[First data concerning the medical supply of patients with non-alcoholic fatty liver disease in Germany - a survey in university hospital centers of hepatology]. / Erste Daten zur Versorgungssituation von Patienten mit nicht alkoholischer Fettlebererkrankung (NAFLD) in Deutschland - Eine Umfrage an universitären hepatologischen Zentren.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) currently is one oft the most common reasons for chronic liver injury in the western world. In the European and American population the prevalence is up to 30 %. The medical supply of German patients with NAFLD is variable and has not been analyzed to date. METHODS: We sent questionnaires to all university liver centers in Germany (11 questions) concerning the medical supply of patients with NAFLD. Questions included the rate of patients with fatty liver disease in the outpatient clinics, metabolic comorbidities and the kind of assignment. Besides that, individual clinical standards were documented. We compared longitudinal changes between 2008 and 2013. RESULTS: The return rate of questionnaires was 65 % (n = 20). Analysis showed that the portion of NAFLD patients in the university outpatient clinics had increased between 2008 and 2013 with the predominant part of patients being assigned from external practitioners and not from internal departments of the hospital. Only few patients were assigned by diabetologists or endocrinologists, but on the other hand most liver outpatient clinics investigated their NAFLD patients for metabolic disorders. Cooperation between liver outpatient clinics and other medical services was moderate and was rated average, joint conferences were held rarely. Follow-up visits of patients with NAFLD take place regularly in all centers, however based on different criterions. A consistent algorithm concerning risk assessment and invasive workup does not exist. CONCLUSION: The awareness concerning patients with NAFLD seems to have grown in recent years. Nevertheless, the medical supply of these patients is quite heterogenous and consistent standards do not exist. Therefore, a common guidline is urgently required.

Navigator based respiratory gating during acquisition and preparation phases for proton liver spectroscopy at 3 T.

Proton magnetic resonance spectroscopy ((1)H MRS) enables the non-invasive investigation of the human liver; however, because of technical difficulties it is not regularly used for diagnosis of liver diseases in clinical routine. Breathing motion is one of the major challenges, as it decreases spectral quality and leads to misplacement of the spectroscopic voxel. To overcome this problem, real-time navigator gating for spectral acquisition and preparation steps (B0 shimming, water frequency determination, receiver gain optimization, and water suppression) combined with short TE , optimized first order projection based B0 shimming, water suppression, and inner-volume saturated point resolved spectroscopy (PRESS) at 3 T is suggested. Simultaneous lipid and trimethylamine quantification is demonstrated by means of phantom, volunteer, and representative patient measurements. Precise localization of the voxel despite respiratory motion, increased spectral quality (higher signal-to-noise ratio and reduced linewidth) compared with measurements without respiratory gating, and the possibility of acquiring data without additional subject instructions regarding breathing enable robust and accurate liver (1)H MRS measurements with this novel acquisition protocol.

[Cohort study of cancer incidence in patients with type 2 diabetes: record linkage of encrypted data from an external cohort with data from the epidemiological Cancer Registry of North Rhine-Westphalia]. / Kohortenstudie zur Krebsinzidenz bei Patienten mit Diabetes mellitus Typ 2 : Record Linkage von kryptografierten Daten einer externen Kohorte mit Daten des Epidemiologischen Krebsregisters Nordrhein-Westfalen.

INTRODUCTION: German epidemiologic cancer registries may store only encrypted personal identifiers. Thus, record linkage with secondary databases needs to be performed via procedures that are based on encrypted identifiers. In this paper, we describe the linkage of patient data from a statutory health insurance company (AOK NordWest) and from the Disease Management Program for diabetes mellitus type 2 with the database of the cancer registry. We report the cancer incidence in patients with type 2 diabetes (T2D). METHODS: Personal identifying variables of the patient cohort were encrypted before being sent electronically to the cancer registry and submitted to a probabilistic record linkage with registry data. The study included T2D patients who were residents of the Münster, Detmold, or Arnsberg districts and who were aged 40-79 years. Only primary cancers occurring between the date of enrolment and the censoring date (31 December 2010) were included. The standardized incidence ratio (SIR) was calculated relative to the number of incident cases expected on the basis of the averaged incidence rates in the general population. RESULTS: The record linkage took about 3 weeks of processing time. A total of 67,447 T2D (49.2 % men) cases were included for analyses. Incident cancer was diagnosed in 2,086 men and 1,578 women. Cohort members showed an elevated risk for cancer of the liver (SIR =1.86; 95% CI =1.47-2.31), pancreas (SIR = 1.62; 95 % CI =1.36-1.91), lung (SIR = 1.21; 95% CI 1.11-1.32), and uterus (SIR = 1.34; 95 % CI 1.08-1.65), and they were less likely to be diagnosed with prostate cancer (SIR =0.72; 95% CI = 0.65-0.79). DISCUSSION: The findings of this study suggest that record linkage of secondary databases with cancer registry data for research purposes can be effectively carried out in compliance with strict data-protection regulations.

