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"text": "\n187843\nKaempferol alleviates calcium oxalate crystal-induced renal injury and crystal deposition via regulation of the AR/NOX2 signaling pathway.\n\nYuan, P\n\nSun, X\n\nLiu, X\n\nHutterer, G\n\nPummer, K\n\nHager, B\n\nYe, Z\n\nChen, Z\n\nBeiträge in Fachzeitschriften\nISI:000652024800011\n33852977.0\n10.1016/j.phymed.2021.153555\nNone\nCalcium oxalate (CaOx) crystal deposition and crystal-induced renal tubular epithelial cell injury have been found to fundamentally contribute to the formation of CaOx nephrolithiasis.\n In the current work, we aim to study the role and mechanism of kaempferol in CaOx crystal kidney deposition and crystal-induced renal injury.\n Mice models and HK-2 cells were used to investigate the effect of kaempferol in CaOx crystal-induced renal injury and crystal deposition in the kidney and its underlying mechanism by a series of experiments.\n CaOx crystal deposition in mice renal tubulars and tubular damage were evaluated. And crystal adhesion to HK-2 cells, as well as cellular injury were identified. Furthermore, the effect of kaempferol on the expression of androgen receptor (AR) in renal tubular epithelial cells was assessed. The interaction between AR and nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2), and the intrinsic molecular mechanism of how AR regulated NOX2 in HK-2 cells were dissected. Additionally, several different assays were applied to analyze the expression levels of various related genes in this study.\n It was revealed that kaempferol reduced CaOx crystal deposition in renal tubulars and crystal adhesion to HK-2 cells. Meanwhile, the results of in vivo and in vitro experiments corroborated that crystal-associated cellular injury, oxidative stress, inflammation and over-expression of OPN and CD44 in the kidney were ameliorated by kaempferol. Moreover, kaempferol functioned on inhibiting the expression of AR in renal tubular epithelial cells, and AR was able to up-regulate the expression of NOX2 at the transcriptional level by directly binding to the promoter of NOX2. Kaempferol decreased crystal deposition and crystal-induced renal oxidative and inflammatory injury by the down-regulation of AR/NOX2 signaling pathway.\n Taken together, our study findings suggest that kaempferol has a suppressive effect on renal AR expression, which can attenuate CaOx crystal deposition and crystal-induced kidney injury through repressing oxidative stress and inflammation in the kidney by modulating the AR/NOX2 signaling pathway. It demonstrates that kaempferol may have preventive and therapeutic potential for CaOx nephrolithiasis.\n Copyright © 2021. Published by Elsevier GmbH.\n\nHutterer, Georg\n\nPummer, Karl\n\n\n"
},
{
"text": "\n3\nAllopurinol reduces bacterial translocation, intestinal mucosal lipid peroxidation, and neutrophil-derived myeloperoxidase activity in chronic portal hypertensive and common bile duct-ligated growing rats.\n\nSchimpl, G\n\nPesendorfer, P\n\nSteinwender, G\n\nFeierl, G\n\nRatschek, M\n\nHöllwarth, ME\n\nBeiträge in Fachzeitschriften\nISI:A1996VD85200010\n8865279.0\n10.1203/00006450-199609000-00010\nNone\nBacterial translocation (BT) from the gastrointestinal tract has been thought to play a role in the pathogenesis of septic complications in patients with chronic portal hypertension (PH) and obstructive jaundice. The purpose of this study was to investigate the incidence of BT and to assess the role of intestinal mucosal malondialdehyde (MDA) levels as an indicator of lipid peroxidation and polymorphonuclear neutrophil-derived myeloperoxidase (MPO) in chronic portal hypertensive and common bile duct-ligated rats. Twenty male rats were subjected to sham laparotomy (SL), 20 rats to calibrated portal vein constriction (PH), 20 rats to common bile duct ligation (CBDL), and 10 rats served as a nonoperated control group (NOP). After 4 wk, 10 animals of each operated group received 50 mg/kg allopurinol intraperitoneally, at 24 h, and again 2 h prior to estimation of BT, intestinal mucosal MDA, and MPO activities. In the NOP and SL groups, BT to the mesenteric lymph nodes (MLN) and spleen was present. In PH and in CBDL rats, BT to liver, portal vein, peritoneum, and caval vein occurred. Allopurinol treatment attenuated the frequence of BT in PH and decreased BT in CBDL rats significantly (p < 0.05). Ileal mucosal MDA levels (nanomoles/g) in untreated rats increased from 45.1 +/- 7.9 in SL to 98.2 +/- 9.1 in PH and to 102.2 +/- 11 in CBDL rats (p < 0.01). In the allopurinol groups the increase of MDA to 49.1 +/- 1.3 in PH, and 66.2 +/- 2.2 in CBDL was significantly lower (p < 0.01). MPO activity (units/g) in the ileal mucosa increased in untreated rats from 319 +/- 129 after SL to 866 +/- 104 after PH and to 1016 +/- 104 after CBDL (p < 0.01). Allopurinol significantly attenuated MPO activity to 369 +/- 44 in PH, and to 372 +/- 60 in CBDL animals (p < 0.01). In PH and CBDL rats significant BT, intestinal mucosal lipid peroxidation, and polymorphonuclear neutrophil-derived MPO activity occurred. Allopurinol reduced BT and improved intestinal mucosal MDA and MPO activities, suggesting that there might be an association between BT and intestinal mucosal lipid peroxidation.\n\nFeierl, Gebhard\n\nHöllwarth, Michael\n\nRatschek, Manfred\n\n\n"
},
{
"text": "\n3252\nPhenotypic and genotypic heterogeneity in hereditary motor neuronopathy type V: a clinical, electrophysiological and genetic study.\n\nAuer-Grumbach, M\n\nLöscher, WN\n\nWagner, K\n\nPetek, E\n\nKörner, E\n\nOffenbacher, H\n\nHartung, HP\n\nBeiträge in Fachzeitschriften\nISI:000089144400007\n10908191.0\n10.1093%2Fbrain%2F123.8.1612\nNone\nWe report on a large four-generation Austrian family with autosomal dominant distal hereditary motor neuronopathy type V (distal HMN V). Forty-seven at-risk family members, of whom 21 were definitely affected, underwent detailed clinical, electrophysiological and genetic studies. The age at onset was in the second decade of life in most affected individuals, but clinical presentation was rather variable. While the majority of patients were primarily disabled by progressive asymmetrical wasting of the thenar and the first dorsal interosseus muscles, others had marked foot deformity and gait disturbance with the occasional absence of hand involvement. Sensation sense was normal except for the reduced response to vibration. Many individuals showed brisk tendon reflexes and some elevated muscle tone in the lower limbs, but extensor plantar responses were rarely observed. Electrophysiological evaluation revealed normal or reduced motor nerve conduction velocities, normal or prolonged distal motor latencies, and low compound motor action potentials, depending on the degree of muscle wasting. Sensory nerve studies were usually