[Diagnostic quality of transluminal biopsy in undetermined biliary duct stenosis by primary PTCD with "cross and push" technique - a prospective monocentric pilot study]. / Diagnostische Güte der transluminalen Biopsie bei unklaren Gallenwegstenosen im Rahmen der primären PTCD-Anlage mit der "Cross and Push"-Technik ­ eine prospektive monozentrische Pilotstudie.

BACKGROUND: Histological characterisation of a biliary duct stenosis can be essential for further therapeutic steps. Access to the stenosis is not given in every patient by endoscopic retrograde cholangiography. In these cases, a percutaneous transhepatic cholangiodrainage (PTCD) may be helpful. The optimal preparation and diagnostic precision of taking a biopsy by PTCD is not sufficiently evaluated. METHODS: After a training phase of 10 patients, PTCDs in 30 patients with a biliary duct stenosis and lack of adequate drainage by ERC were done in a time range of 24 months. The stenosis was passed with a wire and then a directed forceps-biopsy was performed in a "cross and push" technique (Transluminal Biliary Biopsy Forceps Set, Cook Medical™), using a wire-guided introducer (7 Fr. inner diameter). The result of the histological survey was then correlated with the definite diagnosis. The follow-up time was 18 months. RESULT: Out of 30 patients, there were 22 (73 %) with a malignant stenosis (10 biliary duct neoplasms, 12 non-biliary carcinoma/metastases/lymphomas). Eight (27 %) out of 30 patients had a benign stenosis. In case of all 30 patients, there was enough tissue gained by biopsy for histologic survey. Sub-group analysis was performed for biliary duct cancer and non-biliary cancer. Thereby, 8 out of 10 patients with biliary duct neoplasms were also classified as malignant by histology (sensitivity 80 %); whereas, only 8 out of 12 non-biliary cancers could be histologically classified as malignant (sensitivity 66.6 %, difference not significant, p = 0.0577). In all patients with benign stenosis, histological evaluation of biopsies revealed benign histology (specificity 100 %). There were no intervention-related complications. CONCLUSION: This prospective cohort-study shows a high diagnostic precision for the percutaneous transductal biopsy-set to evaluate an undetermined biliary duct stenosis-particularly in biliary processes. Because it can be difficult to gain histology in malignant biliary duct processes using different methods, the "cross and push" biopsy completes the spectrum of diagnostic procedures.

FT-NIR: A Tool for Process Monitoring and More.

With ever-increasing pressure to optimize product quality, to reduce cost and to safely increase production output from existing assets, all combined with regular changes in terms of feedstock and operational targets, process monitoring with traditional instruments reaches its limits. One promising answer to these challenges is in-line, real time process analysis with spectroscopic instruments, and above all Fourier-Transform Near Infrared spectroscopy (FT-NIR). Its potential to afford decreased batch cycle times, higher yields, reduced rework and minimized batch variance is presented and application examples in the field of fine chemicals are given. We demonstrate that FT-NIR can be an efficient tool for improved process monitoring and optimization, effective process design and advanced process control.

Prevention of Rebleeding From Esophageal Varices in Patients With Cirrhosis Receiving Small-Diameter Stents Versus Hemodynamically Controlled Medical Therapy.

