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"text": "\n40145\nMetabolism and DNA binding studies of 4-hydroxyestradiol and estradiol-3,4-quinone in vitro and in female ACI rat mammary gland in vivo.\n\nLi, KM\n\nTodorovic, R\n\nDevanesan, P\n\nHigginbotham, S\n\nKöfeler, H\n\nRamanathan, R\n\nGross, ML\n\nRogan, EG\n\nCavalieri, EL\n\nBeiträge in Fachzeitschriften\nISI:000188792800017\n14578156.0\n10.1093/carcin/bgg191\nNone\nStudies of estrogen metabolism, formation of DNA adducts, carcinogenicity, cell transformation and mutagenicity have led to the hypothesis that reaction of certain estrogen metabolites, predominantly catechol estrogen-3, -quinones, with DNA can generate the critical mutations initiating breast, prostate and other cancers. The endogenous estrogens estrone (E1) and estradiol (E2) are oxidized to catechol estrogens (CE), 2- and 4-hydroxylated estrogens, which can be further oxidized to CE quinones. To determine possible DNA adducts of E1(E2)-3, -quinones [E1(E2)-3, -Q], we reported previously that the reaction of E1(E2)-3, -Q with dG produces the depurinating adduct 4-hydroxyE1(E2)-1-N7Gua [4-OHE1(E2)-1-N7Gua] by 1, -Michael addition (Stack et al., Chem. Res. Toxicol., 1996, 9, 851). We report here that reaction of E1(E2)-3, -Q with Ade results in the formation of 4-OHE1(E2)-1-N3Ade by 1, -Michael addition. The N7Gua and N3Ade depurinating adducts formed both in vitro and in rat mammary gland in vivo were analyzed by HPLC with electrochemical detection and, for some samples, by LC/MS/MS. When E2-3, -Q was reacted with DNA in vitro, the depurinating adducts 4-OHE1(E2)-1-N3Ade and 4-OHE1(E2)-1-N7Gua, which are rapidly lost from DNA by cleavage of the glycosyl bond, were formed (>99% of the total adducts), as well as traces of stable adducts, which remain in DNA unless removed by repair. Similar results were obtained when 4-OHE2 was oxidized by horseradish peroxidase, lactoperoxidase, tyrosinase or phenobarbital-induced rat liver microsomes in the presence of DNA. When 4-OHE2 or E2-3, -Q was injected into the mammary glands of female ACI rats in vivo and the mammary tissue was excised 1 h later, the depurinating adducts 4-OHE2-1-N3Ade and 4-OHE2-1-N7Gua constituted >99% of the total adducts formed. In addition, 4-OHE2 conjugates formed by reaction of E2-3, -Q with glutathione were also detected. These results demonstrate that the 4-CE are metabolized to CE-3, -Q, which react with DNA to form primarily depurinating adducts. These adducts can generate the critical mutations that initiate cancer (Chakravarti et al., Oncogene, 2001, 20, 7945; Chakravarti et al., Proc. Am. Assoc. Cancer Res., 2003, 44, 180).\n\nKöfeler, Harald\n\n\n"
},
{
"text": "\n64239\nEffects of cytokine application on glucocorticoid secretion in an animal model for systemic scleroderma.\n\nBrezinschek, HP\n\nGruschwitz, M\n\nSgonc, R\n\nMoormann, S\n\nHerold, M\n\nGershwin, ME\n\nWick, G\n\nBeiträge in Fachzeitschriften\nISI:A1993MQ70700007\n8155253.0\n10.1006/jaut.1993.1060\nNone\nWe previously reported on an altered immune-endocrine feedback loop via the hypothalamo-pituitary-adrenal (HPA) axis in Obese strain (OS) chickens afflicted with spontaneous autoimmune thyroiditis. These animals are deficient in plasma corticosterone increase after antigenic challenge or application of cytokine-containing conditioned medium of mitogen-stimulated spleen cells (CM). To investigate whether the impaired ability to respond to cytokines with glucocorticoid-increasing factor (GIF) activity, e.g. interleukin 1 (IL 1), is restricted to OS chickens as a model for an organ-specific autoimmune disease, we extended our experiments to another autoimmune-prone animal strain, the chickens of the University of California at Davis line 200 (UCD-200). These animals develop an inherited inflammatory fibrotic disease that closely resembles human progressive systemic sclerosis (scleroderma). Application of GIF-containing CM to UCD-200 chickens leads to a transient increase in glucocorticoid serum levels within 1-2 hours comparable to that of controls. But, while corticosterone levels in the latter returned to normal baseline levels after 4 hours, they were still elevated in autoimmune chickens. Although the peak of the glucocorticoid hormone serum concentrations was equal to that of controls, UCD-200 had to secrete twice as much adrenocorticotropic hormone to achieve this corticosterone serum level due to an apparent hyporesponsiveness of the adrenal gland to this secretagogue. The altered cytokine-induced glucocorticoid secretion is found in early as well as in chronic, sclerotic stages of the disease. Cellular alterations in the peripheral blood of UCD-200 chickens during the prolonged elevated corticosterone section, i.e. between 2-4 hours after CM application, are characterized by a significant decrease in the percentage of CD4+ and CD8+ cells. Furthermore, a significant increase in B cells up to 24 hours with a maximum after 1 hour was found. The proliferative response to the mitogen concanavalin A of peripheral mononuclear cells was inversely correlated to the serum corticosterone level, showing a permanent decrease of 80-90% after 1-4 hours in autoimmune animals. This functional alteration in UCD-200 was accompanied by an 80% decrease in serum interleukin 2 (sIL 2) activity 4 hours after CM application. Twenty-four hours later an eight-fold increase in sIL 2 rebound activity was found, indicating that the inhibitory effect of corticosterone in UCD-200 chickens is not long-lasting.\n\nBrezinsek, Hans-Peter\n\n\n"
},
{
"text": "\n65473\nA randomized multi-center phase II trial of the angiogenesis inhibitor Cilengitide (EMD 121974) and gemcitabine compared with gemcitabine alone in advanced unresectable pancreatic cancer\n\nFriess, H\n\nLangrehr, JM\n\nOettle, H\n\nRaedle, J\n\nNiedergethmann, M\n\nDittrich, C\n\nHossfeld, DK\n\nStoger, H\n\nNeyns, B\n\nHerzog, P\n\nPiedbois, P\n\nDobrowolski, F\n\nScheithauer, W\n\nHawkins, R\n\nKatz, F\n\nBalcke, P\n\nVermorken, J\n\nvan Belle, S\n\nDavidson, N\n\nEsteve, AA\n\nCastellano, D\n\nKleeff, J\n\nTempia-Caliera, AA\n\nKovar, A\n\nNippgen, J\n\nBeiträge in Fachzeitschriften\nISI:000243435300001\n17156477.0\n10.1186/1471-2407-6-285\nPMC1764757\nAnti-angiogenic treatment is believed to have at least cystostatic effects in highly vascularized tumours like pancreatic cancer. In this study, the treatment effects of the angiogenesis inhibitor Cilengitide and gemcitabine were compared with gemcitabine alone in patients with advanced unresectable pancreatic cancer.\n A multi-national, open-label, controlled, randomized, parallel-group, phase II pilot study was conducted in 20 centers in 7 countries. Cilengitide was administered at 600 mg/m2 twice weekly for 4 weeks per cycle and gemcitabine at 1000 mg/m2 for 3 weeks followed by a week of rest per cycle. The planned treatment period was 6 four-week cycles. The primary endpoint of the study was overall survival and the secondary endpoints were progression-free survival (PFS), response rate, quality of life (QoL), effects on biological markers of disease (CA 19.9) and angiogenesis (vascular endothelial growth factor and basic fibroblast growth factor), and safety. An ancillary study investigated the pharmacokinetics of both drugs in a subset of patients.