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"text": "\n186548\nThe Significance of Fetal and Neonatal Spontaneous Movements for Development and Early Identification of Developmental Disorders\n\nEinspieler, C\n\nZhang, DJ\n\nMarschik, PB\n\nBeiträge in Fachzeitschriften\nISI:000607188500003\nNone\n10.1026/0942-5403/a000323\nNone\nTheoretical Background: The human neonate presents a continuum of motor patterns extending from prenatal to early postnatal life. Independent of any external and sensory input, central pattern generators (CPGs) engender a variety of distinct spontaneous movements from the 8th week postmenstrual age onward. These gradually emerging patterns in the fetus include side-to-side movements of the head, startles, breathing movements, hiccupping, stretching, yawning, sucking, swallowing, eye movements, blinking, smiling, as well as the isolated head, arm, or leg movements. Among the rich repertoire of early spontaneous movement patterns, the general movements (GMs) appear most frequently and are more complex. GMs involve the entire body. They are variable flows of elegant and smooth arm, leg, neck, and trunk movements, evidencing the integrity of the developing nervous system. Around the 3rd month postterm age, a distinct transformation occurs. GMs appear as fidgety movements (FMs), referring to the continuous small-amplitude movements of shoulders, wrists, hips, and ankles in all directions and of variable accelerations. FMs gradually fade out after 5 months of age, when voluntary movements become dominant. Objective: This review aims to examine the significance of CPG-generated GMs in neurodevelopmental diagnostics. Method: We summarize the clinical research on the Prechtl general movements assessment (GMA), a diagnostic tool applicable from preterm to 5 months of age. Results: The existing studies revealed that the presence of normal, variable GMs is indicative of typical brain development in general, whereas atypical, monotonous GMs, especially the absence of FMs, is highly suggestive of an adverse neurological development. GMA enables the prediction of cerebral palsy with remarkable sensitivity (98 %; 95 % CI [74, 100]) and specificity (91 %; 95 % CI [83, 93]). In particular, the abnormal cramped-synchronized GMs at perinatal age and the absence of FMs at 3 - 5 months are reliable markers for cerebral palsy. Not only infants with an early brain injury, but also infants with various genetic disorders (e. g., Rett syndrome, Down syndrome, Smith-Magenis syndrome) might not develop FMs. Additionally, the quality of GMs is related to the cognitive outcomes of infants born preterm. GMA has recently been extended to the field of autism spectrum disorders (ASD). Two thirds of infants with a later diagnosis of ASD display atypical GMs and are notable for their monotony in movements. Discussion and Conclusion: GMA has repeatedly proven to be a sensitive readout of the integrity of the developing brain. Especially in regions of limited resources, GMA is highly beneficial in providing a cost-effective and reliable neurodevelopmental diagnosis. GMA plays a critical part in identifying infants with neurological impairments in the very first months of life where early targeted interventions are most efficient and effective.\n\nEinspieler, Christa\n\nMarschik, Dajie\n\nMarschik, Peter\n\n\n"
},
{
"text": "\n187716\nCurrent practice in nutrition after allogeneic hematopoietic stem cell transplantation - Results from a survey among hematopoietic stem cell transplant centers\n\nToenges, R\n\nGreinix, H\n\nLawitschka, A\n\nHalter, J\n\nBaumgartner, A\n\nSimon, A\n\nArends, J\n\nJager, P\n\nMiddeke, M\n\nHilgendorf, I\n\nKlein, S\n\nWagner-Drouet, EM\n\nSchmid, C\n\nBug, G\n\nWolff, D\n\nBeiträge in Fachzeitschriften\nISI:000640403100019\n33744601.0\n10.1016/j.clnu.2021.02.030\nNone\nBackground: Allogeneic hematopoietic stem cell transplantation (alloHSCT) is frequently associated with impaired oral intake and malnutrition, which potentially increases morbidity and mortality. Therefore, nutrition is one of the major challenges in the post-transplant period. Methods: To document the current clinical approach in nutritional treatment, we designed a questionnaire concerning the current practice in nutrition after alloHSCT and distributed it to German speaking centers performing alloHSCT in Germany, Austria and Switzerland between November 2018 and March 2020. Twenty-eight (39%) of 72 contacted centers completed the survey, 23 from Germany, two from Austria and three from Switzerland, representing 50% of alloHSCT activity within the participating countries in 2018. Results: All centers reported having nutritional guidelines for patients undergoing alloHSCT, whereby 86% (n = 24) provided a low-microbial diet during the neutropenic phase. The criteria to start parenteral nutrition (PN) directly after alloHSCT seemed to be consistent, 75% (n = 21) of the corresponding centers started PN if the oral nutritional intake or the bodyweight dropped below a certain limit. In the setting of intestinal graft-versus-host disease (GvHD) the current practice appeared to be more heterogenous. About 64% (n = 18) of the centers followed a special diet, added food stepwise modulated by GvHD symptoms, while only four centers regularly stopped oral intake completely (intestinal GvHD grade >1). Half of the centers (54%, n = 15) applied a lactose-free diet, followed by 43% (n = 12) which provided fatand 18% (n = 5) gluten-free food in patients with intestinal GvHD. Supplementation of micronutrients in acute intestinal GvHD patients was performed by 54% (n = 15) of the centers, whereas vitamin D (89%, n = 25) and vitamin B-12 (68%, n = 19) was added regularly independently of the presence of GvHD. Only 5 (18%) participating centers ever observed a food-associated infection during hospitalization, whereas food-associated infections were reported to occur more often in the outpatient setting (64%, n = 18). Conclusion: The survey documented a general consensus about the need for nutritional guidelines for patients undergoing alloHSCT. However, the nutritional treatment in clinical practice (i.e. lactose-, gluten-or fat-free in intestinal GvHD) as well as the use of food supplements was very heterogeneous. In line with current general recommendations the centers seemed to focus on safe food handling practice rather than providing a strict neutropenic diet. More high-quality data are required to provide evidence-based nutrition to patients during and after alloHSCT. (c) 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.\n\nGreinix, Hildegard\n\n\n"
},
{
"text": "\n95599\nComplications associated with surgical stabilization of high-grade sacral fracture dislocations with spino-pelvic instability.