within the normal range or slightly to moderately abnormal in older or severely affected persons. Electromyography showed high-amplitude motor unit potentials and reduced recruitment compatible with anterior horn cell degeneration. Central motor conduction times were prolonged in two-thirds of the patients. Molecular genetic studies excluded Charcot-Marie-Tooth 1A syndrome and proximal spinal muscular atrophy linked to chromosome 5q as well as the known gene loci for distal HMN II on chromosome 12q, HMN V on chromosome 7p and juvenile amyotrophic lateral sclerosis on chromosome 9q. The findings in this family thus provide detailed clinical and electrophysiological information on HMN V and demonstrate broad phenotypic variability in this disorder. Hallmark features are discussed that appear to be most reliable to differentiate this type of HMN V from other variants of hereditary neuropathies, and a set of diagnostic criteria is proposed. Furthermore, this is the first report of prolonged central motor conduction times in HMN V, which indicates additional involvement of the central motor pathways in this disease. Finally, molecular genetic studies demonstrate genetic heterogeneity, suggesting the existence of at least a second genetic subtype in HMN V.\n\nPetek, Erwin\n\nWagner, Klaus\n\n\n"
},
{
"text": "\n144087\nLaparoscopic peritoneal lavage: a definitive treatment for diverticular peritonitis or a "bridge" to elective laparoscopic sigmoidectomy?: a systematic review.\n\nCirocchi, R\n\nTrastulli, S\n\nVettoretto, N\n\nMilani, D\n\nCavaliere, D\n\nRenzi, C\n\nAdamenko, O\n\nDesiderio, J\n\nBurattini, MF\n\nParisi, A\n\nArezzo, A\n\nFingerhut, A\n\nBeiträge in Fachzeitschriften\nISI:000347633800013\n25569649.0\n10.1097/MD.0000000000000334\nPMC4602849\nTo this day, the treatment of generalized peritonitis secondary to diverticular perforation is still controversial. Recently, in patients with acute sigmoid diverticulitis, laparoscopic lavage and drainage has gained a wide interest as an alternative to resection. Based on this backdrop, we decided to perform a systematic review of the literature to evaluate the safety, feasibility, and efficacy of peritoneal lavage in perforated diverticular disease.A bibliographic search was performed in PubMed for case series and comparative studies published between January 1992 and February 2014 describing laparoscopic peritoneal lavage in patients with perforated diverticulitis.A total of 19 articles consisting of 10 cohort studies, 8 case series, and 1 controlled clinical trial met the inclusion criteria and were reviewed. In total these studies analyzed data from 871 patients. The mean follow-up time ranged from 1.5 to 96 months when reported. In 11 studies, the success rate of laparoscopic peritoneal lavage, defined as patients alive without surgical treatment for a recurrent episode of diverticulitis, was 24.3%. In patients with Hinchey stage III diverticulitis, the incidence of laparotomy conversion was 1%, whereas in patients with stage IV it was 45%. The 30-day postoperative mortality rate was 2.9%. The 30-day postoperative reintervention rate was 4.9%, whereas 2% of patients required a percutaneous drainage. Readmission rate after the first hospitalization for recurrent diverticulitis was 6%. Most patients who were readmitted (69%) required redo surgery. A 2-stage laparoscopic intervention was performed in 18.3% of patients.Laparoscopic peritoneal lavage should be considered an effective and safe option for the treatment of patients with sigmoid diverticulitis with Hinchey stage III peritonitis; it can also be consider as a "bridge" surgical step combined with a delayed and elective laparoscopic sigmoidectomy in order to avoid a Hartmann procedure. This minimally invasive staged approach should be considered for patients without systemic toxicity and in centers experienced in minimally invasive surgery techniques. Further evidence is needed, and the ongoing RCTs will better define the role of the laparoscopic peritoneal lavage/drainage in the treatment of patients with complicated diverticulitis.\n\n\n"
},
{
"text": "\n144401\nThe clinical and biological significance of MIR-224 expression in colorectal cancer metastasis.\n\nLing, H\n\nPickard, K\n\nIvan, C\n\nIsella, C\n\nIkuo, M\n\nMitter, R\n\nSpizzo, R\n\nBullock, M\n\nBraicu, C\n\nPileczki, V\n\nVincent, K\n\nPichler, M\n\nStiegelbauer, V\n\nHoefler, G\n\nAlmeida, MI\n\nHsiao, A\n\nZhang, X\n\nPrimrose, J\n\nPackham, G\n\nLiu, K\n\nBojja, K\n\nGafà, R\n\nXiao, L\n\nRossi, S\n\nSong, JH\n\nVannini, I\n\nFanini, F\n\nKopetz, S\n\nZweidler-McKay, P\n\nWang, X\n\nIonescu, C\n\nIrimie, A\n\nFabbri, M\n\nLanza, G\n\nHamilton, SR\n\nBerindan-Neagoe, I\n\nMedico, E\n\nMirnezami, A\n\nCalin, GA\n\nNicoloso, MS\n\nBeiträge in Fachzeitschriften\nISI:000375570600015\n25804630.0\n10.1136/gutjnl-2015-309372\nPMC4581915\nMicroRNA (miRNA) expression profile can be used as prognostic marker for human cancers. We aim to explore the significance of miRNAs in colorectal cancer (CRC) metastasis.\n We performed miRNA microarrays using primary CRC tissues from patients with and without metastasis, and validated selected candidates in 85 CRC samples by quantitative real-time PCR (qRT-PCR). We tested metastatic activity of selected miRNAs and identified miRNA targets by prediction algorithms, qRT-PCR, western blot and luciferase assays. Clinical outcomes were analysed in six sets of CRC cases (n=449), including The Cancer Genome Atlas (TCGA) consortium and correlated with miR-224 status. We used the Kaplan-Meier method and log-rank test to assess the difference in survival between patients with low or high levels of miR-224 expression.\n MiR-224 expression increases consistently with tumour burden and microsatellite stable status, and miR-224 enhances CRC metastasis in vitro and in vivo. We identified SMAD4 as a miR-224 target and observed negative correlation (Spearman Rs=-0.44, p<0.0001) between SMAD4 and miR-224 expression in clinical samples. Patients with high miR-224 levels display shorter overall survival in multiple CRC cohorts (p=0.0259, 0.0137, 0.0207, 0.0181, 0.0331 and 0.0037, respectively), and shorter metastasis-free survival (HR 6.51, 95% CI 1.97 to 21.51, p=0.0008). In the TCGA set, combined analysis of miR-224 with SMAD4 expression enhanced correlation with survival (HR 4.12, 95% CI 1.1 to 15.41, p=0.0175).\n MiR-224 promotes CRC metastasis, at least in part, through the regulation of SMAD4. MiR-224 expression in primary CRC, alone or combined with its targets, may have prognostic value for survival of patients with CRC.\n Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/\n\nHöfler, Gerald\n\nPichler, Martin\n\n\n"
},
{