\n Eighty-nine patients were randomized. The median overall survival was 6.7 months for Cilengitide and gemcitabine and 7.7 months for gemcitabine alone. The median PFS times were 3.6 months and 3.8 months, respectively. The overall response rates were 17% and 14%, and the tumor growth control rates were 54% and 56%, respectively. Changes in the levels of CA 19.9 went in line with the clinical course of the disease, but no apparent relationships were seen with the biological markers of angiogenesis. QoL and safety evaluations were comparable between treatment groups. Pharmacokinetic studies showed no influence of gemcitabine on the pharmacokinetic parameters of Cilengitide and vice versa.\n There were no clinically important differences observed regarding efficacy, safety and QoL between the groups. The observations lay in the range of other clinical studies in this setting. The combination regimen was well tolerated with no adverse effects on the safety, tolerability and pharmacokinetics of either agent.\n\nStoeger, Herbert\n\n\n"
},
{
"text": "\n116975\nRadiation synovectomy using 165Dy ferric-hydroxide and oxidative DNA damage in patients with different types of arthritis.\n\nPirich, C\n\nPilger, A\n\nSchwameis, E\n\nGermadnik, D\n\nPrüfert, U\n\nHavlik, E\n\nLang, S\n\nKvaternik, H\n\nFlores, JA\n\nAngelberger, P\n\nWanivenhaus, A\n\nRüdiger, HW\n\nSinzinger, H\n\nBeiträge in Fachzeitschriften\nISI:000085259500012\n10688107.0\nNone\nNone\nRadiation synovectomy is an effective treatment for chronic synovitis refractory to pharmacological treatment in patients with rheumatoid or seronegative arthritis. Concerns persist about possible radiation-induced cytogenetic damage after radiation synovectomy leading to recommendations to use this technique only in the elderly. Micronucleus (MN) frequency in lymphocytes and urinary excretion of 8-hydroxy-2'-deoxyguanosine (8OHdG) as an indicator of cellular oxidative DNA base damage are biomarkers of radiation-induced cytogenetic damage. The course of both biomarkers was studied in patients with different types of chronic synovitis undergoing radiation synovectomy with very short-lived Dy-165-ferric-hydroxide (DFH). Methods: Radiation synovectomy of the knee was performed in 13 men and 12 women (mean age, 44 +/- 15 y) using a mean activity of 9.48 +/- 1.65 GBq Dy-165-DFH in 27 consecutive treatments. MN frequency in lymphocytes and urinary excretion of 8OHdG, measured by high-performance liquid chromatography, were assessed before and 4 (MN only) and 20 h after radiation synovectomy. Results: Urinary excretion of 8OHdG in patients (in mu mol/mol creatinine; pretreatment mean, 3.1 +/- 3.4; median, 2.27) was not significantly different from that in healthy volunteers (mean, 2.0 +/- 1.2; median, 1.87) and not altered by radiation synovectomy (post-treatment mean, 2.5 +/- 1.5; median, 2.04, NS). An increase in 8OHdG levels after radiation synovectomy of more than 1 SD was found in only 1 patient, who experienced leakage to the lymph nodes but who already had elevated urinary 8OHdG levels before treatment. The frequency of MN/500 binucleated cells (BNCs) was slightly lower in patients (pretreatment mean, 4.3 +/- 2.6; median, 4.25) than in healthy volunteers (mean, 5.4 +/- 2.3; median, 5.3) and did not significantly change after therapy, either (4-h post-treatment mean, 3.9 +/- 2.1, median, 3.8; 20-h post-treatment mean, 4.1 +/- 2, median 3.8 MN/500 BNC). In 22 of 27 treatments, no leakage to nontarget organs could be monitored, whereas leakage to the local lymph nodes and the liver was detected after 5 treatments. Conclusion: Radiation synovectomy using Dy-165-DFH causes no significant radiation burden to most patients as indicated by the absence of adverse changes in levels of biomarkers of cytogenetic damage and a low incidence of leakage. These data suggest that the risk of malignancy may not be elevated.\n\nKvaternik, Herbert\n\n\n"
},
{
"text": "\n157333\nVisual Acuity Loss and Associated Risk Factors in the Retrospective Progression of Stargardt Disease Study (ProgStar Report No. 2).\n\nKong, X\n\nStrauss, RW\n\nMichaelides, M\n\nCideciyan, AV\n\nSahel, JA\n\nMuñoz, B\n\nWest, S\n\nScholl, HP\n\nProgStar Study Group\n\nBeiträge in Fachzeitschriften\nISI:000389508500018\n27378015.0\n10.1016/j.ophtha.2016.05.027\nNone\nTo examine the association between characteristics of Stargardt disease and visual acuity (VA), to estimate the longitudinal rate of VA loss, and to identify risk factors for VA loss.\n Retrospective, multicenter cohort study.\n A total of 176 patients (332 eyes) with molecularly and clinically confirmed Stargardt disease enrolled from the United States and Europe.\n Standardized data report forms were used to collect retrospective data on participants' characteristics and best-corrected or presenting VA from medical charts. Linear models with generalized estimating equations were used to estimate the cross-sectional associations, and linear mixed effects models were used to estimate the longitudinal VA loss.\n Yearly change in VA.\n The median duration of observation was 3.6 years. At baseline, older age of symptom onset was associated with better VA, and a longer duration of symptoms was associated with worse VA. Longitudinal analysis estimated an average of 0.3 lines loss (P < 0.0001) per year overall, but the rate varied according to baseline VA: (1) eyes with baseline VA ≥20/25 (N = 53) declined at a rate of approximately 1.0 line per year; (2) eyes with VA between 20/25 and 20/70 (N = 65) declined at a rate of approximately 0.9 lines per year; (3) eyes with VA between 20/70 and 20/200 (N = 163) declined at a rate of 0.2 lines per year; and (4) eyes with VA worse than 20/200 (n = 49) improved at a rate of 0.5 lines per year. Older age of onset was associated with slower VA loss: Patients with onset age >30 years showed 0.4 lines slower change of VA per year (P = 0.01) compared with patients with onset age ≤14 years.\n Given the overall slow rate of VA loss, VA is unlikely to be a sensitive outcome measure for treatment trials of Stargardt disease. However, given the faster decline in younger patients and those with no or mild visual impairment, VA may be a potential outcome measure for trials targeting such subgroups of patients. These observations will need to be assessed in a prospective study bearing in mind the inherent limitations of retrospective datasets.\n Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.\n\nStrauß, Rupert\n\n\n"
},
{
