Increase of angiotensin II type 1 receptor auto-antibodies in Huntington’s disease

Background In the recent years, a role of the immune system in Huntington’s disease (HD) is increasingly recognized. Here we investigate the presence of T cell activating auto-antibodies against angiotensin II type 1 receptors (AT1R) in all stages of the disease as compared to healthy controls and patients suffering from multiple sclerosis (MS) as a prototype neurologic autoimmune disease. Results As compared to controls, MS patients show higher titers of anti-AT1R antibodies, especially in individuals with active disease. In HD, anti-AT1R antibodies are more frequent than in healthy controls or even MS and occur in 37.9% of patients with relevant titers ≥ 20 U/ml. In a correlation analysis with clinical parameters, the presence of AT1R antibodies in the sera of HD individuals inversely correlated with the age of onset and positively with the disease burden score as well as with smoking and infection. Conclusions These data suggest a dysfunction of the adaptive immune system in HD which may be triggered by different stimuli including autoimmune responses, infection and possibly also smoking

The non-invasive 13C-methionine breath test detects hepatic mitochondrial dysfunction as a marker of disease activity in non-alcoholic steatohepatitis

<p>Abstract</p> <p>Introduction</p> <p>Mitochondrial dysfunction plays a central role in the general pathogenesis of non-alcoholic fatty liver disease (NAFLD), increasing the risk of developing steatosis and subsequent hepatocellular inflammation. We aimed to assess hepatic mitochondrial function by a non-invasive ¹³C-methionine breath test (MeBT) in patients with histologically proven NAFLD.</p> <p>Methods</p> <p>118 NAFLD-patients and 18 healthy controls were examined by MeBT. Liver biopsy specimens were evaluated according to the NASH scoring system.</p> <p>Results</p> <p>Higher grades of NASH activity and fibrosis were independently associated with a significant decrease in cumulative ¹³C-exhalation (expressed as cPDR(%)). cPDR_1.5hwas markedly declined in patients with NASH and NASH cirrhosis compared to patients with simple steatosis or borderline diagnosis (cPDR1.5h: 3.24 ± 1.12% and 1.32 ± 0.94% vs. 6.36 ± 0.56% and 4.80 ± 0.88% respectively; p < 0.001). ¹³C-exhalation further declined in the presence of advanced fibrosis which was correlated with NASH activity (r = 0.36). The area under the ROC curve (AUROC) for NASH diagnosis was estimated to be 0.87 in the total cohort and 0.83 in patients with no or mild fibrosis (F0-1).</p> <p>Conclusion</p> <p>The ¹³C-methionine breath test indicates mitochondrial dysfunction in non-alcoholic fatty liver disease and predicts higher stages of disease activity. It may, therefore, be a valuable diagnostic addition for longitudinal monitoring of hepatic (mitochondrial) function in non-alcoholic fatty liver disease.</p

Adaptive Algorithm for Fast 3D Characterization of Magnetic Sensors

Magnetic sensors are highly relevant in clinical and industrial applications such as localization tasks and geological investigations. The spatial behavior of these sensors is of great interest for accurate forward modeling and the consequential possibilities for sophisticated applications, e.g., solutions to inverse problems. In this contribution, we present a novel characterization approach using adaptive system identification approaches. We utilize a gradient-based algorithm for estimating impulse and corresponding frequency responses for a directivity analysis in 1D, 2D, and 3D. For this, we built a triaxial Helmholtz coil setup to generate a 3D directive field. This is controlled by an algorithm that exploits similarities in sensor behavior with respect to small differences in excitation field angles. We found advantages for a controlled adaptation, with faster convergence and a smaller system distance between estimations and measurements with a proposed control based on the contraction-expansion approach (CEA). With runtimes averaging less than 1.5 s per direction for full impulse response estimation, this proof of concept shows the potential of the proposed algorithm for enabling a feasible frequency and directivity characterization method

SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models

There are currently no disease-modifying therapies for the neurodegenerative disorder Huntington's disease (HD). This study identified novel thiazole-containing inhibitors of the deacetylase sirtuin-2 (SIRT2) with neuroprotective activity in ex vivo brain slice and Drosophila models of HD. A systems biology approach revealed an additional SIRT2-independent property of the lead-compound, MIND4, as an inducer of cytoprotective NRF2 (nuclear factor-erythroid 2 p45-derived factor 2) activity. Structure-activity relationship studies further identified a potent NRF2 activator (MIND4-17) lacking SIRT2 inhibitory activity. MIND compounds induced NRF2 activation responses in neuronal and non-neuronal cells and reduced production of reactive oxygen species and nitrogen intermediates. These drug-like thiazole-containing compounds represent an exciting opportunity for development of multi-targeted agents with potentially synergistic therapeutic benefits in HD and related disorders

