Biomedical subjects

L Biempica

Publications and source records attributed to L Biempica.

At least 19 recordsLinked to original sources

PubMed1993

Timing of protooncogene expression varies in toxin-induced liver regeneration.

Hepatic expression of the protooncogenes c-fos and c-myc occurs within 2 h after partial hepatectomy, and these immediate early genes are thought to prime the hepatocytes for subsequent proliferation. To examine whether such gene activation occurred in the setting of hepatocyte proliferation after toxic liver injury, protooncogene expression was examined during the regenerative response following liver injury from carbon tetrachloride (CCl4) or galactosamine (GalN). The pattern of protooncogene expression after CCl4 mirrored that seen after partial hepatectomy, with rises in c-fos and c-myc mRNA content within 2 h, and then a rapid return to baseline levels. In contrast, early c-fos and c-myc expression did not occur after GalN injury. Instead GalN-induced regeneration led to a delayed, and prolonged c-fos and c-myc activation which peaked 24-48 h after injury. Increases in c-jun, jun-B, and jun-D mRNA levels also occurred in both models at times similar to the rises of c-fos and c-myc expression. Although the timing of DNA synthesis was identical after GalN or CCl4 treatment, the proliferative response after GalN injury was significantly less than that of CCl4, and marked by the histologic appearance of oval cells. The coadministration of 2-acetylaminofluorene, an inhibitor of differentiated hepatocyte proliferation, together with CCl4 altered the usual pattern of post-CCl4 protooncogene expression to one resembling that seen after GalN injury. Thus, the timing of protooncogene expression during liver regeneration may vary considerably. These variations may influence the nature of the proliferative response in terms of which cell type(s) proliferates, and the amount of regeneration that ensues.

Animals↗

PubMed1992

Unusual patterns of Histoplasma capsulatum meningitis and progressive multifocal leukoencephalopathy in a patient with the acquired immunodeficiency virus.

Disseminated histoplasmosis (DH) and progressive multifocal leukoencephalopathy occur in acquired immunodeficiency syndrome (AIDS). At autopsy, DH patients with central nervous system involvement almost always show extensive involvement of the lungs and reticuloendothelial system in addition to the brain, and progressive multifocal leukoencephalopathy is manifest as multiple demyelinating lesions in several locations in the brain. We describe an AIDS patient with a long history of aggressively treated DH who died with DH in the brain only; fungus was not found elsewhere at autopsy. In addition, there was a papovavirus infection restricted to the cerebellum with predominant involvement of the internal granular cell layer; again, demyelinating lesions were not found elsewhere in the brain. Each of these patterns of brain involvement is rare. As the incidence of AIDS increases and patients are treated aggressively, the frequency of unusual neuropathologic patterns of opportunistic infections may be expected to increase.

Acquired Immunodeficiency Syndrome↗

PubMed1992

The effects of hepatic fibrosis on Ito cell gene expression.

While Ito cells appear to be a major source of increased matrix synthesis during hepatic fibrogenesis, the cellular changes that occur in these cells during liver fibrosis have not been well delineated. In this study we examined Ito cell gene expression in isolated cells from normal rats, and rats with carbon tetrachloride-induced fibrosis, in order to better define the changes occurring in these cells during this pathologic process. Specifically, we addressed three questions: (1) which matrix genes are over expressed in Ito cells in fibrotic liver; (2) do these cells increase their expression of the fibrogenic cytokine transforming growth factor-beta 1 (TGF-beta 1); and (3) do Ito cells change their phenotype during hepatic fibrogenesis as reflected by alterations in the expression of their intermediate filament genes? Northern hybridization analysis revealed that Ito cells isolated from fibrotic livers had significant increases in mRNA levels of types I, III and IV procollagen compared to normal cells, while no increases were found in hepatocytes, and Kupffer/endothelial cells had only an increase in type I procollagen mRNA. Analysis of other matrix proteins which increase during hepatic fibrogenesis revealed elevations in laminin B and fibronectin mRNA levels only in Ito cells. Increased Ito cell matrix gene expression was also associated with a 4-fold increase in TGF-beta 1 levels in these cells. No increase in TGF-beta 1 mRNA was found in hepatocytes, and less than a 2-fold increase was found in Kupffer/endothelial cells isolated from fibrotic livers.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Selective amplification of periportal transitional cells precedes formation of hepatocellular carcinoma in SV40 large tag transgenic mice.