"text": "\n157393\nLevosimendan in patients with left ventricular systolic dysfunction undergoing cardiac surgery on cardiopulmonary bypass: Rationale and study design of the Levosimendan in Patients with Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery Requiring Cardiopulmonary Bypass (LEVO-CTS) trial.\n\nMehta, RH\n\nVan Diepen, S\n\nMeza, J\n\nBokesch, P\n\nLeimberger, JD\n\nTourt-Uhlig, S\n\nSwartz, M\n\nParrotta, J\n\nJankowich, R\n\nHay, D\n\nHarrison, RW\n\nFremes, S\n\nGoodman, SG\n\nLuber, J\n\nToller, W\n\nHeringlake, M\n\nAnstrom, KJ\n\nLevy, JH\n\nHarrington, RA\n\nAlexander, JH\n\nLEVO-CTS Investigators\n\nBeiträge in Fachzeitschriften\nISI:000389136600008\n27914501.0\n10.1016/j.ahj.2016.09.001\nNone\nLow cardiac output syndrome is associated with increased mortality and occurs in 3% to 14% of patients undergoing cardiac surgery on cardiopulmonary bypass (CPB). Levosimendan, a novel calcium sensitizer and KATP channel activator with inotropic, vasodilatory, and cardioprotective properties, has shown significant promise in reducing the incidence of low cardiac output syndrome and related adverse outcomes in patients undergoing cardiac surgery on CPB.\n LEVO-CTS is a phase 3 randomized, controlled, multicenter study evaluating the efficacy, safety, and cost-effectiveness of levosimendan in reducing morbidity and mortality in high-risk patients with reduced left ventricular ejection fraction (≤35%) undergoing cardiac surgery on CPB. Patients will be randomly assigned to receive either intravenous levosimendan (0.2 μg kg-1 min-1 for the first hour followed by 0.1 μg/kg for 23hours) or matching placebo initiated within 8hours of surgery. The co-primary end points are (1) the composite of death or renal replacement therapy through day 30 or perioperative myocardial infarction, or mechanical assist device use through day 5 (quad end point tested at α<.01), and (2) the composite of death through postoperative day 30 or mechanical assist device use through day 5 (dual end point tested at α<.04). Safety end points include new atrial fibrillation and death through 90days. In addition, an economic analysis will address the cost-effectiveness of levosimendan compared with placebo in high-risk patients undergoing cardiac surgery on CPB. Approximately 880 patients will be enrolled at approximately 60 sites in the United States and Canada between July 2014 and September 2016, with results anticipated in January 2017.\n LEVO-CTS, a large randomized multicenter clinical trial, will evaluate the efficacy, safety, and cost-effectiveness of levosimendan in reducing adverse outcomes in high-risk patients undergoing cardiac surgery on CPB.\n ClinicalTrials.gov (NCT02025621).\n Copyright © 2016 Elsevier Inc. All rights reserved.\n\nToller, Wolfgang\n\n\n"
},
{
"text": "\n160777\nEfficacy and Safety of Degludec versus Glargine in Type 2 Diabetes.\n\nMarso, SP\n\nMcGuire, DK\n\nZinman, B\n\nPoulter, NR\n\nEmerson, SS\n\nPieber, TR\n\nPratley, RE\n\nHaahr, PM\n\nLange, M\n\nBrown-Frandsen, K\n\nMoses, A\n\nSkibsted, S\n\nKvist, K\n\nBuse, JB\n\nDEVOTE Study Group\n\nBeiträge in Fachzeitschriften\nISI:000413090000005\n28605603.0\n10.1056/NEJMoa1615692\nPMC5731244\nDegludec is an ultralong-acting, once-daily basal insulin that is approved for use in adults, adolescents, and children with diabetes. Previous open-label studies have shown lower day-to-day variability in the glucose-lowering effect and lower rates of hypoglycemia among patients who received degludec than among those who received basal insulin glargine. However, data are lacking on the cardiovascular safety of degludec.\n We randomly assigned 7637 patients with type 2 diabetes to receive either insulin degludec (3818 patients) or insulin glargine U100 (3819 patients) once daily between dinner and bedtime in a double-blind, treat-to-target, event-driven cardiovascular outcomes trial. The primary composite outcome in the time-to-event analysis was the first occurrence of an adjudicated major cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) with a prespecified noninferiority margin of 1.3. Adjudicated severe hypoglycemia, as defined by the American Diabetes Association, was the prespecified, multiplicity-adjusted secondary outcome.\n Of the patients who underwent randomization, 6509 (85.2%) had established cardiovascular disease, chronic kidney disease, or both. At baseline, the mean age was 65.0 years, the mean duration of diabetes was 16.4 years, and the mean (±SD) glycated hemoglobin level was 8.4±1.7%; 83.9% of the patients were receiving insulin. The primary outcome occurred in 325 patients (8.5%) in the degludec group and in 356 (9.3%) in the glargine group (hazard ratio, 0.91; 95% confidence interval, 0.78 to 1.06; P<0.001 for noninferiority). At 24 months, the mean glycated hemoglobin level was 7.5±1.2% in each group, whereas the mean fasting plasma glucose level was significantly lower in the degludec group than in the glargine group (128±56 vs. 136±57 mg per deciliter, P<0.001). Prespecified adjudicated severe hypoglycemia occurred in 187 patients (4.9%) in the degludec group and in 252 (6.6%) in the glargine group, for an absolute difference of 1.7 percentage points (rate ratio, 0.60; P<0.001 for superiority; odds ratio, 0.73; P<0.001 for superiority). Rates of adverse events did not differ between the two groups.\n Among patients with type 2 diabetes at high risk for cardiovascular events, degludec was noninferior to glargine with respect to the incidence of major cardiovascular events. (Funded by Novo Nordisk and others; DEVOTE ClinicalTrials.gov number, NCT01959529 .).\n\nPieber, Thomas\n\n\n"
},
{
"text": "\n168420\nElectronic Clinical Decision Support System for allergic rhinitis management: MASK e-CDSS.\n\nCourbis, AL\n\nMurray, RB\n\nArnavielhe, S\n\nCaimmi, D\n\nBedbrook, A\n\nVan Eerd, M\n\nDe Vries, G\n\nDray, G\n\nAgache, I\n\nMorais-Almeida, M\n\nBachert, C\n\nBergmann, KC\n\nBosnic-Anticevich, S\n\nBrozek, J\n\nBucca, C\n\nCamargos, P\n\nCanonica, GW\n\nCarr, W\n\nCasale, T\n\nFonseca, JA\n\nHaahtela, T\n\nKalayci, O\n\nKlimek, L\n\nKuna, P\n\nKvedariene, V\n\nLarenas Linnemann, D\n\nLieberman, P\n\nMullol, J\n\nOhehir, R\n\nPapadopoulos, N\n\nPrice, D\n\nRyan, D\n\nSamolinski, B\n\nSimons, FE\n\nTomazic, P\n\nTriggiani, M\n\nValiulis, A\n\nValovirta, E\n\nWagenmann, M\n\nWickman, M\n\nYorgancioglu, A\n\nBousquet, J\n\nBeiträge in Fachzeitschriften\nISI:000451572000007\n29999223.0\n10.1111/cea.13230\nNone\nAllergic rhinitis (AR) management has changed in recent years following the switch from the concept of disease severity to the concept of disease control, publication of the AR clinical decision support system (CDSS) and development of mobile health (m-health) tools for patients (eg Allergy Diary). The Allergy Diary Companion app for healthcare providers is currently being developed and will be launched in 2018. It incorporates the AR CDSS to provide evidence-based treatment recommendations, linking all key stakeholders in AR management.