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Biomedical subjects

A Zimmermann

Publications and source records attributed to A Zimmermann.

At least 145 records · Page 8Linked to original sources
PubMed1997

Hepatic stellate cells (Ito cells) but not collagen IV may partly be responsible for lower portal pressure after reversing secondary biliary cirrhosis in the rat.

BACKGROUND/AIMS: Chronic bile duct obstruction in the rat leads to biliary cirrhosis and portal hypertension. Biliary decompression with Rouxen-Y choledocho-jejunostomy (RY) reverses most but not all of these changes. The aim of the present study was to determine whether hepatic stellate cells, as a main source of extracellular matrix proteins, participate in this process. METHODS: Sprague-Dawley rats were allocated to one of three groups: Bile duct ligation (BDL) for 3 weeks, BDL followed by RY and sham-operated animals as controls (SHAM). At the end of the experimental period, portal pressure was measured, livers subjected to random sampling and hepatocytes, bile ducts/ductules, hepatic stellate cells and collagen IV determined stereologically. Hepatic stellate cells and collagen IV were characterized immunohistochemically with an antibody against desmin and collagen IV, respectively. RESULTS: Volume fraction of hepatocytes decreased from 65.6 +/- 5.3 in sham-operated animals to 27.9 +/- 8.8% in bile duct ligated animals (p < 0.05). In contrast, volume fraction of bile ducts/ductules increased from 0.4 +/- 0.2 in sham-operated animals to 25.3 +/- 8.6% in bile duct ligated ones; similarly, hepatic stellate cells increased from 0.4 +/- 0.2 in sham-operated animals to 2.6 +/- 0.9% in bile duct ligated ones (p < 0.01) and collagen IV from 10.0 +/- 2.3 in sham-operated animals to 24.5 +/- 8.0% (p < 0.01) in bile duct ligated animals. These changes were partially reversed by Roux-en-Y choledocho-jejunostomy; hepatocytes, bile ducts/ductules, hepatic stellate cells and collagen IV averaging 54.8 +/- 13.1, 6.1 +/- 6.8, 1.6 +/- 0.6 and 14.5 +/- 3.6%, respectively (p < 0.05 RY vs. BDL). Portal pressure in sham-operated animals, bile duct ligated animals and those with a Roux-en-Y choledocho-jejunostomy averaged 13.4 +/- 0.7, 20.1 +/- 2.7 and 16.9 +/- 1.6 cm H2O, respectively, and correlated significantly with the volume fraction of hepatic stellate cells (rS = 0.96; p < 0.001) and less with collagen IV (rS = 0.61; p < 0.007). However, by stepwise regression, collagen IV did not significantly add to the ability of the equation to predict portal pressure. CONCLUSIONS: These results lend further support to the notion that hepatic stellate cells are prominently involved in fibrogenesis and in the reversibility of these changes, but hepatic stellate cells do not completely revert to normal even 4 weeks after successful decompression. Furthermore, our data suggest that hepatic stellate cells may be related to maintenance of portal hypertension.

Anastomosis, Roux-en-Y↗
PubMed1997

The apoptosis protector, bcl-2 protein, is downregulated in bile duct epithelial cells of human liver allografts.

BACKGROUND/AIMS: Apoptosis of bile duct cells occurs in hepatic allografts and is correlated with acute rejection. bcl-2 protein counteracts apoptosis and prolongs cell survival. We therefore tested the expression of bcl-2 protein in bile ducts of liver grafts in comparison with those of liver cirrhosis. METHODS: 115 biopsies from 17 liver allografts and 47 biopsies of liver cirrhosis were analyzed and compared with 22 normal controls and with biopsies from patients with primary sclerosing cholangitis or primary biliary cirrhosis. bcl-2 protein and PCNA (proliferating cell nuclear antigen) expression was assessed using immunohistochemistry, and apoptosis was analyzed employing in situ DNA end-labeling. RESULTS: A high apoptotic rate was detected in bile duct cells of allograft biopsies. In contrast to controls, bile duct cells of allografts and liver cirrhosis had high proliferative activity (mean PCNA labeling index: 1.0% vs. 40.7% and 18.6%, respectively). In liver grafts, bcl-2 protein positivity of bile duct and ductular cells was found in 3.6% and 4.4% of sections, respectively, and in cirrhosis in 44% and 79%, respectively (allografts vs. cirrhosis p<0.01). In controls, only one biopsy was bcl-2 positive. CONCLUSIONS: Whereas increased proliferative activity of small bile ducts and ductules in cirrhosis is associated with a high degree of bcl-2 expression, bile duct and ductular cells in liver grafts have a very low bcl-2 protein reactivity, even though their proliferative activity is high. These findings suggest that downregulation of bcl-2 expression in allograft bile duct cells might play a role in the increased apoptosis of these cells in acute rejection.