"text": "\n144642\nPreoperative serum-gamma-glutamyltransferase (GGT) does not represent an independent prognostic factor in a European cohort of patients with non-metastatic renal cell carcinoma.\n\nDalpiaz, O\n\nPichler, M\n\nMrsic, E\n\nReitz, D\n\nKrieger, D\n\nVenturino, L\n\nBezan, A\n\nStojakovic, T\n\nPummer, K\n\nZigeuner, R\n\nHutterer, GC\n\nBeiträge in Fachzeitschriften\nISI:000357867700021\n25862811.0\n10.1136/jclinpath-2014-202683\nNone\nIncreasing evidence suggests that the serum-gamma-glutamyltransferase (GGT) might correlate with tumour development and growth rates in various human cancer types. Thus, we decided to investigate the potential prognostic impact of the preoperatively assessed serum-GGT in a European cohort of patients with non-metastatic renal cell carcinoma (RCC).\n Clinicopathological data from 700 consecutive patients with non-metastatic RCC, operated between 2000 and 2010 at a single tertiary academic centre, were evaluated retrospectively. Preoperative serum-GGT was assessed 1 day before surgery. Patients were categorised using a serum-GGT cut-off value of 40 U/L according to a calculation by receiver operating curve analysis. Patients' cancer-specific survival (CSS), metastasis-free survival (MFS), as well as overall survival (OS) were assessed using the Kaplan-Meier method and Cox proportional models.\n In univariate analysis, an elevated preoperative serum-GGT level (<40 U/L vs ≥40 U/L) was statistically significantly associated with a shorter MFS (HR=1.517, 95% CI 1.047 to 2.197, p=0.027). In multivariate analyses, pathological T-Stage (pT-1 vs pT-2-4, HR=2.065, 95% CI 1.665 to 2.560), tumour grade (G-1+G-2 vs G-3+G-4, HR=1.671, 95% CI 1.261 to 2.213), as well as the presence of histological tumour necrosis (No vs Yes, HR=2.031, 95% CI 1.355 to 3.046) were independent predictors of MFS in patients with RCC, whereas the preoperative serum-GGT failed to reach independent predictor status (<40 U/L vs ≥40 U/L, HR=1.156, 95% CI 0.791 to 1.690). No prognostic role for GGT in OS or CSS could be identified.\n In the cohort studied, patients with an elevated (≥40 U/L) preoperative serum-GGT had a subsequently shorter MFS only in univariate analysis. In contrast to previous studies, our data failed to demonstrate preoperatively assessed serum-GGT as an independent prognostic factor in patients with non-metastatic RCC.\n Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.\n\nDalpiaz, Orietta\n\nHutterer, Georg\n\nPichler, Martin\n\nPummer, Karl\n\nTerbuch, Angelika\n\nZigeuner, Richard\n\n\n"
},
{
"text": "\n159204\nMutations in DCDC2 (doublecortin domain containing protein 2) in neonatal sclerosing cholangitis.\n\nGrammatikopoulos, T\n\nSambrotta, M\n\nStrautnieks, S\n\nFoskett, P\n\nKnisely, AS\n\nWagner, B\n\nDeheragoda, M\n\nStarling, C\n\nMieli-Vergani, G\n\nSmith, J\n\nUniversity of Washington Center for Mendelian Genomics\n\nBull, L\n\nThompson, RJ\n\nBeiträge in Fachzeitschriften\nISI:000389097700017\n27469900.0\n10.1016/j.jhep.2016.07.017\nPMC5116266\nNeonatal sclerosing cholangitis (NSC) is a severe neonatal-onset cholangiopathy commonly leading to liver transplantation (LT) for end-stage liver disease in childhood. Liver biopsy findings histopathologically resemble those in biliary atresia (BA); however, in NSC extrahepatic bile ducts are patent, whilst in BA their lumina are obliterated. NSC is commonly seen in consanguineous kindreds, suggesting autosomal recessive inheritance.\n From 29 NSC patients (24 families) identified, DNA was available in 24 (21 families). Thirteen (7 male) patients (12 families) of consanguineous parentage were selected for whole exome sequencing. Sequence variants were filtered for homozygosity, pathogenicity, minor allele frequency, quality score, and encoded protein expression pattern.\n Four of 13 patients were homozygous and two were compound heterozygous for mutations in the doublecortin domain containing 2 gene (DCDC2), which encodes DCDC2 protein and is expressed in cholangiocyte cilia. Another 11 patients were sequenced: one (with one sibling pair) was compound heterozygous for DCDC2 mutations. All mutations were protein-truncating. In available liver tissue from patients with DCDC2 mutations, immunostaining for human DCDC2 and the ciliary protein acetylated alpha-tubulin (ACALT) showed no expression (n=6) and transmission electron microscopy found that cholangiocytes lacked primary cilia (n=5). DCDC2 and ACALT were expressed in NSC patients without DCDC2 mutations (n=22). Of the patients carrying DCDC2 mutations, one died awaiting LT; five came to LT, of whom one died 2years later. The other 4 are well.\n Among 24 NSC patients with available DNA, 7 had mutations in DCDC2 (6 of 19 families). NSC patients in substantial proportion harbour mutations in DCDC2. Their disease represents a novel liver-based ciliopathy.\n Neonatal sclerosing cholangitis (NSC) is a rare genetic form of liver disease presenting in infancy. Through next generation sequencing we identified mutations in the gene encoding for doublecortin domain containing 2 (DCDC2) protein in a group of NSC children. DCDC2 is a signalling and structural protein found in primary cilia of cholangiocytes. Cholangiocytes are the cells forming the biliary system which is the draining system of the liver.\n Copyright © 2016 European Association for the Study of the Liver. All rights reserved.\n\nKnisely, Alexander\n\n\n"
},
{
"text": "\n165041\nLong-term Efficacy and Safety of Stem Cell Therapy (Cx601) for Complex Perianal Fistulas in Patients With Crohn's Disease.\n\nPanés, J\n\nGarcía-Olmo, D\n\nVan Assche, G\n\nColombel, JF\n\nReinisch, W\n\nBaumgart, DC\n\nDignass, A\n\nNachury, M\n\nFerrante, M\n\nKazemi-Shirazi, L\n\nGrimaud, JC\n\nde la Portilla, F\n\nGoldin, E\n\nRichard, MP\n\nDiez, MC\n\nTagarro, I\n\nLeselbaum, A\n\nDanese, S\n\nADMIRE CD Study Group Collaborators\n\nBeiträge in Fachzeitschriften\nISI:000428978800029\n29277560.0\n10.1053/j.gastro.2017.12.020\nNone\nTherapies for perianal fistulas in patients with Crohn's disease are often ineffective in producing long-term healing. We performed a randomized placebo-controlled trial to determine the long-term efficacy and safety of a single local administration of allogeneic expanded adipose-derived stem cells (Cx601) in patients with Crohn's disease and perianal fistulas.\n We performed a double-blind study at 49 hospitals in Europe and Israel, comprising 212 patients with Crohn's disease and treatment-refractory, draining, complex perianal fistulas. Patients were randomly assigned (1:1) to groups given a single local injection of 120 million Cx601 cells or placebo (control), in addition to the standard of care. Efficacy endpoints evaluated in the modified intention-to-treat population (randomly assigned, treated, and with 1 or more post-baseline efficacy assessment) at week 52 included combined remission (closure of all treated external openings draining at baseline with absence of collections >2 cm, confirmed by magnetic resonance imaging) and clinical remission (absence of draining fistulas).