\n To produce an electronic version of the AR CDSS (e-CDSS) for incorporation into the Allergy Diary Companion, to describe the app interfaces used to collect information necessary to inform the e-CDSS and to summarize some key features of the Allergy Diary Companion.\n The steps involved in producing the e-CDSS and incorporating it into the Allergy Diary Companion were (a) generation of treatment management scenarios; (b) expert consensus on treatment recommendations; (c) generation of electronic decisional algorithms to describe all AR CDSS scenarios; (d) digitization of these algorithms to form the e-CDSS; and (e) embedding the e-CDSS into the app to permit easy user e-CDSS interfacing.\n Key experts in the AR field agreed on the AR CDSS approach to AR management and on specific treatment recommendations provided by Allergy Diary Companion. Based on this consensus, decision processes were developed and programmed into the Allergy Diary Companion using Titanium Appcelerator (JavaScript) for IOS tablets. To our knowledge, this is the first time the development of any m-health tool has been described in this transparent and detailed way, providing confidence, not only in the app, but also in the provided management recommendations.\n The Allergy Diary Companion for providers provides guideline and expert-endorsed AR management recommendations. [MASK paper No 32].\n © 2018 John Wiley & Sons Ltd.\n\nTomazic, Peter Valentin\n\n\n"
},
{
"text": "\n177359\nTHE TRANSFORMATION OF MULTI-MODAL 3 COMPONENT PREVENTIVE SCHEME INTO TREATMENT PROTOCOL FOR NECROTIZING ENTEROCOLITIS IN NEWBORNS\n\nHarutyunyan, AS\n\nMuradyan, AA\n\nHovhannisyan, MG\n\nBadalyan, AR\n\nLorenc, DV\n\nNikogosyan, KV\n\nAtyan, TN\n\nBaveyan, BA\n\nSargsyan, KM\n\nBabloyan, AS\n\nBeiträge in Fachzeitschriften\nISI:000485765800012\nNone\nNone\nNone\nNecrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in premature infants treated in neonatal intensive care unit (NICU) At the present time the unified universally accepted set of informative diagnostic criteria has not been developed yet to allows specifically determine the stage of the disease for the diagnose and treatment strategy. That is why comparing the results of various NEC treatment programs is very difficult. At the Department of Pediatric Surgery and Division of Neonatology of Medical University of Graz (Austria) the implementation of NEC prevention protocol resulted in a very low incidence of NEC. The Graz protocol consists originally of enteral application of a Probiotic (Lactobacillus rhamnosus), in combination with enteral application of an antibiotic (Gentamicin) and an antifungal substance (Nystatin). Methods: The preventive multi-modal 3-component NEC prophylaxis scheme was implemented for NEC treatment in December of 2016 in Neonatology Intensive Care Unit of "Muratsan" clinical complex of Yerevan State Medical University. The retrospective observational study was performed to assess the effectiveness of multi-modal 3-component NEC prophylaxis scheme used as part of the treatment among patients with NEC during 01.12.2015-30.11.2016 (period A), 01.12.2016-30.11.2017 (period B) and 01.12.2017-30.11.2018 (period C). All observed patients were divided in to intervention and control groups. Results: The mortality rate in control group was 38 infants (40%) compared to the intervention group was 13 infants (13%) (p= 0-0001). The implementation of multi-modal 3-component NEC prophylaxis scheme into treatment protocol for NEC resulted in reduction of NEC development from 37% to 12%. Newborns' total mortality decreased from 11% to 6%, wherein the NEC mortality decreased from 16% to zero, and mortality with NEC diagnose included decreased from 34% to 14%. The number of advanced NEC decreased from 33% to 2% and it should be noted that the number of surgical interventions decreased from 21 to zero. The complete recovery at discharge increased from 50% to 86%. Conclusion: The implementation of multi-modal 3-component NEC prophylaxis scheme into treatment protocol for NEC shows significantly reduction in NEC associated morbidity and mortality. The NEC development process in NICU also shows the positive dynamic after multi-modal 3-component NEC prophylaxis scheme administration among newborns with high risk of NEC development.\n\nSargsyan, Karine\n\n\n"
},
{
"text": "\n3474\nScavenger receptor class B, type I is expressed in porcine brain capillary endothelial cells and contributes to selective uptake of HDL-associated vitamin E.\n\nGoti, D\n\nHrzenjak, A\n\nLevak-Frank, S\n\nFrank, S\n\nvan der Westhuyzen, DR\n\nMalle, E\n\nSattler, W\n\nBeiträge in Fachzeitschriften\nISI:000166458200019\n11208913.0\n10.1046%2Fj.1471-4159.2001.00100.x\nNone\nIt is clearly established that an efficient supply to the brain of alpha-tocopherol (alphaTocH), the most biologically active member of the vitamin E family, is of the utmost importance for proper neurological functioning. Although the mechanism of uptake of alphaTocH into cells constituting the blood-brain barrier (BBB) is obscure, we previously demonstrated that high-density lipoprotein (HDL) plays a major role in the supply of alphaTocH to porcine brain capillary endothelial cells (pBCECs). Here we studied whether a porcine analogue of human and rodent scavenger receptor class B, type I mediates selective (without concomitant lipoprotein particle internalization) uptake of HDL-associated alphaTocH in a similar manner to that described for HDL-associated cholesteryl esters (CEs). In agreement with this hypothesis we observed that a major proportion of alphaTocH uptake by pBCECs occurred by selective uptake, exceeding HDL3 holoparticle uptake by up to 13-fold. The observation that selective uptake of HDL-associated CE exceeded HDL3 holoparticle up to fourfold suggested that a porcine analogue of SR-BI (pSR-BI) may be involved in lipid uptake at the BBB. In line with the observation of selective lipid uptake, RT-PCR and northern and western blot analyses revealed the presence of pSR-BI in cells constituting the BBB. Adenovirus-mediated overexpression of the human analogue of SR-BI (hSR-BI) in pBCECs resulted in a fourfold increase in selective HDL-associated alphaTocH uptake. In accordance with the proposed function of SR-BI, selective HDL-CE uptake was increased sixfold in Chinese hamster ovary cells stably transfected with murine SR-BI (mSR-BI). Most importantly stable mSR-BI overexpression mediated a twofold increase in HDL-associated [14C]alphaTocH selective uptake in comparison with control cells. In line with tracer experiments, mass transfer studies with unlabelled lipoproteins revealed that mSR-BI overexpression resulted in a twofold increase in endogenous HDL3-associated alphaTocH uptake. The results of this study indicate that SR-BI promotes the uptake of HDL-associated alphaTocH into cells constituting the BBB and plays an important role during the supply of the CNS with this indispensable micronutrient.\n\nFrank, Sasa\n\nHrzenjak, Andelko\n\nLevak, Sanja\n\nMalle, Ernst\n\nSattler, Wolfgang\n\n\n"
