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M Manns

Publications and source records attributed to M Manns.

At least 37 records · Page 2Linked to original sources
PubMed2000

Tumor necrosis factor alpha in the pathogenesis of human and murine fulminant hepatic failure.

BACKGROUND & AIMS: The tumor necrosis factor (TNF)-alpha/TNF receptor system is critical for liver development because hepatocytes undergo apoptosis if the antiapoptotic cascades resulting in RelA NF-kappaB activation are not effective. Therefore, we studied the role of TNF-alpha in fulminant hepatic failure (FHF) and developed a new therapeutic strategy. METHODS: Serum levels and hepatic expression of TNF-alpha and both TNF receptors were determined by enzyme-linked immunosorbent assay and immunohistochemistry. Adenoviral vectors were constructed expressing dominant-negative proteins interfering with intracellular TNF-alpha-dependent pathways. The relevance of these constructs was studied in primary mouse hepatocytes and in a murine model of FHF. RESULTS: Serum levels of TNF-alpha and TNF receptors are significantly increased in FHF; this increase correlates with patient prognosis. In livers of patients with FHF, infiltrating mononuclear cells express high amounts of TNF-alpha and hepatocytes overexpress TNF receptor 1 (TNF-R1). Apoptotic hepatocytes are significantly increased in FHF, and there is a strong correlation with TNF-alpha expression, which is even more pronounced in areas of mononuclear infiltrates. In an in vivo FHF model, the Fas-associated death domain (FADD), adenovirus selectively blocked the intracellular pathway, leading to mitochondrial cytochrome c release, caspase-3 activation, and, thus, apoptosis of hepatocytes. CONCLUSIONS: The results show that the TNF-alpha/TNF-R1 system is involved in the pathogenesis of FHF in humans. Studies in this animal model indicate that FADD may serve as a molecular target to prevent liver cell death in vivo.

Adaptor Proteins, Signal Transducing↗
PubMed1999

p53 represses CAAT enhancer-binding protein (C/EBP)-dependent transcription of the albumin gene. A molecular mechanism involved in viral liver infection with implications for hepatocarcinogenesis.

p53 is a transcription factor that is activated by genotoxic stress and mediates cell cycle arrest and apoptosis. Here we demonstrate that infection of mouse liver with recombinant E1/E3-deleted adenovirus leads to p53 activation and simultaneously to the down-regulation of albumin gene expression. In vitro transcription assays indicate that transcriptional mechanisms mediated through the albumin promoter are responsible for reduced albumin mRNA levels during viral infection. Albumin expression is maintained in the liver by a combination of liver-enriched transcription factors such as CAAT enhancer-binding protein (C/EBP)alpha and C/EBPbeta. We show that p53 wild type and tumor-derived p53 mutations repress C/EBP-mediated transactivation of the albumin promoter. The binding of C/EBPalpha or -beta to its cognate sequence in the albumin promoter is not inhibited by p53 expression. Deletion analysis and domain swapping experiments show that repression of C/EBPbeta-mediated transactivation is dependent on the N-terminal domain of p53 and the transactivation domain, leucine zipper domain, and the inhibitory domain II (amino acids 163-191) of C/EBPbeta. Our results provide a molecular explanation for the p53-mediated down-regulation of liver-specific gene expression after viral infection. Additionally, as overexpression of p53 mutants is frequently found in undifferentiated hepatocellular carcinomas, the same mechanisms may contribute to the lack of liver-specific gene transcription in these tumors.

Albumins↗
PubMed1999

'Natural' and artificial monocular deprivation effects on thalamic soma sizes in pigeons.

The dominance for visual pattern analysis of the left hemisphere in normal pigeons and the concomitant morphological asymmetries in the optic tectum can be attributed to a 'natural' prehatch monocular deprivation of the left eye resulting from an asymmetrical embryonic position within the egg. Using control animals and pigeons which were monocularly deprived for 10 days after hatching, the present study could show that the cellular soma sizes of the nucleus rotundus within the tectofugal visual pathway are modified by light experience depending on the timepoint and direction of lateralized stimulation. Although rotundal cell size is thus ontogenetically modified in an activity-dependent manner, a detailed comparison makes it likely that the mechanisms which govern developmental plasticity of visual pathways differ between birds and mammals.