BACKGROUND & AIMS: Patients with cirrhosis and variceal hemorrhage have a high risk of rebleeding. We performed a prospective randomized trial to compare the prevention of rebleeding in patients given a small-diameter covered stent vs those given hepatic venous pressure gradient (HVPG)-based medical therapy prophylaxis. METHODS: We performed an open-label study of patients with cirrhosis (92% Child class A or B, 70% alcoholic) treated at 10 medical centers in Germany. Patients were assigned randomly more than 5 days after variceal hemorrhage to groups given a small covered transjugular intrahepatic portosystemic stent-shunt (TIPS) (8 mm; n = 90), or medical reduction of portal pressure (propranolol and isosorbide-5-mononitrate; n = 95). HVPG was determined at the time patients were assigned to groups (baseline) and 2 weeks later. In the medical group, patients with an adequate reduction in HVPG (responders) remained on the drugs whereas nonresponders underwent only variceal band ligation. The study was closed 10 months after the last patient was assigned to a group. The primary end point was variceal rebleeding. Survival, safety (adverse events), and quality of life (based on the Short Form-36 health survey) were secondary outcome measures. RESULTS: A significantly smaller proportion of patients in the TIPS group had rebleeding within 2 years (7%) than in the medical group (26%) (P = .002). A slightly higher proportion of patients in the TIPS group experienced adverse events, including encephalopathy (18% vs 8% for medical treatment; P = .05). Rebleeding occurred in 6 of 23 patients (26%) receiving medical treatment before hemodynamic control was possible. Per-protocol analysis showed that rebleeding occurred in a smaller proportion of the 32 responders (18%) than in nonresponders who received variceal band ligation (31%) (P = .06). Fifteen patients from the medical group (16%) underwent TIPS placement during follow-up evaluation, mainly for refractory ascites. Survival time and quality of life did not differ between both randomized groups. CONCLUSIONS: Placement of a small-diameter, covered TIPS was straightforward and prevented variceal rebleeding in patients with Child A or B cirrhosis more effectively than drugs, which often required step-by-step therapy. However, TIPS did not increase survival time or quality of life and produced slightly more adverse events. Clinical Trial no: ISRCTN 16334693.

Anti-food and anti-microbial IgG subclass antibodies in inflammatory bowel disease.

OBJECTIVES: Inflammatory bowel disease (IBD), particularly Crohn's disease (CD), is associated with increased microbial-specific IgG and IgA antibodies, whereas alterations of anti-food antibodies are still disputed. The knowledge about IgG subclass antibodies in IBD is limited. In this study we analysed IgG subclass antibodies specific for nutritional and commensal antigens in IBD patients and controls. METHODS: Serum IgG1, IgG2, IgG3 and IgG4 specific for wheat and milk extracts, purified ovalbumin, Escherichia coli and Bacteroides fragilis lysates and mannan from Saccharomyces cerevisiae were analysed by ELISA in patients with CD (n = 56), ulcerative colitis (UC; n = 29), acute gastroenteritis/colitis (n = 12) as well as non-inflammatory controls (n = 62). RESULTS: Anti-Saccharomyces cerevisiae antibodies (ASCA) of all IgG subclasses and anti-B. fragilis IgG1 levels were increased in CD patients compared to UC patients and controls. The discriminant validity of ASCA IgG2 and IgG4 was comparable with that of ASCA pan-IgG and IgA, whereas it was inferior for ASCA IgG1/IgG3 and anti-B. fragilis IgG1. Complicated CD defined by the presence of perianal, stricturing or penetrating disease phenotypes was associated with increased ASCA IgG1/IgG3/IgG4, anti-B. fragilis IgG1 and anti-E. coli IgG1 levels. Anti-food IgG subclass levels were not different between IBD patients and controls and did not correlate with food intolerance. In contrast to anti-microbial Abs, food-specific IgG responses were predominately of the IgG4 isotype and all food-specific IgG subclass levels correlated negatively with age. CONCLUSION: Our study supports the notion that the adaptive immune recognition of food and commensal antigens are differentially regulated.

Reviving pegylated interferon as a therapeutic agent for hepatitis D: no more room for nucleos(t)ides?

BACKGROUND: Chronic infection with hepatitis B virus and hepatitis delta virus (HDV) results in the most severe form of viral hepatitis. There is no currently approved treatment. We investigated the safety and efficacy of 48 weeks of treatment with peginterferon alfa-2a plus adefovir dipivoxil, peginterferon alfa-2a alone,and adefovir dipivoxil alone. METHODS: We conducted a randomized trial in which 31 patients with HDV infection received treatment with 180 lg of peginterferon alfa-2a weekly plus 10 mgof adefovir daily, 29 received 180 lg of peginterferon alfa-2a weekly plus placebo, and 30 received 10 mg of adefovir alone weekly for 48 weeks. Follow-up was conducted for an additional 24 weeks. Efficacy end points included clearance of HDV RNA,normalization of alanine aminotransferase levels, and a decline in levels of hepatitis B surface antigen (HBsAg). RESULTS: The primary endpoint­normalization of alanine aminotransferase levels and clearance of HDV RNA at week 48--was achieved in two patients in the group receiving peginterferon alfa-2a plus adefovir and two patients in the group receiving peginterferon alfa-2a plus placebo but in none of the patients in the group receiving adefovir alone. At week 48, the test for HDV RNA was negative in 23% of patients in the first group, 24% of patients in the second, and none of those in the third (P» 0.006 for the comparison of the first and third groups; P» 0.004 for the comparison of the second and third). The efficacy of peginterferon alfa-2a was sustained for 24 weeks after treatment, with 28% of the patients receiving peginterferon alfa-2a plus adefovir or peginterferon alfa-2a alone having negative results on HDV-RNA tests; none of the patients receiving adefovir alone had negative results. A decline in HBsAg levels of more than 1 log10 IU per milliliter from baseline to week 48 was observed in 10 patients in the first group, 2 in the second, and none in the third (P<0.001 for the comparison of the first and third groups and P»0.01 for the comparison of the first and second). CONCLUSIONS: Treatment with peginterferon alfa-2a for 48 weeks, with or without adefovir, resulted in sustained HDV RNA clearance in about one quarter of patients with HDV infection.

