\n\nValent, P\n\nBeiträge in Fachzeitschriften\nISI:A1993MB16300029\n7691941.0\nNone\nNone\nMast cells (MC3) belong to the hemopoietic system and arise from hemopoietic precursor cells. Human MC progenitors can be detected in the bone marrow as well as in the peripheral blood (pb) and are responsive to the mast cell growth factor SCF, the ligand of the c-kit tyrosine kinase receptor. However, little is known about the subsets of cells that become committed to and differentiate into mature human MC. In this study, the identity of the circulating MC progenitor, previously felt to be a monocyte (Mo) or basophil (Ba), was investigated. For this purpose, CD14+ pb monocytes, CD17+ pb basophils and CD34+ cord blood cells were purified to homogeneity (> 95%) from mononuclear cells (normal adult donors, n = 17, cord blood, n = 2) by counter-flow centrifugation followed by cell sorting with mAb. In the presence of rhSCF, MC developed in long term suspension culture from pure CD34+ cells but not from pure Mo, pure Ba, or Ly (MC-tryptase levels on day 42: CD14+ Mo: 3.7 +/- 0.8 vs CD17+ Ba: 3.2 +/- 0.5 vs Ly: 2.0 +/- 1.5 vs control: 196.5 +/- 92.5 ng/ml, p < 0.001). Depletion of CD34+ cells from MNC resulted in a loss of MC in long term suspension culture, whereas depletion of either Mo, Ba, or Ly did not. In methyl-cellulose cultures in the presence of rhSCF, MC and tryptase could be detected in pure (CFU-mast) and mixed (CFU-myeloid/mast) MC colonies. Together, MC do not originate from circulating Mo, Ba, or Ly. The circulating MC progenitor is a CD34+, c-kit+, Ly-, CD14-, CD17- colony-forming cell. This is the first definitive demonstration that mast cells are replenished directly from early hemopoietic progenitors and thus form a unique cell lineage within the hemopoietic system.\n\nStrobl, Herbert\n\n\n"
},
{
"text": "\n138500\nMulticentre prospective validation of a urinary peptidome-based classifier for the diagnosis of type 2 diabetic nephropathy.\n\nSiwy, J\n\nSchanstra, JP\n\nArgiles, A\n\nBakker, SJ\n\nBeige, J\n\nBoucek, P\n\nBrand, K\n\nDelles, C\n\nDuranton, F\n\nFernandez-Fernandez, B\n\nJankowski, ML\n\nAl Khatib, M\n\nKunt, T\n\nLajer, M\n\nLichtinghagen, R\n\nLindhardt, M\n\nMaahs, DM\n\nMischak, H\n\nMullen, W\n\nNavis, G\n\nNoutsou, M\n\nOrtiz, A\n\nPersson, F\n\nPetrie, JR\n\nRoob, JM\n\nRossing, P\n\nRuggenenti, P\n\nRychlik, I\n\nSerra, AL\n\nSnell-Bergeon, J\n\nSpasovski, G\n\nStojceva-Taneva, O\n\nTrillini, M\n\nvon der Leyen, H\n\nWinklhofer-Roob, BM\n\nZürbig, P\n\nJankowski, J\n\nBeiträge in Fachzeitschriften\nISI:000339948100019\n24589724.0\n10.1093/ndt/gfu039\nPMC4118140\nDiabetic nephropathy (DN) is one of the major late complications of diabetes. Treatment aimed at slowing down the progression of DN is available but methods for early and definitive detection of DN progression are currently lacking. The 'Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy In TYpe 2 diabetic patients with normoalbuminuria trial' (PRIORITY) aims to evaluate the early detection of DN in patients with type 2 diabetes (T2D) using a urinary proteome-based classifier (CKD273).\n In this ancillary study of the recently initiated PRIORITY trial we aimed to validate for the first time the CKD273 classifier in a multicentre (9 different institutions providing samples from 165 T2D patients) prospective setting. In addition we also investigated the influence of sample containers, age and gender on the CKD273 classifier.\n We observed a high consistency of the CKD273 classification scores across the different centres with areas under the curves ranging from 0.95 to 1.00. The classifier was independent of age (range tested 16-89 years) and gender. Furthermore, the use of different urine storage containers did not affect the classification scores. Analysis of the distribution of the individual peptides of the classifier over the nine different centres showed that fragments of blood-derived and extracellular matrix proteins were the most consistently found.\n We provide for the first time validation of this urinary proteome-based classifier in a multicentre prospective setting and show the suitability of the CKD273 classifier to be used in the PRIORITY trial.\n © The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.\n\n\n"
},
{