Stent placement in pancreatic disease, when, which and why? – a current perspective

IntroductionStenting of the pancreas is a challenging task for the interventional gastroenterologist. The indications for pancreatic stent implantation are either prophylactic or therapeutic. We give an overview of currently available literature and techniques for the respective indications of pancreatic stent placement.MethodsA structured literature research was conducted (Pubmed.gov) primarily using the following key words: interventional endoscopy, pancreatic stenting, post-ERCP pancreatitis, pancreatic Q8 fistulae, pancreas divisum.ResultsProphylactic stent implantation aims to prevent PEP by using thin (3-5 Fr) and short (3-5 cm) designated pancreatic stents at least in high-risk patients. Therapeutic stent placement is intended to restore the proper flow of pancreatic secretion with stenoses, leaks, fistulas or anatomical malformation of the pancreatic duct. Depending on the etiology, plastic stents or SEMSs are used. Another field of pancreatic stenting represents EUS-guided puncture with stent implantation as an alternative access to the main pancreatic duct when transpapillary access is impossible. In addition to the implantation of plastic stents, which achieve good results, LAMS implantation can be discussed as an alternative access route.DiscussionThe field of pancreatic stenting is complex and belongs in the hands of experienced endoscopists in specialized institutions. This can ensure that the patient receives the optimal treatment with the best possible outcome

Quality standards and curriculum for training in cholangiopancreatoscopy : European Society of Gastrointestinal Endoscopy (ESGE) Position Statement

Competence in cholangioscopy should be defined as the ability to successfully perform the procedure effectively, without trainer assistance, in 80 % of procedures. Cholangioscopy should be performed in endoscopy units with a high yearly volume of endoscopic retrograde cholangiopancreatographies (ERCPs) of all grades of complexity. Cholangiopancreatoscopy practice should be considered as standard or advanced as follows: - STANDARD : Cholangioscopy for extrahepatic biliary stones; evaluation of extrahepatic biliary strictures; selective ductal guidewire cannulation and removal of migrated biliary stents/foreign body extraction - ADVANCED : Cholangioscopy for intrahepatic biliary strictures or complex hepatolithiasis; percutaneous cholangioscopy and pancreatoscopy. Endoscopy units undertaking standard cholangioscopy should have prompt access to the following (on site or within a defined rapidly responsive network): - Endoscopic ultrasound (EUS)- Interventional radiology (on-site) and hepaticopancreaticobiliary (HPB) surgery - HPB multidisciplinary meetings (MDMs). Complete extrahepatic stone clearance at the initial cholangioscopy session should be successful in 80 % of intention-to-treat cases. Cholangioscopy is recommended with visually guided biopsies in the evaluation of undefined biliary strictures, ideally at index ERCP to prevent negative visual and histological effects of prior stenting; except in cases with an associated mass lesion that may allow tissue acquisition by other means (e. g. EUS or percutaneous biopsy). In cholangioscopic evaluation of extrahepatic biliary strictures, visual assessment should be achieved in > 90 % of cases, and at least 4 visually guided biopsies should be undertaken with sufficient tissue for histological assessment being obtained in > 80 % of cases. Percutaneous transhepatic cholangioscopy is indicated in patients with transhepatic bile duct access in cases of altered anatomy or failed ERCP and an indication for cholangioscopy (stone management; biliary stricture evaluation; foreign body removal). Cholangioscopy is considered an advanced adjunct to ERCP, and prior to undertaking supervised cholangioscopic procedures trainees should be competent in the basic skills of ERCP (Schutz level 1 and 2) as defined by ESGE (duodenal intubation; biliary cannulation; distal bile duct stenting; ≤ 10-mm stone extraction). Cholangioscopy training should take place in expert referral centers with a high volume of ERCP and cholangioscopy cases. A trainee's principal trainer should be an experienced trainer ideally with at least 3 years of experience in undertaking independent cholangioscopy to the determined quality standards. Competence in cholangioscopy should be defined as the ability to successfully perform the procedure effectively without trainer assistance in 80 % of procedures