},
{
"text": "\n6256\nCharacteristics of a prevalent vertebral deformity predict subsequent vertebral fracture: results from the European Prospective Osteoporosis Study (EPOS).\n\nLunt, M\n\nO'Neill, TW\n\nFelsenberg, D\n\nReeve, J\n\nKanis, JA\n\nCooper, C\n\nSilman, AJ\n\nEuropean Prospective Osteoporosis Study Group\n\nBeiträge in Fachzeitschriften\nISI:000185990400006\n14555253.0\n10.1016%2FS8756-3282%2803%2900248-5\nNone\nThe presence of a prevalent vertebral deformity increases the risk of a future vertebral fracture. The aim of this study was to determine whether certain characteristics of the prevalent deformity, including its shape and location in the spine, influenced this effect. The 3100 men and 3500 women who took part in this analysis were recruited from population registers for participation in the European Prospective Osteoporosis Study (EPOS). Subjects had lateral thoracic and lumbar spine x-rays at baseline, and again after a mean interval of 3.8 years. Prevalent morphometric vertebral deformities on the baseline film were identified by the McCloskey-Kanis method. Incident fractures were defined as vertebrae that also satisfied the McCloskey-Kanis criterion for prevalent deformities on the follow-up film, and in addition had at least one height (anterior, mid, or posterior) which had reduced by at least 20% between films. Poisson regression was used to assess the association between various characteristics of the prevalent deformity and the risk of an incident vertebral fracture, with generalised estimating equations used to allow for the fact that each subject contributed several vertebrae to the analysis. The risk of an incident fracture increased with the number of prevalent deformities: relative risk (RR) for one prevalent deformity 3.2 (95% confidence interval (CI); 2.1, 4.8); 9.8 (95% CI;6.1, 15.8) for 2; and 23.3 (95% CI;15.3, 35.4) for 3 or more. Relative risks differed significantly according to the shape of the prevalent deformity, ranging from 5.9 (95% CI; 4.1, 8.6) if the anterior and mid heights were reduced to 1.6 (95% CI;0.8, 3.2) if the posterior and mid heights were reduced. Risks varied also according to the severity of the deformity. There were fivefold differences in relative risk of incident fracture depending on the location of the prevalent deformity within the spine. Compared to vertebrae in subjects with no deformities at baseline, the relative risk of an incident fracture within three vertebrae of a prevalent deformity was greater (7.7 (95% CI;5.6, 10.5)) than the risk in more distant vertebrae (4.0 (95% CI;2.6, 6.0)). In summary, the risk of a subsequent vertebral fracture in individuals with preexisting deformities is importantly influenced by the characteristics of these deformities.\n\nWeber, Kurt\n\n\n"
},
{
"text": "\n133216\nGastro 2013 APDW/WCOG Shanghai working party report: chronic diarrhea: definition, classification, diagnosis.\n\nSchiller, LR\n\nPardi, DS\n\nSpiller, R\n\nSemrad, CE\n\nSurawicz, CM\n\nGiannella, RA\n\nKrejs, GJ\n\nFarthing, MJ\n\nSellin, JH\n\nBeiträge in Fachzeitschriften\nISI:000328735600006\n24117999.0\n10.1111/jgh.12392\nNone\nDiarrhea is best defined as passage of loose stools often with more frequent bowel movements. For clinical purposes, the Bristol Stool Form Scale works well to distinguish stool form and to identify loose stools. Laboratory testing of stool consistency has lagged behind. Acute diarrhea is likely to be due to infection and to be self-limited. As diarrhea becomes chronic, it is less likely to be due to infection; duration of 1 month seems to work well as a cut-off for chronic diarrhea, but detailed scientific knowledge is missing about the utility of this definition. In addition to duration of diarrhea, classifications by presenting scenario, by pathophysiology, and by stool characteristics (e.g. watery, fatty, or inflammatory) may help the canny clinician refine the differential diagnosis of chronic diarrhea. In this regard, a careful history remains the essential part of the evaluation of a patient with diarrhea. Imaging the intestine with endoscopy and radiographic techniques is useful, and biopsy of the small intestine and colon for histological assessment provides key diagnostic information. Endomicroscopy and molecular pathology are only now being explored for the diagnosis of chronic diarrhea. Interest in the microbiome of the gut is increasing; aside from a handful of well-described infections because of pathogens, little is known about alterations in the microbiome in chronic diarrhea. Serological tests have well-defined roles in the diagnosis of celiac disease but have less clearly defined application in autoimmune enteropathies and inflammatory bowel disease. Measurement of peptide hormones is of value in the diagnosis and management of endocrine tumors causing diarrhea, but these are so rare that these tests are of little value in screening because there will be many more false-positives than true-positive results. Chemical analysis of stools is of use in classifying chronic diarrhea and may limit the differential diagnosis that must be considered, but interpretation of the results is still evolving. Breath tests for assessment of carbohydrate malabsorption, small bowel bacterial overgrowth, and intestinal transit are fraught with technical limitations that decrease sensitivity and specificity. Likewise, tests of bile acid malabsorption have had limited utility beyond empirical trials of bile acid sequestrants.\n © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.\n\nKrejs, Günter Josef\n\n\n"
},
{
"text": "\n142507\nResults of genoidentical hemopoietic stem cell transplantation with reduced intensity conditioning for acute myelocytic leukemia: higher doses of stem cells infused benefit patients receiving transplants in second remission or beyond--the Acute Leukemia Working Party of the European Cooperative Group for Blood and Marrow Transplantation.\n\nGorin, NC\n\nLabopin, M\n\nBoiron, JM\n\nTheorin, N\n\nLittlewood, T\n\nSlavin, S\n\nGreinix, H\n\nCahn, JY\n\nAlessandrino, EP\n\nRambaldi, A\n\nNagler, A\n\nPolge, E\n\nRocha, V\n\nAcute Leukemia Working Party of the European Cooperative Group for Blood and Marrow Transplantation\n\nBeiträge in Fachzeitschriften\nISI:000240052300024\n16880451.0\n10.1200/JCO.2006.05.5855\nNone\nNucleated cell dose is an important and modifiable factor in hematopoietic stem cell transplantation (HSCT), however its association with outcomes in the context of reduced intensity conditioning regimen (RIC) HSCT for adults with acute myelocytic leukemia (AML) is not known.