Cancer detection rates following enrolment in a disease management programme for type 2 diabetes.

AIMS/HYPOTHESIS: Recent prospective studies found an elevated cancer risk shortly after diabetes diagnosis, and this was probably due to increased ascertainment. This study investigated whether site-specific cancer risks are also raised following enrolment in a disease management programme for type 2 diabetes mellitus (DMP-DM2). METHODS: We linked records from a DMP-DM2 to population cancer registry data. The study period was from June 2003 to December 2009. Standardised incidence ratios (SIRs) were calculated for time intervals following DMP enrolment using the cancer incidence rates of the general source population. Additionally, Poisson regression with natural splines was used to assess time-dependent cancer incidence by diabetes duration. RESULTS: There were 2,034 first invasive cancer cases identified over 163,738 person-years of follow-up. Pancreatic cancer risk was significantly increased mainly in the first year after enrolment (SIR 1.62); the increment was only seen for patients in whom diabetes had been diagnosed less than 1 year before DMP-DM2 enrolment. Risk of endometrial cancer was similarly raised in the first year after DMP-DM2 enrolment among individuals newly diagnosed with diabetes but decreased rapidly thereafter. There was no time dependence in the incidence of cancers of the liver, lung, colon, breast and prostate. CONCLUSIONS/INTERPRETATION: Enrolment in a DMP-DM2 did not appear to induce ascertainment bias for most cancers. Cancer risks were initially increased, especially for pancreatic cancer, potentially as a result of reverse causality. Ascertainment bias and time-dependent incidence of cancer appear to be less of a problem in settings using DMP-like structures for the study of the association between diabetes duration, glucose-lowering medication and cancer incidence.

Critical review of the use of erythropoietin in the treatment of anaemia during therapy for chronic hepatitis C.

Combined pegylated interferon (PegIFN) and ribavirin represents the standard therapy for patients with chronic hepatitis C (CHC), which allows for sustained viral response (SVR) in up to 90% of patients depending on certain viral and host factors. Clinical studies have demonstrated the importance of adherence to therapy, that is, the ability of patients to tolerate and sustain a fully dosed therapy regimen. Adherence is markedly impaired by treatment-related adverse effects. In particular, haemolytic anaemia often requires dose reduction or termination of ribavirin treatment, which compromises treatment efficacy. Recent evidence points to a beneficial role of recombinant erythropoietin (EPO) in alleviating ribavirin-induced anaemia thereby improving quality of life, enabling higher ribavirin dosage and consequently improving SVR. However, no general consensus exists regarding the use of EPO for specific indications: its optimal dosing, treatment benefits and potential risks or cost efficiency. The Swiss Association for the Study of the Liver (SASL) has therefore organized an expert meeting to critically review and discuss the current evidence and to phrase recommendations for clinical practice. A consensus was reached recommending the use of EPO for patients infected with viral genotype 1 developing significant anaemia below 100 g/L haemoglobin and a haematocrit of <30% during standard therapy to improve quality of life and sustain optimal ribavirin dose. However, the evidence supporting its use in patients with pre-existing anaemia, non-1 viral genotypes, a former relapse or nonresponse, liver transplant recipients and cardiovascular or pulmonary disease is considered insufficient.

[Musculoskeletal modeling of the patellofemoral joint. Dynamic analysis of patellar tracking]. / Muskuloskelettale Modellierung des patellofemoralen Gelenks. Dynamische Analyse der patellaren Führung.

Numerical simulations contribute to the understanding of patellofemoral diseases. Whereas cadaveric studies are limited with respect to reproducibility of results, the impact of different operative approaches can be systematically evaluated based on mathematical models. The objective of this study was to introduce a musculoskeletal model which is capable of describing the dynamic interactions within the patellofemoral joint. It contains major bony and soft tissue structures of the right leg including the medial patellofemoral ligament (MPFL). Two operative approaches were considered based on the model to illustrate the effect on patellofemoral biomechanics during active knee flexion: On the one hand the effect of femoral insertion during MPFL reconstruction on medial soft tissue tension, and on the other hand the difference in patella kinematics before and after total knee arthroplasty. Finally, the potential of musculoskeletal models is discussed.