\n\nBellabarba, C\n\nSchildhauer, TA\n\nVaccaro, AR\n\nChapman, JR\n\nBeiträge in Fachzeitschriften\nISI:000237518800014\n16685241.0\n10.1097/01.brs.0000217949.31762.be\nNone\nSTUDY DESIGN: Retrospective evaluation of 19 consecutive patients with sacral fracture dislocations and cauda equina syndrome. OBJECTIVE: To review the safety and patient impact of early surgical decompression, and rigid segmental stabilization in patients with high-grade sacral fracture dislocations. SUMMARY OF BACKGROUND DATA: The ideal treatment for patients presenting with fracture dislocations of the sacrum resulting from high-energy mechanisms remains unknown. Previous studies consisted of multicenter case reviews that showed satisfactory outcomes with either nonoperative or a variety of surgical methods. However, over the last 20 years, no consistent treatment algorithm for these severe injuries has emerged. The advent of rigid, low-profile segmental fixation of the lumbar spine to the pelvic ring has offered a solution to many of the surgical challenges. This study evaluates the rate of complications of this method. It is intended to serve as a foundation for further evaluation and development of this treatment strategy, and as a basis for future comparison studies. METHODS: Patients were treated with a formally established algorithm, including resuscitation, and clinical assessment with detailed neurologic assessment and radiographic workup with pelvic computerized tomography and reformatted views. Electrophysiologic testing was conducted to confirm the presence of sacral plexus injuries in patients who were unable to be examined. Patients received neural element decompression and open reduction with segmental internal fixation through a midline posterior approach by connecting lower lumbar pedicle screws to long iliac screws when the patient's general medical condition allowed for surgical intervention. A formal sacroiliac arthrodesis was not performed. For the purposes of this study, patients were assessed specifically for the following adverse events: (1) infection, (2) wound healing, (3) neurologic deterioration following surgical treatment, (4) postoperative loss of sacral fracture reduction, (5) instrumentation failure, (6) axial lumbopelvic pain requiring further treatment, and (7) unplanned secondary surgery. RESULTS: There were 19 patients with an average age of 32 years treated according to this algorithm. Fracture reduction was successfully maintained in all patients. During the index surgical intervention, 14/19 patients (74%) had had either a traumatic dural tear or nerve root avulsion. Major complications involved fracture of the connecting rods in 6/19 patients (31%) and wound healing disturbances in 5/19 (26%). There were no lasting complications such as chronic osteomyelitis noted. In patients followed over a 1-year period, the visual analog score, referable to the sacral injury, averaged 5.5 on a scale of 0-10. CONCLUSIONS: Rigid segmental lumbopelvic stabilization allowed for reliable fracture reduction of the lumbosacral spine and posterior pelvic ring, permitting early mobilization without external immobilizaton and neurologic improvement in a large number of patients. Complications were primarily related to infection, wound healing, and asymptomatic rod breakage, and were without long-term sequelae.\n\n\n"
},
{
"text": "\n141862\nDiagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus.\n\nKhan, AA\n\nMorrison, A\n\nHanley, DA\n\nFelsenberg, D\n\nMcCauley, LK\n\nO'Ryan, F\n\nReid, IR\n\nRuggiero, SL\n\nTaguchi, A\n\nTetradis, S\n\nWatts, NB\n\nBrandi, ML\n\nPeters, E\n\nGuise, T\n\nEastell, R\n\nCheung, AM\n\nMorin, SN\n\nMasri, B\n\nCooper, C\n\nMorgan, SL\n\nObermayer-Pietsch, B\n\nLangdahl, BL\n\nAl Dabagh, R\n\nDavison, KS\n\nKendler, DL\n\nSándor, GK\n\nJosse, RG\n\nBhandari, M\n\nEl Rabbany, M\n\nPierroz, DD\n\nSulimani, R\n\nSaunders, DP\n\nBrown, JP\n\nCompston, J\n\nInternational Task Force on Osteonecrosis of the Jaw\n\nBeiträge in Fachzeitschriften\nISI:000346914600002\n25414052.0\n10.1002/jbmr.2405\nNone\nThis work provides a systematic review of the literature from January 2003 to April 2014 pertaining to the incidence, pathophysiology, diagnosis, and treatment of osteonecrosis of the jaw (ONJ), and offers recommendations for its management based on multidisciplinary international consensus. ONJ is associated with oncology-dose parenteral antiresorptive therapy of bisphosphonates (BP) and denosumab (Dmab). The incidence of ONJ is greatest in the oncology patient population (1% to 15%), where high doses of these medications are used at frequent intervals. In the osteoporosis patient population, the incidence of ONJ is estimated at 0.001% to 0.01%, marginally higher than the incidence in the general population (<0.001%). New insights into the pathophysiology of ONJ include antiresorptive effects of BPs and Dmab, effects of BPs on gamma delta T-cells and on monocyte and macrophage function, as well as the role of local bacterial infection, inflammation, and necrosis. Advances in imaging include the use of cone beam computerized tomography assessing cortical and cancellous architecture with lower radiation exposure, magnetic resonance imaging, bone scanning, and positron emission tomography, although plain films often suffice. Other risk factors for ONJ include glucocorticoid use, maxillary or mandibular bone surgery, poor oral hygiene, chronic inflammation, diabetes mellitus, ill-fitting dentures, as well as other drugs, including antiangiogenic agents. Prevention strategies for ONJ include elimination or stabilization of oral disease prior to initiation of antiresorptive agents, as well as maintenance of good oral hygiene. In those patients at high risk for the development of ONJ, including cancer patients receiving high-dose BP or Dmab therapy, consideration should be given to withholding antiresorptive therapy following extensive oral surgery until the surgical site heals with mature mucosal coverage. Management of ONJ is based on the stage of the disease, size of the lesions, and the presence of contributing drug therapy and comorbidity. Conservative therapy includes topical antibiotic oral rinses and systemic antibiotic therapy. Localized surgical debridement is indicated in advanced nonresponsive disease and has been successful. Early data have suggested enhanced osseous wound healing with teriparatide in those without contraindications for its use. Experimental therapy includes bone marrow stem cell intralesional transplantation, low-level laser therapy, local platelet-derived growth factor application, hyperbaric oxygen, and tissue grafting.\n © 2014 American Society for Bone and Mineral Research.\n\nObermayer-Pietsch, Barbara\n\n\n"
},
{
"text": "\n143600\nPeripheral markers of oxidative stress and antioxidative defense in euthymia of bipolar disorder--Gender and obesity effects.\n\nBengesser, SA\n\nLackner, N\n\nBirner, A\n\nFellendorf, FT\n\nPlatzer, M\n\nMitteregger, A\n\nUnterweger, R\n\nReininghaus, B\n\nMangge, H\n\nWallner-Liebmann, SJ\n\nZelzer, S\n\nFuchs, D\n\nMcIntyre, RS\n\nKapfhammer, HP\n\nReininghaus, EZ\n\nBeiträge in Fachzeitschriften\nISI:000346643000052\n25451439.0\n10.1016/j.jad.2014.10.014\nNone\nOxidative and nitrosative stress are implicated in the pathogenesis of uni- and bipolar disorder. Herein we primarily sought to characterize markers of oxidative/nitrosative stress during euthymia in adults with bipolar disorder (BD). Oxidative markers were further evaluated in this BD sample in synopsis with excess overweight or obesity and/or comorbid metabolic syndrome (MetS).\n Peripheral markers of oxidative stress [i.e. thiobarbituric acid reactive substance, (TBARS), malondialdehyde (MDA), and carbonyl proteins] and antioxidant markers [e.g. total antioxidative capacity (TAC), superoxide dismutase (SOD), glutathione S-transferase (GST)] were obtained in a cohort of euthymic adults with BD (N=113) and compared to healthy controls (CG) (N=78). Additionally, anthropometric measures included the body mass index (BMI) [kg/m(2)], waist and hip circumference [cm], waist-to-hip-ratio (WHR), waist to height ratio (WtHR) as well as the IDF-defined MetS.\n The major finding was a significantly decreased TAC in BD compared to the CG (p<0.01; BD: M 1.18, SD 0.47; CG: M 1.39, SD 0.49). MDA was significantly and TBARS by trend higher in the CG compared to the euthymic bipolar test persons (MDA: p<0.01, BD: M 0.70, SD 0.18; CG: M 0.81, SD 0.25; TBARS: p<0.1, BD: M 0.78, SD 0.28; CG: M 0.76, SD 0.30). The antioxidative enzyme GST was significantly elevated in both patients and controls (BD: M 298.24, SD 133.02; CG: M 307.27 SD 118.18). Subgroup analysis revealed that the CG with concurrent MetS and obesity had significantly elevated TAC when compared to CG without concurrent MetS (p<0.05, no MetS: M 1.33, SD 0.50; MetS: M 1.67, SD 0.32), as well as persons with BD with or without current MetS (no MetS: M 1.18, SD 0.44; MetS: M 1.15, SD 0.49). Significant correlations between GST and anthropometric variables were found in male study participants. Multivariate analysis indicated a significant gender effect concerning TBARS values in all patients and CG (p<0.01, females: M 0.73, SD 0.29; males: M 0.83, SD 0.28).\n Euthymic bipolar adults exhibit peripheral evidence of a disturbed biosignature of oxidative stress and antioxidative defense. Male test persons showed significantly higher peripheral markers of oxidative stress than women- female sex may exert protective effects. Furthermore, the biosignature of oxidative stress obtained herein was more pronounced in males with concurrent metabolic disorders. Our results further extend knowledge by introducing the moderating influence of gender and obesity on oxidative stress and BD.\n Copyright © 2014 Elsevier B.V. All rights reserved.\n\nBengesser, Susanne\n\nBirner, Armin\n\nDalkner, Nina\n\nFellendorf, Frederike\n\nHolasek, Sandra Johanna\n\nKapfhammer, Hans-Peter\n\nMangge, Harald\n\nPlatzer, Martina\n\nReininghaus, Eva\n\nUnterweger, Renate\n\nZelzer, Sieglinde\n\n\n"