\n From 1998 to 2003, 253 patients with de novo AML, received transplants with RIC and peripheral blood from a genoidentical donor. Median age was 55 years (range, 18 to 72) and the median follow-up was 17 months (range, 2 to 67). One hundred forty one patients received transplants in first remission (CR1), 47 received transplants in second remission (CR2), and 65 patients received transplants in a more advanced phase. Fludarabin-based RIC was used in 91% of patients and low-dose (< 4 Gy) total-body radiation in 23% of patients. The median nucleated and CD34 cell dose infused were 9.1x 10(8)/kg and 5.8x 10(6)/kg, respectively.\n Overall, 2-year leukemia-free survival (LFS) was 41% +/- 4% and it was 46% +/- 5% for patients receiving a higher cell dose (> 9.1x 10(8)/kg) and 37% +/- 5% for the remainders (P = .03). Higher cell doses exclusively benefited patients who received transplantations in CR2 or beyond, with LFS of 47 +/- 8 versus 20 +/- 8, with no detectable effect for patients who received transplants in CR1. In a multivariate analysis of the overall patient population, higher nucleated cell dose cells were associated with higher LFS (P = .04), higher incidence of chronic graft-versus-host disease (P = .01), and there was a trend towards a lower relapse incidence (P = .06). Interestingly, CD34+ cell dose was not associated with any outcomes.\n Nucleated cell dose is an important factor that can be modified to improve results of RIC for patients with AML transplanted later than in CR1.\n\nGreinix, Hildegard\n\n\n"
},
{
"text": "\n156070\nLong-term results of paediatric kidney transplantation at the University of Heidelberg: a 35 year single-centre experience\n\nMehrabi, A\n\nKashfi, A\n\nTonshoff, B\n\nFeneberg, R\n\nMehls, O\n\nSchemmer, P\n\nKraus, T\n\nWiesel, M\n\nBuchler, MW\n\nSchmidt, J\n\nBeiträge in Fachzeitschriften\nISI:000223205100014\n15240854.0\n10.1093/ndt/gfh1046\nNone\nKidney transplantation remains the most effective treatment for children with end-stage renal disease. We analysed data from the University of Heidelberg transplant programme to present our results on paediatric kidney transplantations over the past 35 years.\n From 1967 to 2003, 354 paediatric kidney transplantations were performed at the University of Heidelberg. Data were obtained from the paediatric kidney transplantation records consisting of 291 (82%) cadaveric and 63 (18%) living donated transplants. Demographic data, family relationship of the living donors, surgical technique, immunosuppressive drugs, graft and patient survival rates were assessed.\n The mean age of cadaveric and living donors was 32.0+/-17.1 and 37.6+/-7.5 years, respectively. The family relationship of the living donors included the mother in 65% of cases, the father in 31%, and other relatives in 4%. In the last 4 years, the respective mean cold ischaemia time was 1.6+/-0.5 h for living donated and 13.5+/-4.1 h for cadaveric donors. The mean age of children who received kidneys from cadaveric and living donors was 11.3+/-4.5 and 10.4+/-4.5 years, respectively, with a male to female ratio of 57 to 43%. Overall patient survival rates were 95% after 1 year and 89% after 5 years. The patient 5 and 10 year survival rates for living donor renal transplantations were 95 and 95%, respectively. Graft survival rates improved since 1990 compared with the period prior to 1990: 82.5 vs 56.7% graft survival at 1 year and 82.5 vs 50% after 5 years (P = 0.03). Comparing the operating technique in a subgroup of our patients that received the same immunosuppressive regimen, anastomoses with the aorta and vena cava (51%, n = 31) were associated with a graft survival of 86.6 and 83.3% after 1 and 5 years, whereas anastomoses with iliac vessels (49%, n = 30) were associated with a graft survival of 55.8 and 51.6% after 1 and 5 years, respectively (P = 0.01).\n There has been a gradual improvement in our paediatric kidney transplantation results over time. Living donor paediatric kidney transplants have higher patient and better graft survival rates than cadaveric donor kidney transplants. Using the aorta and inferior vena cava for graft anastomosis, utilizing newer immunosuppressive drugs and implementing living kidney donation have positively affected the results of our paediatric kidney transplantations.\n\nSchemmer, Peter\n\n\n"
},
{
"text": "\n160419\nFCγ Chimeric Receptor-Engineered T Cells: Methodology, Advantages, Limitations, and Clinical Relevance.\n\nCaratelli, S\n\nSconocchia, T\n\nArriga, R\n\nCoppola, A\n\nLanzilli, G\n\nLauro, D\n\nVenditti, A\n\nDel Principe, MI\n\nBuccisano, F\n\nMaurillo, L\n\nFerrone, S\n\nSconocchia, G\n\nBeiträge in Fachzeitschriften\nISI:000400314700001\n28496440.0\n10.3389/fimmu.2017.00457\nPMC5406408\nFor many years, disappointing results have been generated by many investigations, which have utilized a variety of immunologic strategies to enhance the ability of a patient's immune system to recognize and eliminate malignant cells. However, in recent years, immunotherapy has been used successfully for the treatment of hematologic and solid malignancies. The impressive clinical responses observed in many types of cancer have convinced even the most skeptical clinical oncologists that a patient's immune system can recognize and reject his tumor if appropriate strategies are implemented. The success immunotherapy is due to the development of at least three therapeutic strategies. They include tumor-associated antigen (TAA)-specific monoclonal antibodies (mAbs), T cell checkpoint blockade, and TAA-specific chimeric antigen receptors (CARs) T cell-based immunotherapy. However, the full realization of the therapeutic potential of these approaches requires the development of strategies to counteract and overcome some limitations. They include off-target toxicity and mechanisms of cancer immune evasion, which obstacle the successful clinical application of mAbs and CAR T cell-based immunotherapies. Thus, we and others have developed the Fc gamma chimeric receptors (Fcγ-CRs)-based strategy. Like CARs, Fcγ-CRs are composed of an intracellular tail resulting from the fusion of a co-stimulatory molecule with the T cell receptor ζ chain. In contrast, the extracellular CAR single-chain variable fragment (scFv), which recognizes the targeted TAA, has been replaced with the extracellular portion of the FcγRIIIA (CD16). Fcγ-CR T cells have a few intriguing features. First, given in combination with mAbs, Fcγ-CR T cells mediate anticancer activity in vitro and in vivo by an antibody-mediated cellular cytotoxicity mechanism. Second, CD16-CR T cells can target multiple cancer types provided that TAA-specific mAbs with the appropriate specificity are available. Third, the off-target effect of CD16-CR T cells may be controlled by withdrawing the mAb administration. The goal of this manuscript was threefold. First, we review the current state-of-the-art of preclinical CD16-CR T cell technology. Second, we describe its in vitro and in vivo antitumor activity. Finally, we compare the advantages and limitations of the CD16-CR T cell technology with those of CAR T cell methodology.\n\nSconocchia, Tommaso\n\n\n"
},
{