The role of bile acid retention and a common polymorphism in the ABCB11 gene as host factors affecting antiviral treatment response in chronic hepatitis C.

The outcome of hepatitis C virus (HCV) infection and the likelihood of a sustained virological response (SVR) to antiviral therapy depends on both viral and host characteristics. In vitro studies demonstrated that bile acids (BA) interfere with antiviral interferon effects. We investigate the influence of plasma BA concentrations and an ABCB11 polymorphism associated with lower transporter expression on viral load and SVR. Four hundred and fifty-one Caucasian HCV-patients treated with PEG-interferon and ribavirin were included in the study. ABCB11 1331T>C was genotyped, and plasma BA levels were determined. The 1331C allele was slightly overrepresented in HCV-patients compared to controls. In HCV-patients, a significant difference between patients achieving SVR vs non-SVR was observed for HCV-2/3 (5 vs 9 µm; P=0.0001), while median BA levels in HCV-1 were marginally elevated. Normal BA levels <8 µm were significantly associated with SVR (58.3%vs 36.3%; OR 2.48; P=0.0001). This difference was significant for HCV-2/3 (90.7%vs 67.6%; P=0.002) but marginal in HCV-1 (38.7%vs 27.8%; P=0.058). SVR rates were equivalent between ABCB11 genotypes for HCV-1, but increased for HCV-2/3 (TT 100%vs CC 78%; OR 2.01; P=0.043). IL28B genotype had no influence on these associations. No correlation between BA levels and HCV RNA was detected for any HCV genotype. The higher allelic frequency of ABCB11 1331C in HCV-patients compared to controls may indirectly link increased BA to HCV chronicity. Our data support a role for BA as host factor affecting therapy response in HCV-2/3 patients, whereas a weaker association was found for HCV-1.

Lessons from a transplant patient with diarrhea, cryptosporidial infection, and possible mycophenolate mofetil-associated colitis.

Diarrhea in a transplant recipient may be caused by infection, metabolic problems, or adverse drug effects. The immunosuppressive drug most frequently associated with diarrhea in transplant recipients is mycophenolate mofetil (MMF). We present the case of a patient with 2 potential explanations for diarrhea lasting several weeks, which occurred years after liver transplantation. Whereas stool samples were positive for cryptosporidia, the histopathological findings were compatible with MMF colitis. However, diarrhea resolved after treatment of cryptosporidial infection, despite continued MMF medication. This case shows that histopathological findings of MMF colitis may be misleading and do not prove that diarrhea is drug induced.

Effect of surgical parameters on the biomechanical behaviour of bicondylar total knee endoprostheses - A robot-assisted test method based on a musculoskeletal model.

The complicated interplay of total knee replacement (TKR) positioning and patient-specific soft tissue conditions still causes a considerable number of unsatisfactory outcomes. Therefore, we deployed a robot-assisted test method, in which a six-axis robot moved and loaded a bicondylar cruciate-retaining (CR)-TKR in a virtual lower extremity emulated by a musculoskeletal multibody model. This enabled us to systematically analyse the impact of the posterior cruciate ligament (PCL), tibial slope, and tibial component rotation on TKR function while considering the physical implant components and physiological-like conditions during dynamic motions. The PCL resection yielded a decrease of femoral rollback by 4.5 mm and a reduction of tibiofemoral contact force by 50 N. A reduced tibial slope led to an increase of tibiofemoral contact force by about 170 N and a decrease of femoral rollback up to 1.7 mm. Although a higher tibial slope reduced the contact force, excessive tibial slopes should be avoided to prevent joint instability. Contrary to an external rotation of the tibial component, an internal rotation clearly increased the contact force and lateral femoral rollback. Our data contribute to improved understanding the biomechanics of TKRs and show the capabilities of the robot-assisted test method based on a musculoskeletal multibody model as a preoperative planning tool.

Treatment of refractory ascites with an automated low-flow ascites pump in patients with cirrhosis.