Acute Disease↗
PubMed1997

Dynamic phosphorus-31 spectroscopy after fructose load in experimental biliary liver cirrhosis.

RATIONALE AND OBJECTIVES: The authors investigated the usefulness of dynamic phosphorus-31 magnetic resonance (MR) spectroscopy in the assessment of hepatic function by studying the effect of a fructose load on a rat model of liver cirrhosis. METHODS: In vivo P-31 MR liver spectra of eight rats with bile duct ligature and 10 control rats were obtained every 4.6 minutes before and after intraperitoneal fructose load (10 mmol per kilogram of body weight). RESULTS: In the basal spectra of the experimental group, the phosphomonoester peak was higher than in the control group (P = .026). After the fructose load, the phosphomonoester peak increase and the inorganic phosphate peak decrease were significantly less marked in the experimental group (P = .003). There was a linear correlation between the serum level of bilirubin and the phosphomonoester increase (r = .61, P < .001). CONCLUSION: Dynamic P-31 MR spectroscopy may be useful in the assessment of hepatic function in chronic liver disease.

Analysis of Variance↗
PubMed1997

Presence of two signaling TGF-beta receptors in human pancreatic cancer correlates with advanced tumor stage.

Transforming growth factor-beta (TGF-beta) signal transduction is mediated via specific cell surface signaling TGF-beta receptors, most notably the type I ALK5 (TbetaR-I[ALK5]) and the type II (TbetaR-II). We evaluated TbetaR-I(ALK5) and TbetaR-II expression in 41 human pancreatic cancer tissue samples and correlated these findings with clinical data of the patients. Northern blot analysis indicated that, in comparison with the normal pancreas, pancreatic adenocarcinomas exhibited 8.0-fold and 4.5-fold increases (P < 0.01), respectively, in mRNA levels encoding TbetaR-I(ALK5) and TbetaR-II. In situ hybridization showed that both TbetaR-I(ALK5) and TbetaR-II mRNA were highly expressed in the majority of pancreatic cancer cells. Immunohistochemical analysis of TbetaR-I(ALK5) and TbetaR-II revealed positive immunostaining in 73% and 56% of the tumors, respectively. Both receptors were concomitantly present in 54% of the pancreatic cancer samples. The presence of TbetaR-I(ALK5) or TbetaR-II and the concomitant presence of TbetaR-I(ALK5) and TbetaR-II in the cancer cells was associated with advanced tumor stage (P < 0.01). These findings show that in many human pancreatic cancers, increased levels of the two signaling TbetaRs are present. The presence of the signaling TbetaRs in advanced tumor stages indicates a role in disease progression.

Adenocarcinoma↗
PubMed1997

Enhanced expression of urokinase plasminogen activator and its receptor in pancreatic carcinoma.

