Histological grading and staging of chronic hepatitis.
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Biopsy↗
Biomedical subjects
H Denk
Publications and source records attributed to H Denk.
Expression of three- and four-repeat tau isoforms in mouse liver.
Tau protein is a member of the family of microtubule-associated proteins, which support microtubule polymerization and stability. Under pathological conditions, tau is a major constituent of neurofibrillary tangles in nerve cells of patients with Alzheimer's disease. Neurofibrillary tangles share some morphological, biochemical and immunological properties with cytoplasmic inclusions associated with other diseases, such as Mallory bodies in the livers of patients with alcoholic hepatitis and in corresponding mouse models. Recently a Mallory body component was identified that in molecular mass and isoelectric point resembles the abnormally phosphorylated tau of neurofibrillary tangles. There has been, however, so far no report describing the occurrence of tau in normal liver. We now demonstrate the expression of two tau isoforms containing three and four repeats, respectively, of the microtubule-binding domains in normal mouse liver and kidney. This finding provides evidence for a physiological role of tau in the liver and, consequently, the basis for the involvement of tau in pathological situations.
Animals↗
Coexistence of papillary and medullary carcinoma of the thyroid gland-mixed or collision tumour? Clinicopathological analysis of three cases.
We present three thyroid carcinomas displaying medullary and papillary components. In two cases the papillary component was characterized by typical papillae with a fibrovascular core; in one a follicular variant of papillary carcinoma was found. The papillary component was dominant in two and the medullary in one case. One tumour showed clear-cut borders between the two components, the others displayed an intermingled pattern. Both tumour components were seen in lymph node metastases with immunostaining with antibodies to calcitonin, chromogranin A, carcinoembryonic antigen, other neuroendocrine markers and thyroglobulin. At least two of our cases are true mixed carcinomas probably arising from a common stem cell.
Adult↗
Guidelines for the diagnosis and interpretation of hepatic granulomas.
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Data Interpretation, Statistical↗
Radical surgery (R2 resection) for gastric cancer. A multivariate analysis.
BACKGROUND: Extended lymphadenectomy remains controversial in the Western world. Its evaluation and the identification of high-risk patients after surgery are important tasks. METHODS: A retrospective prognostic study of 318 patients treated for potential cure of gastric cancer was performed. All patients underwent extended lymphadenectomy. Clinical histopathologic and surgical factors were examined for their influence on survival by univariate and multivariate analysis. RESULTS: Postoperative mortality was 4.4% (14 of 318), and the 5-year adjusted survival rate was 57.8%. Multivariate analysis using the Cox model identified seven factors as having independent influence on survival. Detrimental factors were male gender, age over 65 years, high pN category, increasing number of lymph nodes invaded by metastases, total gastric resection, splenectomy, and increasing number of perioperatively required blood units. CONCLUSION: Extended lymphadenectomy was possible without sacrificing low postoperative mortality rates. The importance of certain prognostic factors, in particular lymph node status, could be confirmed.
Aged↗
Posttranslational events involved in griseofulvin-induced keratin cytoskeleton alterations.
Alcoholic hepatitis is a disease associated with profound alterations of the hepatocytic intermediate filament cytoskeleton. Similar cytoskeletal alterations can be induced in mice with prolonged feeding of the fungistatic drug griseofulvin. Murine hepatocytic intermediate filaments are composed of equimolar amounts of keratin polypeptides A (type II) and D (type I). Griseofulvin intoxication of mice leads to diminution, derangement and even loss of the cytoplasmic keratin meshwork and formation of keratin-containing cytoplasmic inclusions, termed Mallory bodies. To study protein alterations leading to disturbance of keratin filament architecture, soluble keratin polypeptides and keratin filaments were purified from griseofulvin-damaged and control mouse livers. In griseofulvin-damaged livers, more acidic isoforms occurred in soluble keratin D, whereas the corresponding filaments had a polypeptide composition similar to that in controls. In vivo [32P]orthophosphate incorporation revealed that the shift of isoelectric forms toward more acidic spots was due to hyperphosphorylation of keratin D. The nature of the kinase(s) involved has yet to be elucidated. In addition, rapid proteolysis only of soluble keratin A was detected in vitro, and there is evidence for increased proteolysis in griseofulvin damage in vivo. The enzyme involved has features of a calpain-type protease. Posttranslational modifications play a substantial role in the disturbance of keratin intermediate filament homeostasis in vivo.