"text": "\n147455\nRepeat HIV-testing is associated with an increase in behavioral risk among men who have sex with men: a cohort study.\n\nHoenigl, M\n\nAnderson, CM\n\nGreen, N\n\nMehta, SR\n\nSmith, DM\n\nLittle, SJ\n\nBeiträge in Fachzeitschriften\nISI:000367627700001\n26444673.0\n10.1186/s12916-015-0458-5\nPMC4596465\nThe Center for Disease Control and Prevention recommends that high-risk groups, like sexually active men who have sex with men (MSM), receive HIV testing and counseling at least annually. The objective of this study was to investigate the relationship between voluntary repeat HIV testing and sexual risk behavior in MSM receiving rapid serologic and nucleic acid amplification testing.\n We performed a cohort study to analyze reported risk behavior among MSM receiving the "Early Test", a community-based, confidential acute and early HIV infection screening program in San Diego, California, between April 2008 and July 2014. The study included 8, 35 MSM receiving 17, 33 "Early Tests". A previously published risk behavior score for HIV acquisition in MSM (i.e. Menza score) was chosen as an outcome to assess associations between risk behaviors and number of repeated tests.\n At baseline, repeat-testers (n = 3, 02) reported more male partners and more condomless receptive anal intercourse (CRAI) when compared to single-testers (n = 5, 05, all P <0.001). In 2, 57 repeat testers there was a strong association observed between repeated HIV tests obtained and increased risk behavior, with number of male partners, CRAI with high risk persons, non-injection stimulant drug use, and sexually transmitted infections all increasing between the first and last test. There was also a linear increase of risk (i.e. high Menza scores) with number of tests up to the 17th test. In the multivariable mixed effects model, more HIV tests (OR = 1.18 for each doubling of the number of tests, P <0.001) and younger age (OR = 0.95 per 5-year increase, P = 0.006) had significant associations with high Menza scores.\n This study found that the highest risk individuals for acquiring HIV (e.g. candidates for antiretroviral pre-exposure prophylaxis) can be identified by their testing patterns. Future studies should delineate causation versus association to improve prevention messages delivered to repeat testers during HIV testing and counseling sessions.\n\nHönigl, Martin\n\n\n"
},
{
"text": "\n159490\nPotential Targets' Analysis Reveals Dual PI3K/mTOR Pathway Inhibition as a Promising Therapeutic Strategy for Uterine Leiomyosarcomas-an ENITEC Group Initiative.\n\nCuppens, T\n\nAnnibali, D\n\nCoosemans, A\n\nTrovik, J\n\nTer Haar, N\n\nColas, E\n\nGarcia-Jimenez, A\n\nVan de Vijver, K\n\nKruitwagen, RP\n\nBrinkhuis, M\n\nZikan, M\n\nDundr, P\n\nHuvila, J\n\nCarpén, O\n\nHaybaeck, J\n\nMoinfar, F\n\nSalvesen, HB\n\nStukan, M\n\nMestdagh, C\n\nZweemer, RP\n\nMassuger, LF\n\nMallmann, MR\n\nWardelmann, E\n\nMints, M\n\nVerbist, G\n\nThomas, D\n\nGommé, E\n\nHermans, E\n\nMoerman, P\n\nBosse, T\n\nAmant, F\n\nBeiträge in Fachzeitschriften\nISI:000396015600019\n28232476.0\n10.1158/1078-0432.CCR-16-2149\nNone\nPurpose: Uterine sarcomas are rare and heterogeneous tumors characterized by an aggressive clinical behavior. Their high rates of recurrence and mortality point to the urgent need for novel targeted therapies and alternative treatment strategies. However, no molecular prognostic or predictive biomarkers are available so far to guide choice and modality of treatment.Experimental Design: We investigated the expression of several druggable targets (phospho-S6S240 ribosomal protein, PTEN, PDGFR-α, ERBB2, and EGFR) in a large cohort of human uterine sarcoma samples (288), including leiomyosarcomas, low-grade and high-grade endometrial stromal sarcomas, undifferentiated uterine sarcomas, and adenosarcomas, together with 15 smooth muscle tumors of uncertain malignant potential (STUMP), 52 benign uterine stromal tumors, and 41 normal uterine tissues. The potential therapeutic value of the most promising target, p-S6S240, was tested in patient-derived xenograft (PDX) leiomyosarcoma models.Results: In uterine sarcomas and STUMPs, S6S240 phosphorylation (reflecting mTOR pathway activation) was associated with higher grade (P = 0.001) and recurrence (P = 0.019), as shown by logistic regression. In addition, p-S6S240 correlated with shorter progression-free survival (P = 0.034). Treatment with a dual PI3K/mTOR inhibitor significantly reduced tumor growth in 4 of 5 leiomyosarcoma PDX models (with tumor shrinkage in 2 models). Remarkably, the 4 responding models showed basal p-S6S240 expression, whereas the nonresponding model was scored as negative, suggesting a role for p-S6S240 in response prediction to PI3K/mTOR inhibition.Conclusions: Dual PI3K/mTOR inhibition represents an effective therapeutic strategy in uterine leiomyosarcoma, and p-S6S240 expression is a potential predictive biomarker for response to treatment. Clin Cancer Res; 23(5); 1274-85. ©2017 AACR.\n ©2017 American Association for Cancer Research.\n\nHaybäck, Johannes\n\nMoinfar, Farid\n\n\n"