Urokinase plasminogen activator (uPA) is a serine proteinase that has been suggested to play an important role in cancer invasion and metastasis. It binds to a specific membrane receptor denominated uPA receptor (uPAR). uPA activates plasminogen to form plasmin, which participates in tissue degradation and proteolysis. Binding of uPA to its receptor accelerates UPA's own activation from pro-uPA, enhancing the activity of the uPA/uPAR cascade. Using immunohistochemistry and Northern blot analysis, we analysed the role of uPA and uPAR in 30 human pancreatic cancers. Immunohistochemical analysis demonstrated moderate to strong immunostaining of both factors in most pancreatic cancers. Cancer lesions with signs of invasion exhibited the strongest immunohistochemical signals for both factors. In addition, in desmoplastic areas adjacent to the cancer cells, moderate uPA and uPAR immunoreactivity was detectable. Northern blot analysis revealed a sixfold and a fourfold increase in uPA and uPAR mRNA levels in pancreatic cancer, respectively, in comparison with normal controls (P<0.01). Correlation of the Northern blot data with the clinical parameters of the patients indicated that patients with concomitant overexpression of uPA and uPAR had a shorter post-operative survival (median 9 months; mean+/-s.d. 10.2+/-3.6 months) than patients in whom only one or none of these factors were overexpressed (median 18 months; mean+/-s.d. 20.3+/-8.7 months) (P<0.002). Our data suggest that uPA and uPAR may serve as prognostic markers in human pancreatic cancer and that the marked overexpression of both factors may create an environment that enables pancreatic cancer cells to invade surrounding tissues.

Adolescent↗
PubMed1997

Flow cytometric analysis of herpes simplex virus type 1 susceptibility to acyclovir, ganciclovir, and foscarnet.

We established a quantitative flow cytometric method for determination of herpes simplex virus type 1 (HSV-1) susceptibility to acyclovir (ACV), ganciclovir, and foscarnet in vitro. Susceptibility was defined in terms of the drug concentration which reduced the number of cells expressing HSV-1 glycoprotein C (gpC) with a fluorescence intensity of > or =10(2) by 50% (IC50). Flow cytometry allowed us to use a high (1.0) as well as a low (0.005) multiplicity of infection, and determination of the IC50 was possible after one or more viral replicative cycles. IC50s were dependent on virus input and on time postinfection. In mixture experiments, 1 to 2% resistant viruses added to a sensitive strain could be detected. The results obtained by flow cytometry showed a good qualitative correlation with those achieved by cytopathic effect inhibitory assay. However, flow cytometry might detect more quantitative differences in drug susceptibility, especially among resistant strains, as confirmed also by determination of intracellular drug phosphorylation. The mean IC50s for ACV-sensitive strains were 0.45 to 1.47 microM, and those for ACV-resistant strains were between 140 and 3,134 microM. Flow cytometric analysis was fast and accurate, automatizable, and highly reproducible. Flow cytometry may be a more powerful tool than standard cytopathic effect-based assays and could have advantages for the detection of low levels of drug resistance or mixtures of sensitive and resistant virus strains.

Acyclovir↗
PubMed1997

Association of Ureaplasma urealyticum biovars with clinical outcome for neonates, obstetric patients, and gynecological patients with pelvic inflammatory disease.

In this prospective study, the prevalence of the two Ureaplasma urealyticum biovars, parvo and T960, was determined in pregnant women and in gynecological patients colonized by ureaplasmas. Furthermore, we investigated the association of these biovars with gynecological complications and adverse pregnancy outcome. Isolates of U. urealyticum from 254 women were biotyped by a PCR method recently developed. The parvo biovar was found in 81% (206 of 254) of the patients, and the T960 biovar was found in 30% (76 of 254) of the patients; 6% (14 of 254) of the women were coinfected. Identical biovars were detected in mothers and their infants. Serial isolations or cultures from different sampling sites of the same individual revealed the same biovar. T960 was dominant in patients with pelvic inflammatory disease (57%) and patients who had had a miscarriage (42%), showed a higher rate of tetracycline resistance than did parvo isolates (55 versus 18%), and seemed to have more adverse effects on pregnancy outcome with regard to birth weight (2,500 versus 1,720 g), gestational age (35 versus 30 weeks), and preterm delivery (35 versus 77%).

Female↗
PubMed1997

Apoptosis in human hepatocellular carcinoma and in liver cell dysplasia is correlated with p53 protein immunoreactivity.

