145 research outputs found
Notch1 signaling in the hepatic microcirculation and chronic liver disease
No full textThe Notch signaling pathway is an evolutionary conserved pathway that plays essential roles during vascular development and in the regulation of normal and pathological angiogenesis in the adulthood. These roles include angioblast specification, arteriovenous differentiation, regulation of blood vessel sprouting and branching, as well as control of vessel maintenance. In mammals there are four Notch receptors (Notch1 – 4), but only Notch1 and Notch4 are expressed in endothelial cells. Endothelial-specific loss of Notch1 is embryonic lethal, demonstrating its pivotal function in the vascular system. Nevertheless, the role of Notch1 signaling in postnatal vascular physiology is not fully understood. Inducible deletion of Notch1 in mice has been shown to cause nodular regenerative hyperplasia (NRH), which is a histopathological entity of the liver also seen in humans. NRH is thought to appear secondary to microcirculatory disturbances, however the exact pathogenesis is not known. NRH is an important cause of non-cirrhotic portal hypertension. The increased portal pressure can lead to complications including splenomegaly, ascites, or variceal bleeding; the latter is associated with high mortality.
The aim of this thesis is to elucidate the role of Notch1 signaling in the hepatic microcirculation in normal and pathologic conditions. Further, we want to shed some light on the molecular mechanisms implicated in the development of NRH.
In a conditional Notch1 knockout (KO) mouse model we investigated the impact of Notch1 signaling deficiency on the blood vessel homeostasis in the liver. LSEC are normally quiescent. After observing LSEC activation in livers of Notch1 KO mice, resulting in increased cell proliferation, we wanted to explore the ultrastructure of sinusoids in more detail. Scanning electron microscopy analysis of the liver microvasculature revealed phenotypic changes of LSEC, identified by loss of fenestrae. By performing vascular casts, we could discover three-dimensional changes of the hepatic microvasculature. While livers of control mice showed a highly differentiated vascular network, the liver vasculature of Notch1 KO mice was remodeled showing increased branching with larger vessel diameters. In addition, we identified features of intussusceptive angiogenesis in Notch1 KO casts. Time course experiments revealed that vascular changes occur first and that development of portal hypertension and NRH is a secondary phenomenon. To exclude that the observed phenotypic changes are due to loss of Notch1 in cells other than LSEC, a hepatocyte-specific Notch1 KO mouse was generated. This mouse had a completely normal phenotype. Furthermore, different cell populations were isolated from global Notch1 KO mice. Gene expression analysis of the different cell types confirmed that loss of Notch1 mainly affects the endothelium. Vascular dedifferentiation was found to be mediated by Notch, ephrin, and TEK signaling, all of which are known to regulate LSEC differentiation and quiescence. A very crucial finding, supporting our hypothesis that the NRH phenotype is driven by vascular changes, is the spontaneous development of liver angiosarcoma in Notch1 KO mice. Disruption of Notch1 signaling is sufficient enough to induce malignant transformation of endothelial cells in the liver, reflecting the pivotal role of Notch1 in the hepatic microcirculation.
In a translational study using liver biopsies from NRH patients we assessed the vascular contribution to the development of NRH. Using morphological and molecular approaches, this part of the thesis addressed two main questions: one from a clinical point of view, the other from a basic science perspective.
First, we assessed whether there is an association between the presence of portal hypertension and NRH severity. So far, no one has investigated the relationship between pathologic features and the clinical condition in NRH. Notably, histological assessed nodular transformation correlates well with the presence of portal hypertension. Since most complications occurring in NRH patients are due to increased portal pressure, patients presenting with advanced nodular transformation should be advised to undergo endoscopic screening for varices, since they can cause life-threatening complications.
Based on our findings from the animal study we have hypothesized that NRH is caused by a vascular injury of the sinusoids. In our NRH mouse model we identified dysregulation of a number of genes upon Notch1 deletion, which are involved in endothelial differentiation. Therefore, we wanted to explore if the same set of genes is also regulated in human NRH. To our surprise, the same genes were also found to be dysregulated in the liver of NRH patients, irrespective of the underlying cause of disease. Thus we conclude: Despite different etiologic factors associated with NRH, there is evidence that in all cases the hepatic condition can be traced back to an endotheliopathy mediated by the final common pathway of Notch1/Dll4 and EphrinB2/EphB4 signaling.