},
{
"text": "\n167793\nAdvanced cutaneous squamous cell carcinoma: A retrospective analysis of patient profiles and treatment patterns-Results of a non-interventional study of the DeCOG.\n\nHillen, U\n\nLeiter, U\n\nHaase, S\n\nKaufmann, R\n\nBecker, J\n\nGutzmer, R\n\nTerheyden, P\n\nKrause-Bergmann, A\n\nSchulze, HJ\n\nHassel, J\n\nLahner, N\n\nWollina, U\n\nZiller, F\n\nUtikal, J\n\nHafner, C\n\nUlrich, J\n\nMachens, HG\n\nWeishaupt, C\n\nHauschild, A\n\nMohr, P\n\nPföhler, C\n\nMaurer, J\n\nWolff, P\n\nWindemuth-Kieselbach, C\n\nSchadendorf, D\n\nLivingstone, E\n\nDermatologic Cooperative Oncology Group (DeCOG)\n\nBeiträge in Fachzeitschriften\nISI:000432907800005\n29665511.0\n10.1016/j.ejca.2018.01.075\nNone\nAdvanced cutaneous squamous cell carcinoma (aSCC) is an area of unmet medical need and no treatment standards are established. Recently, an anti-PD-1 inhibitor received FDA breakthrough therapy designation. The aim of the study was to describe the clinical course, therapeutic management and prognosis of aSCC under real-life conditions.\n In a retrospective study performed in 24 German and Austrian hospitals and doctor's offices, patient and tumour characteristics of patients diagnosed with aSCC between January 1, 2010 and December 31, 2011 and their disease course was documented. Advanced SCC comprised either locally advanced SCCs (laSCC) or metastatic SCCs (mSCC) with any kind of metastatic spread.\n Data of 190 patients with aSCC were analysed. Median age at time of diagnosis of aSCC was 78 years. LaSCC was diagnosed in 76 patients (40%), 114 patients (60%) had mSCC. Once diagnosed with laSCC, most patients (59%) did not receive any therapy, whereas in 92% of mSCC patients at least one type of therapy was performed. Only 32 patients (29 mSCC, 3 laSCC) received systemic antitumour therapies, mostly EGFR inhibitor-based regimens. Mean duration of response was short (17-months laSCC patients, 3-months mSCC patients). Only 2 patients achieved a complete response, 27% had a partial response, 43% disease stabilisation. At diagnosis of aSCC, ECOG status was 0-1 in most patients. Non-malignant comorbidities influenced the decision on SCC-specific therapy in 39 patients (21%).\n Our data show the high medical need for efficient and tolerable antitumour therapies and demonstrate that despite older age and comorbidities, most patients can be expected to be fit for treatment. This study provides a historical context for emerging aSCC treatments.\n Copyright © 2018 Elsevier Ltd. All rights reserved.\n\n\n"
},
{
"text": "\n177338\n2019 updated consensus statement on the diagnosis and treatment of pediatric pulmonary hypertension: The European Pediatric Pulmonary Vascular Disease Network (EPPVDN), endorsed by AEPC, ESPR and ISHLT.\n\nHansmann, G\n\nKoestenberger, M\n\nAlastalo, TP\n\nApitz, C\n\nAustin, ED\n\nBonnet, D\n\nBudts, W\n\nD'Alto, M\n\nGatzoulis, MA\n\nHasan, BS\n\nKozlik-Feldmann, R\n\nKumar, RK\n\nLammers, AE\n\nLatus, H\n\nMichel-Behnke, I\n\nMiera, O\n\nMorrell, NW\n\nPieles, G\n\nQuandt, D\n\nSallmon, H\n\nSchranz, D\n\nTran-Lundmark, K\n\nTulloh, RMR\n\nWarnecke, G\n\nWåhlander, H\n\nWeber, SC\n\nZartner, P\n\nBeiträge in Fachzeitschriften\nISI:000484756800001\n31495407.0\n10.1016/j.healun.2019.06.022\nNone\nThe European Pediatric Pulmonary Vascular Disease Network is a registered, non-profit organization that strives to define and develop effective, innovative diagnostic methods and treatment options in all forms of pediatric pulmonary hypertensive vascular disease, including pulmonary hypertension (PH) associated with bronchopulmonary dysplasia, PH associated with congenital heart disease (CHD), persistent PH of the newborn, and related cardiac dysfunction. The executive writing group members conducted searches of the PubMed/MEDLINE bibliographic database (1990-2018) and held face-to-face and