Animals↗
PubMed1999

Autoantibodies in human chronic graft-versus-host disease after hematopoietic cell transplantation.

Primary biliary cirrhosis (PBC) and graft-versus-host disease (GVHD) are thought to have common immunopathologic features and previous studies have reported that 5.2 to 81% of patients with chronic GVHD after allogeneic hematopoietic cell transplant have antimitochondrial antibodies (AMA). We studied a total of 89 patients with chronic GVHD and 60 controls for AMA reactivity by ELISA and immunoblotting using recombinant PDC-E2, BCOADC-E2, and OGDC-E2, immunoblotting of beef heart mitochondrial proteins, and reactivity to nuclei, smooth muscle (ASMA), ribonucleoprotein JO-1, extractable nuclear antigen, nuclear proteins SSA/ SSB, ribonucleic P proteinase III, cardiolipin (ACA), liver kidney microsomal, thyroid microsomal, myeloperoxidase, and the reactivity of rheumatoid factor. A subset of 60 chronic GVHD sera were tested for reactivity to gp210 and LBR. Finally, liver tissue from patients with chronic GVHD and PBC was studied by immunohistochemistry to determine whether there was comparable abnormal apical staining of biliary epithelial cells using PDC-E2-specific monoclonal antibodies. Surprisingly, there were no AMA found in the sera from the 89 patients with chronic GVHD. Review of published data on AMA in GVHD suggests that previous results were primarily false positives. In contrast, sera from the patients with GVHD did have a variety of other autoantibodies and, in particular, 20/89 (22.4%) positive ANA, 23/89 (25.8%) positive ASMA, and 9/89 (10.1%) positive ACA. The other autoantibodies assayed were not statistically different from controls. Finally, abnormal biliary epithelial luminal staining of bile ducts was found, as expected, in liver tissue of patients with PBC but was absent in chronic GVHD.

Adult↗
PubMed1999

The tumor necrosis factor-alpha promoter correlates with progression of primary biliary cirrhosis.

BACKGROUND/AIMS: There have been many studies attempting to identify genes that determine susceptibility to primary biliary cirrhosis (PBC), but few studies have attempted to define the genes that modulate the natural history of the disease. There is a biallelic polymorphism, coined TNF1 and TNF2, in the TNFalpha promoter region at -308. We investigated the relative frequency of the TNF1 and TNF2 alleles in patients with PBC, based on the hypothesis that a polymorphism of the TNFalpha promoter region may be associated with the rate of progression and prognosis of PBC. METHODS: Seventy-one Caucasoid patients with PBC and 133 healthy and unrelated Caucasoid individuals were studied. Genomic DNA was extracted from blood, and the mutation at position -308 of the TNFalpha gene analyzed by PCR and NcoI digestion. RESULTS: In 71 patients with PBC, 56/71 (78.9%) patients were TNF1/TNF1 homozygotes, 14/71 (19.7%) were TNF1/TNF2 heterozygotes and 1/71 (1.4%) were TNF2/TNF2 homozygotes. In 133 healthy individuals, 109/133 (80.5%) patients were TNF1/TNF1 homozygotes, 24/133 (18%) were TNF1/TNF2 heterozygotes. No control individuals were TNF2/TNF2 homozygotes. The difference between the two groups was not statistically significant (p = 0.3684). However, in patients with TNF1/TNF1 the Mayo score for disease severity was 4.596+/-0.157 (mean +/- SEM), compared to 5.637+/-0.420 for patients with TNF1/TNF2. This Mayo score was significantly higher in patients with the TNF1/TNF2 genotype than those with TNF1/TNF1 (p = 0.0140), with an odds ratio of 4.9. CONCLUSIONS: Our data demonstrate that the presence of the TNF2 allele may be associated with a higher Mayo score, and thus with patients in a more advanced clinical stage. These data have both theoretical and clinical implications.

Alleles↗
PubMed1999

Monocular deprivation alters the direction of functional and morphological asymmetries in the pigeon's (Columba livia) visual system.