},
{
"text": "\n162226\nDay-to-day fasting glycaemic variability in DEVOTE: associations with severe hypoglycaemia and cardiovascular outcomes (DEVOTE 2).\n\nZinman, B\n\nMarso, SP\n\nPoulter, NR\n\nEmerson, SS\n\nPieber, TR\n\nPratley, RE\n\nLange, M\n\nBrown-Frandsen, K\n\nMoses, A\n\nOcampo Francisco, AM\n\nBarner Lekdorf, J\n\nKvist, K\n\nBuse, JB\n\nDEVOTE Study Group\n\nBeiträge in Fachzeitschriften\nISI:000417272300007\n28913575.0\n10.1007/s00125-017-4423-z\nPMC6002963\nThe Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) was a double-blind, randomised, event-driven, treat-to-target prospective trial comparing the cardiovascular safety of insulin degludec with that of insulin glargine U100 (100 units/ml) in patients with type 2 diabetes at high risk of cardiovascular events. This paper reports a secondary analysis investigating associations of day-to-day fasting glycaemic variability (pre-breakfast self-measured blood glucose [SMBG]) with severe hypoglycaemia and cardiovascular outcomes.\n In DEVOTE, patients with type 2 diabetes were randomised to receive insulin degludec or insulin glargine U100 once daily. The primary outcome was the first occurrence of an adjudicated major adverse cardiovascular event (MACE). Adjudicated severe hypoglycaemia was the pre-specified secondary outcome. In this article, day-to-day fasting glycaemic variability was based on the standard deviation of the pre-breakfast SMBG measurements. The variability measure was calculated as follows. Each month, only the three pre-breakfast SMBG measurements recorded before contact with the site were used to determine a day-to-day fasting glycaemic variability measure for each patient. For each patient, the variance of the three log-transformed pre-breakfast SMBG measurements each month was determined. The standard deviation was determined as the square root of the mean of these monthly variances and was defined as day-to-day fasting glycaemic variability. The associations between day-to-day fasting glycaemic variability and severe hypoglycaemia, MACE and all-cause mortality were analysed for the pooled trial population with Cox proportional hazards models. Several sensitivity analyses were conducted, including adjustments for baseline characteristics and most recent HbA1c.\n Day-to-day fasting glycaemic variability was significantly associated with severe hypoglycaemia (HR 4.11, 95% CI 3.15, 5.35), MACE (HR 1.36, 95% CI 1.12, 1.65) and all-cause mortality (HR 1.58, 95% CI 1.23, 2.03) before adjustments. The increased risks of severe hypoglycaemia, MACE and all-cause mortality translate into 2.7-, 1.2- and 1.4-fold risk, respectively, when a patient's day-to-day fasting glycaemic variability measure is doubled. The significant relationships of day-to-day fasting glycaemic variability with severe hypoglycaemia and all-cause mortality were maintained after adjustments. However, the significant association with MACE was not maintained following adjustment for baseline characteristics with either baseline HbA1c (HR 1.19, 95% CI 0.96, 1.47) or the most recent HbA1c measurement throughout the trial (HR 1.21, 95% CI 0.98, 1.49).\n Higher day-to-day fasting glycaemic variability is associated with increased risks of severe hypoglycaemia and all-cause mortality.\n ClinicalTrials.gov NCT01959529.\n\nPieber, Thomas\n\n\n"
},
{
"text": "\n172967\nMortality Not Correlated With Paclitaxel Exposure: An Independent Patient-Level Meta-Analysis of a Drug-Coated Balloon.\n\nSchneider, PA\n\nLaird, JR\n\nDoros, G\n\nGao, Q\n\nAnsel, G\n\nBrodmann, M\n\nMicari, A\n\nShishehbor, MH\n\nTepe, G\n\nZeller, T\n\nBeiträge in Fachzeitschriften\nISI:000468283300009\n30690141.0\n10.1016/j.jacc.2019.01.013\nNone\nFive years of prospective clinical trials confirm that the paclitaxel drug-coated balloon (DCB) (IN.PACT Admiral, Medtronic, Dublin, Ireland) is safe and effective to treat femoropopliteal artery disease. A recent meta-analysis of heterogeneous trials of paclitaxel-based balloons and stents reported that they are associated with increased mortality and that higher doses are linked to higher mortality from 2 to 5 years.\n The purpose of this study was to determine if there is a correlation between paclitaxel exposure and mortality by conducting an independent patient-level meta-analysis of 1, 80 patients with up to 5-year follow-up.\n Data from 2 single-arm and 2 randomized independently adjudicated prospective studies of a paclitaxel DCB (n = 1, 37) and uncoated percutaneous transluminal angioplasty (PTA) (n = 143) were included. Analyses of baseline, procedure, and follow-up data of individual patients were performed to explore correlations of paclitaxel dose with long-term mortality. Survival time by paclitaxel dose tercile was analyzed with adjustment of inverse probability weighting to correct baseline imbalances and study as random effect. A standard cohort was defined to compare DCB- and PTA-treated patients with similar characteristics by applying criteria from pivotal studies (n = 712 DCB, n = 143 PTA).\n A survival analysis stratified nominal paclitaxel dose by low, mid, and upper terciles; mean doses were 5, 19.0, 10, 07.5, and 19, 78.2 μg, respectively. Rates of freedom from all-cause mortality between the 3 groups through 5 years were 85.8%, 84.2%, and 88.2%, respectively (p = 0.731). There was no significant difference in all-cause mortality between DCB and PTA through 5 years comparing all patients (unadjusted p = 0.092) or patients with similar characteristics (adjusted p = 0.188).\n This independent patient-level meta-analysis demonstrates that this paclitaxel DCB is safe. Within DCB patients, there was no correlation between level of paclitaxel exposure and mortality. (Randomized Trial of IN.PACT Admiral® Drug Coated Balloon vs Standard PTA for the Treatment of SFA and Proximal Popliteal Arterial Disease [INPACT SFA I], NCT01175850; IN.PACT Admiral Drug-Coated Balloon vs. Standard Balloon Angioplasty for the Treatment of Superficial Femoral Artery [SFA] and Proximal Popliteal Artery [PPA] [INPACT SFA II], NCT01566461; MDT-2113 Drug-Eluting Balloon vs. Standard PTA for the Treatment of Atherosclerotic Lesions in the Superficial Femoral Artery and/or Proximal Popliteal Artery [MDT-2113 SFA], NCT01947478; The IN.PACT SFA Clinical Study for the Treatment of Atherosclerotic Lesions in the Superficial Femoral Artery and/or Proximal Popliteal Artery Using the IN.PACT Admiral™ Drug-Eluting Balloon in a Chinese Patient Population, NCT02118532; and IN.PACT Global Clinical Study, NCT01609296).\n Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.\n\nBrodmann, Marianne\n\n\n"
},
{