"text": "\n177349\nImpact of a Nomadic Pastoral Lifestyle on the Gut Microbiome in the Fulani Living in Nigeria.\n\nAfolayan, AO\n\nAyeni, FA\n\nMoissl-Eichinger, C\n\nGorkiewicz, G\n\nHalwachs, B\n\nHögenauer, C\n\nBeiträge in Fachzeitschriften\nISI:000485332400001\n31572342.0\n10.3389/fmicb.2019.02138\nPMC6753190\nThe co-evolution of the gut microbiota with its human host has revolutionized our current scientific viewpoint about the contribution of diet and lifestyle on human health. Most studies so far have focused on populations living in the United States and Europe or compared those with communities from other geographic areas in the world. In order to determine the taxonomic and predicted functional profile of the gut microbiome of a hitherto unstudied human community, we investigated the phylogenetic diversity of the gut microbiota in a community of Fulani nomadic pastoralists, and their semi-urbanized neighbors - the Jarawa. The Jarawa reside in a city (Jos) in the north-central part of Nigeria, and are adapted in part to a westernized lifestyle. The nomadic Fulani lifestyle resembles a mix of Paleolithic and Neolithic lifestyle patterns with a greater predisposition to diseases. The fecal microbiota of the Fulani and the Jarawa were characterized by paired-end Illumina MiSeq sequencing of the 16S rRNA gene, followed by downstream bioinformatics analysis of the sequence reads. The Fulani harbored increased numbers of signatures of microbes that are known to be associated with a foraging lifestyle such as the Bacteroidetes, Spirochaetes, and Prevotellaceae, while the Jarawa were dominated by signatures of Firmicutes, Ruminococcaceae, Lachnospiraceae, and Christensenellaceae. Notably, the gut microbiota of the Fulani showed less taxonomic diversity than those of the Jarawa. Although they reside in the same geographical zone, microbial community composition was significantly different between the two groups. Pathogens were predicted to be more abundant in the gut microbiota of the Fulani than of the Jarawa. Predicted pathogenic pathways and pathways associated with the breakdown of fiber-rich diet were enriched in the Fulani, including glutathione metabolism, while pathways associated with the consumption of low-fiber diet and xenobiotics, including fructose and mannose metabolic pathways, and nitrotoluene degradation pathways, respectively, were enriched in the Jarawa. Significant differences in composition between both groups were likely due to differences in diet and lifestyle and exposure to pathogens. These results suggest that microbial diversity may not always be higher in non-industrialized societies than in westernized societies, as previously assumed.\n Copyright © 2019 Afolayan, Ayeni, Moissl-Eichinger, Gorkiewicz, Halwachs and Högenauer.\n\nGorkiewicz, Gregor\n\nHoegenauer, Christoph\n\nMoissl-Eichinger, Christine\n\n\n"
},
{
"text": "\n183554\nLoss-of-Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities.\n\nSteel, D\n\nZech, M\n\nZhao, C\n\nBarwick, KES\n\nBurke, D\n\nDemailly, D\n\nKumar, KR\n\nZorzi, G\n\nNardocci, N\n\nKaiyrzhanov, R\n\nWagner, M\n\nIuso, A\n\nBerutti, R\n\nŠkorvánek, M\n\nNecpál, J\n\nDavis, R\n\nWiethoff, S\n\nMankad, K\n\nSudhakar, S\n\nFerrini, A\n\nSharma, S\n\nKamsteeg, EJ\n\nTijssen, MA\n\nVerschuuren, C\n\nvan Egmond, ME\n\nFlowers, JM\n\nMcEntagart, M\n\nTucci, A\n\nCoubes, P\n\nBustos, BI\n\nGonzalez-Latapi, P\n\nTisch, S\n\nDarveniza, P\n\nGorman, KM\n\nPeall, KJ\n\nBötzel, K\n\nKoch, JC\n\nKmieć, T\n\nPlecko, B\n\nBoesch, S\n\nHaslinger, B\n\nJech, R\n\nGaravaglia, B\n\nWood, N\n\nHoulden, H\n\nGissen, P\n\nLubbe, SJ\n\nSue, CM\n\nCif, L\n\nMencacci, NE\n\nAnderson, G\n\nKurian, MA\n\nWinkelmann, J\n\nGenomics England Research Consortium\n\nBeiträge in Fachzeitschriften\nISI:000571344400001\n32808683.0\n10.1002/ana.25879\nNone\nThe majority of people with suspected genetic dystonia remain undiagnosed after maximal investigation, implying that a number of causative genes have not yet been recognized. We aimed to investigate this paucity of diagnoses.\n We undertook weighted burden analysis of whole-exome sequencing (WES) data from 138 individuals with unresolved generalized dystonia of suspected genetic etiology, followed by additional case-finding from international databases, first for the gene implicated by the burden analysis (VPS16), and then for other functionally related genes. Electron microscopy was performed on patient-derived cells.\n Analysis revealed a significant burden for VPS16 (Fisher's exact test p value, 6.9 × 109 ). VPS16 encodes a subunit of the homotypic fusion and vacuole protein sorting (HOPS) complex, which plays a key role in autophagosome-lysosome fusion. A total of 18 individuals harboring heterozygous loss-of-function VPS16 variants, and one with a microdeletion, were identified. These individuals experienced early onset progressive dystonia with predominant cervical, bulbar, orofacial, and upper limb involvement. Some patients had a more complex phenotype with additional neuropsychiatric and/or developmental comorbidities. We also identified biallelic loss-of-function variants in VPS41, another HOPS-complex encoding gene, in an individual with infantile-onset generalized dystonia. Electron microscopy of patient-derived lymphocytes and fibroblasts from both patients with VPS16 and VPS41 showed vacuolar abnormalities suggestive of impaired lysosomal function.\n Our study strongly supports a role for HOPS complex dysfunction in the pathogenesis of dystonia, although variants in different subunits display different phenotypic and inheritance characteristics. ANN NEUROL 2020;88:867-877.\n © 2020 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.\n\nPlecko, Barbara\n\n\n"
},
{
"text": "\n184180\nInverse agonism of cannabinoid CB1 receptor blocks the adhesion of encephalitogenic T cells in inflamed brain venules by a protein kinase A-dependent mechanism.