web-based meetings. Ten section task forces voted on the updated recommendations, based on the 2016 executive summary. Clinical trials, meta-analyses, guidelines, and other articles that include pediatric data were searched using the term "pulmonary hypertension" and other keywords. Class of recommendation (COR) and level of evidence (LOE) were assigned based on European Society of Cardiology/American Heart Association definitions and on pediatric data only, or on adult studies that included >10% children or studies that enrolled adults with CHD. New definitions by the World Symposium on Pulmonary Hypertension 2018 were included. We generated 10 tables with graded recommendations (COR/LOE). The topics include diagnosis/monitoring, genetics/biomarkers, cardiac catheterization, echocardiography, cardiac magnetic resonance/chest computed tomography, associated forms of PH, intensive care unit/lung transplantation, and treatment of pediatric PH. For the first time, a set of specific recommendations on the management of PH in middle- and low-income regions was developed. Taken together, these executive, up-to-date guidelines provide a specific, comprehensive, detailed but practical framework for the optimal clinical care of children and young adults with PH.\n Copyright © 2019. Published by Elsevier Inc.\n\nKoestenberger, Martin\n\n\n"
},
{
"text": "\n181350\nThe role of environmental stress and DNA methylation in the longitudinal course of bipolar disorder.\n\nComes, AL\n\nCzamara, D\n\nAdorjan, K\n\nAnderson-Schmidt, H\n\nAndlauer, TFM\n\nBudde, M\n\nGade, K\n\nHake, M\n\nKalman, JL\n\nPapiol, S\n\nReich-Erkelenz, D\n\nKlohn-Saghatolislam, F\n\nSchaupp, SK\n\nSchulte, EC\n\nSenner, F\n\nJuckel, G\n\nSchmauss, M\n\nZimmermann, J\n\nReimer, J\n\nReininghaus, E\n\nAnghelescu, IG\n\nKonrad, C\n\nThiel, A\n\nFigge, C\n\nvon Hagen, M\n\nKoller, M\n\nDietrich, DE\n\nStierl, S\n\nScherk, H\n\nWitt, SH\n\nSivalingam, S\n\nDegenhardt, F\n\nForstner, AJ\n\nRietschel, M\n\nNothen, MM\n\nWiltfang, J\n\nFalkai, P\n\nSchulze, TG\n\nHeilbronner, U\n\nBeiträge in Fachzeitschriften\nISI:000512780000001\nNone\n10.1186/s40345-019-0176-6\nNone\nBackground Stressful life events influence the course of affective disorders, however, the mechanisms by which they bring about phenotypic change are not entirely known. Methods We explored the role of DNA methylation in response to recent stressful life events in a cohort of bipolar patients from the longitudinal PsyCourse study (n = 96). Peripheral blood DNA methylomes were profiled at two time points for over 850, 00 methylation sites. The association between impact ratings of stressful life events and DNA methylation was assessed, first by interrogating methylation sites in the vicinity of candidate genes previously implicated in the stress response and, second, by conducting an exploratory epigenome-wide association analysis. Third, the association between epigenetic aging and change in stress and symptom measures over time was investigated. Results Investigation of methylation signatures over time revealed just over half of the CpG sites tested had an absolute difference in methylation of at least 1% over a 1-year period. Although not a single CpG site withstood correction for multiple testing, methylation at one site (cg15212455) was suggestively associated with stressful life events (p < 1.0 x 10(-5)). Epigenetic aging over a 1-year period was not associated with changes in stress or symptom measures. Conclusions To the best of our knowledge, our study is the first to investigate epigenome-wide methylation across time in bipolar patients and in relation to recent, non-traumatic stressful life events. Limited and inconclusive evidence warrants future longitudinal investigations in larger samples of well-characterized bipolar patients to give a complete picture regarding the role of DNA methylation in the course of bipolar disorder.\n\nReininghaus, Eva\n\n\n"
},
{