\n The study's primary endpoint, at week 24, was previously reported (combined remission in 51.5% of patients given Cx601 vs 35.6% of controls, for a difference of 15.8 percentage points; 97.5% confidence interval [CI] 0.5-31.2; P = .021). At week 52, a significantly greater proportion of patients given Cx601 achieved combined remission (56.3%) vs controls (38.6%) (a difference of 17.7 percentage points; 95% CI 4.2-31.2; P = .010), and clinical remission (59.2% vs 41.6% of controls, for a difference of 17.6 percentage points; 95% CI 4.1-31.1; P = .013). Safety was maintained throughout week 52; adverse events occurred in 76.7% of patients in the Cx601 group and 72.5% of patients in the control group.\n In a phase 3 trial of patients with Crohn's disease and treatment-refractory complex perianal fistulas, we found Cx601 to be safe and effective in closing external openings, compared with placebo, after 1 year. ClinicalTrials.gov no: NCT01541579.\n Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.\n\n\n"
},
{
"text": "\n178054\nAssociation of an organ transplant-based approach with a dramatic reduction in postoperative complications following radical nephrectomy and tumor thrombectomy in renal cell carcinoma.\n\nGonzález, J\n\nGaynor, JJ\n\nMartínez-Salamanca, JI\n\nCapitanio, U\n\nTilki, D\n\nCarballido, JA\n\nChantada, V\n\nDaneshmand, S\n\nEvans, CP\n\nGasch, C\n\nGontero, P\n\nHaferkamp, A\n\nHuang, WC\n\nEspinós, EL\n\nMaster, VA\n\nMcKiernan, JM\n\nMontorsi, F\n\nPahernik, S\n\nPalou, J\n\nPruthi, RS\n\nRodriguez-Faba, O\n\nRusso, P\n\nScherr, DS\n\nShariat, SF\n\nSpahn, M\n\nTerrone, C\n\nVera-Donoso, C\n\nZigeuner, R\n\nHohenfellner, M\n\nLibertino, JA\n\nCiancio, G\n\nBeiträge in Fachzeitschriften\nISI:000491301600035\n31155470.0\n10.1016/j.ejso.2019.05.009\nNone\nOur aim was to determine whether using an organ transplant-based(TB) approach reduces postoperative complications(PCs) following radical nephrectomy(RN) and tumor thrombectomy(TT) in renal cell carcinoma(RCC) patients with level II-IV thrombi.\n A total of 390(292 non-TB/98 TB) IRCC-VT Consortium patients who received no preoperative embolization/IVC filter were included. Stepwise linear/logistic regression analyses were performed to determine significant multivariable predictors of intraoperative estimated blood loss(IEBL), number blood transfusions received, and overall/major PC development within 30days following surgery. Propensity to receive the TB approach was controlled.\n The TB approach was clearly superior in limiting IEBL, blood transfusions, and PC development, even after controlling for other significant prognosticators/propensity score(P < .000001 in each case). Median IEBL for non-TB/TB approaches was 1000 cc/300 cc and 1500 cc/500 cc for tumor thrombus Level II-III patients, respectively, with no notable differences for Level IV patients(2000 cc each). In comparing PC outcomes between non-TB/TB patients with a non-Right-Atrium Cranial Limit, the observed percentage developing a: i) PC was 65.8%(133/202) vs. 4.3%(3/69) for ECOG Performance Status(ECOG-PS) 0-1, and 84.8%(28/33) vs. 25.0%(4/16) for ECOG-PS 2-4, and ii) major PC was 16.8%(34/202) vs. 1.4%(1/69) for ECOG-PS 0-1, and 27.3%(9/33) vs. 12.5%(2/16) for ECOG-PS 2-4. Major study limitation was the fact that all TB patients were treated by a single, experienced, high volume surgeon from one center (non-TB patients were treated by various surgeons at 13 other centers).\n Despite this major study limitation, the observed dramatic differences in PC outcomes suggest that the TB approach offers a major breakthrough in limiting operative morbidity in RCC patients receiving RN and TT.\n Copyright © 2019. Published by Elsevier Ltd.\n\nZigeuner, Richard\n\n\n"
},
{
"text": "\n183139\nBroadening the spectrum of NTRK rearranged mesenchymal tumors and usefulness of pan-TRK immunohistochemistry for identification of NTRK fusions.\n\nBrčić, I\n\nGodschachner, TM\n\nBergovec, M\n\nIgrec, J\n\nTill, H\n\nLackner, H\n\nScheipl, S\n\nKashofer, K\n\nBrodowicz, T\n\nLeithner, A\n\nSzkandera, J\n\nLiegl-Atzwanger, B\n\nBeiträge in Fachzeitschriften\nISI:000563609900003\n32860002.0\n10.1038/s41379-020-00657-x\nPMC7817523\nFusions involving NTRK1, NTRK2, and NTRK3 are oncogenic drivers occurring in a spectrum of mesenchymal neoplasms ranging from benign to highly malignant tumors. To gain further insights into the staining profile with the pan-TRK assay, we analyzed a large number of soft tissue sarcomas and correlated our findings with molecular testing. Additionally, we expand the spectrum of NTRK-fusion tumors by reporting a mesenchymal lesion in the lung as well as a mesenchymal skin lesion in the spectrum of benign fibrous histiocytoma with NTRK-fusion. We retrospectively reviewed soft tissue sarcomas diagnosed at the Diagnostic and Research Institute of Pathology, Medical University of Graz, between 1999 and 2019, and cases from the consultation files of one of the authors (BLA). In total, 494 cases were analyzed immunohistochemically with pan-TRK antibody (clone EPR17341, RTU, Roche/Ventana) and positive cases (defined as any cytoplasmic/nuclear staining in more than 1% of tumor cells) underwent next-generation sequencing (NGS). Immunohistochemical staining was observed in 16 (3.2%) cases. Eleven cases with focal weak and moderate cytoplasmic/membranous or focal moderate to strong nuclear staining did not harbor an NTRK-fusion (three synovial sarcomas, three leiomyosarcomas, two extraskeletal myxoid chondrosarcomas, and one each: dedifferentiated liposarcoma, pleomorphic liposarcoma, and myxofibrosarcoma). Four cases showed strong diffuse nuclear and/or cytoplasmatic staining, and one case showed diffuse, but weak cytoplasmic staining. All these cases demonstrated an NTRK-fusion (LMNA-NTRK1, IRF2BP2-NTRK1, TMB3-NTRK1, ETV6-NTRK3, RBPMS-NTRK3). Pan-TRK assay (clone EPR17341, RTU, Roche, Ventana) immunohistochemistry serves as a reliable diagnostic marker that can also be expressed in non-NTRK-rearranged mesenchymal neoplasms. It can be used as a surrogate marker for identification of NTRK fusion, nevertheless, an RNA-based NGS for detection of the specific fusion should be performed to confirm the rearrangement, if patients are undergoing targeted therapy. Additionally, we identified NTRK-fusion-positive, primary mesenchymal tumors of the lung and the skin.\n\nBergovec, Marko\n\nBrcic, Iva\n\nGodschachner, Theresa Marie\n\nKashofer, Karl\n\nLackner, Herwig\n\nLeithner, Andreas\n\nLiegl-Atzwanger, Bernadette\n\nScheipl, Susanne\n\nSzkandera, Joanna\n\nTill, Holger\n\n\n"
},
{