\n\nRossi, B\n\nZenaro, E\n\nAngiari, S\n\nOttoboni, L\n\nBach, S\n\nPiccio, L\n\nPietronigro, EC\n\nScarpini, E\n\nFusco, M\n\nLeon, A\n\nConstantin, G\n\nBeiträge in Fachzeitschriften\nISI:000290070000013\n21216016.0\n10.1016/j.jneuroim.2010.12.005\nNone\nIt is well known that the cannabinoid system has a significant role in the regulation of the immune responses. Cannabinoid receptors CB1 and CB2 are expressed on T lymphocytes and mediate the immunomodulatory effects of cannabinoids on T cell functions. Here we show that the treatment of proteolipid protein (PLP)139-151-specific T cells with SR141716A, a CB1 inverse agonist and prototype of the diarylpyrazoles series, induced a strong inhibition of firm adhesion in inflamed brain venules in intravital microscopy experiments. In contrast, SR144528, a potent CB2 inverse agonist, had no significant effect on both rolling and arrest of activated T cells. In addition, two analogs of SR141716A and CB1 inverse agonists, AM251 and AM281 inhibited encephalitogenic T cell adhesion suggesting that selective CB1 inverse agonism interfere with lymphocyte trafficking in the CNS. Flow cytometry experiments showed that CB1 inverse agonists have no effect on adhesion molecule expression suggesting that CB1 blockade interferes with signal transduction pathways controlling T cell adhesion in inflamed brain venules. In addition, integrin clustering was not altered after treatment with CB1 inverse agonists suggesting that adhesion blockade is not due to the modulation of integrin valency. Notably, the inhibitory effect exerted by AM251 and AM281 on the adhesive interactions was completely reverted in the presence of protein kinase A (PKA) inhibitor H89, suggesting that cAMP and PKA activation play a key role in the adhesion blockade mediated by CB1 inverse agonists. To further strengthen these results and unveil a previously unknown inhibitory role of cAMP on activated T cell adhesion in vivo in the context of CNS inflammation, we showed that intracellular increase of cAMP induced by treatment with Bt2cAMP, a permeable analog of cAMP, and phosphodiesterase (PDE) inhibitor theophylline efficiently blocked the arrest of encephalitogenic T cells in inflamed brain venules. Our data show that modulation of CB1 function has anti-inflammatory effects and suggests that inverse agonism of CB1 block signal transduction mechanisms controlling encephalitogenic T cells adhesion in inflamed brain venules by a PKA-dependent mechanism.\n Copyright © 2010 Elsevier B.V. All rights reserved.\n\nAngiari, Stefano\n\n\n"
},
{
"text": "\n185700\nSix-month pivotal results of tack optimized balloon angioplasty using the Tack Endovascular System in below-the-knee arteries.\n\nGeraghty, PJ\n\nAdams, G\n\nSchmidt, A\n\nTOBA II BTK Investigators\n\nBeiträge in Fachzeitschriften\nNone\n32956797.0\n10.1016/j.jvs.2020.08.135\nNone\nNo vascular implant is commercially available in the United States to treat post-angioplasty dissections in below-the-knee (BTK) arteries. The Tack Endovascular System (Intact Vascular, Wayne, Pa) is purpose-built to repair postpercutaneous transluminal angioplasty (PTA) BTK dissections. A trial was conducted to investigate the safety and efficacy of the first-of-a-kind implantable BTK device to treat post-PTA dissections in the setting of critical limb ischemia.\n The present prospective, single-arm, multicenter study evaluated the Tack Endovascular System for treating post-PTA dissections in the mid/distal popliteal, tibial, and peroneal arteries. The primary safety endpoint was major adverse limb events (MALE) plus perioperative death (POD), assessed at 30 days after the index procedure. The primary efficacy endpoint was a composite of MALE at 6 months and POD. The unpowered secondary endpoint was primary patency at 6 months. With no available on-label comparator, the primary endpoints of the present trial were determined using objective performance goals from a systematic literature search. The secondary endpoints included Tacked segment patency and target limb salvage at 6 months. The 6-month results are reported.\n Of the 233 patients enrolled, 117 (50.2%) had Rutherford class 5 and 78 (33.5%) had Rutherford class 4. A total of 341 post-PTA dissections were treated. Each patient received at least one Tack implant, and 100% of the dissections resolved according to the angiographic core laboratory findings. The primary safety and efficacy endpoints were both met. The rate of MALE plus POD at 30 days was 1.3% (3 of 228) and freedom from MALE at 6 months plus POD at 30 days was 95.6% (196 of 205). The 6-month Tacked segment patency was 82.1% (247 of 301) and target limb salvage was 98.5% (202 of 205). The Kaplan-Meier freedom from clinically driven target lesion revascularization and amputation-free survival at 6 months was 92.0% and 95.7%, respectively. Rutherford improvement was reported in 79.4% (158 of 199). Most (90 of 122; 73.8%) preexisting wounds had healed or were improving.\n The Tack Endovascular System is safe and effective for treating post-PTA BTK dissections through 6 months, with favorable rates of MALE plus POD, patency, clinically driven target lesion revascularization, limb salvage, and wound healing.\n Copyright © 2020 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.\n\nBrodmann, Marianne\n\n\n"
},
{
"text": "\n186801\nVenous thromboembolism: additional diagnostic value and radiation dose of pelvic CT venography in patients with suspected pulmonary embolism.\n\nReichert, M\n\nHenzler, T\n\nKrissak, R\n\nApfaltrer, P\n\nHuck, K\n\nBuesing, K\n\nSueselbeck, T\n\nSchoenberg, SO\n\nFink, C\n\nBeiträge in Fachzeitschriften\nNone\n21497470.0\n10.1016/j.ejrad.2010.12.101\nNone\nTo assess the additional diagnostic value of indirect CT venography (CTV) of the pelvis and upper thighs performed after pulmonary CT angiography (CTA) for the diagnosis of venous thromboembolism (VTE).\n In a retrospective analysis, the radiology information system entries between January 2003 and December 2007 were searched for patients who received pulmonary CTA and additional CTV of the pelvis and upper thighs. Of those patients, the radiology reports were reviewed for the diagnosis of pulmonary embolism (PE) and deep venous thrombosis (DVT) in the pelvic veins and veins of the upper thighs. In cases with an isolated pelvic thrombosis at CTV (i.e. which only had a thrombosis in the pelvic veins but not in the veins of the upper thigh) ultrasound reports were reviewed for the presence of DVT of the legs. The estimated radiation dose was calculated for pulmonary CTA and for CTV of the pelvis.\n In the defined period 3670 patients were referred to our institution for exclusion of PE. Of those, 642 patients (353 men, 289 women; mean age, 65±15 years, age range 18-98 years) underwent combined pulmonary CTA and CTV. Among them, PE was found in 227 patients (35.4%). In patients without PE CTV was negative in all cases. In patients with PE, CTV demonstrated pelvic thrombosis in 24 patients (3.7%) and thrombosis of the upper thighs in 43 patients (6.6%). Of those patients 14 (2.1%) had DVT in the pelvis and upper thighs. In 10 patients (1.5%) CTV showed an isolated pelvic thrombosis. Of those patients ultrasound reports were available in 7 patients, which revealed DVT of the leg veins in 5 cases (1%). Thus, the estimated prevalence of isolated pelvic thrombosis detected only by pelvic CTV ranges between 1-5/642 patients (0.1-0.7%). Radiation dose ranges between 4.8 and 9.7 mSv for additional CTV of the pelvis.\n CTV of the pelvis performed after pulmonary CTA is of neglectable additional diagnostic value for the detection of VTE, because the additional radiation dose is high and isolated pelvic DVT is very rare. Venous imaging of the legs (preferably by radiation-free ultrasound) is sufficient for the diagnosis of underlying DVT in patients with suspected PE.\n Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.\n\nApfaltrer, Paul\n\n\n"
}
]
}