"text": "\n142768\nEfficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid.\n\nHirschfield, GM\n\nMason, A\n\nLuketic, V\n\nLindor, K\n\nGordon, SC\n\nMayo, M\n\nKowdley, KV\n\nVincent, C\n\nBodhenheimer, HC\n\nParés, A\n\nTrauner, M\n\nMarschall, HU\n\nAdorini, L\n\nSciacca, C\n\nBeecher-Jones, T\n\nCastelloe, E\n\nBöhm, O\n\nShapiro, D\n\nBeiträge in Fachzeitschriften\nISI:000351639000022\n25500425.0\n10.1053/j.gastro.2014.12.005\nNone\nWe evaluated the efficacy and safety of obeticholic acid (OCA, α-ethylchenodeoxycholic acid) in a randomized controlled trial of patients with primary biliary cirrhosis who had an inadequate response to ursodeoxycholic acid therapy.\n We performed a double-blind study of 165 patients with primary biliary cirrhosis (95% women) and levels of alkaline phosphatase (ALP) 1.5- to 10-fold the upper limit of normal. Patients were randomly assigned to groups given 10 mg, 25 mg, or 50 mg doses of OCA or placebo, once daily for 3 months. Patients maintained their existing dose of ursodeoxycholic acid throughout the study. The primary outcome was change in level of ALP from baseline (day 0) until the end of the study (day 85 or early termination). We also performed an open-label extension of the trial in which 78 patients were enrolled and 61 completed the first year.\n OCA was superior to placebo in achieving the primary end point. Subjects given OCA had statistically significant relative reductions in mean ALP from baseline to the end of the study (P < .0001 all OCA groups vs placebo). Levels of ALP decreased 21%-25% on average from baseline in the OCA groups and 3% in the placebo group. Sixty-nine percent (68 of 99) of patients given OCA had at least a 20% reduction in ALP compared with 8% (3 of 37) of patients given placebo (P < .0003). Among secondary end points, levels of γ-glutamyl transpeptidase decreased 48%-63%, on average, among subjects given OCA, vs a 7% decrease in the group given placebo; levels of alanine aminotransferase decreased 21%-35% on average among subjects given OCA vs none of the patients given placebo. Pruritus was the principal adverse event; incidence values in the OCA 10 mg, 25 mg, and 50 mg groups were 47% (not significantly different), 87% (P < .0003), and 80% (P < .006), respectively, vs 50% in the placebo group. In the extension study, levels of ALP continued to decrease to a mean level of 202 ± 11 U/L after 12 months vs 285 ± 15 U/L at baseline.\n Daily doses of OCA, ranging from 10 to 50 mg, significantly reduced levels of ALP, γ-glutamyl transpeptidase, and alanine aminotransferase, compared with placebo, in patients with primary biliary cirrhosis who had inadequate responses to ursodeoxycholic acid. The incidence and severity of pruritus were lowest among patients who received 10 mg/d OCA. Biochemical responses to OCA were maintained in a 12-month open-label extension trial. ClinicalTrials.gov ID: NCT00550862.\n Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.\n\n\n"
},
{
"text": "\n180692\nDapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes.\n\nWiviott, SD\n\nRaz, I\n\nBonaca, MP\n\nMosenzon, O\n\nKato, ET\n\nCahn, A\n\nSilverman, MG\n\nZelniker, TA\n\nKuder, JF\n\nMurphy, SA\n\nBhatt, DL\n\nLeiter, LA\n\nMcGuire, DK\n\nWilding, JPH\n\nRuff, CT\n\nGause-Nilsson, IAM\n\nFredriksson, M\n\nJohansson, PA\n\nLangkilde, AM\n\nSabatine, MS\n\nDECLARE–TIMI 58 Investigators\n\nBeiträge in Fachzeitschriften\nISI:000456459400008\n30415602.0\n10.1056/NEJMoa1812389\nNone\nThe cardiovascular safety profile of dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 that promotes glucosuria in patients with type 2 diabetes, is undefined.\n We randomly assigned patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease to receive either dapagliflozin or placebo. The primary safety outcome was a composite of major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, or ischemic stroke. The primary efficacy outcomes were MACE and a composite of cardiovascular death or hospitalization for heart failure. Secondary efficacy outcomes were a renal composite (≥40% decrease in estimated glomerular filtration rate to <60 ml per minute per 1.73 m2 of body-surface area, new end-stage renal disease, or death from renal or cardiovascular causes) and death from any cause.\n We evaluated 17, 60 patients, including 10, 86 without atherosclerotic cardiovascular disease, who were followed for a median of 4.2 years. In the primary safety outcome analysis, dapagliflozin met the prespecified criterion for noninferiority to placebo with respect to MACE (upper boundary of the 95% confidence interval [CI], <1.3; P<0.001 for noninferiority). In the two primary efficacy analyses, dapagliflozin did not result in a lower rate of MACE (8.8% in the dapagliflozin group and 9.4% in the placebo group; hazard ratio, 0.93; 95% CI, 0.84 to 1.03; P=0.17) but did result in a lower rate of cardiovascular death or hospitalization for heart failure (4.9% vs. 5.8%; hazard ratio, 0.83; 95% CI, 0.73 to 0.95; P=0.005), which reflected a lower rate of hospitalization for heart failure (hazard ratio, 0.73; 95% CI, 0.61 to 0.88); there was no between-group difference in cardiovascular death (hazard ratio, 0.98; 95% CI, 0.82 to 1.17). A renal event occurred in 4.3% in the dapagliflozin group and in 5.6% in the placebo group (hazard ratio, 0.76; 95% CI, 0.67 to 0.87), and death from any cause occurred in 6.2% and 6.6%, respectively (hazard ratio, 0.93; 95% CI, 0.82 to 1.04). Diabetic ketoacidosis was more common with dapagliflozin than with placebo (0.3% vs. 0.1%, P=0.02), as was the rate of genital infections that led to discontinuation of the regimen or that were considered to be serious adverse events (0.9% vs. 0.1%, P<0.001).\n In patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease, treatment with dapagliflozin did not result in a higher or lower rate of MACE than placebo but did result in a lower rate of cardiovascular death or hospitalization for heart failure, a finding that reflects a lower rate of hospitalization for heart failure. (Funded by AstraZeneca; DECLARE-TIMI 58 ClinicalTrials.gov number, NCT01730534 .).\n\nBugger, Heiko Matthias\n\n\n"
},
{
"text": "\n131740\nEpilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A.\n\nKasperaviciute, D\n\nCatarino, CB\n\nMatarin, M\n\nLeu, C\n\nNovy, J\n\nTostevin, A\n\nLeal, B\n\nHessel, EV\n\nHallmann, K\n\nHildebrand, MS\n\nDahl, HH\n\nRyten, M\n\nTrabzuni, D\n\nRamasamy, A\n\nAlhusaini, S\n\nDoherty, CP\n\nDorn, T\n\nHansen, J\n\nKrämer, G\n\nSteinhoff, BJ\n\nZumsteg, D\n\nDuncan, S\n\nKälviäinen, RK\n\nEriksson, KJ\n\nKantanen, AM\n\nPandolfo, M\n\nGruber-Sedlmayr, U\n\nSchlachter, K\n\nReinthaler, EM\n\nStogmann, E\n\nZimprich, F\n\nThéâtre, E\n\nSmith, C\n\nO'Brien, TJ\n\nMeng Tan, K\n\nPetrovski, S\n\nRobbiano, A\n\nParavidino, R\n\nZara, F\n\nStriano, P\n\nSperling, MR\n\nBuono, RJ\n\nHakonarson, H\n\nChaves, J\n\nCosta, PP\n\nSilva, BM\n\nda Silva, AM\n\nde Graan, PN\n\nKoeleman, BP\n\nBecker, A\n\nSchoch, S\n\nvon Lehe, M\n\nReif, PS\n\nRosenow, F\n\nBecker, F\n\nWeber, Y\n\nLerche, H\n\nRössler, K\n\nBuchfelder, M\n\nHamer, HM\n\nKobow, K\n\nCoras, R\n\nBlumcke, I\n\nScheffer, IE\n\nBerkovic, SF\n\nWeale, ME\n\nUK Brain Expression Consortium\n\nDelanty, N\n\nDepondt, C\n\nCavalleri, GL\n\nKunz, WS\n\nSisodiya, SM\n\nBeiträge in Fachzeitschriften\nISI:000325166500028\n24014518.0\n10.1093/brain/awt233\nPMC3784283\nEpilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10(-9), odds ratio (A) = 1.42, 95% confidence interval: 1.26-1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and open avenues for investigation of prognostic factors and possible prevention of epilepsy in some children with febrile seizures.\n\n\n"
},
{