Computer-based classification of small colorectal polyps by using narrow-band imaging with optical magnification.

BACKGROUND: Recent studies have shown that narrow-band imaging (NBI) is a powerful diagnostic tool for the differentiation between neoplastic and non-neoplastic colorectal polyps. OBJECTIVE: To develop a computer-based method for classification of colorectal polyps. DESIGN: A prospective study. SETTING: University hospital. PATIENTS: A total of 214 patients with colorectal polyps who underwent a zoom NBI colonoscopy. INTERVENTIONS: A total of 434 detected polyps 10 mm or smaller were imaged and subsequently removed for histological analysis. MAIN OUTCOME MEASUREMENTS: Diagnostic performance in polyp classification by 2 experts, 2 nonexperts, and a computer-based algorithm. RESULTS: The expert group and the computer-based algorithm achieved a comparable diagnostic performance (expert group: 93.4% sensitivity, 91.8% specificity, and 92.7% accuracy; computer-based algorithm: 95.0% sensitivity, 90.3% specificity, and 93.1% accuracy) and were both significantly superior to the nonexpert group (86.0% sensitivity, 87.8% specificity, and 86.8% accuracy) in terms of sensitivity, negative predictive value, and accuracy. Subgroup analysis of 255 polyps 5 mm or smaller revealed comparable results without significant differences in the overall analysis of all polyps. LIMITATIONS: No fully automatic classification system. CONCLUSIONS: The study demonstrates that computer-based classification of colon polyps can be achieved with high diagnostic performance.

Gp130 signaling promotes development of acute experimental colitis by facilitating early neutrophil/macrophage recruitment and activation.

IL-6 is known to play a crucial role in the pathogenesis of chronic intestinal inflammation by modulating T cell functions. In this study, we investigated the role of gp130, the common signal transducer for all IL-6 cytokines, in a murine model of acute T cell independent colitis to better characterize the impact of gp130 on innate immune cells and the early stages of inflammation. Experimental colitis was induced by dextran sulfate sodium treatment of mice with inducible systemic deletion of gp130 (MxCre/gp130(-/-)), macrophage/neutrophil-specific gp130-deficiency (LysCre/gp130(-/-)), or bone marrow chimeric mice and compared with wild-type controls (gp130(f/f)). Systemic deletion of gp130 (MxCre/gp130(-/-)) protected mice from severe colitis and wasting and attenuated the mucosal inflammatory infiltrate as well as local cytokine, chemokine, and adhesion molecule expression. Experiments in newly generated macrophage/neutrophil-specific gp130-deleted animals (LysCre/gp130(-/-)) and gp130 bone marrow chimeric mice, revealed a dual mechanism of proinflammatory effects mediated by gp130. Leukocyte recruitment was impaired in gp130-deleted animals and gp130-deleted recipients of wild-type bone marrow, demonstrating a central role of gp130-dependent signals in nonmyeloid cells for directing leukocytes to sites of inflammation, which was further confirmed in a model of sterile peritonitis. In contrast, macrophage/neutrophil-specific gp130 deficiency delayed and attenuated the disease but only marginally affected the inflammatory infiltrate, indicating a defective activation of mucosal leukocytes. We provide evidence that IL-6 cytokines acting via gp130 are required in the acute stages of intestinal inflammation by modulating the dynamics of innate immune cell recruitment and activation.