"text": "\n181599\nThe IN.PACT DEEP Clinical Drug-Coated Balloon Trial: 5-Year Outcomes.\n\nZeller, T\n\nMicari, A\n\nScheinert, D\n\nBaumgartner, I\n\nBosiers, M\n\nVermassen, FEG\n\nBanyai, M\n\nShishehbor, MH\n\nWang, H\n\nBrodmann, M\n\nIN.PACT DEEP Trial Investigators\n\nBeiträge in Fachzeitschriften\nISI:000513913200008\n32081236.0\n10.1016/j.jcin.2019.10.059\nNone\nThe goal of this study was to evaluate the 5-year follow-up data of the IN.PACT DEEP (Randomized IN.PACT Amphirion Drug-Coated Balloon [DCB] vs. Standard Percutaneous Transluminal Angioplasty [PTA] for the Treatment of Below-the-Knee Critical Limb Ischemia [CLI]) trial.\n Initial studies from randomized controlled trials have shown comparable short-term outcomes of DCB angioplasty versus PTA in patients with CLI with infrapopliteal disease. However, the long-term safety and effectiveness of DCB angioplasty remain unknown in this patient population.\n IN.PACT DEEP was an independently adjudicated prospective, multicenter, randomized controlled trial that enrolled 358 subjects with CLI. Subjects were randomized 2:1 to DCB angioplasty or PTA. Assessments through 5 years included freedom from clinically driven target lesion revascularization, amputation, and all-cause death. Additional assessments were conducted to identify risk factors for death and major amputation, including paclitaxel dose tercile.\n Freedom from clinically driven target lesion revascularization through 5 years was 70.9% and 76.0% (log-rank p = 0.406), and the incidence of the safety composite endpoint was 59.8% and 57.5% (log-rank p = 0.309) in the DCB angioplasty and PTA groups, respectively. The rate of major amputation was 15.4% for DCB angioplasty compared with 10.6% for PTA (log-rank p = 0.108). Given the recent concern regarding a late mortality signal in patients treated with paclitaxel-coated devices, additional analyses from this study showed no increase in all-cause mortality with DCB angioplasty (39.4%) compared with PTA (44.9%) (log-rank p = 0.727). Predictors of mortality included age, Rutherford category >4, and previous revascularization but not paclitaxel by dose tercile.\n Tibial artery revascularization in patients with CLI using DCB angioplasty resulted in comparable long-term safety and effectiveness as PTA. Paclitaxel exposure was not related to increased risk for amputation or all-cause mortality at 5-year follow-up. (Study of IN.PACT Amphirion™ Drug Eluting Balloon vs. Standard PTA for the Treatment of Below the Knee Critical Limb Ischemia [INPACT-DEEP]; NCT00941733).\n Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.\n\nBrodmann, Marianne\n\n\n"
},
{
"text": "\n187229\nSlack K<sup>+</sup> channels attenuate NMDA-induced excitotoxic brain damage and neuronal cell death.\n\nEhinger, R\n\nKuret, A\n\nMatt, L\n\nFrank, N\n\nWild, K\n\nKabagema-Bilan, C\n\nBischof, H\n\nMalli, R\n\nRuth, P\n\nBausch, AE\n\nLukowski, R\n\nBeiträge in Fachzeitschriften\nNone\n33817875.0\n10.1096/fj.202002308RR\nNone\nThe neuronal Na+ -activated K+ channel Slack (aka Slo2.2, KNa 1.1, or Kcnt1) has been implicated in setting and maintaining the resting membrane potential and defining excitability and firing patterns, as well as in the generation of the slow afterhyperpolarization following bursts of action potentials. Slack activity increases significantly under conditions of high intracellular Na+ levels, suggesting this channel may exert important pathophysiological functions. To address these putative roles, we studied whether Slack K+ channels contribute to pathological changes and excitotoxic cell death caused by glutamatergic overstimulation of Ca2+ - and Na+ -permeable N-methyl-D-aspartic acid receptors (NMDAR). Slack-deficient (Slack KO) and wild-type (WT) mice were subjected to intrastriatal microinjections of the NMDAR agonist NMDA. NMDA-induced brain lesions were significantly increased in Slack KO vs WT mice, suggesting that the lack of Slack renders neurons particularly susceptible to excitotoxicity. Accordingly, excessive neuronal cell death was seen in Slack-deficient primary cerebellar granule cell (CGC) cultures exposed to glutamate and NMDA. Differences in neuronal survival between WT and Slack KO CGCs were largely abolished by the NMDAR antagonist MK-801, but not by NBQX, a potent and highly selective competitive antagonist of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type ionotropic glutamate receptors. Interestingly, NMDAR-evoked Ca2+ signals did not differ with regard to Slack genotype in CGCs. However, real-time monitoring of K+ following NMDAR activation revealed a significant contribution of this channel to the intracellular drop in K+ . Finally, TrkB and TrkC neurotrophin receptor transcript levels were elevated in NMDA-exposed Slack-proficient CGCs, suggesting a mechanism by which this K+ channel contributes to the activation of the extracellular-signal-regulated kinase (Erk) pathway and thereby to neuroprotection. Combined, our findings suggest that Slack-dependent K+ signals oppose the NMDAR-mediated excitotoxic neuronal injury by promoting pro-survival signaling via the BDNF/TrkB and Erk axis.\n © 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.\n\nMalli, Roland\n\n\n"