"text": "\n148102\nA comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease.\n\nNikpay, M\n\nGoel, A\n\nWon, HH\n\nHall, LM\n\nWillenborg, C\n\nKanoni, S\n\nSaleheen, D\n\nKyriakou, T\n\nNelson, CP\n\nHopewell, JC\n\nWebb, TR\n\nZeng, L\n\nDehghan, A\n\nAlver, M\n\nArmasu, SM\n\nAuro, K\n\nBjonnes, A\n\nChasman, DI\n\nChen, S\n\nFord, I\n\nFranceschini, N\n\nGieger, C\n\nGrace, C\n\nGustafsson, S\n\nHuang, J\n\nHwang, SJ\n\nKim, YK\n\nKleber, ME\n\nLau, KW\n\nLu, X\n\nLu, Y\n\nLyytikäinen, LP\n\nMihailov, E\n\nMorrison, AC\n\nPervjakova, N\n\nQu, L\n\nRose, LM\n\nSalfati, E\n\nSaxena, R\n\nScholz, M\n\nSmith, AV\n\nTikkanen, E\n\nUitterlinden, A\n\nYang, X\n\nZhang, W\n\nZhao, W\n\nde Andrade, M\n\nde Vries, PS\n\nvan Zuydam, NR\n\nAnand, SS\n\nBertram, L\n\nBeutner, F\n\nDedoussis, G\n\nFrossard, P\n\nGauguier, D\n\nGoodall, AH\n\nGottesman, O\n\nHaber, M\n\nHan, BG\n\nHuang, J\n\nJalilzadeh, S\n\nKessler, T\n\nKönig, IR\n\nLannfelt, L\n\nLieb, W\n\nLind, L\n\nLindgren, CM\n\nLokki, ML\n\nMagnusson, PK\n\nMallick, NH\n\nMehra, N\n\nMeitinger, T\n\nMemon, FU\n\nMorris, AP\n\nNieminen, MS\n\nPedersen, NL\n\nPeters, A\n\nRallidis, LS\n\nRasheed, A\n\nSamuel, M\n\nShah, SH\n\nSinisalo, J\n\nStirrups, KE\n\nTrompet, S\n\nWang, L\n\nZaman, KS\n\nArdissino, D\n\nBoerwinkle, E\n\nBorecki, IB\n\nBottinger, EP\n\nBuring, JE\n\nChambers, JC\n\nCollins, R\n\nCupples, LA\n\nDanesh, J\n\nDemuth, I\n\nElosua, R\n\nEpstein, SE\n\nEsko, T\n\nFeitosa, MF\n\nFranco, OH\n\nFranzosi, MG\n\nGranger, CB\n\nGu, D\n\nGudnason, V\n\nHall, AS\n\nHamsten, A\n\nHarris, TB\n\nHazen, SL\n\nHengstenberg, C\n\nHofman, A\n\nIngelsson, E\n\nIribarren, C\n\nJukema, JW\n\nKarhunen, PJ\n\nKim, BJ\n\nKooner, JS\n\nKullo, IJ\n\nLehtimäki, T\n\nLoos, RJF\n\nMelander, O\n\nMetspalu, A\n\nMärz, W\n\nPalmer, CN\n\nPerola, M\n\nQuertermous, T\n\nRader, DJ\n\nRidker, PM\n\nRipatti, S\n\nRoberts, R\n\nSalomaa, V\n\nSanghera, DK\n\nSchwartz, SM\n\nSeedorf, U\n\nStewart, AF\n\nStott, DJ\n\nThiery, J\n\nZalloua, PA\n\nO'Donnell, CJ\n\nReilly, MP\n\nAssimes, TL\n\nThompson, JR\n\nErdmann, J\n\nClarke, R\n\nWatkins, H\n\nKathiresan, S\n\nMcPherson, R\n\nDeloukas, P\n\nSchunkert, H\n\nSamani, NJ\n\nFarrall, M\n\nBeiträge in Fachzeitschriften\nISI:000361969900007\n26343387.0\n10.1038/ng.3396\nPMC4589895\nExisting knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185, 00 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.\n\nMärz, Winfried\n\n\n"
},
{
"text": "\n168845\nBaseline characteristics and patterns of care in testicular cancer patients: first data from the Swiss Austrian German Testicular Cancer Cohort Study (SAG TCCS).\n\nRothermundt, C\n\nThurneysen, C\n\nCathomas, R\n\nMüller, B\n\nMingrone, W\n\nHirschi-Blickenstorfer, A\n\nWehrhahn, T\n\nRuf, C\n\nRothschild, S\n\nSeifert, B\n\nTerbuch, A\n\nGrassmugg, T\n\nWoelky, R\n\nFankhauser, C\n\nKunit, T\n\nFischer, NF\n\nInauen, R\n\nKamradt, J\n\nZiegler, K\n\nHaynes, A\n\nJüni, P\n\nGillessen, S\n\nBeiträge in Fachzeitschriften\nISI:000440407800002\n30044478.0\n10.4414/smw.2018.14640\nNone\nThe majority of germ cell tumour (GCT) patients can be cured by orchiectomy followed by active surveillance or subsequent systemic and/or local treatments. There are various guidelines for a structured follow-up including radiographic and clinical examinations.\n The Swiss Austrian German Testicular Cancer Cohort Study (SAG TCCS) prospectively evaluates follow-up, indicator of relapse and late toxicities. This is a descriptive analysis; we present baseline characteristics and treatment strategies for the first 299 patients with primary GCT or relapsed GCT after completion of treatment.\n Of the patients included in this study, 192 (64.2%) had seminoma and 107 (35.8%) non-seminoma tumour. Mean age was 41 years (standard deviation [SD] 11.7) for seminoma and 31 (SD 9.3) years for non-seminoma patients. Median tumour size was 3.5 cm (interquartile range 0-12) in both histological groups. Among seminoma patients, 81 (42.2%) had primary tumours >4cm; 154 (80.2%) seminoma patients had stage I, 26 (13.5%) stage II and 12 (6.3%) stage III disease. Fifty-seven (53.3%) non-seminoma tumours were stage I, 29 (27.1%) stage II and 21(19.6%) stage III. Marker-positive disease was present in 58 (30.2%) seminoma patients and 78 (72.9%) non-seminoma patients. Of 154 stage I seminoma patients, 89 (57.8%) chose active surveillance and 65 (42.2%) adjuvant chemotherapy. Twenty-six (45.6%) stage I non-seminoma patients had high-risk disease; 23 of these were treated with adjuvant chemotherapy and 3 chose active surveillance. Among the 30 (52.6%) low risk stage I patients, all opted for active surveillance. Twelve (46.2%) stage II seminoma patients had radiotherapy, 14 (53.8%) were treated with three to four cycles of chemotherapy. All stage III seminoma patients, and all stage II and III non-seminoma patients were treated with three to four cycles of chemotherapy. Treatment decisions were made at the respective centre. Five patients did not receive therapy that conformed with guidelines.\n It is important to enrol GCT patients in prospective studies in general, but also in follow-up studies to assess baseline characteristics, oncological outcome, and long-term toxicity and to validate the performance of follow-up schedules. This is the first time that the distribution of disease, detailed baseline characteristics and the respective treatment of men with GCT is collected in a prospective manner in German speaking countries (Switzerland, Austria and Germany) and therefore patterns of care have been evaluated. SAG TCCS results will inform on future modifications of surveillance schedules and follow-up procedures.\n NCT02229916 (Clinicaltrials.gov).\n\nTerbuch, Angelika\n\n\n"
},
{
"text": "\n91316\nKRJ-I and BON cell lines: defining an appropriate enterochromaffin cell neuroendocrine tumor model.\n\nSiddique, ZL\n\nDrozdov, I\n\nFloch, J\n\nGustafsson, BI\n\nStunes, K\n\nPfragner, R\n\nKidd, M\n\nModlin, IM\n\nBeiträge in Fachzeitschriften\nISI:000266882500010\n19295186.0\n10.1159/000209330\nNone\nBackground: Neuroendocrine tumors (NETs) of the gastrointestinal (GI) system are increasing in incidence with minimal improvement in prognosis. Although the cell of origin has been identified as the enterochromaffin (EC) cell, its secretory and proliferative regulation has not been defined at a mechanistic level. To date, the BON cell line has been the most widely used in vitro EC cell model despite its pancreatic origin. Using whole-genome mathematical analysis as well as secretory and proliferative studies, we compared the BON cell line to the small intestine ( SI) EC cell-derived NET cell line, KRJ-I, to assess individual cell line validity and applicability for the investigation of GI-NET disease. Methods and Results: Principal component analysis and ANOVA of KRJ-I and BON transcriptomes (U133 Plus 2) identified substantially different (<10%) overlap in transcripts with minimal (R-2 = 0.24) correlation in gene expression profiles. RTPCR detected large variability (>12%) in neuroendocrine ( NE) marker transcripts in the BON cell line and the absence of Tph-2, DDC, TGF beta R2, and M3 transcripts in KRJ-I. The KRJ-I cell line secreted serotonin (5-HT) in response to isoproterenol (EC50 = 100 nM), noradrenaline (EC50 = 1.7 nM), and pituitary adenylate cyclase (PACAP, EC50 = 0.03 nM). Cholecystokinin (IC50 = 430 nM), somatostatin (IC50 = 400 nM), acetylcholine (IC50 = 3.7 nM), and gamma-aminobutyric acid A (GABA(A), IC50 = 2 nM) all inhibited 5-HT release, while gastrin and bombesin had no effect. 5-HT secretion in the BON cell line was stimulated by isoproterenol (EC50 = 900 nM), noradrenaline (EC50 = 20 nM), cholecystokinin (EC50 = 130 nM), PACAP (EC50 = 0.12 nM), bombesin (EC50 = 15 nM), and acetylcholine (EC50 = 0.2 nM). It was inhibited by somatostatin (IC50 = 300 nM) but not GABA A. KRJ-I responded with proliferation to connective tissue growth factor (CTGF, EC50 = 0.002 ng/ml), transforming growth factor-alpha (TGF alpha, EC50 = 0.63 ng/ml) and transforming growth factor-beta (TGF beta, EC50 = 0.63 ng/ml). Epidermal growth factor (EGF) and somatostatin had no significant effect. BON cell proliferation was stimulated only by EGF and TGF alpha (EC50 = 15.8 and 10 ng/ml). TGF beta (IC50 = 0.16 ng/ml), MZ-4-147 (IC50 = 0.5 nM), and BIM23A761 (IC50 = 0.06 nM) all inhibited proliferation. CTGF and somatostatin had no effect. Conclusion: KRJ-I and BON cell lines demonstrate substantial differences in gene level transcripts, inconsistent receptor profile expression, wide variability in NE marker transcript levels, and significantly differential proliferative and secretory responses. Given the EC cell origin of KRJ-I, these results provide evidence that the BON cell line does not represent an EC cell system and is not a valid study model of (carcinoid) EC cell-derived NET. Copyright (C) 2009 S. Karger AG, Basel\n\n\n"
