Cardiac volume overload and pulmonary hypertension in long-term follow-up of patients with a transjugular intrahepatic portosystemic shunt.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPSS) cause haemodynamic changes in patients with cirrhosis, yet little is known about long-term cardiopulmonary outcomes. AIM: To evaluate the long-term cardiopulmonary outcome after TIPSS. METHODS: We evaluated cardiopulmonary parameters including echocardiography during long-term follow-up after TIPSS. Results at 1-5 years after TIPSS were compared to those of cirrhotic controls. Pulmonary hypertension (PH) diagnoses rates were included. Endothelin 1, thromboxane B2 and serotonin were measured. RESULTS: We found significant differences 1-5 years after TIPSS compared to pre-implantation values: median left atrial diameter (LAD) increased from 37 mm [interquartile range (IQR): 33-43] to 40 mm (IQR: 37-47, P = 0.001), left ventricular end-diastolic diameter (LV-EDD) increased from 45 mm (range: 41-49) to 48 mm (IQR: 45-52, P < 0.001), pulmonary artery systolic pressure (PASP) increased from 25 mmHg (IQR: 22-33) to 30 mmHg (IQR: 25-36, P = 0.038). Comparing results 1-5 years post-implantation to the comparison cohort revealed significantly higher (P < 0.05) LAD, LV-EDD and PASP values in TIPSS patients. PH prevalence was higher in the shunt group (4.43%) compared to controls (0.91%, P = 0.150). Thromboxane B2 levels correlated with PASP in the TIPSS cohort (P = 0.033). There was no transhepatic gradient observed for the vasoactive substances analysed. CONCLUSIONS: TIPSS placement is accompanied by long-term cardiovascular changes, including cardiac volume overload, and is associated with an increased rate of pulmonary hypertension. The need for regular cardiac follow-up after TIPSS requires further evaluation.

[Direct antiviral treatment strategies in chronic hepatitis C]. / Direkt antivirale Therapieansätze bei der chronischen Hepatitis C.

The standard antiviral therapy for chronic hepatitis C is pegylated interferon-alfa (PegIFN) and ribavirin since about 10 years. This treatment regimen leads to a sustained virological response (SVR) in 40-50 % of patients infected with HCV genotype 1 and in approx. 80 % of those infected with HCV genotype 2 or 3. In recent years, many direct antiviral agents (DAA) have been developed and are being explored in clinical studies. These antiviral agents target different viral proteins that are central for HCV replication, incl. the NS3/4A protease, NS5B polymerase, and the NS5A protein. The protease inhibitors telaprevir and boceprevir have recently been approved for the treatment of chronic HCV genotype 1 infection in combination with PegIFN and ribavirin. These triple therapies increase the SVR rates in HCV genotype 1 patients from 40-50 % to approx. 70 %. Other DAAs will likely be approved in the near future and may result in an IFN-free antiviral therapy.

[Protective role of HLA-B27 in HIV and hepatitis C virus infection]. / Protektiver Effekt von HLA-B27 auf den Verlauf der HIV- und Hepatitis-C-Virus-Infektion.

The human leukocyte antigen (HLA) B27 has been linked to rheumatic diseases such as ankylosing spondylitis nearly 40 years ago, but its role in pathogenesis remains unclear. Apart from this association, HLA-B27 has a positive effect in two of the most threatening human viral infections: in HIV infection, HLA-B27 positive patients have low viral loads, CD4+ T cell counts decline slowly and AIDS progresses slowly. In acute hepatitis C virus (HCV) infection, HLA-B27 is associated with a very high rate of spontaneous viral clearance. The mechanisms of protection by HLA-B27 in HIV and HCV infection have been characterized in the recent years and will be discussed in this article.

[RNA interference as antiviral strategy]. / RNA-Interferenz als antivirale Strategie.

RNA interference is the inhibition of gene expression at the level of messenger RNA (mRNA) mediated by small RNA molecules. Small interfering RNA (siRNA) is an important immune defence mechanism in plants and non-vertebrates. In addition, synthetic siRNAs can be used to inhibit gene expression also in human cells. More than 500 microRNAs (miRNAs), however, are involved in the natural regulation of gene expression in humans, e. g., in development-specific gene expression in embryogenesis or organ development. Although a role of miRNAs in antiviral immune defence has been discussed for some time, only recently virus-promoting as well as antiviral properties of defined miRNAs have been identified in hepatitis C virus (HCV) infection. The understanding of the mechanisms of action of miRNA might lead to new antiviral and preventive strategies.

Reversal of visceral adiposity in candy-diet fed female Wistar rats by the CB1 receptor antagonist rimonabant.