},
{
"text": "\n4407\nManagement of acute coronary syndromes. Variations in practice and outcome; findings from the Global Registry of Acute Coronary Events (GRACE).\n\nFox, KA\n\nGoodman, SG\n\nKlein, W\n\nBrieger, D\n\nSteg, PG\n\nDabbous, O\n\nAvezum, A\n\nBeiträge in Fachzeitschriften\nISI:000177498100008\n12127920.0\n10.1053/euhj.2001.3081\nNone\nDespite advances in the treatment of acute coronary syndromes based on randomized trial data and published guidelines, the extent to which such treatments are applied in practice remains uncertain. Data from clinical trials derive from selected geographical areas and in highly selected populations of patients, and hence may not reflect the overall population. The aim of the study was to investigate variations in hospital management and outcome using unselected data collected in the prospective Global Registry of Acute Coronary Events (GRACE).Methods and Results The 95 hospitals in GRACE were organized into 18 population-based clusters in 14 countries. Information was recorded about patient management and outcome during hospitalization and after discharge. Data on treatments administered. were analysed by baseline condition, hospital type, by the presence or absence of a catheterization laboratory, and by geographical region. Of 11 543 patients, 44% had an admission diagnosis of unstable angina, 36% presented with myocardial infarction, 9% were admitted to rule out a myocardial infarction, 7% had chest pain and 4% were hospitalized for 'other cardiac' and 'non-cardiac' diagnoses. Of the total GRACE population 38% had a final diagnosis of unstable angina, 30% ST-segment elevation myocardial infarction, 25% non-ST-segment elevation myocardial infarction, and 7% of 'other cardiac' and 'non-cardiac' final diagnoses. The event rates for hospital death or reinfarction were six and 2% for non-ST-segment elevation myocardial infarction, seven and 3% for ST-segment elevation myocardial infarction, and 3% hospital death for unstable angina. The use of aspirin was similar across all hospital types and geographical regions. In contrast, the use of percutaneous coronary intervention and glycoprotein IIb/IIIa inhibitors was higher (P<0(.)0001) in teaching hospitals and hospitals with catheterization laboratories and was also higher in the United States. At discharge a higher percentage (P<0(.)0001) of patients received angiotensin-converting enzyme inhibitors in hospitals without catheterization laboratories. The use of statins was lower in non-teaching hospitals and in centres without a catheterization laboratory.\n\n\n"
},
{
"text": "\n5207\nThe PARK8 locus in autosomal dominant parkinsonism: confirmation of linkage and further delineation of the disease-containing interval.\n\nZimprich, A\n\nMüller-Myhsok, B\n\nFarrer, M\n\nLeitner, P\n\nSharma, M\n\nHulihan, M\n\nLockhart, P\n\nStrongosky, A\n\nKachergus, J\n\nCalne, DB\n\nStoessl, J\n\nUitti, RJ\n\nPfeiffer, RF\n\nTrenkwalder, C\n\nHomann, N\n\nOtt, E\n\nWenzel, K\n\nAsmus, F\n\nHardy, J\n\nWszolek, Z\n\nGasser, T\n\nBeiträge in Fachzeitschriften\nISI:000187723500002\n14691730.0\n10.1086/380647\nPMC1181898\nRecently, a new locus (PARK8) for autosomal dominant parkinsonism has been identified in one large Japanese family. Linkage has been shown to a 16-cM centromeric region of chromosome 12, between markers D12S1631 and D12S339. We tested 21 white families with Parkinson disease and an inheritance pattern compatible with autosomal dominant transmission for linkage in this region. Criteria for inclusion were at least three affected individuals in more than one generation. A total of 29 markers were used to saturate the candidate region. One hundred sixty-seven family members were tested (84 affected and 83 unaffected). Under the assumption of heterogeneity and through use of an affecteds-only model, a maximum multipoint LOD score of 2.01 was achieved in the total sample, with an estimated proportion of families with linkage of 0.32. This LOD score is significant for linkage in a replication study and corresponds to a P value