AIMS: To investigate the prevalence of apoptosis in human hepatocellular carcinomas (HCC) of different types and grades and in liver cell dysplasia, and to test whether the apoptotic rate is correlated with the p53 protein status. METHODS: 37 HCC and 66 six liver samples with liver cell dysplasia were analysed for apoptosis using in situ DNA end labelling (ISEL), and for p53 protein expression by immunohistochemistry. In HCCs, proliferative activity was quantitatively assessed using proliferating cell nuclear antigen labelling. RESULTS: The apoptotic index in HCC as based on ISEL ranged from 0.1 to 13.5 per 1000 cells analysed and was not related to type or grade. No nuclear staining was observed in multinuclear tumour cells. There was a significant correlation between the apoptotic rate and both the proliferative activity and p53 protein reactivity. In liver samples containing p53 protein positive liver cell dysplasia cells, there was a significantly higher apoptotic rate of these cells. CONCLUSIONS: Apoptosis is detectable in HCC, and is not related to type and grade. There is a highly significant positive correlation between the apoptotic rate in HCC and both the proliferative activity and p53 protein expression. A similar phenomenon occurs for putative cancer precursors. The findings support the role of p53 in regulating apoptosis in preneoplastic and neoplastic liver lesions.

Apoptosis↗
PubMed1997

Endotheliitis-like changes in chronic hepatitis C.

Liver biopsies in hepatitis C frequently show bile duct damage, lymphoid follicles, large and small droplet fat, hepatocyte multinucleation. Mallory body-like material, and activation of sinusoidal inflammatory cells. Even though these lesions are useful parameters in the diagnosis of hepatitis C, their specificity remains uncertain. Endotheliitis-like changes of small portal veins have been described for various liver diseases, including viral hepatitis. The aim of the present study was to investigate the prevalence and severity of endotheliitis-like changes in chronic hepatitis C in comparison with chronic hepatitis B. For this purpose, liver biopsies of 50 patients with chronic hepatitis C and 48 patients which chronic hepatitis B were systematically analyzed for the presence of endotheliitis-like changes. Endotheliitis-like changes were defined as lymphocytic infiltration of venous walls, subendothelial lymphocyte accumulation, adherence of lymphocytes to the endothelium, and endothelial cell damage. Endotheliitis-like change severity was graded (borderline/questionable; slight to moderate; severe), and endotheliitis-like changes were analyzed in small portal veins and in central veins. Endotheliitis-like changes were significantly more frequent in chronic hepatitis C than in chronic hepatitis B (41.5% vs. 6.9%; p < 0.05). In chronic hepatitis C, endotheliitis-like changes predominated in small portal veins, but 27% of small hepatic veins were involved as well. The findings indicate that endotheliitis-like changes may represent a useful histological parameter in the diagnosis of chronic hepatitis C.

Bile Ducts↗
PubMed1997

Hepatocyte apoptosis in hepatic iron overload diseases.

In this retrospective study, we systematically analyzed hepatocyte apoptosis in three situations of hepatic iron overload (hereditary hemochromatosis; hepatic iron overload of unknown reason; iron overload due to hyperhemolysis or exogenous iron administration). Apoptosis was assessed by use of DNA nick end-labelling. The results suggest that hepatic iron overload is associated with an increased apoptotic rate of hepatocytes, and that iron-laden hepatocytes in hemochromatosis behave, with respect to apoptosis, differently from those in other states of iron overload. The hepatocyte apoptotic rate tended to increase as a function of the degree of iron storage. As in other pathological liver changes studied so far, an elevated apoptotic rate of hepatocytes predominated in the pericentral parts of liver acini in hemochromatosis, but not in the two other groups of hepatic iron overload. Possible mechanisms for this difference are discussed, particularly with respect to a participation of the Kupffer cell system.

Adult↗
PubMed1997

Apoptosis in hepatocellular carcinomas with neuroendocrine differentiation.