Henoch-Schönlein purpura complicated by cardiac involvement: case report and review of the literature.

Involvement of the kidneys in Henoch-Schönlein purpura (HSP) occurs in approximately 50% of patients with HSP, with varying severity. In general, disease outcome is favorable for adolescents. However, severe courses with vasculitis impairing multiple organ systems in addition to the kidney, including brain, heart, and intestine, may occur. This involvement, often manifesting more subtly, requires alertness for diagnosis and escalation of immunosuppressive therapy for treatment. We report a case of severe HSP nephritis with cardiac involvement in a young man. Cardiac involvement was noted initially on an electrocardiogram and visualized by using cardiac magnetic resonance imaging. HSP remission was induced with aggressive cytotoxic therapy, consisting of cyclophosphamide (750 mg/m(2) every 4 weeks) in addition to high-dose prednisolone. The case presentation is followed by a review of the literature for manifestations, treatments, and outcomes in patients with HSP complicated by cardiac involvement.

The neurovascular coupling bears properties of a feedforward and feedback regulative mechanism.

Temporal profiles of mediators involved in the neurovascular coupling bear feedforward and feedback characteristics, which are supported by mathematical modeling of evoked hemodynamic responses. However, cerebral autoregulation was expressed as a feedback control system. Therefore, question of overdetermination of the neurovascular coupling model arises. Addressing this issue, we analyzed both models for their appropriateness in describing the neurovascular coupling. Visually evoked flow velocities were recorded from healthy volunteers (aged 24.7 +/- 1.6 SD; 9 females, 11 males) with transcranial Doppler in the posterior cerebral artery. Control system parameters of the two models were specified according to the least-square-fitting technique. Mean square errors between measured and modeled curves and Akaike's information criterion (AIC) supported the feedforward-feedback model. Mean square differences decreased from 27.2 +/- 37.9 to 2.3 +/- 2 and the AIC from 2.7 +/- 0.6 %(2) to 2 +/- 0.3 %(2). The feedforward element increased the accuracy of the control system model in describing the fast initial response. Biologically, the parameter decreases the initial mismatch between the fast neuronal but slow vascular response because of visual activation.

Primary sclerosing cholangitis: diagnosis and treatment.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease that involves progressive destruction of the bile ducts. Its prevalence is 4 to 16 cases per 100,000 persons. Its incidence has risen over the last 20 years, with a more than 35% increase in the last 10 years alone. PSC tends to arise in patients with chronic inflammatory bowel diseases. It is associated with an increased risk of various types of cancer (13%-14%), most prominently cholangiocellular carcinoma (CCC). METHOD: This review is based on a selective search in PubMed for original articles, meta-analyses, and review articles about PSC that appeared from January 1980 to May 2013. RESULTS: The diagnosis is generally established with a bile duct imaging study--typically, magnetic resonance cholangiopancreaticography (MRCP): this test is more than 80% sensitive and more than 90% specific for the diagnosis of PSC. The time from diagnosis to death or liver transplantation is 12 to 18 years, and the risk that a patient with PSC will die of cancer is 40% to 58%. Options for drug treatment are limited. Randomized, controlled trials have not shown any improvement of outcomes from the administration of ursodeoxycholic acid (UDCA). Interventional endoscopy is used to treat dominant stenoses and cholangitis, even though this method of treatment is supported only by low-level evidence. Liver transplantation results in a 10-year survival rate above 80%. CONCLUSION: There is no causally directed treatment for PSC. Early diagnosis, complication management, and the evaluation of an optimally timed liver transplantation are the main determinants of outcome.

Management of primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease with major morbidity and mortality. Therapeutic management is difficult, due to lack of conclusive data and individual disease progression. High-dose UDCA was used for years as a pharmacotherapeutic agent to prevent disease progression, based on a positive trend in pilot studies, but has recently been proven to have a negative effect in advanced disease. Immunosuppressants might be useful in patients with overlap syndromes. Dominant bile duct stenoses should be treated endoscopically, and cholangiocellular carcinoma (CCC) still remains a therapeutic challenge in PSC patients. Early diagnosis of CCC must be improved and new strategies such as neoadjuvant radiochemotherapy with subsequent liver transplantation in selected patients are further options to be considered.