Animals↗
[Molecular pathology: fashion? Necessity?].
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Animals↗
[Miliary tuberculosis of the liver as a cause of septic shock with multi-organ failure].
A woman aged 63 presented with septic fever, followed by hepatocellular jaundice. Viral hepatitis was ruled out by serologic tests, but no definite diagnosis could be made. Due to severe disturbance of the plasmatic coagulatory system and a serum bilirubin level above 4 mg/dl, a liver biopsy was not performed. The patient had a persistent septicemia refractory to Imipenem. In spite of intensive care measures, the patient died of disseminated intravascular coagulation and multiorgan failure caused by septic shock. The correct diagnosis of miliary tuberculosis was made only post mortem by histopathological examination of liver specimens and confirmed by detection of Mycobacterium tuberculosis DNA in the patient's liver by polymerase chain reaction.
DNA, Bacterial↗
Involucrin expression in breast carcinomas: an immunohistochemical study.
The expression of involucrin, a structural component of the envelope of mature squamous epithelium, was studied in 166 paraffin-embedded breast carcinomas. In 41 cases (24.7%) involucrin-positive, light microscopically non squamous tumour cells were detected. The number of involucrin-positive tumour cells varied considerably from case to case. For further characterization, involucrin-positive cases were studied using monoclonal antibodies to various cytokeratins (PKK1, EAB 903, EAB 904) and, in selected cases, double immunostaining with antibodies to cytokeratins and involucrin were performed. Coexpression of involucrin and cytokeratins demonstrated by PKK1 was seen in all tumour cells, whereas coexpression of involucrin and cytokeratins detected by EAB 904 was only seen in single and scattered cells in a few cases. Cytokeratins detected by EAB 903 were not coexpressed with involucrin in our cases. Our results indicate heterogeneity of cytokeratins in breast carcinomas and suggest a dissociation in the regulation of involucrin and cytokeratin expression.
Breast Neoplasms↗
Immunohistochemical detection of tumor necrosis factor-alpha, other cytokines and adhesion molecules in human livers with alcoholic hepatitis.
This immunohistochemical study was designed to investigate the possible contribution to and topographical distribution of some important cytokines, such as tumour necrosis factor alpha (TNF alpha) and interleukins, in acute alcoholic hepatitis. The well-known inductive capacity of these cytokines with respect to the expression and/or up-regulation of adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and endothelial leukocyte adhesion molecule-1 (ELAM-1), was a further point to be studied. Moreover, the proposed induction of adhesion molecules might also be associated with the activation and attraction of a special population of inflammatory cells characteristic for alcoholic hepatitis. Frozen liver samples from patients who died with signs of acute alcoholic hepatitis were evaluated using the alkaline phosphatase anti-alkaline phosphatase immunostaining technique and also single and double indirect immunofluorescence. In acute alcoholic hepatitis TNF alpha could be detected predominantly in ballooned hepatocytes, which often contained alcoholic hyalin (Mallory bodies). Moreover, TNF alpha showed a co-distribution with ICAM-1 expressed in the membranes of hepatocytes and with the occurrence of CD11b positive polymorphonuclear leukocytes (neutrophils) suggesting a possible major role of the beta 2-integrin Mac-1 as a ligand for ICAM-1. No induction of ELAM-1 could be found. In alcoholic hepatitis cytokines may be responsible for the induction of the adhesion molecule ICAM-1 on hepatocytic membranes and activate a defined population of inflammatory cells, thus contributing to the characteristic histological picture of acute alcoholic hepatitis with its concentration of neutrophils especially in areas with ballooned Mallory body-containing hepatocytes. Our results are in line with clinical findings showing high levels of TNF alpha and interleukin-1 in sera of patients with alcoholic hepatitis and with the already reported expression of ICAM-1 on hepatocytes.
Antigens, CD↗
Disturbance of keratin homeostasis in griseofulvin-intoxicated mouse liver.