Taken together, our study identifies Notch1 as an important player in LSEC differentiation and quiescence. We provide first insights into the molecular mechanism of human NRH, which are in line with our findings from the NRH mouse model. In addition, we showed an oncosuppressive role of Notch1 in the murine liver endothelium, resulting in vascular neoplasms after loss of Notch1
Driving Dynamics of Motorcycles
No full textThis diploma thesis called Motorcycle Race Dynamics captures the development and development of motorcycles, a description of types, design elements and the techniques of riding a motorcycle. However, the aim of this work is to organize, perform and evaluate the measurement of braking deceleration and the crossing of motorcycles. Before separate data processing, a theoretical methodology for measuring transverse displacement and braking deceleration is proposed. This requires enough motorcycles, experienced riders, two cameras, a measuring instrument and precisely dimensioned lines. The lateral displacement and braking deceleration measurements are then performed and subsequently evaluated. Output of this work include, in addition to videos, an overview of transverse displacement times, or longitudinal deceleration output values gained from braking
Impact of Narcotics and Psychoactive Drugs on Driver´s Behaviour and Possibilities od Detection During Police Road Control
No full textThe result of this diploma thesis is based on the collected data, to evaluate the success of the detection of narcotic and psychotropic substances by a policeman, with subsequent measuring and professional expression. The thesis is divided into three parts. In the theoretical part, this is mainly an evaluation of existing information dealing with drug issues related to road accidents. In the analytical part, the thesis deals with real methods and equipment with OPL detection. The practical part contains data obtained from qualitative research, through interviews, which are compared and evaluated with a quantitative survey of the questionnaire survey, which can help to improve expert judgment and improve transport safety
Hepatitis C – Diagnostik und Therapie
No full text Zusammenfassung. Die Hepatitis C Virus Infektion ist die häufigste durch Blut übertragene Infektion und ist global wie auch in der Schweiz eine der führenden Ursachen von Leberzirrhose, hepatozellulären Karzinomen und chronischer Hepatitis. Seit der Entdeckung im Jahr 1989 wurde die Diagnostik und Therapie der Hepatitis C Virus Infektion enorm vorangebracht. In der Schweiz wird ein risikobasiertes Screening auf Hepatitis C empfohlen. Neben zuverlässigen diagnostischen Testen ist 2014 der therapeutische Durchbruch gelungen. Heute können 90 bis 100 % der Betroffenen mit einer gut verträglichen Therapie über zwei bis drei Monate geheilt werden. In dieser Übersichtsarbeit wird schwerpunktmässig auf die Diagnostik, Epidemiologie, Prävention und aktuelle Therapien der Hepatitis C Virus Infektion eingegangen. </jats:p
Ultrasound Doppler technique for the diagnosis of focal nodular hyperplasia - case series and systematic review.
No full textWith the Superb Micro-Vascular Imaging (SMI), the established Doppler technology has been extended by another mode. With this technique, microvascular structures with slow blood flow can now also be displayed in real time. As with the introduction of Doppler ultrasound, this new technique opens further diagnostic fields for the examiner, which were previously reserved for magnetic resonance imaging (MRI), computed tomography (CT) or contrast ultrasound (CEUS). Focal nodular hyperplasia (FNH) of the liver is characterized by a typical spoke-wheel vascular malformation (spoke-wheel sign, SWS) anda good example using SMI for the diagnostic profit of our patients. The aim of this report is to describe the use of SMI as a new non-invasive, quick, and probably cost-effective diagnostic imaging tool
SDF-1/CXCR4 signalling is involved in blood vessel growth and remodelling by intussusception.
No full textThe precise mechanisms of SDF-1 (CXCL12) in angiogenesis are not fully elucidated. Recently, we showed that Notch inhibition induces extensive intussusceptive angiogenesis by recruitment of mononuclear cells and it was associated with increased levels of SDF-1 and CXCR4. In the current study, we demonstrated SDF-1 expression in liver sinusoidal vessels of Notch1 knockout mice with regenerative hyperplasia by means of intussusception, but we did not detect any SDF-1 expression in wild-type mice with normal liver vessel structure. In addition, pharmacological inhibition of SDF-1/CXCR4 signalling by AMD3100 perturbs intussusceptive vascular growth and abolishes mononuclear cell recruitment in the chicken area vasculosa. In contrast, treatment with recombinant SDF-1 protein increased microvascular density by 34% through augmentation of pillar number compared to controls. The number of extravasating mononuclear cells was four times higher after SDF-1 application and two times less after blocking this pathway. Bone marrow-derived mononuclear cells (BMDC) were recruited to vessels in response to elevated expression of SDF-1 in endothelial cells. They participated in formation and stabilization of pillars. The current study is the first report to implicate SDF-1/CXCR4 signalling in intussusceptive angiogenesis and further highlights the stabilizing role of BMDC in the formation of pillars during vascular remodelling
Strategies to manage hepatitis C virus (HCV) disease burden