Haplotype analysis of the 5,10-methylenetetrahydrofolate reductase (MTHFR) c.1298A>C (E429A) polymorphism.

BACKGROUND: The polymorphism 5,10-methylenetetrahydrofolate reductase (MTHFR) c.1298A>C is associated with various diseases. 45 DNA samples homozygous for the A allele and 40 DNA probes homozygous for the C allele were taken from healthy German subjects of white Caucasian origin to analyze the haplotype of the two MTHFR c.1298A>C alleles. Samples were genotyped for the polymorphism MTHFR c.677C>T and for the silent polymorphisms MTHFR c.129C>T, IVS2 533 G>A, c.1068C>T and IVS10 262C>G. FINDINGS: Haplotype construction revealed that the C-allele of MTHFR c.1298A>C was more frequently observed in cis with c.129T, IVS2 533A, c.677C, c.1068T, and IVS10 262 G than expected from normal distribution. Estimation of the most recent common ancestor with the DMLE + 2.3 program resulted in an estimated age of approximately 36,660 years of the MTHFR c.1298C allele. CONCLUSION: Given that the era from 30,000 to 40,000 years ago is characterised by the spread of modern humans in Europe and that the prevalence of the MTHFR c.1298C allele is significantly higher in Central Europe in comparison to African populations, a selective advantage of MTHFR c.1298C could be assumed, e. g. by adaption to changes in the nutritional environment. The known founder ancestry of the T allele of MTHFR c.677C>T allele, together with the present data suggests that the MTHFR mutant alleles c.677T and 1298C arose from two independent ancestral alleles, that both confer a selective advantage.

Molecular dissection of gp130-dependent pathways in hepatocytes during liver regeneration.

Interleukin-6 (IL-6) via its signal transducer gp130 is an important mediator of liver regeneration involved in protecting from lipopolysaccharide (LPS)-induced liver injury after partial hepatectomy (PH). Here we generated mice either defective (Delta) in hepatocyte-specific gp130-dependent Ras or STAT activation to define their role during liver regeneration. Deletion of gp130-dependent signaling had major impact on acute phase gene (APG) regulation after PH. APG expression was blocked in gp130-DeltaSTAT animals, whereas gp130-DeltaRas mice showed an enhanced APG response and stronger SOCS3 regulation correlating with delayed hepatocyte proliferation. To define the role of SOCS3 during hepatocyte proliferation, primary hepatocytes were co-stimulated with IL-6 and hepatocyte growth factor. Higher SOCS3 expression in gp130-DeltaRas hepatocytes correlated with delayed hepatocyte proliferation. Next, we tested the impact of LPS, mimicking bacterial infection, on liver regeneration. LPS and PH induced SOCS3 and APG in all animal strains and delayed cell cycle progression. Additionally, IL-6/gp130-dependent STAT3 activation in hepatocytes was essential in mediating protection and thus required for maximal proliferation. Unexpectedly, oncostatin M was most strongly induced in gp130-DeltaSTAT animals after PH/LPS-induced stress and was associated with hepatocyte proliferation in this strain. In summary, gp130-dependent STAT3 activation and concomitant SOCS3 during liver regeneration is involved in timing of DNA synthesis and protects hepatocyte proliferation during stress conditions.

Binding of copper is a mechanism of homocysteine toxicity leading to COX deficiency and apoptosis in primary neurons, PC12 and SHSY-5Y cells.

Children with hereditary severe hyperhomocysteinemia present with a variety of neurological impairment, and mild hyperhomocysteinemia has been associated with neurodegeneration in the elderly. The link of hyperhomocysteinemia to neurological dysfunction is unknown. We investigated mitochondrial mechanisms of homocysteine (HCys) neurotoxicity in rat dopaminergic pheochromocytoma cells, human neuroblastoma cells and primary rat cerebellar granule neurons. HCys dose dependently impaired cytochrome c oxidase (COX) activity as well as stability and induced reactive oxygen species and apoptotic cell death. We found that HCys binds the COX cofactor Cu(2+), and Cu(2+) supplementation prior to HCys treatment preserved COX activity and prevented cell death. The Cu(2+) chelating action of HCys and impairement of COX activity represent novel mechanisms of HCys neurotoxicity, which might be preventable by supplementation of Cu(2+).