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Wilson protein expression, copper excretion and sweat production in sweat glands of Wilson disease patients and controls
Mark Schaefer, Mavi Schellenberg, Uta Merle, Karl Weiss, Wolfgang Stremmel
BMC Gastroenterology , 2008, DOI: 10.1186/1471-230x-8-29
Abstract: Immunofluorescent analysis of the Wilson protein in skin samples from normal rat, LEC rat and human skin biopsies were performed. Pilocarpin-induced sweat gland stimulation by iontophoretic transfer adapted from the methods used for cystic fibrosis sweat test was used for sweat induction. Sweat volume, sweat copper concentration, serum ceruloplasmin and serum copper were analysed in 28 Wilson patients and 21 controls.The Wilson protein is expressed in human and rat sweat gland epithelia. Copper concentration in sweat is not significantly different between controls and Wilson patients. Wilson patients produce significantly smaller volumes of sweat compared to controls. Sweat production is partially reversible in Wilson patients under medical treatment for Wilson disease or after liver transplantationWilson patients show a reduced sweat production with unaltered sweat copper concentration. The Wilson protein might play an important role in physiological sweat production.Wilson disease is an autosomal recessive disease of copper metabolism [1-3]. Mutations in the Wilson gene Atp7b result in an absence or malfunction of the Wilson protein [4]. The Wilson protein is a transmembranous copper ATPase located in the trans-Golgi-network of human cells providing copper to cuproenzyms such as ceruloplasmin. The Wilson protein can move within the cell from the trans-Golgi-network to a late endosomal compartment when intracellular copper concentrations are elevated. In this cellular localization it has an important function in copper excretion out of the cell as copper is excreted via this late endosomal compartment out of the cell. The Wilson protein is mainly expressed in hepatocytes. Biliary excretion of excessive copper is one of the central functions of the Wilson protein [5]. However, Wilson protein is also expressed in other tissues such as kidney, brain, intestine and heart [6]. Patients with Wilson disease usually develop symptoms between the age of 5–70 years. Patients
Sensitivity and specificity of plasma disappearance rate of indocyanine green as a prognostic indicator in acute liver failure
Uta Merle, Olivia Sieg, Wolfgang Stremmel, Jens Encke, Christoph Eisenbach
BMC Gastroenterology , 2009, DOI: 10.1186/1471-230x-9-91
Abstract: Prospectively markers of hepatocellular injury, synthesis and excretion, including ICG-PDR were measured daily until liver transplantation, death, discharge from intensive care unit, or up to 7 days in 25 patients with acute liver failure. Receiver operating curve (ROC) analysis was performed to assess the value of ICG-PDR to predict outcome in ALF.The 25 patients analyzed included 18 that recovered spontaneously and 7 that underwent liver transplantation (n = 6) or died (n = 1). Causes of ALF included viral hepatitis (n = 4), toxic liver injury (n = 15), ischemic liver injury (n = 2), and cryptogenic liver failure (n = 4). King's college criteria were fulfilled in 85.7% of patients not recovering spontaneously and in 16.7% of patients recovering spontaneously. The mean ICG-PDR measured on day 1 in patients recovering spontaneously was 12.0 ± 7.8%/min and in patients not recovering spontaneously 4.3 ± 2.0%/min (P = 0.002). By ROC analysis the sensitivity and specificity of an ICG-PDR value ≤ 6.3%/min on study day 1 were 85.7% and 88.9%, respectively, for predicting a non spontaneous outcome in ALF.ICG-PDR allows early and sensitive bedside assessment of liver dysfunction in ALF. Measurement of ICG-PDR might be helpful in predicting the outcome in acute liver failure.Clinicaltrials.gov, NCT 00245310Acute liver failure (ALF) is a rare condition in which rapid deterioration of liver function occurs in previously healthy individuals. The most prominent causes include drug-induced liver injury, viral or autoimmune hepatitis, Wilson disease, ischemia, or unknown reasons [1]. The most widely accepted definition of ALF includes evidence of coagulopathy, usually an INR ≥ 1.5, and any degree of encephalopathy in a patient without pre-existing liver disease and with an illness of <26 weeks duration [2]. Liver transplantation is the treatment of choice, but because this is only clearly justifiable in patients who would otherwise die, criteria for determining such patients have