of.0047. Two families (family A [German Canadian] and family D [from western Nebraska]) reached significant linkage on their own, with a combined maximum multipoint LOD score of 3.33, calculated with an affecteds-only model (family A: LOD score 1.67, P=.0028; family D: LOD score 1.67, P=.0028). When a penetrance-dependent model was calculated, the combined multipoint LOD score achieved was 3.92 (family A: LOD score 1.68, P=.0027; family D: LOD score 2.24, P=.0007). On the basis of the multipoint analysis for the combined families A and D, the 1-LOD support interval suggests that the most likely disease location is between a CA repeat polymorphism on genomic clone AC025253 (44.5 Mb) and marker D12S1701 (47.7 Mb). Our data provide evidence that the PARK8 locus is responsible for the disease in a subset of families of white ancestry with autosomal dominant parkinsonism, suggesting that it could be a more common locus.\n\nHomann, Carl\n\nWenzel, Karoline\n\n\n"
},
{
"text": "\n5795\nCapacitive requirement for acute in-patient care of patients with psychosomatic diseases in bavaria\n\nKappauf, H\n\nVon Rad, M\n\nGaluska, J\n\nIrle, H\n\nKindt, H\n\nNosper, M\n\nKapfhammer, HP\n\nWolfersdorf, M\n\nZaudig, M\n\nBeiträge in Fachzeitschriften\nISI:000175784200011\n12012268.0\n10.1055/s-2002-28527\nNone\nEstimations of the requirement for acute in-patient care of patients with psychosomatic diseases in Bavaria have to rely on respective data on their incidence and prevalence as valid requirement data are missing. The required capacity of in-patient beds depends on several, inconsistently figured parameters: hospitalization rate, length of stay, occupancy rate. Based on conservative assumptions the hospitalization rate was calculated to be at least 1.3 admissions per 1000 and for adequate treatment the average length of stay should not be limited to less than 50 days. In order to avoid unnecessary delay of treatment a realistic occupancy rate has to be 90 %. Thus the minimal capacity for in-patient care is assessed to be 2453 beds. At present patients with psychosomatic diseases in Bavaria receive in-patient treatment in psychosomatic departments of general hospitals, hospitals and rehab clinics of psychosomatic and psychotherapeutic medicine, and in hospitals of psychiatry and psychotherapy, in each with a different focus. When the expertise was drafted these acute care and rehab hospitals provided some 2500 beds - with only 76 beds in general hospitals. For quality assessment of the available beds for in-patient care and future planning minimal standards of structural quality have to be consented. At present it is not possible to make a clear and substantial distinction between the treatment for patients with psychosomatic diseases in acute-care hospitals and in psychosomatic rehab clinics respectively. Thus, the necessary in-patient rehab capacity can only be assessed roughly. The existing pluralism of the in-patient care providing system for patients with psychosomatic diseases is considered to be appropriate for different needs of this patient group. In the future excellent care for this patient group will acknowledge options for a more flexible and interconnected care-providing system. This is a publication of the complete expertise by the project group "Acute In-patient Care for Patients with Psychosomatic Diseases in Bavaria" which has been handed to the Bavarian Ministry of Social Affairs in December 1999.\n\nKapfhammer, Hans-Peter\n\n\n"
},
{
"text": "\n17986\nMRI results from the European Study on Intravenous Immunoglobulin in Secondary Progressive Multiple Sclerosis (ESIMS).\n\nFazekas, F\n\nSørensen, PS\n\nFilippi, M\n\nRopele, S\n\nLin, X\n\nKoelmel, HW\n\nFernandez, O\n\nPozzilli, C\n\nO'Connor, P\n\nEnriquez, MM\n\nHommes, OR\n\nESIMS\n\nBeiträge in Fachzeitschriften\nISI:000230730900011\n16042226.0\n10.1191/1352458505ms1196oa\nNone\nBackground. Monthly application of high-dose intravenous immunoglobulin (IVIG) to patients with secondary progressive multiple sclerosis (MS) showed no clinical benefit in the European Study on Immunoglobulin in MS (ESIMS). Magnetic resonance imaging (MRI) results may provide insights into the morphologic consequences of such treatment. Methods: A total of 318 patients (mean age 44 +/- 7 years) were enrolled in 31 European and Canadian centres and treated monthly with 1 g/kg body weight of IVIG or equivalent amounts of