"text": "\n187364\nEffects of a combined therapy of bortezomib and ionizing radiation on chondrosarcoma three-dimensional spheroid cultures.\n\nLohberger, B\n\nGlaenzer, D\n\nEck, N\n\nSteinecker-Frohnwieser, B\n\nLeithner, A\n\nRinner, B\n\nKerschbaum-Gruber, S\n\nGeorg, D\n\nBeiträge in Fachzeitschriften\nISI:000640292800001\n33868466.0\n10.3892/ol.2021.12689\nPMC8045153\nChondrosarcomas represent a heterogeneous group of primary bone cancers that are characterized by hyaline cartilaginous neoplastic tissue and are predominantly resistant to radiation and chemotherapy. However, adjuvant radiotherapy is often recommended in inoperable cases or after incomplete resections. To improve the efficiency of treatment, the present study tested a combination therapy with ionizing radiation (IR) and the proteasome inhibitor bortezomib. Using a three-dimensional (3D) spheroid model, 0-20 Gy of IR was applied to chondrosarcoma cells and healthy human chondrocytes. Following combined treatment with IR and bortezomib, the cell cycle distribution, apoptotic induction, the survivin pathway, autophagy and DNA damage were evaluated. Both cell types exhibited a slight decrease in viability following increasing doses of IR; the chondrosarcoma cells demonstrated a significant dose-dependent increase in the expression levels of the DNA damage marker histone H2AX phosphorylation at serine 139 (γH2AX). The combination treatment with bortezomib significantly decreased the cell viability after 48 h compared with that in irradiated cells. High-dose IR induced a G2/M phase arrest, which was accompanied by a decrease in the number of cells at the G1 and S phase. Co-treatment with bortezomib changed the distribution of the cell cycle phases. The mRNA expression levels of the proapoptotic genes Bcl-2-associated X protein (Bax) and Bak were significantly increased by bortezomib treatment and combination therapy with IR. In addition, the combination therapy resulted in a synergistic decrease of the expression levels of survivin and its corresponding downstream pathway molecules, including heat shock protein 90, X-linked inhibitor of apoptosis protein, smad 2 and smad 3. Comparative analyses of γH2AX at 1 and 24 h post-IR revealed efficient DNA repair in human chondrosarcoma cells. Therefore, additional bortezomib treatment may only temporarily improve the radiation sensitivity of chondrosarcoma cells. However, the inhibition of the survivin pathway by the combined treatment with IR and bortezomib, observed in the present study, revealed a novel aspect in the tumor biology of chondrosarcoma 3D spheroid cultures and may represent a potential target for therapy.\n Copyright: © Lohberger et al.\n\nEck, Nicole\n\nGlänzer, Dietmar\n\nLeithner, Andreas\n\nLohberger, Birgit\n\nRinner, Beate\n\nSteinecker-Frohnwieser, Bibiane\n\n\n"
},
{
"text": "\n32656\nEndogenous neuropeptide Y depresses the afferent signaling of gastric acid challenge to the mouse brainstem via neuropeptide Y type Y2 and Y4 receptors.\n\nWultsch, T\n\nPainsipp, E\n\nThoeringer, CK\n\nHerzog, H\n\nSperk, G\n\nHolzer, P\n\nBeiträge in Fachzeitschriften\nISI:000234458200010\n16216428.0\n10.1016/j.neuroscience.2005.08.038\nNone\nVagal afferents signal gastric acid challenge to the nucleus tractus solitarii of the rat brainstem. This study investigated whether nucleus tractus solitarii neurons in the mouse also respond to gastric acid challenge and whether this chemonociceptive input is modified by neuropeptide Y acting via neuropeptide Y receptors of type Y2 or Y4. The gastric mucosa of female mice was exposed to different concentrations of HCl or saline, excitation of neurons in the nucleus tractus solitarii visualized by c-Fos immunohistochemistry, gastric emptying deduced from the gastric volume recovery, and gastric lesion formation evaluated by planimetry. Relative to saline, intragastric HCl (0.15-0.35 M) increased the number of c-Fos-expressing cells in the nucleus tractus solitarii in a concentration-dependent manner, inhibited gastric emptying but failed to cause significant hemorrhagic injury in the stomach. Mice in which the Y2 or Y4 receptor gene had been deleted responded to gastric acid challenge with a significantly higher expression of c-Fos in the nucleus tractus solitarii, the increases amounting to 39 and 31%, respectively. The HCl-induced inhibition of gastric emptying was not altered by deletion of the Y2 or Y4 receptor gene. BIIE0246 ((S)-N2-[[1-[2-[4-[(R, )-5, 1-dihydro-6(6H)-oxodibenz[b, ] azepin-11-yl]-1-piperazinyl]-2-oxoethyl]cyclopentyl] acetyl]-N-[2-[1, -dihydro-3, (4H)-dioxo-1, -diphenyl-3H-1, , -triazol-4-yl]ethyl]-argininamide; 0.03 mmol/kg s.c.), a Y2 receptor antagonist which does not cross the blood-brain barrier, did not modify the c-Fos response to gastric acid challenge. The Y2 receptor agonist peptide YY-(3-36) (0.1 mg/kg intraperitoneally) likewise failed to alter the gastric HCl-evoked expression of c-Fos in the nucleus tractus solitarii. BIIE0246, however, prevented the effect of peptide YY-(3-36) to inhibit gastric acid secretion as deduced from measurement of intragastric pH. The current data indicate that gastric challenge with acid concentrations that do not induce overt injury but inhibit gastric emptying is signaled to the mouse nucleus tractus solitarii. Endogenous neuropeptide Y acting via Y2 and Y4 receptors depresses the afferent input to the nucleus tractus solitarii by a presumably central site of action.\n\nHolzer, Peter\n\n\n"
},
{
"text": "\n117446\nAbsence of adipose triglyceride lipase protects from hepatic endoplasmic reticulum stress in mice.\n\nFuchs, CD\n\nClaudel, T\n\nKumari, P\n\nHaemmerle, G\n\nPollheimer, MJ\n\nStojakovic, T\n\nScharnagl, H\n\nHalilbasic, E\n\nGumhold, J\n\nSilbert, D\n\nKoefeler, H\n\nTrauner, M\n\nBeiträge in Fachzeitschriften\nISI:000305947200030\n22271167.0\n10.1002/hep.25601\nNone\nNonalcoholic fatty liver disease (NAFLD) is characterized by triglyceride (TG) accumulation and endoplasmic reticulum (ER) stress. Because fatty acids (FAs) may trigger ER stress, we hypothesized that the absence of adipose triglyceride lipase (ATGL/PNPLA2)-the main enzyme for intracellular lipolysis, releasing FAs, and closest homolog to adiponutrin (PNPLA3) recently implicated in the pathogenesis of NAFLD-protects against hepatic ER stress. Wild-type (WT) and ATGL knockout (KO) mice were challenged with tunicamycin (TM) to induce ER stress. Serum biochemistry, hepatic TG and FA profiles, liver histology, and gene expression for markers of hepatic lipid metabolism, ER stress, and inflammation were explored. Moreover, cell-culture experiments were performed in Hepa1.6 cells after the knockdown of ATGL before FA and TM treatment. TM increased hepatic TG accumulation in ATGL KO, but not in WT, mice. Lipogenesis and β-oxidation were repressed at the gene-expression level (sterol regulatory element-binding transcription factor 1c, fatty acid synthase, acetyl coenzyme A carboxylase 2, and carnitine palmitoyltransferase 1 alpha) in both WT and ATGL KO mice. Genes for very-low-density lipoprotein (VLDL) synthesis (microsomal triglyceride transfer protein and apolipoprotein B) were down-regulated by TM in WT and even more in ATGL KO mice, which displayed strongly reduced serum VLDL cholesterol levels. Notably, ER stress markers glucose-regulated protein, C/EBP homolog protein, spliced X-box-binding protein, endoplasmic-reticulum-localized DnaJ homolog 4, and inflammatory markers Tnfα and iNos were induced exclusively in TM-treated WT, but not ATGL KO, mice. Total hepatic FA profiling revealed a higher palmitic acid/oleic acid (PA/OA) ratio in WT mice, compared to ATGL KO mice, at baseline. Phosphoinositide-3-kinase inhibitor-known to be involved in FA-derived ER stress and blocked by OA-was increased in TM-treated WT mice only. In line with this, in vitro OA protected hepatocytes from TM-induced ER stress.