One-day-old pigeons (Columba livia) were monocularly deprived by occluding the left or the right eye for 10 days. Up to 3 years later, degree and direction of functional and morphological asymmetries of deprived and control pigeons were analyzed. In control pigeons, the usual right-eye superiority was obtained in a visual discrimination task. In left-eye deprived pigeons, this behavioral asymmetry was strengthened, whereas the direction of lateralization was reversed in right-eye deprived birds. A morphological tectum analysis revealed that control and left-eye deprived pigeons displayed similar asymmetries, with the left-monocular deprived pigeons exhibiting more pronounced left-right differences. Tectal morphometry of right-eye deprived pigeons displayed a reversed pattern. Overall, the present study shows that a short period of posthatch monocular deprivation is sufficient to alter behavioral and morphological visual asymmetry for several years.

Animals↗
PubMed1999

[Atypical gallstone ileus: radiologic and sonographic findings].

We report on a case of an atypically located gallstone ileus as a rare complication of cholecystolithiasis. A 61-year old lady with a history of diabetes type II and nephrolitiasis presented with abdominal pain lasting for 8 days and with vomiting and diarrhoea. Physical examination revealed a palpable tumour and pain in the left lower abdomen. An extensive elevation of blood sugar, CRP and leukocytosis was found. Initially X-ray of the abdomen and sonography showed signs of a subileus. Additionally a 5 x 2 cm mass with dorsal shadowing was detected by ultrasound. Gallbladder and the biliary system were normal. The sonographic suspicion of a gallstone ileus was confirmed by a subsequent CT scan. Under operation the gallstone was found in the distal Jejunum. A gallstone ileus must be included in the differential diagnosis of a tumour in the left lower abdomen. A tumour with dorsal shadowing and signs of a subileus may be the only sonographic findings of a gallstone ileus.

Cholelithiasis↗
PubMed1999

Is there a serological difference between men and women with primary biliary cirrhosis?

OBJECTIVE: Primary biliary cirrhosis (PBC) is an autoimmune disease affecting small intrahepatic bile ducts of the liver, causing destruction of the epithelium that results in eventual fibrosis and scarring. We still lack a complete epidemiological description of this disease, although interesting geographic differences in prevalence have been described. One consistent feature has been the relative scarcity of men with PBC. In fact, published ratios of women to men range from 3:1 to as high as 22:1. Thus far, the only clinical difference reported between men and women with PBC is a putative higher risk of hepatocarcinoma in men. Previous serological studies have shown that about 95% of all patients possess antimitochondrial antibodies to members of the highly conserved 2-oxo-acid dehydrogenase family of proteins, namely pyruvate dehydrogenase complex E2 (PDC-E2), branched-chain 2-oxo-acid dehydrogenase complex E2 (BCOADC-E2), and 2-oxo glutarate dehydrogenase complex E2 (OGDC-E2). However, there has been no information as to whether there is a difference in serological response between men and women. Using the serological hallmark of antimitochondrial antibodies (AMAs) and taking advantage of the availability of recombinant mitochondrial autoantigens, investigations were performed to determine if there were any serological differences between men and women with PBC. METHODS: Sera were collected from 88 patients with PBC, of whom 46 were men and 42 were women. Using a combination of immunoblotting and enzyme-linked immunoabsorbent assay (ELISA) against beef heart mitochondria (BHM), recombinant PDC-E2, BCOADC-E2, and OGDC-E2, we determined the relative autoantibody reactivities of our study population. RESULTS: Both men and women with PBC produced high titer antimitochondrial antibodies. The frequency of reactivity was similar in both groups and included, in descending order, PDC-E2, E3BP (Protein X), BCOADC-E2, and finally OGDC-E2. More importantly, antigenic specificity was nearly identical regardless of gender. CONCLUSIONS: AMAs are the serological hallmark of PBC in both men and women, and there is no significant difference in reactivity between the two groups of patients.

Adult↗
PubMed1999

High clearance continuous renal replacement therapy with a modified dialysis machine.