Entecavir as treatment for reactivation of hepatitis B in immunosuppressed patients
Sylvia Brost, Paul Schnitzler, Wolfgang Stremmel, Christoph Eisenbach
World Journal of Gastroenterology , 2010,
Abstract: AIM: To study the efficacy and safety of entecavir (ETV) as first-line therapy for hepatitis B virus (HBV) reactivation due to immunosuppression.METHODS: Four patients that were treated with different immunosuppressive regimens for hematological malignancies, who presented with HBV reactivation were treated with ETV. Clinical outcome, biochemical and virological factors, including quantitative hepatitis B surface antigen (HBsAg) were studied.RESULTS: In all patients, ETV induced suppression of HBV, and rapid clinical improvement without side effects. In one patient with an alanine aminotransferase (ALT) flare, tenofovir was added after 3 mo of treatment. Until death from disease progression at 6 mo after treatment initiation, this patient did not clear HBV infection. Retrospectively, it is highly probable that the patient had been non-adherent. In the other three patients, the virological responses were associated with an expeditious decrease in quantitative HBsAg titers with negativity after 2 mo, and all three had HBsAg seroconversion. In one patient, HBV DNA reached a plateau after 3 mo, before becoming undetectable after 1 year, despite early ALT normalization and undetectable quantitative HBsAg.CONCLUSION: ETV seems to be effective and safe treatment for HBV reactivation. Monitoring of quantitative HBsAg might be an additional useful tool to monitor treatment response.
Analysis of the human Atox 1 homologue in Wilson patients
Isabel Simon, Mark Schaefer, Jürgen Reichert, Wolfgang Stremmel
World Journal of Gastroenterology , 2008,
Abstract: AIM: To analyze the metallochaperone antioxidant-1 (Atox1) gene sequence in Wilson disease patients.METHODS: Mutation analysis of the four exons of the Atox1 gene including the intron- exon boundaries was performed in 63 Wilson disease patients by direct sequencing.RESULTS: From 63 selected patients no mutations were identified after the entire coding region including the intron- exon boundaries of Atox1 were sequenced. One known polymorphism within the Atox1 gene (5’UTR -99 T>C) in 31 (49%) of the Wilson patients as well as one previously undescribed variation (5’UTR -68 C>T) in 2 of the Wilson patients could be detected. Statistical analyses revealed that the existence of a variation within the Atox1- gene showed a tendency towards an earlier onset of the disease.CONCLUSION: Based on the data of this study, no major role can be attributed to Atox1 in the pathophysiology or clinical variation of Wilson disease.
Lipid Based Therapy for Ulcerative Colitis—Modulation of Intestinal Mucus Membrane Phospholipids as a Tool to Influence Inflammation
Hannah Schneider,Annika Braun,Joachim Füllekrug,Wolfgang Stremmel,Robert Ehehalt
International Journal of Molecular Sciences , 2010, DOI: 10.3390/ijms11104149
Abstract: Ulcerative colitis (UC) is the result of an inappropriate colonic inflammatory response triggered by environmental and genetic factors. We have recently shown that mucus from UC patients has a decreased phosphatidylcholine (PC) content, while clinical trials revealed that therapeutic addition of PC to the colonic mucus alleviated the inflammatory activity. The mechanisms behind this are still unclear. We hypothesized that PC has at least two possible functions in the intestine: First, it establishes the surface hydrophobicity of the mucus and therefore protects the underlying tissue against intraluminal aggressors; recent experiments on surgical specimens revealed reduced surface tension and hydrophobicity in UC patients. Second, mucus phospholipids might also be integrated into the plasma membranes of enterocytes and thereby influence the signaling state of the mucosa. PC has been shown to inhibit TNF-α induced pro-inflammatory responses including: (1) assembly of plasma membrane actin; (2)?activation of MAP kinases ERK and p38; and (3) activation of NF-κB and synthesis of pro-inflammatory gene products. Other phospholipids like phosphatidylethanolamine or sphingomyelin ?had no effect. PC also inhibited latex bead phagosome actin assembly, killing of M. tuberculosis in macrophages, and sphingosine-1-phosphate induced actin assembly in macrophages. Collectively, these results provide a molecular foundation that shows PC, firstly, as an anti-inflammatory, and secondly, as a surface hydrophobicity increasing compound with promising therapeutic potential in the treatment of inflammatory bowel disease.