\n Lack of ATGL may protect from hepatic ER stress through alterations in FA composition. ATGL could constitute a new therapeutic strategy to target ER stress in NAFLD.\n Copyright © 2012 American Association for the Study of Liver Diseases.\n\nKöfeler, Harald\n\nPollheimer, Marion\n\nScharnagl, Hubert\n\nSilbert-Wagner, Dagmar\n\nSommer, Judith\n\n\n"
},
{
"text": "\n138283\nContribution of TRPC3 to store-operated calcium entry and inflammatory transductions in primary nociceptors.\n\nAlkhani, H\n\nAse, AR\n\nGrant, R\n\nO'Donnell, D\n\nGroschner, K\n\nSéguéla, P\n\nBeiträge in Fachzeitschriften\nISI:000339633700001\n24965271.0\n10.1186/1744-8069-10-43\nPMC4118315\nProlonged intracellular calcium elevation contributes to sensitization of nociceptors and chronic pain in inflammatory conditions. The underlying molecular mechanisms remain unknown but store-operated calcium entry (SOCE) components participate in calcium homeostasis, potentially playing a significant role in chronic pain pathologies. Most G protein-coupled receptors activated by inflammatory mediators trigger calcium-dependent signaling pathways and stimulate SOCE in primary afferents. The aim of the present study was to investigate the role of TRPC3, a calcium-permeable non-selective cation channel coupled to phospholipase C and highly expressed in DRG, as a link between activation of pro-inflammatory metabotropic receptors and SOCE in nociceptive pathways.\n Using in situ hybridization, we determined that TRPC3 and TRPC1 constitute the major TRPC subunits expressed in adult rat DRG. TRPC3 was found localized exclusively in small and medium diameter sensory neurons. Heterologous overexpression of TRPC3 channel subunits in cultured primary DRG neurons evoked a significant increase of Gd3+-sensitive SOCE following thapsigargin-induced calcium store depletion. Conversely, using the same calcium add-back protocol, knockdown of endogenous TRPC3 with shRNA-mediated interference or pharmacological inhibition with the selective TRPC3 antagonist Pyr10 induced a substantial decrease of SOCE, indicating a significant role of TRPC3 in SOCE in DRG nociceptors. Activation of P2Y2 purinoceptors or PAR2 protease receptors triggered a strong increase in intracellular calcium in conditions of TRPC3 overexpression. Additionally, knockdown of native TRPC3 or its selective pharmacological blockade suppressed UTP- or PAR2 agonist-evoked calcium responses as well as sensitization of DRG neurons. These data show a robust link between activation of pro-inflammatory receptors and calcium homeostasis through TRPC3-containing channels operating both in receptor- and store-operated mode.\n Our findings highlight a major contribution of TRPC3 to neuronal calcium homeostasis in somatosensory pathways based on the unique ability of these cation channels to engage in both SOCE and receptor-operated calcium influx. This is the first evidence for TRPC3 as a SOCE component in DRG neurons. The flexible role of TRPC3 in calcium signaling as well as its functional coupling to pro-inflammatory metabotropic receptors involved in peripheral sensitization makes it a potential target for therapeutic strategies in chronic pain conditions.\n\nGroschner, Klaus\n\n\n"
},
{
"text": "\n138411\nThe dynamic range of circulating tumor DNA in metastatic breast cancer.\n\nHeidary, M\n\nAuer, M\n\nUlz, P\n\nHeitzer, E\n\nPetru, E\n\nGasch, C\n\nRiethdorf, S\n\nMauermann, O\n\nLafer, I\n\nPristauz, G\n\nLax, S\n\nPantel, K\n\nGeigl, JB\n\nSpeicher, MR\n\nBeiträge in Fachzeitschriften\nISI:000344310300027\n25107527.0\n10.1186/s13058-014-0421-y\nPMC4303230\nThe management of metastatic breast cancer needs improvement. As clinical evaluation is not very accurate in determining the progression of disease, the analysis of circulating tumor DNA (ctDNA) has evolved to a promising noninvasive marker of disease evolution. Indeed, ctDNA was reported to represent a highly sensitive biomarker of metastatic cancer disease directly reflecting tumor burden and dynamics. However, at present little is known about the dynamic range of ctDNA in patients with metastatic breast cancer.\n In this study, 74 plasma DNA samples from 58 patients with metastasized breast cancer were analyzed with a microfluidic device to determine the plasma DNA size distribution and copy number changes in the plasma were identified by whole-genome sequencing (plasma-Seq). Furthermore, in an index patient we conducted whole-genome, exome, or targeted deep sequencing of the primary tumor, metastases, and circulating tumor cells (CTCs). Deep sequencing was done to accurately determine the allele fraction (AFs) of mutated DNA fragments.\n Although all patients had metastatic disease, plasma analyses demonstrated highly variable AFs of mutant fragments. We analyzed an index patient with more than 100, 00 CTCs in detail. We first conducted whole-genome, exome, or targeted deep sequencing of four different regions from the primary tumor and three metastatic lymph node regions, which enabled us to establish the phylogenetic relationships of these lesions, which were consistent with a genetically homogeneous cancer. Subsequent analyses of 551 CTCs confirmed the genetically homogeneous cancer in three serial blood analyses. However, the AFs of ctDNA were only 2% to 3% in each analysis, neither reflecting the tumor burden nor the dynamics of this progressive disease. These results together with high-resolution plasma DNA fragment sizing suggested that differences in phagocytosis and DNA degradation mechanisms likely explain the variable occurrence of mutated DNA fragments in the blood of patients with cancer.\n The dynamic range of ctDNA varies substantially in patients with metastatic breast cancer. This has important implications for the use of ctDNA as a predictive and prognostic biomarker.\n\nAuer, Martina\n\nGeigl, Jochen Bernd\n\nHeitzer, Ellen\n\nLafer, Ingrid\n\nPetru, Edgar\n\nPristauz-Telsnigg, Gunda\n\nSpeicher, Michael\n\nUlz, Peter\n\n\n"