BACKGROUND: Alterations of the hepatocytic intermediate filament (IF) cytoskeleton, i.e., derangement and diminution of the keratin network and appearance of cytoplasmic aggregates of keratin-containing material, termed Mallory bodies, are characteristic features of human alcoholic hepatitis. Mallory bodies can be experimentally produced in mouse liver by chronic griseofulvin (GF) administration. GF intoxication of mice is, therefore, a suitable model to study the mechanisms of Mallory body formation and related cytoskeletal changes. EXPERIMENTAL DESIGN: To investigate the correlation between morphologic alterations of the keratin cytoskeletal network and the mRNA levels for liver keratins A (8) and D (18) in this pathologic situation immunohistochemical studies and northern blot analyses were performed. The amount of mRNA for both keratins was also analyzed by nuclease S1 protection assay. RESULTS: In GF-treated livers (4 months of treatment) an increase of mRNA for both liver keratins was found. This increase of mRNA was unexpected under these conditions, since in longterm GF-fed animals, the amount of keratin IFs was reduced as revealed by immunofluorescence and electron microscopy and by biochemical analysis of keratin proteins. In livers treated for 2 months with GF the IF meshwork seemed to be still intact, but the increase of RNA was already detectable indicating that alterations of keratin mRNA precede detectable morphologic alterations. When using this mRNA for in vitro translation experiments, strong keratin polypeptide spots could be detected by autoradiography of 2-dimensional gels. CONCLUSIONS: These results strongly suggest that in vivo under the conditions of GF intoxication posttranslational modifications, like phosphorylation, proteolysis and covalent cross-linking, could influence IF homeostasis and interfere with IF assembly. Increase of mRNA for liver keratins despite IF protein reduction might be due to negative feedback regulation.
Animals↗
Distribution of cytokeratins, vimentin and desmoplakins in normal renal tissue, renal cell carcinomas and oncocytoma as revealed by immunofluorescence microscopy.
Forty-two renal cell carcinomas, one oncocytoma and normal renal tissue were studied for the presence of cytokeratins and vimentin. The investigations were performed by immunofluorescence microscopy applying a panel of mono- and polyclonal antibodies to intermediate filament proteins. In all tumours except chromophobic renal cell carcinoma (CRCC) and oncocytoma a co-expression of cytokeratins and vimentin could be shown. The intermediate filament expression was often, however, very heterogeneous particularly with respect to the distribution of cytokeratins and vimentin, to the clonality of the antibodies used and to the tumour areas studied. The latter could be impressively demonstrated by examining a whole tumour. In CRCC and oncocytoma all tumour cells expressed cytokeratins and, in addition, single tumour cells also expressed vimentin. In normal renal tissue we could show vimentin-positive epithelia of proximal and distal tubules, which is reported for the first time.
Adenoma↗
Extended radical surgery against gastric cancer: low complication and high survival rates.
The present study examines survival benefits for 338 gastric cancer patients from radical surgical treatments, including radical lymphadenectomy of group 3 nodes and combined resection of infiltrated adjacent organs. Curative surgery, with no detectable residual tumor, was possible for 236 patients (69.8%). The radical surgical approach was constant in execution, with 330 of the 338 patients (97.6%) being operated upon by the same surgeon. The remaining patients were operated upon in a similarly radical manner which always included a lymphadenectomy of the N-3 region. Anastomotic leakage was observed in seven patients (3.0%). The postoperative mortality rate was 4.8% for total gastrectomy cases and 3.3% for subtotal gastrectomy cases. The actuarial five-year survival rate for patients receiving curative surgery was 50.0%. These low complication and high survival rates support the concept of extended radical surgery for gastric cancer.
Adenocarcinoma, Mucinous↗
High amount of epsilon-(gamma-glutamyl)lysine cross-links in Mallory bodies.
Alcoholic hepatitis, the most severe form of alcoholic liver disease, is associated with inflammation, liver cell necrosis, and the appearance of Mallory bodies (MBs) in hepatocytes. Identical MBs can be experimentally induced in mouse livers by chronic griseofulvin or 3,5-diethoxycarbonyl-1,4-dihydrocollidine treatment. MBs are filamentous cytoplasmic inclusions containing insoluble high molecular weight protein material. Covalent polymerization of intracellular proteins may occur through formation of epsilon-(gamma-glutamyl)lysine cross-links catalyzed by Ca(2+)-dependent transglutaminases. Therefore, isolated experimentally-induced MBs were analyzed for the presence of epsilon-(gamma-glutamyl)lysine bonds. Highly purified MBs contained 19.7 nmole (griseofulvin-induced) and 14.4 nmoles (3,5-diethoxycarbonyl-1,4-dihydrocollidine induced) of isodipeptide linkage, respectively, per mg of protein. These results suggest that transglutaminase-induced cross-linking of proteins plays a major role in MB formation.