Recent studies suggest that the dialysis dose significantly affects survival in acute renal failure (ARF) patients and that bicarbonate dialysate improves acid-base balance during continuous renal replacement therapy (CRRT). These data inspired us to use slow continuous dialysis (SCD) in the treatment of ARF. SCD is defined by the following parameters: (a) blood flow (Q(B)) = 100 to 200 ml/min, (b) dialysate flow (Q(D)) = 100 to 300 ml/min, (c) the use of a modified hemodialysis machine with controlled ultrafiltration and online production of bicarbonate-based dialysate, and (d) continuous or extended daily treatment for 8 to 24 hours. SCD provides a urea clearance in the 70 to 80 ml/min range. Preliminary data from an ongoing clinical trial demonstrate the safety, efficiency, and simplicity of the treatment.

Acute Kidney Injury↗
PubMed1998

Safety and immunogenicity of hepatitis A vaccine in patients with chronic liver disease.

Acute hepatitis A superimposed on chronic liver disease (CLD) has been associated with severe or fulminant hepatitis. An open, multicenter study was performed to compare the safety and immunogenicity of an inactivated hepatitis A vaccine in patients with CLD with that in healthy subjects. A secondary objective was to compare the safety of the hepatitis A vaccine with that of a commercial hepatitis B vaccine in subjects with chronic hepatitis C. A total of 475 subjects over the age of 18 years were enrolled into 1 of 5 groups according to history, serological data, and previous diagnosis. Patients in groups 1 (healthy adults), 2 (chronic hepatitis B), 3 (chronic hepatitis C), and 5 (other CLD not caused by viral hepatitis) were vaccinated with two doses of inactivated hepatitis A vaccine, 6 months apart. Patients in group 4 (chronic hepatitis C) received 3 doses of a recombinant hepatitis B vaccine, according to a 0-, 1-, and 6-month schedule. Local injection-site symptoms were the most common reactions reported following vaccination in all groups (35.5% of all doses), with the hepatitis B vaccine eliciting fewer injection-site symptoms than the hepatitis A vaccine (19.8% compared with 37.5%). Although a higher percentage of healthy subjects (93%) seroconverted after a single dose of the hepatitis A vaccine than did subjects with chronic hepatitis C (73.7%) or CLD of nonviral etiologies (83.1%), more than 94% of all vaccinees were seropositive for anti-HAV after the complete vaccination course. At each time point, a lower geometric mean concentration of anti-HAV was observed for each group of CLD patients compared with the healthy control subjects. In conclusion, hepatitis A vaccine was well tolerated and induced a satisfactory immune response in patients with chronic hepatitis B, chronic hepatitis C, and miscellaneous CLD.

Adolescent↗
PubMed1998

The acu-men: a new device for continuous renal replacement therapy in acute renal failure.

BACKGROUND: We sought to design a simple machine to safely provide continuous veno-venous hemofiltration to acute renal failure patients. RESULTS: The acu-men device uses a pneumatic blood pump with tidal blood flow as the driving force. A volumetric balancing system balances the filtrate with the replacement fluid, and the blood-air interface is eliminated by replacing the conventional venous drip chamber with two air-separating membranes. The extracorporeal circuit is integrated in a disposable cartridge, which is inserted into the machine at the beginning of treatment. The priming and rinsing is done automatically. CONCLUSION: While preliminary data from an ongoing clinic trial on the efficacy of the device are encouraging, further long-term studies are necessary to evaluate its potential to decrease morbidity and mortality in acute renal failure patients.

Acute Kidney Injury↗
PubMed1998

Continuous renal replacement therapies: an update.

Continuous renal replacement modalities have found widespread use and acceptance over the last decade. The various modalities differ in the kind of access (arteriovenous v venovenous); in the application of convective clearance (continuous hemofiltration), diffusive clearance (continuous hemodialysis), or a combination of both (continuous hemodiafiltration); and in the location where the replacement fluid enters the circuit (predilution v postdilution). Continuous therapies incorporate several advantages, such as improved hemodynamic stability, the possibility for unlimited alimentation, optimal fluid balance, and gradual urea removal without fluctuations. However, it has not yet been shown whether these advantages have a significant impact on outcome and prognosis, the ultimate measure of treatment efficiency. Major disadvantages of continuous therapies are the ongoing necessity for continuous anticoagulation, immobilization of the patient, and possible side effects from lactate-containing replacement fluid or dialysate. Continuous renal replacement procedures have certainly made the management of critically ill patients easier. In particular, oligoanuric patients with diuretic resistant volume overload and hemodynamically unstable patients with acute renal failure and concomitant sepsis or multiorgan failure appear to benefit most from continuous treatment. The role of continuous hemofiltration as a method of removing serum cytokines in septic patients without renal failure is still controversial and needs further clinical assessment. Due to slow efficacy, continuous renal replacement is indicated only in rare circumstances for intoxication; this therapy also is of rather limited use in severe hyperkalemia or acidosis. Noncritically ill patients with uncomplicated renal failure (eg, due to the use of dye or antibiotics) should be treated with intermittent hemodialysis or peritoneal dialysis. Furthermore, intermittent hemodialysis is preferable in patients with hemorrhagic diathesis because it can be easily performed without anticoagulants.