No full textThe number of hepatitis C virus (HCV) infections is projected to decline while those with advanced liver disease will increase. A modeling approach was used to forecast two treatment scenarios: (i) the impact of increased treatment efficacy while keeping the number of treated patients constant and (ii) increasing efficacy and treatment rate. This analysis suggests that successful diagnosis and treatment of a small proportion of patients can contribute significantly to the reduction of disease burden in the countries studied. The largest reduction in HCV-related morbidity and mortality occurs when increased treatment is combined with higher efficacy therapies, generally in combination with increased diagnosis. With a treatment rate of approximately 10%, this analysis suggests it is possible to achieve elimination of HCV (defined as a >90% decline in total infections by 2030). However, for most countries presented, this will require a 3-5 fold increase in diagnosis and/or treatment. Thus, building the public health and clinical provider capacity for improved diagnosis and treatment will be critical
Historical epidemiology of hepatitis C virus (HCV) in selected countries
No full textChronic infection with hepatitis C virus (HCV) is a leading indicator for liver disease. New treatment options are becoming available, and there is a need to characterize the epidemiology and disease burden of HCV. Data for prevalence, viremia, genotype, diagnosis and treatment were obtained through literature searches and expert consensus for 16 countries. For some countries, data from centralized registries were used to estimate diagnosis and treatment rates. Data for the number of liver transplants and the proportion attributable to HCV were obtained from centralized databases. Viremic prevalence estimates varied widely between countries, ranging from 0.3% in Austria, England and Germany to 8.5% in Egypt. The largest viremic populations were in Egypt, with 6,358,000 cases in 2008 and Brazil with 2,106,000 cases in 2007. The age distribution of cases differed between countries. In most countries, prevalence rates were higher among males, reflecting higher rates of injection drug use. Diagnosis, treatment and transplant levels also differed considerably between countries. Reliable estimates characterizing HCV-infected populations are critical for addressing HCV-related morbidity and mortality. There is a need to quantify the burden of chronic HCV infection at the national level
The present and future disease burden of hepatitis C virus (HCV) infection with today's treatment paradigm
No full textThe disease burden of hepatitis C virus (HCV) is expected to increase as the infected population ages. A modelling approach was used to estimate the total number of viremic infections, diagnosed, treated and new infections in 2013. In addition, the model was used to estimate the change in the total number of HCV infections, the disease progression and mortality in 2013-2030. Finally, expert panel consensus was used to capture current treatment practices in each country. Using today's treatment paradigm, the total number of HCV infections is projected to decline or remain flat in all countries studied. However, in the same time period, the number of individuals with late-stage liver disease is projected to increase. This study concluded that the current treatment rate and efficacy are not sufficient to manage the disease burden of HCV. Thus, alternative strategies are required to keep the number of HCV individuals with advanced liver disease and liver-related deaths from increasing
Contrast-enhanced ultrasound can guide the therapeutic strategy by improving the detection of colorectal liver metastases.
No full textBACKGROUND & AIMS
CT may miss up to 30% of cases of colorectal liver metastases (CRLMs). We assessed the impact of contrast-enhanced ultrasound (CEUS) on the detection of CRLMs and on changes to the therapeutic strategy; additionally, we assessed the accuracy of CEUS in differentiating unclear focal liver lesions (FLLs) compared to staging-CT.
METHODS
We prospectively analyzed all patients with newly diagnosed and histologically confirmed colorectal cancer (CRC) at our tertiary gastroenterological center between December 2015 and May 2019. CEUS was performed in a total of 296 patients without CRLMs after staging-CT using the contrast agent (SonoVue®). Standard of reference was obtained by MRI or histology to diagnose CRLMs missed by CT. Benign FLLs were confirmed by MRI or follow-up CT (mean follow-up interval: 18 months).
RESULTS
Eight additional CRLMs were detected by CEUS (overall 2.7%; sensitivity 88.9%, specificity 99.0%, positive predictive value 100%, negative predictive value 99.6%). All patients with CRLMs detected only by CEUS were in tumor stage T3/T4 (4.0% additionally detected CRLMs). The number needed to screen to detect 1 additional CRLM by CEUS was 37 in all patients and 24.5 in T3/T4-patients. When results were reviewed by a board-certified radiologist and oncologist, the therapeutic strategy changed in 6 of these 8 patients. Among the 62 patients (20.9%) with unclear FLLs after staging-CT, CEUS determined the dignity (malignant vs. benign) of 98.4% of the FLLs.
CONCLUSION
Overall, CEUS detected 2.7% additional CRLMs (including 4.0% in tumor stage T3/T4) with a significant impact on the oncological therapeutic strategy for 75% of these patients. Patients with tumor stage T3/T4 would particularly benefit from CEUS. We propose CEUS as the first imaging modality for CT-detected lesions of unknown dignity.
LAY SUMMARY
In patients with newly diagnosed colorectal cancer, contrast-enhanced ultrasound (CEUS) detected additional liver metastases after computed tomography (CT). In the majority of these patients, the oncological therapy was changed after obtaining the CEUS results. After staging-CT, 21% of hepatic lesions remained unclear. In these cases, CEUS was accurate to either reveal or exclude liver metastasis in nearly all patients and could reduce costs (e.g., number of MRI scans)
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