Animals↗
Common epitopes of human and murine Mallory bodies and Lewy bodies as revealed by a neurofilament antibody.
The antibody SMI 31, which is directed against a phosphorylated epitope, associated with neurofilaments and recognizes Lewy bodies in brains of patients with Parkinson's disease (Bancher C, Lassmann H, Budka H, Jellinger K, Grundgke-Iqbal I, Iqbal K, Wiche G, Seitelberger F, Wisniewski H: J Neuropathol Exp Neurol 1:81, 1989), decorated in immunofluorescence microscopy Mallory bodies (MBs) present in livers of mice chronically treated with griseofulvin and 3,5-diethoxycarbonyl-1,4-dihydrocollidine. In immunoblots it recognized very acidic MB components in a molecular weight range between 55 and 69.5 kilodaltons in addition to poorly soluble high molecular weight material. Moreover, an antibody to tau protein showed similar reactivities in immunofluorescence microscopy and immunoblotting experiments. Both antibodies also stained MBs in human liver with alcoholic hepatitis. These observations support and extend earlier findings which indicate that several intermediate filament-related cellular inclusion bodies, including MBs, share a variety of morphologic, structural and antigenic features. They also suggest the involvement of tau or tau-like proteins in MB formation.
Animals↗
Alcoholic liver disease. Parenchyma to stroma relationship in fibrosis and cirrhosis as revealed by three-dimensional reconstruction and immunohistochemistry.
Severe ethanol-induced liver damage is characterized by fibrous dissociation of liver cell plates leading to many apparently isolated hepatocytes. Three-dimensional reconstruction, however, revealed hepatocytes that were surrounded by connective tissue as endpoints of "parenchymal pillars" or in association with liver cell plates and bile ductules. Double immunofluorescence studies displayed the expression of cytokeratin (CK) 7 in bile ducts, including bile ductules, but also in some hepatocytes still organized in liver cell plates. The other bile duct, typical CK, namely CK 19, was only detectable in few hepatocytes. However, the expression of CK 7 and/or CK 19 was less frequent in hepatocytes that were closely associated with bile ductules. CK 7 and CK 19 were also found in some, but not all, Mallory bodies. These observations indicate that the expression of these two CKs is neither related to a transformation of hepatocytes to bile duct-like structures ("ductal metaplasia") nor to the formation of Mallory bodies. Furthermore, double immunofluorescence studies revealed small groups of hepatocytes and bile ductules that were encircled by basement membrane material, thus suggesting the formation of "secretory units."
Aged↗
Modulation of protein composition of nuclear lamina. Reduction of lamins B1 and B2 in livers of griseofulvin-treated mice.
Chronic griseofulvin (GF) intoxication of mice leads to severe alterations of the hepatocytic intermediate filament cytoskeleton similar to that found in alcoholic hepatitis in humans (i.e., derangement and diminution of the keratin filament network and appearance of cytoplasmic aggregates of keratin-containing material, termed Mallory bodies). To investigate eventual alterations of nuclear lamins under these pathologic situations monoclonal antibodies were produced. One of these, GL-35, was directed to lamin B1 and lamin B2. Immunofluorescence microscopy revealed in GF-treated livers, in comparison to normal mouse livers, a highly reduced immunoreaction for lamins B1 and B2, whereas the staining for lamins A and C was unchanged. This reduction of both B-type lamins occurred before detectable alterations of keratin filaments and was reversible after cessation of GF intoxication. A diminished content of both B-type lamins in relation to lamins A and C in GF-intoxicated livers was also revealed by analysis of isolated nuclear envelopes on two-dimensional gels. Moreover, there was a clear predominance of more acidic isoelectric variants of lamins B1 and B2. In contrast to the reduced amount of B-type lamin proteins no reduction in the concentration of the mRNA for lamin B1 was found. For lamin B2 even an increase of mRNA was detected in GF-treated livers. These results indicate that GF not only interferes with expression of the keratin intermediate filament skeleton of hepatocytes but also leads to selective alterations of the nuclear lamins, most likely by posttranslational modifications of intermediate filament proteins.
Animals↗