},
{
"text": "\n150318\nReaction of bone nanostructure to a biodegrading Magnesium WZ21 implant - A scanning small-angle X-ray scattering time study.\n\nGrünewald, TA\n\nOgier, A\n\nAkbarzadeh, J\n\nMeischel, M\n\nPeterlik, H\n\nStanzl-Tschegg, S\n\nLöffler, JF\n\nWeinberg, AM\n\nLichtenegger, HC\n\nBeiträge in Fachzeitschriften\nISI:000370086100040\n26621693.0\n10.1016/j.actbio.2015.11.049\nNone\nUnderstanding the implant-bone interaction is of prime interest for the development of novel biodegrading implants. Magnesium is a very promising material in the class of biodegrading metallic implants, owing to its mechanical properties and excellent immunologic response during healing. However, the influence of degrading Mg implants on the bone nanostructure is still an open question of crucial importance for the design of novel Mg implant alloys. This study investigates the changes in the nanostructure of bone following the application of a degrading WZ21 Mg implant (2wt% Y, 1wt% Zn, 0.25wt% Ca and 0.15wt% Mn) in a murine model system over the course of 15months by small angle X-ray scattering. Our investigations showed a direct response of the bone nanostructure after as little as 1month with a realignment of nano-sized bone mineral platelets along the bone-implant interface. The growth of new bone tissue after implant resorption is characterized by zones of lower mineral platelet thickness and slightly decreased order in the stacking of the platelets. The preferential orientation of the mineral platelets strongly deviates from the normal orientation along the shaft and still roughly follows the implant direction after 15months. We explain our findings by considering geometrical, mechanical and chemical factors during the process of implant resorption.\n The advancement of surgical techniques and the increased life expectancy have caused a growing demand for improved bone implants. Ideally, they should be bio-resorbable, support bone as long as necessary and then be replaced by healthy bone tissue. Magnesium is a promising candidate for this purpose. Various studies have demonstrated its excellent mechanical performance, degradation behaviour and immunologic properties. The structural response of bone, however, is not well known. On the nanometer scale, the arrangement of collagen fibers and calcium mineral platelets is an important indicator of structural integrity. The present study provides insight into nanostructural changes in rat bone at different times after implant placement and different implant degradation states. The results are useful for further improved magnesium alloys.\n Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.\n\nWeinberg, Annelie-Martina\n\n\n"
},
{
"text": "\n171314\nTransgenic short-QT syndrome 1 rabbits mimic the human disease phenotype with QT/action potential duration shortening in the atria and ventricles and increased ventricular tachycardia/ventricular fibrillation inducibility.\n\nOdening, KE\n\nBodi, I\n\nFranke, G\n\nRieke, R\n\nRyan de Medeiros, A\n\nPerez-Feliz, S\n\nFürniss, H\n\nMettke, L\n\nMichaelides, K\n\nLang, CN\n\nSteinfurt, J\n\nPantulu, ND\n\nZiupa, D\n\nMenza, M\n\nZehender, M\n\nBugger, H\n\nPeyronnet, R\n\nBehrends, JC\n\nDoleschall, Z\n\nZur Hausen, A\n\nBode, C\n\nJolivet, G\n\nBrunner, M\n\nBeiträge in Fachzeitschriften\nISI:000461141900013\n30496390.0\n10.1093/eurheartj/ehy761\nNone\nShort-QT syndrome 1 (SQT1) is an inherited channelopathy with accelerated repolarization due to gain-of-function in HERG/IKr. Patients develop atrial fibrillation, ventricular tachycardia (VT), and sudden cardiac death with pronounced inter-individual variability in phenotype. We generated and characterized transgenic SQT1 rabbits and investigated electrical remodelling.\n Transgenic rabbits were generated by oocyte-microinjection of β-myosin-heavy-chain-promoter-KCNH2/HERG-N588K constructs. Short-QT syndrome 1 and wild type (WT) littermates were subjected to in vivo ECG, electrophysiological studies, magnetic resonance imaging, and ex vivo action potential (AP) measurements. Electrical remodelling was assessed using patch clamp, real-time PCR, and western blot. We generated three SQT1 founders. QT interval was shorter and QT/RR slope was shallower in SQT1 than in WT (QT, 147.8 ± 2 ms vs. 166.4 ± 3, P < 0.0001). Atrial and ventricular refractoriness and AP duration were shortened in SQT1 (vAPD90, 118.6 ± 5 ms vs. 154.4 ± 2, P < 0.0001). Ventricular tachycardia/fibrillation (VT/VF) inducibility was increased in SQT1. Systolic function was unaltered but diastolic relaxation was enhanced in SQT1. IKr-steady was increased with impaired inactivation in SQT1, while IKr-tail was reduced. Quinidine prolonged/normalized QT and action potential duration (APD) in SQT1 rabbits by reducing IKr. Diverse electrical remodelling was observed: in SQT1, IK1 was decreased-partially reversing the phenotype-while a small increase in IKs may partly contribute to an accentuation of the phenotype.\n Short-QT syndrome 1 rabbits mimic the human disease phenotype on all levels with shortened QT/APD and increased VT/VF-inducibility and show similar beneficial responses to quinidine, indicating their value for elucidation of arrhythmogenic mechanisms and identification of novel anti-arrhythmic strategies.\n Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.\n\nBugger, Heiko Matthias\n\n\n"
},
{
"text": "\n171423\nCharacterization of diabetes following pancreatic surgery in patients with congenital hyperinsulinism.\n\nWelters, A\n\nMeissner, T\n\nGrulich-Henn, J\n\nFröhlich-Reiterer, E\n\nWarncke, K\n\nMohnike, K\n\nBlankenstein, O\n\nMenzel, U\n\nDatz, N\n\nBollow, E\n\nHoll, RW\n\nBeiträge in Fachzeitschriften\nISI:000454254800002\n30577875.0\n10.1186/s13023-018-0970-8\nPMC6304089\nCongenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycaemia in infancy that leads to unfavourable neurological outcome if not treated adequately. In patients with severe diffuse CHI it remains under discussion whether pancreatic surgery should be performed or intensive medical treatment with the acceptance of recurrent episodes of mild hypoglycaemia is justified. Near-total pancreatectomy is associated with high rates of insulin-dependent diabetes mellitus and exocrine pancreatic insufficiency. Little is known about the management and long-term glycaemic control of CHI patients with diabetes after pancreatic surgery. We searched the German/Austrian DPV database and compared the course of 42 CHI patients with diabetes to that of patients with type 1 diabetes mellitus (T1DM). Study groups were compared at diabetes onset and after a follow-up period of 6.1 [3.3-9.7] (median [interquartile range]) years.