BACKGROUND: Refractory ascites (RA) is a frequent complication of cirrhosis, requiring large volume paracentesis or placement of a transjugular intrahepatic portosystemic shunt (TIPSS). The automated low-flow ascites pump (alfapump, Sequana Medical AG, Zurich, Switzerland) is an innovative treatment option for patients with RA. AIM: To assess safety and efficacy of this treatment in patients with a contraindication to TIPSS. METHODS: Fifty-six patients (43 males; mean age 62 years) from centres in Germany, Switzerland, UK and Spain were included and followed for up to 24 months. Complications, device deficiencies, paracentesis frequency and patient survival were recorded. RESULTS: At the time of this analysis, 3 patients completed the 24-month observation period, monitoring of 3 was ongoing, 9 underwent liver transplantation, 17 patients were withdrawn due to serious adverse events and 23 patients died. Most frequently observed technical complication was blocking of the peritoneal catheter. Twenty-three pump-related reinterventions (17 patients) and 12 pump exchanges (11 patients) were required during follow-up. The pump system was explanted in 48% of patients (in 17 patients due to serious adverse events, in 9 at the time of liver transplantation and in 1 due to recovery from RA). Median frequency of paracentesis dropped from 2.17 to 0.17 per month. CONCLUSIONS: The alfapump can expand therapeutic options for cirrhotic patients with RA. Continuous drainage of ascites in a closed loop automated system led to significant reduction in paracentesis frequency. Technical and procedural improvements are required to reduce the rate of adverse events and reinterventions. https://clinicaltrials.gov/ct2/show/NCT01532427.

Differences in the association of the progesterone receptor ligated by antiprogestin RU38486 or progestin ORG 2058 to chromatin components.

We assessed the hypothesis that due to variations in the conformation of the progesterone receptor induced by the antiprogestin RU38486 compared to the progestin ORG 2058, differences may result in the association of the receptor with some of the chromatin components. The physical properties of the receptor-bound chromatin fragments released by micrococcal nuclease digestion were characterized by sucrose gradient sedimentation and by gel filtration on Agarose A-1.5m or Agarose A-5m columns. The nuclear fraction was isolated from T47D cells previously exposed to 0.1 microM [3H]RU38486 or 0.1 microM [3H]ORG 2058. Micrococcal nuclease digestion solubilized two receptor forms sedimenting at 4.4 S and 6.3 S for the antiprogestin bound receptor and only one receptor at 4.4 S for the progestin ligated receptor. High-salt buffer dissociated either the antiprogestin or the progestin-bound receptor to smaller receptor forms sedimenting at 3.5 S. Chemical cross-linking with the cross-linker 2-iminothiolane of the micrococcal nuclease solubilized receptor forms resulted in 6.7-S and 4.4-S forms sedimenting on 0.4 M KCl gradients for the antiprogestin and progestin ligated receptors, respectively. Stokes radii of 7.3 nm and 6.4 nm were determined by gel filtration in 0.4 M KCl for the 6.7-S and the 4.4-S receptor forms, respectively. Using the sedimentation coefficient and the Stokes radius, molecular weights of 202,000 and 116,000 were calculated for the antiprogestin and progestin ligated receptors. We conclude that the micrococcal nuclease solubilized antiprogestin ligated receptor is associated with additional or different chromatin components compared to the progestin bound receptor.

PIP: The hypothesis that variations in the conformation of the progesterone receptor induced by the antiprogesterone RU38486 compared to the progestin ORG2058 may cause differences in the association of the receptor with some of the chromatin components was investigated. The approach to analyzing the functional organization of the receptor in the chromatin was to study the receptor-bound fragments released by nuclear digestion. The physical properties of these receptor-bound chromatin fragments were characterized by sucrose gradient sedimentation and gel filtration. Micrococcal nuclease digestion solubilized 2 receptor forms sedimenting at 4.4 S and 6.3 S for the antiprogestin bound receptor and only 1 receptor at 4.4 S for the progestin ligated receptor. High-salt buffer dissociated either the antiprogestin or the progestin-bound receptor to smaller receptor forms sedimenting at 3.5 S. Chemical cross-linking resulted in 6.7 S forms for the antiprogestin receptors and 4.4 S forms for the progestin ligated receptors. Use of the sedimentation coefficient and the Stokes radius yielded molecular weights of 202,000 and 116,000 for the antiprogestin and progestin ligated receptors, respectively. Overall, these kinetic studies were unable to explain the variation in responses of the target cell to agonist or antagonist ligands. It is postulated that the antagonist exerts a subtle, but important, conformational change in the receptor, which alters the receptor's ability to associate with some chromatin components and thus affects the normal events in gene expression.