Early treatment of imported falciparum malaria in the intermediate and intensive care unit setting: an 8-year single-center retrospective study
Lukas Schwake, Judith Streit, Lutz Edler, Jens Encke, Wolfgang Stremmel, Thomas Junghanss
Critical Care , 2008, DOI: 10.1186/cc6796
Abstract: We conducted a retrospective cohort study at the 14-bed combined IMC/ICU of a 1,685-bed university hospital. A cohort of 122 patients with imported falciparum malaria admitted from 1 January 1996 to 31 December 2003 was included.Thirty-four patients (27.9%) developed complications, defined according to the current World Health Organization classification. Most patients (80.3%) studied did not take the recommended chemoprophylaxis against malaria. The majority of patients (89.3% [n = 109]) could be adequately treated in the IMC. Life-threatening complications requiring ICU support occurred in 13 patients (10.7%). All complications were successfully managed. Fifty-five patients (45.1%) fulfilling recently published criteria for outpatient treatment had an excellent therapeutic response and did not require ICU support.This retrospective evaluation demonstrated favourable therapeutic results in hospitalized patients with imported falciparum malaria. Both initial treatment in the medical IMC/ICU and close collaboration between intensivists and specialists in tropical medicine may improve disease outcome among affected patients. Prospective studies are needed to confirm these preliminary findings.With 10,000 to 12,000 diagnoses per year in the European Union and 1,300 in the USA, imported malaria represents a growing challenge for health practitioners in the Western world [1,2]. In Germany, 800 to 1,000 cases of imported malaria are registered each year, two-thirds of which are caused by Plasmodium falciparum, the causative agent of falciparum malaria. Severe or complicated falciparum malaria is characterized by a broad spectrum of life-threatening complications, in particular acute respiratory distress syndrome, renal failure, circulatory shock and coma [3-8]. The course of the disease is often precipitous, requiring rapid diagnosis and initiation of both specific antimalarial chemotherapy and appropriate supportive care [5,9]. Despite improvements in intensive care mana
Budd-Chiari Syndrome: Long term success via hepatic decompression using transjugular intrahepatic porto-systemic shunt
Alexandra Zahn, Daniel Gotthardt, Karl Weiss, G?tz Richter, Jan Schmidt, Wolfgang Stremmel, Peter Sauer
BMC Gastroenterology , 2010, DOI: 10.1186/1471-230x-10-25
Abstract: 20 patients with acute, subacute or chronic BCS were treated between 1988 and 2008. Clinical records were analysed with respect to underlying disease, therapeutic interventions, complications and overall outcome.16 women and 4 men with a mean age of 34 ± 12 years (range: 14-60 years) at time of diagnosis were included. Myeloproliferative disorders or a plasmatic coagulopathy were identified as underlying disease in 13 patients, in the other patients the cause of BCS remained unclear. 12 patients presented with an acute BCS, 8 with a subacute or chronic disease. 13 patients underwent TIPS, 4 patients OLT as initial therapy, 2 patients required only symptomatic therapy, and one patient died from liver failure before any specific treatment could be initiated. Eleven of 13 TIPS patients required 2.5 ± 2.4 revisions (range: 0-8). One patient died from his underlying hematologic disease. The residual 12 patients still have stable liver function not requiring OLT. All 4 patients who underwent OLT as initial treatment, required re-OLT due to thrombembolic complications of the graft. Survival in the TIPS group was 92.3% and in the OLT group 75% during a median follow-up of 4 and 11.5 years, respectively.Our results confirm the role of TIPS in the management of patients with acute, subacute and chronic BCS. The limited number of patients with OLT does not allow to draw a meaningful conclusion. However, the underlying disease may generate major complications, a reason why OLT should be limited to patients who cannot be managed by TIPS.Budd-Chiari syndrome (BCS) is a rare disorder defined as a hepatic venous outflow obstruction at any level between the hepatic veins and the right atrium [1] but generally implies thrombosis of the hepatic veins and/or the intrahepatic or suprahepatic inferior vena cava (IVC). Up to 50% of all cases of BCS are due to chronic myeloproliferative disorders like polycythemia vera (PV) [2] or coagulopathies like factor V (Leiden) gene mutation [3-5].