We have studied apoptosis in a subset of thirty hepatocellular carcinomas (HCCs) exhibiting neuroendocrine differentiation (ND). Apoptosis was assessed by use of in situ DNA end labelling, and was quantified employing a TdT labelling index. It turned out that apoptosis occurred in HCCs with ND, albeit at different rates. Apoptosis was visualized as a clearly detectable reaction product mostly localized in tumor cell nuclei and in apoptotic bodies. Almost no staining was observed in nuclei of multinuclear tumor giant cells. In HCCs with ND, apoptosis was not related to type or grade, but tumors mainly consisting of hepatocyte-like cells and/or clear cells showed a significantly higher apoptotic rate. This was also the cell type most frequently disclosing neuroendocrine features. The apoptotic rate was significantly higher in HCCs with ND than in a control group of HCCs not showing ND. The findings suggest that neuroendocrine differentiation in liver cell tumors is associated with an altered pattern of programmed cell death, and that this phenomenon may therefore have an influence on clinical behavior.

Adult↗
PubMed1997

[Collagen colitis and lymphocytic (microscopic) colitis: different or common origin?].

Collagenous and lymphocytic colitis are two chronic inflammatory colonic diseases characterized by chronic watery diarrhea. They can only be diagnosed by histological examination of colonic biopsies. The pathogenesis is unknown, but may be of an inflammatory possibly autoimmune nature. Others hypothesize that a bacterial toxin or another noxious luminal factor is responsible for the development of the microscopic colitis syndrome. Some studies suggest that NSAIDs may be an etiologic factor in collagenous colitis in a subgroup of patients with this disease. These disorders may be different entities, although some data support the possibility that they are only different manifestations of the same disease. Therapy with 5-aminosalicylate and in severe cases corticosteroids, is successful in most patients. The course of these chronic diseases is commonly benign and is characterized by periods of spontaneous remissions and relapses, but clinical and histopathological resolutions are occasionally seen. On the basis of our own two cases and the literature, these two diseases will be discussed. These patients were admitted to our hospital within a month of each other due to therapy-refractive chronic watery diarrhea. A 70-year-old woman had been suffering from diarrhea for more than ten years. The histological examination produced a diagnosis of collagenous colitis. Lymphocytic colitis was diagnosed from a histological examination in a 30-year-old man who had been suffering from diarrhea for six months. Both received a therapy of mesalazine and the symptoms disappeared within three weeks.

Adult↗
PubMed1996

Epithelioid hemangioendothelioma of the liver. A rare hepatic tumor.

BACKGROUND: Epithelioid hemangioendothelioma (EH) is a rare neoplasm of vascular origin that may develop at different sites, such as in soft tissue, the lungs, or the liver. It usually affects adult females, and its unpredictable malignant potential has a range between benign hemangioma and clearly malignant hemangioendotheliosarcoma. METHODS: In the current study, the authors describe 2 patients with primary EH of the liver and review 127 previously published cases found in the literature. RESULTS: Most patients presented with nonspecific symptoms, such as right upper quadrant abdominal pain or weight loss. The tumors usually presented as multiple nodular lesions involving both lobes of the liver. Overall metastasis rate was 45.1%, with preferential involvement of the lungs and bones. In general, the key to diagnosis was the demonstration of cells containing factor-VIII-related antigen. CONCLUSIONS: EH of the liver is a very rare clinical entity. The primary treatments of choice are radical hepatic resection or orthotopic liver transplantation. The 5-year survival of 55.5% is significantly better than for other hepatic malignancies.

Adult↗
PubMed1996

KAI1 expression is up-regulated in early pancreatic cancer and decreased in the presence of metastases.

KAI1 is a metastasis suppressor gene for prostate cancer that is located on chromosome 11p11.2-13. Using Northern blot analysis and in situ hybridization, we studied expression of KAI1 mRNA in specimens from 14 normal pancreases and 27 primary pancreatic cancers, and then correlated the findings with the clinical and histopathological parameters of the patients. Northern blot analysis showed increased steady-state levels of KAI1 mRNA expression in 24 of 27 (89%) pancreatic cancer samples. In situ hybridization showed enhanced KAI1 mRNA levels in the pancreatic cancer cells in 82% cancer tissues. The stroma surrounding the cancer mass and normal pancreatic tissue adjacent to the cancer cells exhibited very low levels of KAI1 mRNA expression. Correlation of the mRNA levels obtained by Northern blot analysis with clinical parameters of the patients revealed that KAI1 mRNA levels were significantly higher (P < 0.01) in earlier tumor stages (I, II), compared with advanced tumor stages (III, IV) in which lymph node or distant metastases were present. Furthermore, poorly differentiated tumors had significantly higher KAI1 mRNA levels than those that were moderately or well differentiated (P < 0.05). No association between KAI1 expression and survival was found. Our results indicate that KAI1 mRNA expression is reduced in patients with advanced tumor stages. This suggests that reduction of KAI1 expression might enable pancreatic cancer cells to spread in lymph nodes and to distant organs.