OBJECTIVE: The severity of obesity is often more determined by the distribution of fat depots rather than by body weight itself. Therefore, the effect of rimonabant on fat distribution pattern was investigated in female candy-fed Wistar rats. DESIGN: Female Wistar rats were fed a high fat, high carbohydrate (candy-) diet for 12 weeks. During the last 6 weeks rats were treated with rimonabant. Food intake and body weight development were investigated, as well as effects on total body fat, especially visceral fat and ectopic lipid accumulation in skeletal muscle and liver, determined by in vivo magnetic resonance imaging/magnetic resonance spectroscopy. RESULTS: Candy-diet increased body weight, which was predominantly due to the increased total fat mass with predominance of visceral fat accumulation. Treatment with rimonabant fully reversed the weight gain and fat deposition in the visceral cavity and skeletal muscle, in contrast to pair feeding. In spite of an only transient reduction of food intake, body weight reduction, as well as normalized body fat, reduced visceral fat and intramyocellular lipids were maintained over the treatment period. CONCLUSIONS: We conclude that additional factors other than reduced caloric intake must be responsible for the improvements in these lipid parameters. The complete cluster of results is consistent with increased lipid oxidation caused by rimonabant.

[Immunopathogenesis of viral hepatitis]. / Immunpathogenese der Virushepatitis: Neue Aspekte.

The different components of the immune system play important roles in the outcome of hepatitis B and C. In > 90% of HBV-infected individuals, these immune responses successfully clear the virus, while 50-80% of chronically HCV-infected individuals experience viral persistence. During the last years, the mechanisms of viral persistence, e.g. viral escape mutations and T cell dysfunction, have been characterised in more detail. The exact knowledge of the mechanisms contributing to viral clearance and persistence are prerequisite to the successful development of prophylactic and therapeutic immunostrategies.

Impact of the genetic restriction of virus-specific T-cell responses in hepatitis C virus infection.

The immunobiology of hepatitis C virus (HCV) is significantly influenced by the host immune response to the virus, especially by virus-specific T-cell responses. Virus-specific T cells are restricted by human leucocyte antigen class I and II molecules. Of note, associations between these polymorphic loci and outcome and course of HCV infection have been reported in large and well-documented cohorts. This review will briefly summarize these studies and focus especially on the immunological and virological basis for the reported associations. The outcome and course of HCV infection is most likely determined by a complex interplay of genetic, immunological and virological factors. A better understanding of these host-virus interactions is essential not only to gain better insights into the mechanisms of viral clearance and persistence but also for the development of new antiviral vaccine strategies.

Correlation between insulin resistance and intramyocellular lipid levels in rats.

Increased intramyocellular lipid (IMCL) content has been proposed as biomarker for insulin resistance (IR). An inverse correlation between IMCL and insulin sensitivity (IS) was found in nonathletic humans, whereas in animal models only a few validation studies have been performed. The aim of this study was to investigate the interrelation between IS indices determined by the glucose clamp technique (glucose disposal (GD), exogenous glucose infusion rates (GIR)) and IMCL content in the tibialis (TIB) and the soleus (SOL) muscle obtained by magnetic resonance spectroscopy in different rat models of IR. Diet-induced insulin-resistant Wistar rats as well as genetic disease models (ZDF rats) were used. In both muscles, elevated IMCL correlated with an impaired IS in all models of IR. The correlation of IMCL with both parameters for IS was comparable in TIB and SOL. The best fit between IMCL and IS was obtained using TIB and GIR data (r = -0.69, P < 0.001). Diabetic male ZDF rats exhibited comparatively low IMCL levels due to their catabolic state: exclusion of this group improved r. In summary, IMCL, especially in TIB, is a valid biomarker for IS in various rat models of IR with the advantage of a fast repeatable noninvasive measurement in individual animals.

T cell response in hepatitis C virus infection.

Hepatitis C virus (HCV) is a hepatotropic RNA virus that causes acute and chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. It is widely accepted that cellular immune responses play an important role in viral clearance and disease pathogenesis. However, HCV often evades effective immune recognition and has a propensity to persist in the majority of acutely infected individuals (ca. 80%). The immunological and virological basis for the inefficiency of the cellular immune response to clear or control the virus is not known. Recent studies, however, have provided new insights into the mechanisms of viral clearance and persistence that will be discussed in detail.

[Suppressor T-cells: immunologic regulator cells and clinical perspectives]. / Suppressor-T-Zellen: Immunologische Regulatorzellen mit klinischer Perspektive.

Regulatory T cells modulate immune responses in different clinical settings. Here, we summarize the role of CD4(+)CD25(+) regulatory T cells in autoimmunity, transplantation, infectious diseases and tumor immunity.

[The role of the virus specific T-cell response in acute and chronic HBV and HCV infection]. / Die Rolle der virusspezifischen T-Zellantwort bei der akuten und chronischen Hepatitis-B- und -C-Virusinfektion.

Infections with hepatitis B (HBV) and hepatitis C virus (HCV) are worldwide one of the most frequent causes for chronic liver disease, liver cirrhosis and hepatocellular carcinoma. The mechanisms responsible for the elimination or the persistence of the virus are not well understood. The immunopathogenesis of HBV and HCV infection is primarily mediated by virus specific CD4+- and CD8+-T-cells. During acute infection a strong and multispecific T-cell response against different viral epitopes can be detected and is associated with the clearance of the virus. In case of viral persistence virus specific T-cells contribute to liver inflammation. In this article we summarize the current concepts about the role of the virus specific T-cell response in acute and chronic HBV and HCV infection.