Truncating mutations in the Wilson disease gene ATP7B are associated with very low serum ceruloplasmin oxidase activity and an early onset of Wilson disease
Uta Merle, Karl Weiss, Christoph Eisenbach, Sabine Tuma, Peter Ferenci, Wolfgang Stremmel
BMC Gastroenterology , 2010, DOI: 10.1186/1471-230x-10-8
Abstract: The clinical phenotype of 59 genetically confirmed WD patients was analyzed retrospectively. Serum ceruloplasmin was measured by its oxidase activity with o-dianisidine dihydrochloride as substrate and immunologically.Thirty-nine patients had two MMs, 15 had the genotype SM/MM, and 5 patients had two SMs on their ATP7B alleles. Enzymatic and immunologic serum ceruloplasmin levels differed significantly between the three groups (P < 0.001 and P < 0.01, respectively). The lowest levels were measured in patients with two SMs (0.0 U/L; IQR, 0.0-0.0 U/L and 0.02 g/L; IQR, 0.01-0.02 g/L, respectively) and the highest in patients with two MMs (17.8 U/L; IQR, 5.8-35.1 U/L and 0.11 g/L; IQR,0.10-0.17 g/L, respectively). The age of onset was also significantly different between the three patient groups (P < 0.05), with SM/SM patients showing the earliest onset (13 years; IQR, 9-13 years) and patients with two MMs showing the latest onset (22 years; IQR, 14-27 years). By ROC curve analysis a ceruloplasmin oxidase level ≤ 5 U/L can predict the presence of at least one SM with a sensitivity of 80% and a specificity of 79.5%.In our German study cohort truncating ATP7B mutations were associated with lower ceruloplasmin serum oxidase levels and an earlier age of onset when compared to MMs. Measurement of serum ceruloplasmin oxidase might help to predict presence of truncating ATP7B mutations and might facilitate the mutation analysis.Wilson disease (WD) is a rare, autosomal-recessively inherited disorder of copper metabolism due to mutations of the WD gene ATP7B [1,2]. The WD gene ATP7B codes for a membrane-bound, copper-binding protein that is expressed primarily in the liver [1,2]. Disease causing mutations in the ATP7B gene result in a reduced biliary copper excretion [3]. WD is clinically characterized by hepatic (e.g. liver cirrhosis) and neurological manifestations related to the accumulation of copper in the liver and the brain [3]. The onset of signs and symptoms of WD typi
Transcript levels of different cytokines and chemokines correlate with clinical and endoscopic activity in ulcerative colitis
Alexandra Zahn, Thomas Giese, Max Karner, Annika Braun, Ulf Hinz, Wolfgang Stremmel, Robert Ehehalt
BMC Gastroenterology , 2009, DOI: 10.1186/1471-230x-9-13
Abstract: Cytokine and chemokine transcripts were quantified using real-time PCR in 49 mucosal biopsies from 27 different patients with UC. Cytokine transcript levels were correlated with CAI and EAI.There was a statistically significant positive correlation between CXCL8 (r = 0.30; p < 0.05), CXCL10 (r = 0.40; p < 0.02), calgranulin B (r = 0.36; p < 0.03), CXCL2 (r = 0.31; p < 0.05) and CAI. Concerning EAI significant positive correlations for CXCL8 (r = 0.37; p < 0.02), CXCL10 (r = 0.33; p < 0.04), calgranulin B (r = 0.31; p < 0.05) and CXCL2 (r = 0.44; p < 0.05) were found. Low clinical and endoscopic activity was accompanied by low cytokine levels whereas high CAI and EAI were associated with high cytokine levels.From our data, we conclude that real-time PCR quantification of CXCL8, CXCL10, calgranulin B and CXCL2 in colonic biopsies is a simple and objective method for