albumin 0.1% for 27 months. MRI was performed at baseline and after 12 and 24 months and comprised of conventional dual-echo T2-weighted and T1-weighted scans before and after application of 0.1 mmol/kg Gd-DTPA. Results: Similar to clinical variables, MRI measures at baseline were well comparable between treatment groups except for a somewhat lower mean number of contrast-enhancing lesions and number of active scans in IVIG-treated patients. Over the trial period there was almost no change of the T2-lesion load and the 'black hole'volume in both treatment groups and the cumulative number of contrast-enhancing lesions were similar. There was only a trend for fewer new or enlarged T2-lesions in IVIG patients, which disappeared after correction for the imbalance in the number of contrast-enhancing lesions at baseline. Brain volume in terms of a partial cerebral fraction decreased significantly less with IVIG than placebo treatment (final visit. -0.62 +/- 0.88% versus -0.88 +/- 0.91%, P=0.009). This difference remained statistically significant with correction for active lesions at baseline (P=0.02) and was seen primarily in male patients and those with an Expanded Disability Status Scale score >= 6 and no relapses in the two years before the study. Conclusion: The absence of significant differences in conventional MRI measures between both treatment groups parallels the negative clinical results of ESIMS. The causes for and possible long-term clinical effects of a lower rate of brain volume loss in IVIG patients should be explored further.\n\nFazekas, Franz\n\nRopele, Stefan\n\n\n"
},
{
"text": "\n21958\nAmplification of the pulmonary vasodilatory response to inhaled iloprost by subthreshold phosphodiesterase types 3 and 4 inhibition in severe pulmonary hypertension.\n\nGhofrani, HA\n\nRose, F\n\nSchermuly, RT\n\nOlschewski, H\n\nWiedemann, R\n\nWeissmann, N\n\nSchudt, C\n\nTenor, H\n\nSeeger, W\n\nGrimminger, F\n\nBeiträge in Fachzeitschriften\nISI:000179322900014\n12441759.0\n10.1097/01.CCM.0000034559.25857.90\nNone\nOBJECTIVE: Aerosolized iloprost causes specific pulmonary vasodilation for about 60 mins in patients with severe primary and secondary pulmonary hypertension. Repeated daily inhalations are currently in use for chronic treatment. The aim of the current study was to evaluate if phosphodiesterase type 3 and 4 inhibition might amplify the prostanoid effect on pulmonary vasodilatation by stabilization of intracellular second messenger cyclic adenosine monophosphate. DESIGN: Uncontrolled clinical trial. SETTING: Medical intensive care unit, Department of Internal Medicine, University Hospital, Giessen, Germany. PATIENTS: A total of 11 patients with precapillary pulmonary hypertension (eight with primary pulmonary hypertension; one with pulmonary hypertension associated with calcinosis, Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia [CREST syndrome]; one with pulmonary hypertension associated with systemic lupus erythematodes, and one with chronic pulmonary embolism) were included. All were classified as New York Heart Association class III or class IV. INTERVENTIONS: During right heart catheterization, a single inhalation with iloprost (1.4 microg per inhalation) was performed, and hemodynamics and gas exchange variables were recorded for the next 2.5 hrs. After the iloprost effects had completely leveled off, the dual-selective phosphodiesterase types 3 and 4 inhibitor tolafentrine was infused in seven patients and aerosolized in five patients at doses that were per se ineffective (80 mg per 2.5 hrs intravenously; approximately 0.8 mg deposited by aerosol), followed by a second iloprost inhalation procedure. MEASUREMENTS: Decrease in pulmonary vascular resistance, duration of drug effect, safety, and tolerability of combined pharmacologic intervention. RESULTS: The decrease in pulmonary vascular resistance to sole iloprost nebulization lasted for approximately 60 mins. This response was enhanced and prolonged to approximately 120 mins in the presence of both infused and aerosolized tolafentrine, without loss of pulmonary selectivity. No adverse events were observed. CONCLUSIONS: These data support the principle that subthreshold selective phosphodiesterase types 3 and 4 inhibition amplifies the lung vasodilatory response to inhaled iloprost, with minute doses being sufficient via the inhalative route.\n\nOlschewski, Horst\n\n\n"
}
]
}