In a major urinary protein (MUP)-promoter/simian virus 40 (SV40)Tag transgenic mouse line (MT-D2) the liver-directed, androgen-regulated transgene expression leads to synchronized pathology resulting in a stepwise progression to multiple hepatocellular carcinomas. SV40Tag-activated replication gives rise to two different preneoplastic alterations in hepatocytes, which are characterized in detail: 1) dysplasia and finally cell death in the original hepatocyte population and 2) amplification of periportal transitional hepatocytes leading to multifocal hyperplasia and hepatocellular carcinoma. Multifocal hyperplasia, most probably the equivalent of SV40Tag-immortalization, grows confluent and leads to hepatomegaly. SV40Tag-independent, secondary events are necessary for the tumor development from confluent hyperplasia. This allows further investigation of the steps involved in malignant transformation and progression during hepatocarcinogenesis in vivo.

Animals↗

PubMed1990

Clinical utility of liver biopsy in patients with serum antibodies to the human immunodeficiency virus.

PURPOSE: Patients with the acquired immunodeficiency syndrome (AIDS) frequently have liver dysfunction, which may be due to a number of causes. Determination of the patients who are likely to benefit from liver biopsy, an invasive procedure, is therefore important. In this study, the results of liver biopsy in patients with AIDS were compared to those in human immunodeficiency virus (HIV)-infected patients without AIDS. PATIENTS AND METHODS: Thirty-six consecutive patients with antibodies to HIV present in the serum underwent liver biopsy from 1984 through 1988 at the Bronx Municipal Hospital. Twenty (56%) of the patients had AIDS diagnosed prior to the liver biopsy. Indications for the liver biopsy were unexplained fever in 83%, and abnormal serum levels of biochemical parameters of liver function in 89%. RESULTS: Liver biopsy was diagnostic in 18 cases (50%), including findings of hepatic infection by mycobacteria in 15, cytomegalovirus in two, and schistosoma in one; these infections had been previously detected at an extrahepatic site in only two cases. Helpful clinical information in 10 others included findings of granulomas of undetermined etiology in four, cirrhosis in five, and chronic persistent hepatitis in one. Patients with a diagnostic biopsy, as compared to patients with a nondiagnostic biopsy, had a statistically significant increase in the frequency of having AIDS diagnosed before the biopsy, longer duration of AIDS (in patients with AIDS diagnosed before the biopsy), greater number of different prior opportunistic infections, and a more elevated serum alkaline phosphatase level. For example, 70% of patients with AIDS, as compared to 25% of patients with serum antibodies to HIV but without AIDS, had diagnostic liver biopsies. Patients with a diagnostic biopsy also had statistically significantly more frequent pulmonary symptoms, possibly due to more frequent occurrence of Pneumocystis carinii pneumonia. In particular, the 15 patients with hepatic mycobacterial infection, as compared to the other patients, had a statistically significant increase in the frequency of having AIDS diagnosed prior to the biopsy, longer duration of AIDS, more frequent prior opportunistic infections, more severe leukopenia, and a more elevated serum alkaline phosphatase level. Liver biopsy was more sensitive than bone marrow aspiration and biopsy at detecting mycobacterial infection. CONCLUSION: Liver biopsy, when indicated, is useful to detect opportunistic infection in HIV-infected patients who are not known to have AIDS.

Acquired Immunodeficiency Syndrome↗

PubMed1990

Two rat models of hepatic fibrosis. A morphologic and molecular comparison.

We present a morphologic and molecular comparison of two models of hepatic fibrosis. Immune complexes are the source of insult in one model. In the other model, CCl4 induces fibrosis. For the immune complex model, rats were immunized intraperitoneally over the course of 4 weeks with human albumin, then injected through a tail vein three times a week for at least 5 more weeks with the same albumin. Seventy-five percent of all treated animals developed fibrosis characterized by fine collagen bands. There was a mild degree of hepatocyte trapping and necrosis as well as some bile duct hyperplasia and tissue eosinophilia. However, there was no significant Kupffer cell hyperplasia or inflammatory reaction. Quantification of specific mRNA species was determined by Northern blot hybridization analysis of total RNA. In comparison with CCl4-induced fibrosis in rats, a hepatotoxin-mediated model with a much greater inflammatory response, this immune complex model showed a less pronounced increase in type I procollagen mRNA, but a relatively greater increase in types III and IV procollagen mRNA. Whereas transforming growth factor-beta 1 mRNA levels were markedly increased in CCl4-induced fibrosis, there was only a slight increase in this cytokine, known to stimulate type I collagen synthesis, in the immune complex model. A comparison of the two model systems indicates that a variety of mechanisms may be involved in the process of hepatic fibrogenesis. It appears that an inflammatory response and elevated transforming growth factor-beta 1 levels are associated with a marked increased synthesis of type I collagen in a hepatotoxin model while other, as yet undefined, mediators may be responsible for the increase in types III and IV procollagen mRNA species found in the immune complex model.