},
{
"text": "\n147079\nThe demise of Archbishop Wolf Dietrich--A historical note on a fatal status epilepticus documented at Salzburg in 1617.\n\nKalss, G\n\nHöfler, J\n\nRohracher, A\n\nDeak, I\n\nDobesberger, J\n\nKuchukhidze, G\n\nLeitinger, M\n\nOgris, K\n\nMc Coy, M\n\nTrinka, E\n\nBeiträge in Fachzeitschriften\nISI:000359314900002\n25934588.0\n10.1016/j.yebeh.2015.03.024\nNone\nWolf Dietrich of Raitenau (WD) ruled the archiepiscopal Salzburg from March 2nd 1587 to December 17th 1611. He was condemned by his successor Archbishop Markus Sittikus of Hohenems to spend his last years imprisoned at the Fortress Hohensalzburg, where he died on January 16th 1617. This historical note describes the causes of his death.\n The original Latin handwriting, including the detailed medical history and the autopsy of the Archbishop's body performed by his personal physician, was analyzed in conjunction with historical handwritings provided by St. Peter's Abbey, Salzburg handwriting assigned to Markus Sittikus.\n Wolf Dietrich of Raitenau had his first well-documented left hemispheric stroke in winter 1604/05. He had palsy of his right arm, was unable to write, and, therefore, used a stamp instead of his signature until October 1605. After another stroke, right hemispheric in origin with persisting palsy of his left arm ["leva corporis pars iam pridem simili ex apoplectico assultu in paralysin resoluta"], he developed symptomatic epilepsy with recurring seizures ["epileptico insultu quo etiam alias correptus est"]. On January 15th 1617, he suffered from a secondarily generalized convulsive status epilepticus ["toto corpore convellitur epileptico insultu"] with stertorous breathing and distortion of his face ["spuma stertore insigni faciei perversione"] and was unconscious for 8h. He recovered from coma and showed dysphagia, buccofacial apraxia ["abolitam diglutiendi facultatem"], reversible speech disturbance ["accisa etiam verba loqui"], and left-sided hemiplegia ["leva corporis pars… immobilis prorsus est reddita"]. The following day, he had speech disturbances, and he died at noon. His autopsy showed large but intact liver ["hepar magnum sanum"] and heart ["cor magnum in quo lapsus nullus"]. There was intrapulmonal mucus ["pituita imbutus"], and part of the lungs adhered to its pleura. He had five kidney stones and a partly cirrhotic spleen. The cause of his death was assumed to be intracerebral ["causa mortis in capite requienda fuisset"].\n The terminal suffering of Wolf Dietrich of Raitenau is the first witnessed case report on a fatal status epilepticus in Salzburg. Most likely, he suffered from vascular epilepsy due to a right hemispheric stroke, leading to status epilepticus with left-sided Todd's palsy and speech disturbances. An acute symptomatic etiology of this disease cannot be ruled out, as for religious reasons, the Archbishop's brain was not autopsied.\n Meticulous medical reporting including autopsy was already available in Salzburg in 1617, and the symptomatic etiology of epilepsy was diagnosed correctly. This article is part of a Special Issue entitled "Status Epilepticus".\n Copyright © 2015 Elsevier Inc. All rights reserved.\n\nOgris, Kathrin\n\n\n"
},
{
"text": "\n171049\nInterdisciplinary Screening, Diagnosis, Therapy and Follow-up of Breast Cancer. Guideline of the DGGG and the DKG (S3-Level, AWMF Registry Number 032/045OL, December 2017) - Part 2 with Recommendations for the Therapy of Primary, Recurrent and Advanced Breast Cancer.\n\nWöckel, A\n\nFestl, J\n\nStüber, T\n\nBrust, K\n\nKrockenberger, M\n\nHeuschmann, PU\n\nJírů-Hillmann, S\n\nAlbert, US\n\nBudach, W\n\nFollmann, M\n\nJanni, W\n\nKopp, I\n\nKreienberg, R\n\nKühn, T\n\nLanger, T\n\nNothacker, M\n\nScharl, A\n\nSchreer, I\n\nLink, H\n\nEngel, J\n\nFehm, T\n\nWeis, J\n\nWelt, A\n\nSteckelberg, A\n\nFeyer, P\n\nKönig, K\n\nHahne, A\n\nBaumgartner, T\n\nKreipe, HH\n\nKnoefel, WT\n\nDenkinger, M\n\nBrucker, S\n\nLüftner, D\n\nKubisch, C\n\nGerlach, C\n\nLebeau, A\n\nSiedentopf, F\n\nPetersen, C\n\nBartsch, HH\n\nSchulz-Wendtland, R\n\nHahn, M\n\nHanf, V\n\nMüller-Schimpfle, M\n\nHenscher, U\n\nRoncarati, R\n\nKatalinic, A\n\nHeitmann, C\n\nHonegger, C\n\nParadies, K\n\nBjelic-Radisic, V\n\nDegenhardt, F\n\nWenz, F\n\nRick, O\n\nHölzel, D\n\nZaiss, M\n\nKemper, G\n\nBudach, V\n\nDenkert, C\n\nGerber, B\n\nTesch, H\n\nHirsmüller, S\n\nSinn, HP\n\nDunst, J\n\nMünstedt, K\n\nBick, U\n\nFallenberg, E\n\nTholen, R\n\nHung, R\n\nBaumann, F\n\nBeckmann, MW\n\nBlohmer, J\n\nFasching, P\n\nLux, MP\n\nHarbeck, N\n\nHadji, P\n\nHauner, H\n\nHeywang-Köbrunner, S\n\nHuober, J\n\nHübner, J\n\nJackisch, C\n\nLoibl, S\n\nLück, HJ\n\nvon Minckwitz, G\n\nMöbus, V\n\nMüller, V\n\nNöthlings, U\n\nSchmidt, M\n\nSchmutzler, R\n\nSchneeweiss, A\n\nSchütz, F\n\nStickeler, E\n\nThomssen, C\n\nUntch, M\n\nWesselmann, S\n\nBücker, A\n\nBuck, A\n\nStangl, S\n\nBeiträge in Fachzeitschriften\nISI:000451318500007\n30581198.0\n10.1055/a-0646-4630\nPMC6261741\nPurpose The aim of this official guideline coordinated and published by the German Society for Gynecology and Obstetrics (DGGG) and the German Cancer Society (DKG) was to optimize the screening, diagnosis, therapy and follow-up care of breast cancer. Method The process of updating the S3 guideline published in 2012 was based on the adaptation of identified source guidelines. They were combined with reviews of evidence compiled using PICO (Patients/Interventions/Control/Outcome) questions and with the results of a systematic search of literature databases followed by the selection and evaluation of the identified literature. The interdisciplinary working groups took the identified materials as their starting point and used them to develop suggestions for recommendations and statements, which were then modified and graded in a structured consensus process procedure. Recommendations Part 2 of this short version of the guideline presents recommendations for the therapy of primary, recurrent and metastatic breast cancer. Loco-regional therapies are de-escalated in the current guideline. In addition to reducing the safety margins for surgical procedures, the guideline also recommends reducing the radicality of axillary surgery. The choice and extent of systemic therapy depends on the respective tumor biology. New substances are becoming available, particularly to treat metastatic breast cancer.\n\nBjelic-Radisic, Vesna\n\n\n"
},
{