Anticoagulants↗
PubMed1998

Sonography under Daylight Conditions.

PURPOSE: Gray scale image assessment in clinical ultrasound requires working in dim light or a dark room. Daylight conditions offer the advantage of shorter visual reaction time and enhanced visual perception. Look-up table manipulations could improve image brightness. MATERIALS AND METHODS: We investigated the possibility of brightness and contrast enhancement of coloured adaptive linear look-up tables (CALUT's) and their artifact resistance. Therefore under real-time conditions red/brown, green and blue CALUT's were calculated using the gray scale distribution (mean and standard deviation) of the actual image. The changes in contrast of several structural features (echo-poor and echogenic lesions, artifacts) were assessed by clinical investigators (n = 7). RESULTS: The CALUT's produced, independent of the original, images with constant brightness and contrast. Even under daylight conditions no artifacts appeared. Under scotopic conditions the red/brown CALUT's showed the best results compared to the unchanged image and the gray, green, and blue CALUT's. Hyper and hypoechoic differences with small contrast to the surrounding tissue are enhanced and can be detected more easily. CONCLUSION: Daylight sonography allows examination even in non-darkened rooms without loss of information. Eye adaptation to changing light conditions is no longer necessary; the offered image information is more suitable for the eye.

Algorithms↗
PubMed1998

Percutaneous sonographic gastrostomy: method, indications, and problems.

OBJECTIVES: This study evaluated the application of ultrasound (US) guidance in the percutaneous placement of gastric feeding tubes in patients in whom endoscopic placement of a nutrition tube is not possible. METHODS: Thirty-eight patients with upper gastrointestinal obstruction were entered in a prospective study with US-guided nutrition tube application. Feasibility of placement, side effects, and nutritional states were monitored for a mean follow-up of 4 months. RESULTS: Ultrasound allowed rapid puncture after filling of the stomach with water through a nasal tube in 34/38 cases. In four cases a total upper gastrointestinal obstruction required an initial stomach insufflation through a direct puncture. Puncture-related major complications were not observed. Minor complications during the observation time were one late dislocation, five cases with broken material after about 6 months (four could be changed by using the Seldinger technique), and two minor local infections. The nutrition through feeding tubes stabilized body weight and body composition parameters. CONCLUSION: The percutaneous sonographic gastrostomy (PSG) is a safe and minimally invasive procedure for enteral nutrition in all cases with upper gastrointestinal obstruction when endoscopic placement of a feeding tube is not possible. Percutaneous sonographic gastrostomy may help to stabilize the nutritional parameters and general condition in patients with malignant diseases.

Adult↗
PubMed1998

Hereditary hemorrhagic telangiectasia: effective protocol for embolization of hepatic vascular malformations--experience in five patients.

PURPOSE: To develop a hepatic artery embolization protocol and investigate its efficacy in a prospective study treating patients with hereditary hemorrhagic telangiectasia and predominant hepatic involvement. MATERIALS AND METHODS: One man and four women with hereditary hemorrhagic telangiectasia presented with symptoms of high-output heart failure, abdominal angina, or severe portal hypertension. The hepatic arteries were embolized in stages in three to five sessions at 1- to 15-week intervals. After peripheral embolization with polyvinyl alcohol particles, proximal arteries were embolized with coils. Computed tomography and assessment of cardiac output were performed before and after therapy and at the end of follow-up (median, 25 months; range, 12-55 months). RESULTS: After embolization, analgesics and antiemetics were necessary for a median of 5 and 2 days, respectively. Other than ischemic cholangitis (one patient), no complications were observed. The mean cardiac output decreased significantly (P < .05) from 14.2 L/min to 8.0 L/min. Symptoms of high-output heart failure, abdominal angina, and portal hypertension resolved in all patients. Seven months after embolization, one patient died of postoperative sepsis after an unsuccessful surgical attempt to create a portacaval shunt. Delayed recurrence of symptoms was not noted in the other patients. CONCLUSION: In symptomatic patients with hereditary hemorrhagic telangiectasia and predominant hepatic involvement, embolization of the hepatic arteries in stages is well tolerated by the patients and results in good clinical improvement at midterm follow-up.