Adult↗
PubMed1996

Inhibition of protein kinase C-dependent protein phosphorylation correlates with increased polarity and locomotion in Walker 256 carcinosarcoma cells.

Signal transduction pathways controlling tumor cell locomotion are not yet well understood. We have studied the role of protein kinase C (PKC)-dependent protein phosphorylation associated with changes in cell shape and locomotor activity of Walker carcinosarcoma cells in culture. We show that the inhibitory effect of phorbol-12-myristate-13-acetate (PMA), an activator of PKC, on cell polarity and locomotion can be suppressed by the PKC-selective inhibitor Ro 31-8220. PMA induces increased phosphorylation of at least 2 proteins, of 65 and 80 kDa, in intact Walker carcinosarcoma cells. These bands are enriched in cytosolic fractions isolated from cells incubated with 32PO4. Pre-incubation with Ro 31-8220 inhibits the PMA-induced phosphorylation of both bands in a concentration-dependent manner. This effect is very likely not due to inhibition of translocation of PKC to the membrane as Ro 31-8220 enhances, rather than inhibits, PMA-induced transfer of PKC beta(II) to the particulate fraction. We have carried out a quantitative analysis of phosphorylation of the 80-kDa band. Ro 31-8220 reverses both PMA-induced phosphorylation of this band and PMA-induced suppression of cell polarity in parallel. Increased phosphorylation of proteins via PKC may thus be a stop signal for locomoting Walker carcinosarcoma cells.

Animals↗
PubMed1996

Fibrous tumor-liver interface in large hepatic neoplasms: its significance for tumor resection and enucleation.

Based on the clinical observation that large tumors located in the liver may be resected or enucleated with relative ease, the present retrospective study aimed at the detailed assessment of the tumor/liver interface in large hepatic neoplasms. For this purpose, a systematic light microscopic and immunohistochemical study on resection specimens of 10 giant hemangiomas, 10 hepatocellular carcinomas, and 9 liver metastases was performed. In giant hemangiomas, four distinct interface patterns were identified: fibrous interface (pattern A), interdigitating interface (pattern B), compression interface (pattern C), and irregular/spongy interface (pattern D). In 5 of 10 of these tumors, a single interface type (pattern A) was observed, whereas the other five tumors exhibited a mixed interface type, although two of them had a predominance of pattern A. Overall, 7 of 10 giant hemangiomas were exclusively or partially separated from liver substance by a distinct fibrous interface. Similarly, a fibrous interface of variable thickness and containing remnants of preexisting portal tracts was observed in 18 of 19 malignant epithelial tumors, and in 10 of 18 tumors, this fibrous zone was complete, ie, totally covering the tumor border facing the resection surface. These findings indicate that large hepatic tumors, both benign and malignant, can induce a distinct fibrous interface in a large proportion of cases. We suggest that such an interface, grossly visible as a capsulelike structure, plays a significant role for the resectability of large liver tumors.

Adult↗
PubMed1996

Polymerase chain reaction versus culture for detection of Ureaplasma urealyticum and Mycoplasma hominis in the urogenital tract of adults and the respiratory tract of newborns.

The efficiency of the polymerase chain reaction (PCR) was compared with that of culture for detection of Ureaplasma urealyticum and Mycoplasma hominis in 726 clinical specimens comprising 189 gynecological samples, 362 urological samples, and 175 samples from newborn infants. The sensitivity of PCR versus culture was 95% for both organisms, while the sensitivity of culture versus PCR was 91% for Ureaplasma urealyticum and 84% for Mycoplasma hominis. Furthermore, PCR tests were faster than culture tests, allowing the time to diagnosis to be reduced from two to five days to 24 h.

Adult↗