"text": "\n180681\nTemporary intraurethral prostatic bridge-catheter compared with neoadjuvant and adjuvant alpha-blockade to improve early results of high-energy transurethral microwave thermotherapy.\n\nDjavan, B\n\nGhawidel, K\n\nBasharkhah, A\n\nHruby, S\n\nBursa, B\n\nMarberger, M\n\nBeiträge in Fachzeitschriften\nISI:000081251100017\n10414730.0\n10.1016/s0090-4295(99)00029-1\nNone\nThe maximal effect of transurethral microwave thermotherapy (TUMT) for lower urinary tract symptoms (LUTS) of benign prostatic hyperplasia (BPH) occurs 3 to 6 months after treatment. In the acute period after TUMT, little change in symptoms, quality of life (QOL), and peak urinary flow rate (Qmax) is observed versus baseline. Some men may also develop acute urinary retention secondary to thermally induced edema. Recent reports suggest that early results of TUMT may be improved with concomitant use of either a temporary intraurethral prostatic bridge-catheter (PBC) or neoadjuvant and adjuvant alpha-blocker therapy. This report compares the results of these two adjunctive modalities directly.\n This nonrandomized retrospective comparison of results in 186 patients with LUTS of BPH is based on findings of three recently reported prospective clinical trials. All patients underwent targeted high-energy TUMT. Ninety-one patients received no further treatment (TUMT alone group), 54 an indwelling PBC for up to 1 month (TUMT + PBC group), and 41 neoadjuvant and adjuvant tamsulosin (0.4 mg daily) treatment (TUMT + tamsulosin group). The International Prostate Symptom Score (IPSS), QOL score, and Qmax were determined at baseline and 2 weeks after TUMT.\n All three study groups experienced statistically significant improvements in mean IPSS and QOL score at 2 weeks versus baseline (P <0.0005). Nevertheless, the magnitude of improvement was greater in the TUMT + PBC group than the other two groups and greater in the TUMT + tamsulosin group than the TUMT alone group. A high proportion of the TUMT + PBC group (87.8%) attained a 50% or more IPSS improvement, compared with 4.5% of the TUMT alone group and none of the TUMT + tamsulosin group, and a similar pattern of between-group differences was noted with respect to the proportion of patients having 50% or more improvement in QOL score. The TUMT + PBC group was the only group to achieve significant Qmax improvement at 2 weeks compared with baseline. In the TUMT alone group, urinary retention 1 week or longer in duration occurred in 10 (11%) of 91 patients compared with 1 (2.4%) of 41 in the TUMT + tamsulosin group and none in the TUMT + PBC group. Early PBC removal was required in 11% of the TUMT + PBC group as a consequence of urinary retention secondary to clot formation or PBC migration.\n Both PBC placement and neoadjuvant and adjuvant alpha-blocker treatment are effective in alleviating symptoms and improving QOL during the acute period after TUMT. PBC usage also resulted in substantial early Qmax improvement. Either of these adjunctive modalities may be appropriate to consider in the treatment of TUMT patients during the early postprocedure recovery period.\n\n\n"
},
{
"text": "\n65913\nBiosensing of arteriosclerotic nanoplaque formation and interaction with an HMG-CoA reductase inhibitor.\n\nAbletshauser, C\n\nKlüssendorf, D\n\nSchmidt, A\n\nWinkler, K\n\nMärz, W\n\nBuddecke, E\n\nMalmsten, M\n\nSiegel, G\n\nBeiträge in Fachzeitschriften\nISI:000178277300009\n12354173.0\n10.1046/j.1365-201X.2002.01020.x\nNone\nProteoheparan sulphate can be adsorbed to a methylated silica surface in a monomolecular layer via its transmembrane hydrophobic protein core domain. As a result of electrostatic repulsion, its anionic glycosaminoglycan side chains are stretched out into the blood substitute solution, thereby representing one receptor site for specific lipoprotein binding through basic amino acid-rich residues within their apolipoproteins. The binding process was studied by ellipsometric techniques suggesting that high-density lipoprotein (HDL) has a high binding affinity and a protective effect on interfacial heparan sulphate proteoglycan layers with respect to low-density lipoprotein (LDL) and Ca2+ complexation. Low-density lipoprotein was found to deposit strongly at the proteoheparan sulphate-coated surface, particularly in the presence of Ca2+, apparently through complex formation 'proteoglycan-LDL-calcium'. This ternary complex build-up may be interpreted as arteriosclerotic nanoplaque formation on the molecular level responsible for the arteriosclerotic primary lesion. On the other hand, HDL bound to heparan sulphate proteoglycan protected against LDL deposition and completely suppressed calcification of the proteoglycan-lipoprotein complex. In addition, HDL was able to decelerate the ternary complex deposition. Therefore, HDL attached to its proteoglycan receptor sites is thought to raise a multidomain barrier, selection and control motif for transmembrane and paracellular lipoprotein uptake into the arterial wall. Although much remains unclear regarding the mechanism of lipoprotein depositions at proteoglycan-coated surfaces, it seems clear that the use of such systems offers possibilities for investigating lipoprotein deposition at a 'nanoscopic' level under close to physiological conditions. In particular, Ca2+-promoted LDL deposition and the protective effect of HDL even at high Ca2+ and LDL concentrations agree well with previous clinical observations regarding risk and beneficial factors for early stages of atherosclerosis. Considering this, the system was tested on its reliability in a biosensor application in order to unveil possible acute pleiotropic effects of the lipid lowering drug fluvastatin. The very low-density lipoprotein (VLDL)/intermediate-density lipoprotein (IDL)/LDL plasma fraction from a high risk patient with dyslipoproteinaemia and type 2 diabetes mellitus showed beginning arteriosclerotic nanoplaque formation already at a normal blood Ca2+ concentration, with a strong increase at higher Ca2+ concentrations. Fluvastatin, whether applied to the patient (one single 80 mg slow release matrix tablet) or acutely in the experiment (2.2 micromol L-1), markedly slowed down this process of ternary aggregational nanoplaque complexation at all Ca2+ concentrations used. This action resulted without any significant change in lipid concentrations of the patient. Furthermore, after ternary complex build-up, fluvastatin, similar to HDL, was able to reduce nanoplaque adsorption and size. These immediate effects of fluvastatin have to be taken into consideration while interpreting the clinical outcome of long-term studies.\n\nMärz, Winfried\n\n\n"
},
{
"text": "\n117846\nIntravitreal bevacizumab (Avastin) therapy for persistent diffuse diabetic macular edema.\n\nHaritoglou, C\n\nKook, D\n\nNeubauer, A\n\nWolf, A\n\nPriglinger, S\n\nStrauss, R\n\nGandorfer, A\n\nUlbig, M\n\nKampik, A\n\nBeiträge in Fachzeitschriften\nISI:000246985700004\n17151486.0\n10.1097/01.iae.0000247165.38655.bf\nNone\nPurpose: To evaluate the efficacy of bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA) for the treatment of diabetic macular edema. Methods: This prospective, consecutive, noncomparative case series included 51 consecutive patients (26 females and 25 males; mean age, 64 years) with diffuse diabetic macular edema. Inclusion criteria were determined independently of the size of edema, retinal thickness, visual acuity, age, metabolic control, type of diabetes, or previous treatments beyond a 6-month period. At each visit, patients underwent complete eye examination, including determination of best-corrected visual acuity, slit-lamp examination, intraocular pressure measurement, stereoscopic biomicroscopy of the macula, retinal thickness measurement by optical coherence tomography, fluorescein angiography, and fundus photography. After written informed consent was obtained, all patients were treated with a 0.05-mL injection containing 1.25 mg of bevacizumab. Results: All patients completed 6 weeks of follow-up; 23 (45%) completed 12 weeks of follow-up. Sixteen patients (70%) had received at least two intravitreal injections. All patients had undergone previous treatments, such as focal laser therapy (35%), full-scatter panretinal laser therapy (37%), vitrectomy (12%), and intravitreal injection of triamcinolone (33%). The mean diameter of the foveal avascular zone was 503 mu m, with 49% with values of >500 mu m. At baseline, mean visual acuity +/- SID was 25.88 +/- 14.43 ETDRS letters (0.86 +/- 0.38 logMAR of Snellen letters). Mean central retinal thickness by optical coherence tomography +/- SD was 501 +/- 163 mu m (range, 252-1, 31 