Prediction of hemorrhagic transformation after thrombolytic therapy of clot embolism: an MRI investigation in rat brain.

BACKGROUND AND PURPOSE: Thrombolytic treatment of stroke carries the risk of hemorrhagic transformation. Therefore, the potential of MRI for prediction of recombinant tissue plasminogen activator (rtPA)-induced bleeding is explored to identify patients in whom rtPA treatment may provoke such complications. METHODS: Spontaneously hypertensive rats (SHR) (n=9) were submitted to middle cerebral artery (MCA) clot embolism, followed 3 hours later by intra-arterial infusion of 10 mg/kg rtPA. Untreated SHR (n=9) were infused with saline. MRI imaging was performed before treatment and included apparent diffusion coefficient (ADC), T2, and perfusion mapping and contrast enhancement with gadolinium-DTPA. The distribution of intracerebral hemorrhages was studied 3 days later by histological staining. RESULTS: Clot embolism led to the rapid decline of ADC in the territory of the occluded artery. Tissue lesion volume derived from ADC imaging increased by 155+/-69% in the untreated animals and by 168+/-87% in the treated animals (P=NS), determined on the histological sections after 3 days. This same lesion growth in both groups indicated absence of therapeutic effect after 3-hour treatment delay. Hemorrhagic transformations were significantly more frequent in treated SHR (P<0.05). In untreated rats, hemorrhages were found in the border zone of the ischemic territory; in treated animals, hemorrhagic transformations occurred in the ischemic core region. rtPA-induced hemorrhages were predicted by a disturbance of the blood-brain barrier in 3 of 4 animals before treatment by Gd-DTPA contrast enhancement but not by ADC, T2, or perfusion imaging. The region of contrast enhancement colocalized with subsequent bleeding in these animals. CONCLUSIONS: The disturbance of blood-brain barrier but not of other MR parameters allows risk assessment for hemorrhagic transformation induced by subsequent thrombolytic treatment.

SRP-dependent co-translational targeting and SecA-dependent translocation analyzed as individual steps in the export of a bacterial protein.

Recently it has been recognized that the signal recognition particle (SRP) of Escherichia coli represents a specific targeting device for hydrophobic inner membrane proteins. It has remained unclear, however, whether the bacterial SRP functions in concert with SecA, which is required for the translocation of secretory proteins across the inner membrane. Here, we have analyzed a hybrid protein constructed by fusing the signal anchor sequence of an SRP-dependent inner membrane protein (MtlA) to the mature part of an exclusively SecA-requiring secretory protein (OmpA). We show that the signal anchor sequence of MtlA confers the novel properties onto nascent chains of OmpA of being co-translationally recognized and targeted to SecY by SRP. Once targeted to SecY, ribosome-associated nascent chains of the hybrid protein, however, remain untranslocated unless SecA is present. These results indicate that SRP and SecA cooperate in a sequential, non-overlapping manner in the topogenesis of those membrane proteins which, in addition to a signal anchor sequence, harbor a substantial hydrophilic domain to be translocated into the periplasm.

In vitro studies with purified components reveal signal recognition particle (SRP) and SecA/SecB as constituents of two independent protein-targeting pathways of Escherichia coli.

The molecular requirements for the translocation of secretory proteins across, and the integration of membrane proteins into, the plasma membrane of Escherichia coli were compared. This was achieved in a novel cell-free system from E. coli which, by extensive subfractionation, was simultaneously rendered deficient in SecA/SecB and the signal recognition particle (SRP) components, Ffh (P48), 4. 5S RNA, and FtsY. The integration of two membrane proteins into inside-out plasma membrane vesicles of E. coli required all three SRP components and could not be driven by SecA, SecB, and DeltamicroH+. In contrast, these were the only components required for the translocation of secretory proteins into membrane vesicles, a process in which the SRP components were completely inactive. Our results, while confirming previous in vivo studies, provide the first in vitro evidence for the dependence of the integration of polytopic inner membrane proteins on SRP in E. coli. Furthermore, they suggest that SRP and SecA/SecB have different substrate specificities resulting in two separate targeting mechanisms for membrane and secretory proteins in E. coli. Both targeting pathways intersect at the translocation pore because they are equally affected by a blocked translocation channel.

[Poliomyelitis in the German Federal Republic 1974-1975 (author's transl)]. / Poliomyelitis in der Bundesrepublik Deutschland

The virological surveillance of poliomyelitis in 1974-1975 led to the detection of specific characteristics of wild viruses in 57 out of 221 cases of poliovirus isolation. The disease symptoms were typical for poliomyelitis in 36 of these cases, less characteristic in 13. Polio wildvirus was isolated 8 times from the surroundings of the patients. In 36 foreign patients and one German the causative agent was imported from an endemic area. In these cases and in a further 7 German patients the disease was sporadic. In contrast 5 cases in German children in late autumn 1975 constitute a local epidemic of poliomyelitis.