grading inflammation of intestinal mucosa in UC. CXCL8, CXCL10, calgranulin B and CXCL2 might be used as biomarkers and thus as an objective tool especially in clinical trials to evaluate anti-inflammatory and immunomodulatory regimens.Inflammatory bowel disease (IBD) like ulcerative colitis (UC) and Crohn's disease (CD) are characterized by a relapsing and remitting clinical course. Disease activity and severity are variable and include both segmental processes with slight impairment of state of health and pancolitis with extensive gastrointestinal and systemic symptoms. Thus, the definition of disease activity in UC is often difficult. The clinical activity index (CAI) is only an indirect assessment tool of bowel inflammation and the endoscopic activity index (EAI) is sometimes unable to reflect the severity of disease to the full extent.Cytokine and chemokine mRNA expression profiles in UC have been characterized in former studies [1-3] and interleukin 8 (CXCL8), interferon γ inducible protein 10 (CXCL10), myeloid-related protein 14 (calgranulin B) and macrophage inflammatory protein 2 α (CXCL2) were id
Uptake of long chain fatty acids is regulated by dynamic interaction of FAT/CD36 with cholesterol/sphingolipid enriched microdomains (lipid rafts)
Robert Ehehalt, Richard Sparla, Hasan Kulaksiz, Thomas Herrmann, Joachim Füllekrug, Wolfgang Stremmel
BMC Cell Biology , 2008, DOI: 10.1186/1471-2121-9-45
Abstract: Dynamic association of FAT/CD36 a candidate fatty acid transporter with lipid rafts was analysed by isolation of detergent resistant membranes (DRMs) and by clustering of lipid rafts with antibodies on living cells. Lipid raft integrity was modulated by cholesterol depletion using methyl-β-cyclodextrin and sphingolipid depletion using myriocin and sphingomyelinase. Functional analyses were performed using an [3H]-oleate uptake assay.Overexpression of FAT/CD36 and FATP4 increased long chain fatty acid uptake. The uptake of long chain fatty acids was cholesterol and sphingolipid dependent. Floating experiments showed that there are two pools of FAT/CD36, one found in DRMs and another outside of these domains. FAT/CD36 co-localized with the lipid raft marker PLAP in antibody-clustered domains at the plasma membrane and segregated away from the non-raft marker GFP-TMD. Antibody cross-linking increased DRM association of FAT/CD36 and accelerated the overall fatty acid uptake in a cholesterol dependent manner. Another candidate transporter, FATP4, was neither present in DRMs nor co-localized with FAT/CD36 at the plasma membrane.Our observations suggest the existence of two pools of FAT/CD36 within cellular membranes. As increased raft association of FAT/CD36 leads to an increased fatty acid uptake, dynamic association of FAT/CD36 with lipid rafts might regulate the process. There is no direct interaction of FATP4 with lipid rafts or raft associated FAT/CD36. Thus, lipid rafts have to be considered as targets for the treatment of lipid disorders.Uptake of long chain fatty acids (LCFAs) is important for many cellular functions and the understanding of the uptake mechanisms is an important target for treatment of lipid disorders [1-4]. The molecular mechanisms of fatty acid transport across the plasma membrane are still a matter of debate and the predominating mechanism likely differs from cell to cell (for reviews see [5-8]). In general, two possible groups of mechanisms ar
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