Imaging Inflammation - From Whole Body Imaging to Cellular Resolution

Imaging techniques have evolved impressively lately, allowing whole new concepts like multimodal imaging, personal medicine, theranostic therapies, and molecular imaging to increase general awareness of possiblities of imaging to medicine field. Here, we have collected the selected (3D) imaging modalities and evaluated the recent findings on preclinical and clinical inflammation imaging. The focus has been on the feasibility of imaging to aid in inflammation precision medicine, and the key challenges and opportunities of the imaging modalities are presented. Some examples of the current usage in clinics/close to clinics have been brought out as an example. This review evaluates the future prospects of the imaging technologies for clinical applications in precision medicine from the pre-clinical development point of view

Digital single-operator pancreatoscopy for the treatment of symptomatic pancreatic duct stones: a prospective multicenter cohort trial

BACKGROUND  Digital single-operator pancreatoscopy (DSOP)-guided lithotripsy is a novel treatment modality for pancreatic endotherapy, with demonstrated technical success in retrospective series of between 88 % and 100 %. The aim of this prospective multicenter trial was to systematically evaluate DSOP in patients with chronic pancreatitis and symptomatic pancreatic duct stones. METHODS  Patients with symptomatic chronic pancreatitis and three or fewer stones ≥ 5mm in the main pancreatic duct (MPD) of the pancreatic head or body were included. The primary end point was complete stone clearance (CSC) in three or fewer treatment sessions with DSOP. Current guidelines recommend extracorporeal shock wave lithotripsy (ESWL) for MPD stones > 5 mm. A performance goal was developed to show that the CSC rate of MPD stones using DSOP was above what has been previously reported for ESWL. Secondary end points were pain relief measured with the Izbicki pain score (IPS), number of interventions, and serious adverse events (SAEs). RESULTS  40 chronic pancreatitis patients were included. CSC was achieved in 90 % of patients (36/40) on intention-to-treat analysis, after a mean (SD) of 1.36 (0.64) interventions (53 procedures in total). The mean (SD) baseline IPS decreased from 55.3 (46.2) to 10.9 (18.3). Overall pain relief was achieved in 82.4 % (28/34) after 6 months of follow-up, with complete pain relief in 61.8 % (21/34) and partial pain relief in 20.6 % (7/34). SAEs occurred in 12.5 % of patients (5/40), with all treated conservatively. CONCLUSION  DSOP-guided endotherapy is effective and safe for the treatment of symptomatic MPD stones in highly selected patients with chronic pancreatitis. It significantly reduces pain and could be considered as an alternative to standard ERCP techniques for MPD stone treatment in these patients

Open Surgical versus Minimal Invasive Necrosectomy of the Pancreas-A Retrospective Multicenter Analysis of the German Pancreatitis Study Group

Background Necrotising pancreatitis, and particularly infected necrosis, are still associated with high morbidity and mortality. Since 2011, a step-up approach with lower morbidity rates compared to initial open necrosectomy has been established. However, mortality and complication rates of this complex treatment are hardly studied thereafter. Methods The German Pancreatitis Study Group performed a multicenter, retrospective study including 220 patients with necrotising pancreatitis requiring intervention, treated at 10 hospitals in Germany between January 2008 and June 2014. Data were analysed for the primary endpoints "severe complications" and "mortality" as well as secondary endpoints including "length of hospital stay", "follow up", and predisposing or prognostic factors. Results Of all patients 13.6% were treated primarily with surgery and 86.4% underwent a step-up approach. More men (71.8%) required intervention for necrotising pancreatitis. The most frequent etiology was biliary (41.4%) followed by alcohol (29.1%). Compared to open necrosectomy, the step-up approach was associated with a lower number of severe complications (primary composite endpoint including sepsis, persistent multiorgan dysfunction syndrome (MODS) and erosion bleeding: 44.7% vs. 73.3%), lower mortality (10.5% vs. 33.3%) and lower rates of diabetes mellitus type 3c (4.7% vs. 33.3%). Low hematocrit and low blood urea nitrogen at admission as well as a history of acute pancreatitis were prognostic for less complications in necrotising pancreatitis. A combination of drainage with endoscopic necrosectomy resulted in the lowest rate of severe complications. Conclusion A step-up approach starting with minimal invasive drainage techniques and endoscopic necrosectomy results in a significant reduction of morbidity and mortality in necrotising pancreatitis compared to a primarily surgical intervention