Adult↗
PubMed1997

Target gene modulation in hepatocellular carcinomas by decreased DNA-binding of p53 mutations.

The crystallographic structure of the p53 core domain showed that most of the p53 mutations found in human tumors are located in conserved regions of the p53 DNA-binding domain. The aim of our study was to investigate the effect on DNA-binding and transactivation of three p53 mutations frequently found in hepatocellular carcinomas (HCC). Two of these mutations are located near the DNA-binding surface and are induced by aflatoxin B1 (249ser) and oxiradicals (249met). In contrast, mutation 220cys is not associated with a specific carcinogen in HCCs and is located outside the DNA binding structures of p53. Cotransfection experiments in two HCC cell lines, with mutated or deleted P53 genes, showed that all three mutations did not enhance reporter gene activity (RGC-CAT), in contrast to wt p53. However, in hepatoma cell lines all three mutations did suppress the p53 wildtype (wt) transactivation in a dose-dependent fashion. DNA-binding was monitored by gel shift assays using the consensus-, Waf-, and RGC-p53 binding sites. All three p53 mutations did decrease DNA-binding versus all binding sites included. Interestingly although all mutations showed the same DNA-binding and transactivation properties, differences in the ectopic expression in different hepatoma cells were observed. Therefore our results indicate that p53 mutations in HCC found in the DNA-binding domain and outside the conserved DNA-binding structures modulate target gene expression by decreasing sequence specific DNA-binding in a dominant negative fashion. The cellular environment may contribute to an additional selection advantage of some mutations.

Base Sequence↗
PubMed1997

Persistence of autoantibodies against recombinant mitochondrial and nuclear pore proteins after orthotopic liver transplantation for primary biliary cirrhosis.

Primary biliary cirrhosis is an autoimmune disease characterized by high titer autoantibodies predominantly against mitochondrial antigens PDC-E2, BCOADC-E2 and OGDC-E2. Currently orthotopic liver transplant (OLT) is the major form of treatment for end-stage primary biliary cirrhosis (PBC), but it is still unclear whether the autoimmune response continues post-transplantation. In this study we took advantage of a well-defined collection of sera collected serially before and after liver transplantation. We assayed these sera for quantitative and isotype-specific titers of antibodies against a set of recombinant mitochondrial autoantigens. We also studied reactivity to gp210. Serum samples were taken before transplantation and at intervals of 6 months, 1, 2, and 3 years after OLT. Before OLT 24/35 patients were AMA-positive, including seven out of the 35 to PDC-E2 alone, eight to both PDC-E2 and OGDC-E2, six to both PDC-E2 and BCOADC-E2, two to BCOADC-E2 alone and one to OGDC-E2. Following OLT, the frequency of sera that responded to PDC-E2 alone increased from seven to 12/35. Similarly, reactivity to BCOADC-E2 slightly increased from two to four out of 35. However, there was an overall decrease in sera that responded to more than one antigen. Neither Ig isotype nor subclass of the autoimmune response changed following OLT. Findings with gp210 were similar, in that reactivity to gp210 was found in nine out of 35 patients pre-OLT; following OLT the frequency decreased to seven out of 35 patients. Overall, the titers of AMAs decline slightly during the first year post-OLT, but are equivalent to pre-OLT values by 6 months. Moreover, the antibody subclass/ isotype remained unchanged. These data suggest that the removal of a diseased PBC liver has little, if any, impact on the serological characteristics of PBC. Moreover, it provides information regarding the natural history of PBC, particularly on the long latency time for disease development.

Antibodies, Monoclonal↗