mu m). Mean visual acuity +/- SD increased to 0.75 +/- 0.37 logMAR of Snellen letters at 6 weeks after injection (P = 0.001), with some regression to 0.84 +/- 0.41 logMAR of Snellen letters after 12 weeks. Changes in ETDRS letters were not significant throughout follow-up. Mean retinal thickness SD decreased to 425 +/- 180 mu m at 2 weeks (P = 0.002), 416 - 180 mu m at 6 weeks (P = 0.001), and 377 +/- 117 mu m at 12 weeks (P = 0.001). Changes of retinal thickness and visual acuity correlated weakly (r = -0.480 and P = 0.03 at 6 weeks; r = -0.462 and P = 0.07 at 12 weeks). The increase of visual acuity after 6 weeks as measured by ETDRS charts could be predicted best by baseline visual acuity. No other factors investigated, such as age, thickness by optical coherence tomography, or previous treatments, were predictive for the increase in visual acuity. Conclusion: Even in cases of diffuse diabetic macular edema not responding to previous treatments such as photocoagulation, intravitreal injection of triamcinolone, or vitrectomy, improvement of visual acuity and decrease of retinal thickness could be observed after intravitreal injection of bevacizumab. Although our follow-up period was too short to provide specific treatment recommendations, the short-term results encourage further prospective studies with different treatment groups and longer follow-up.\n\nStrauß, Rupert\n\n\n"
},
{
"text": "\n65133\nMaternal undernutrition during late gestation-induced intrauterine growth restriction in the rat is associated with impaired placental GLUT3 expression, but does not correlate with endogenous corticosterone levels.\n\nLesage, J\n\nHahn, D\n\nLéonhardt, M\n\nBlondeau, B\n\nBréant, B\n\nDupouy, JP\n\nBeiträge in Fachzeitschriften\nISI:000176948400005\n12098661.0\n10.1677/joe.0.1740037\nNone\nFetal intrauterine growth restriction (IUGR) is a frequently occurring and serious complication of pregnancy. Infants exposed to IUGR are at risk for numerous perinatal morbidities, including hypoglycemia in the neonatal period, as well as increased risk of later physical and/or mental impairments, cardiovascular disease and non-insulin-dependent diabetes mellitus. Fetal growth restriction most often results from uteroplacental dysfunction during the later stage of pregnancy. As glucose, which is the most abundant nutrient crossing the placenta, fulfills a large portion of the fetal energy requirements during gestational development, and since impaired placental glucose transport is thought to result in growth restriction, we investigated the effects of maternal 50% food restriction (FR50) during the last week of gestation on rat placental expression of glucose transporters, GLUT1, GLUT3 and GLUT4, and on plasma glucose content in both maternal and fetal compartments. Moreover, as maternal FR50 induces fetal overexposure to glucocorticoids and since these hormones are potent regulators of placental glucose transporter expression, we investigated whether putative alterations in placental GLUT expression correlate with changes in maternal and/or fetal corticosterone levels. At term (day 21 of pregnancy), plasma glucose content was significantly reduced (P<0.05) in mothers subjected to FR50, but was not affected in fetuses. Food restriction reduced maternal body weight (P<0.001) but did not affect placental weight. Plasma corticosterone concentration, at term, was increased (P<0.05) in FR50 mothers. Fetuses from FR50 mothers showed reduced body weight (P<0.001) but higher plasma corticosterone levels (P<0.05). Adrenalectomy (ADX) followed by corticosterone supplementation of the mother prevented the FR50-induced rise in maternal plasma corticosterone at term. Food restriction performed on either sham-ADX or ADX mothers induced a similar reduction in the body weight of the pups at term (P<0.01). Moreover, plasma corticosterone levels were increased in pups from sham-ADX FR50 mothers (P<0.01) and in pups from ADX control mothers (P<0.01). Western blot analysis of placental GLUT proteins showed that maternal FR50 decreased placental GLUT3 protein levels in all experimental groups at term (P<0.05 and P<0.01), but did not affect either GLUT1 or GLUT4 protein levels. Northern blot analysis of placental GLUT expression showed that both GLUT1 and GLUT3 mRNA were not affected by the maternal feeding regimen or surgery. We concluded that prolonged maternal malnutrition during late gestation decreases maternal plasma glucose content and placental GLUT3 glucose transporter expression, but does not obviously affect fetal plasma glucose concentration. Moreover, the present results are not compatible with a role of maternal corticosterone in the development of growth-restricted rat fetuses.\n\n\n"
},
{
"text": "\n162965\nEffect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Clinical Trial.\n\nDavies, M\n\nPieber, TR\n\nHartoft-Nielsen, ML\n\nHansen, OKH\n\nJabbour, S\n\nRosenstock, J\n\nBeiträge in Fachzeitschriften\nISI:000413187300018\n29049653.0\n10.1001/jama.2017.14752\nPMC5817971\nGlucagon-like peptide-1 (GLP-1) receptor agonists are effective therapies for the treatment of type 2 diabetes and are all currently available as an injection.\n To compare the effects of oral semaglutide with placebo (primary) and open-label subcutaneous semaglutide (secondary) on glycemic control in patients with type 2 diabetes.\n Phase 2, randomized, parallel-group, dosage-finding, 26-week trial with 5-week follow-up at 100 sites (hospital clinics, general practices, and clinical research centers) in 14 countries conducted between December 2013 and December 2014. Of 1106 participants assessed, 632 with type 2 diabetes and insufficient glycemic control using diet and exercise alone or a stable dose of metformin were randomized. Randomization was stratified by metformin use.\n Once-daily oral semaglutide of 2.5 mg (n = 70), 5 mg (n = 70), 10 mg (n = 70), 20 mg (n = 70), 40-mg 4-week dose escalation (standard escalation; n = 71), 40-mg 8-week dose escalation (slow escalation; n = 70), 40-mg 2-week dose escalation (fast escalation, n = 70), oral placebo (n = 71; double-blind) or once-weekly subcutaneous semaglutide of 1.0 mg (n = 70) for 26 weeks.\n The primary end point was change in hemoglobin A1c (HbA1c) from baseline to week 26. Secondary end points included change from baseline in body weight and adverse events.\n Baseline characteristics were comparable across treatment groups. Of the 632 randomized patients (mean age, 57.1 years [SD, 10.6]; men, 395 (62.7%); diabetes duration, 6.3 years [SD, 5.2]; body weight, 92.3 kg [SD, 16.8]; BMI, 31.7 [SD, 4.3]), 583 (92%) completed the trial. Mean change in HbA1c level from baseline to week 26 decreased with oral semaglutide (dosage-dependent range, -0.7% to -1.9%) and subcutaneous semaglutide (-1.9%) and placebo (-0.3%); oral semaglutide reductions were significant vs placebo (dosage-dependent estimated treatment difference [ETD] range for oral semaglutide vs placebo, -0.4% to -1.6%; P = .01 for 2.5 mg, <.001 for all other dosages). Reductions in body weight were greater with oral semaglutide (dosage-dependent range, -2.1 kg to -6.9 kg) and subcutaneous semaglutide (-6.4 kg) vs placebo (-1.2 kg), and significant for oral semaglutide dosages of 10 mg or more vs placebo (dosage-dependent ETD range, -0.9 to -5.7 kg; P < .001). Adverse events were reported by 63% to 86% (371 of 490 patients) in the oral semaglutide groups, 81% (56 of 69 patients) in the subcutaneous semaglutide group, and 68% (48 of 71 patients) in the placebo group; mild to moderate gastrointestinal events were most common.\n Among patients with type 2 diabetes, oral semaglutide resulted in better glycemic control than placebo over 26 weeks. These findings support phase 3 studies to assess longer-term and clinical outcomes, as well as safety.\n clinicaltrials.gov Identifier: NCT01923181.\n\nPieber, Thomas\n\n\n"
}
]
}