\n The majority of CHI patients with diabetes were treated with insulin (85.2% [70.9-99.5] at diabetes onset, and 90.5% [81.2-99.7] at follow-up). However, compared to patients with T1DM, significantly more patients in the CHI group with diabetes were treated with conventional insulin therapy (47.8% vs. 24.4%, p = 0.03 at diabetes onset, and 21.1% vs. 6.4% at follow-up, p = 0.003), and only a small number of CHI patients were treated with insulin pumps. Daily insulin dose was significantly lower in CHI patients with diabetes than in patients with T1DM, both at diabetes onset (0.3 [0.2-0.5] vs. 0.6 IE/kg/d [0.4-0.8], p = 0.003) and follow-up (0.8 [0.4-1.0] vs. 0.9 [0.7-1.0] IE/kg/d, p = 0.02), while daily carbohydrate intake was comparable in both groups. Within the first treatment year, HbA1c levels were significantly lower in CHI patients with diabetes (6.2% [5.5-7.9] vs. 7.2% [6.5-8.2], p = 0.003), but increased to a level comparable to that of T1DM patients at follow-up. Interestingly, in CHI patients, the risk of severe hypoglycaemia tends to be higher only at diabetes onset (14.8% vs. 5.8%, p = 0.1).\n In surgically treated CHI patients insulin treatment needs to be intensified in order to achieve good glycaemic control. Our data furthermore emphasize the need for improved medical treatment options for patients with diazoxide- and/or octreotide-unresponsive CHI.\n\nFröhlich-Reiterer, Elke\n\n\n"
},
{
"text": "\n176811\nExperimental necrotizing enterocolitis induces neuroinflammation in the neonatal brain.\n\nBiouss, G\n\nAntounians, L\n\nLi, B\n\nO'Connell, JS\n\nSeo, S\n\nCatania, VD\n\nGuadagno, J\n\nRahman, A\n\nZani-Ruttenstock, E\n\nSvergun, N\n\nPierro, A\n\nZani, A\n\nBeiträge in Fachzeitschriften\nISI:000467545000002\n31077225.0\n10.1186/s12974-019-1481-9\nPMC6511222\nNecrotizing enterocolitis (NEC) is an inflammatory gastrointestinal disease primarily affecting preterm neonates. Neonates with NEC suffer from a degree of neurodevelopmental delay that is not explained by prematurity alone. There is a need to understand the pathogenesis of neurodevelopmental delay in NEC. In this study, we assessed the macroscopic and microscopic changes that occur to brain cell populations in specific brain regions in a neonatal mouse model of NEC. Moreover, we investigated the role of intestinal inflammation as part of the mechanism responsible for the changes observed in the brain of pups with NEC.\n Brains of mice were assessed for gross morphology and cerebral cortex thickness (using histology). Markers for mature neurons, oligodendrocytes, neural progenitor cells, microglia, and astrocytes were used to quantify their cell populations in different regions of the brain. Levels of cell apoptosis in the brain were measured by Western blotting and immunohistochemistry. Endoplasmic reticulum (ER) stress markers and levels of pro-inflammatory cytokines (in the ileum and brain) were measured by RT-qPCR and Western blotting. A Pearson test was used to correlate the levels of cytokines (ELISA) in the brain and ileum and to correlate activated microglia and astrocyte populations to the severity of NEC.\n NEC pups had smaller brain weights, higher brain-to-body weight ratios, and thinner cortices compared to control pups. NEC pups had increased levels of apoptosis and ER stress. In addition, NEC was associated with a reduction in the number of neurons, oligodendrocytes, and neural progenitors in specific regions of the brain. Levels of pro-inflammatory cytokines and the density of activated microglia and astrocytes were increased in the brain and positively correlated with the increase in the levels pro-inflammatory cytokines in the gut and the severity of NEC damage respectively.\n NEC is associated with severe changes in brain morphology, a pro-inflammatory response in the brain that alters cell homeostasis and density of brain cell populations in specific cerebral regions. We show that the severity of neuroinflammation is associated with the severity of NEC. Our findings suggest that early intervention during NEC may reduce the chance of acute neuroinflammation and cerebral damage.\n\n\n"
},
{
"text": "\n185387\nSecondary stroke in patients with polytrauma and traumatic brain injury treated in an Intensive Care Unit, Karlovac General Hospital, Croatia.\n\nBelavić, M\n\nJančić, E\n\nMišković, P\n\nBrozović-Krijan, A\n\nBakota, B\n\nŽunić, J\n\nBeiträge in Fachzeitschriften\nNone\n26620118.0\n10.1016/j.injury.2015.10.057\nNone\nTraumatic brain injury (TBI) is divided into primary and secondary brain injury. Primary brain injury occurs at the time of injury and is the direct consequence of kinetic energy acting on the brain tissue. Secondary brain injury occurs several hours or days after primary brain injury and is the result of factors including shock, systemic hypotension, hypoxia, hypothermia or hyperthermia, intracranial hypertension, cerebral oedema, intracranial bleeding or inflammation. The aim of this retrospective analysis of a prospective database was to determine the prevalence of secondary stroke and stroke-related mortality, causes of secondary stroke, treatment and length of stay in the ICU and hospital. This study included patients with TBI with or without other injuries who were hospitalised in a general ICU over a five-year period. The following parameters were assessed: demographics (age, sex), scores (Glasgow Coma Score, APACHE II, SOFA), secondary stroke (prevalence, time of occurrence after primary brain injury, causes of stroke and associated mortality), length of stay in the ICU and hospital, vital parameters (state of consciousness, cardiac function, respiration, circulation, thermoregulation, diuresis) and laboratory values (leukocytes, C-reactive protein [CRP], blood glucose, blood gas analysis, urea, creatinine). Medical data were analysed for 306 patients with TBI (median age 56 years, range 18-93 years) who were treated in the general ICU. Secondary stroke occurred in 23 patients (7.5%), 10 of whom died, which gives a mortality rate of 43.4%. Three patients were excluded as the cause of the injury was missile trauma. The study data indicate that inflammation is the most important cause of secondary insults. Levels of CRP were elevated in 65% of patients with secondary brain injury; leukocytosis was present in 87% of these patients, and blood glucose was elevated in 73%. The lungs and urinary tract were the most common sites of infection. In conclusion, elevated inflammatory markers (white blood cell count and CRP) and hyperglycaemia are associated with secondary brain injury. The lack of routine use of intracranial pressure (ICP) monitoring may explain the high mortality rate and the occurrence of secondary stroke in patients with TBI. \n Copyright © 2015 Elsevier Ltd. All rights reserved.\n\n\n"
}
]
}