Animals↗

PubMed1989

Gamma-interferon treatment inhibits collagen deposition in murine schistosomiasis.

Since interferons have been shown to affect the synthesis of matrix proteins such as collagen in several in vitro systems, the potential role of gamma-interferon in inhibiting hepatic fibrosis was investigated. Hepatic cells, consisting primarily of hepatocytes, were treated with recombinant gamma-interferon for 24 hr. Northern blot hybridization showed that gamma-interferon treatment caused a profound decrease in pro-alpha 2(I)collagen mRNA levels but an increase in beta-actin mRNA content. The effects of gamma-interferon were then studied in an in vivo model of hepatic fibrogenesis, murine schistosomiasis. Schistosoma-infected mice were treated with daily i.m. injections of gamma-interferon for a 4-week period starting 4 weeks after the initial infection. gamma-Interferon treatment decreased collagen deposition as determined by histologic evaluation and measurement of total liver collagen content. Northern blots showed Types I and III procollagen mRNA levels for treated, infected animals to be only 32 and 29% that of infected controls, but beta-actin mRNA levels were significantly elevated. These results indicate a potential role for gamma-interferon as an antifibrogenic agent in vivo.

Actins↗

PubMed1989

In vitro and in vivo association of transforming growth factor-beta 1 with hepatic fibrosis.

Despite extensive efforts, little progress has been made in identifying the factors that induce hepatic fibrosis. Transforming growth factor-beta (TGF-beta) has been shown to enhance collagen production, therefore its role in hepatic fibrosis was investigated. Treatment of cultured hepatic cells with TGF-beta 1 increased type I procollagen mRNA levels 13-fold due to post-transcriptional gene regulation. When two animal models of hepatic fibrosis, murine schistosomiasis and CCl4-treated rats, were examined, they both exhibited increased levels of TGF-beta 1 gene expression at times that somewhat preceded the increase in collagen synthesis. In contrast, in murine schistosomiasis, mRNA levels of tumor necrosis factor and interleukin-1 peaked early in the fibrogenic process. Immunohistochemical analysis showed TGF-beta 1 to be present in normal mouse liver and to be markedly increased in mice infected with schistosomiasis. TGF-beta 1 appeared in the hepatic parenchyma, primarily in hepatocytes. These findings strongly suggest a role for TGF-beta 1 in a pathophysiological state.

Animals↗

PubMed1989

Esophageal perforation at a Barrett's ulcer.

An alcoholic man with known reflux esophagitis and Barrett's esophagus developed fever, epigastric pain, subcutaneous crepitus, and leukocytosis from an esophageal perforation at a Barrett's ulcer. Possible risk factors for perforation in this patient included alcoholism, severe gastroesophageal reflux, corticosteroid therapy, noncompliance with antacid and H2 blocker therapy, and the presence of acid-secreting parietal cells in the Barrett's epithelium. Five cases of this complication have previously been reported in a review of the literature, which included 536 cases of Barrett's esophagus or esophageal perforation. This entity may present with a clinical triad of a patient (a) in acute distress with fever and epigastric or noncardiac chest pain and without signs of peritonitis, (b) with symptoms of or known gastroesophageal reflux, and (c) with chest examination revealing subcutaneous crepitus, or chest roentgenogram revealing subcutaneous emphysema, pneumomediastinum, or hydropneumothorax.

Adult↗

PubMed1989

Expression of tumor necrosis factor-alpha and transforming growth factor-beta 1 in acute liver injury.

Tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta 1 (TGF-beta 1) have a number of in vitro functions that could be important in vivo in acute liver injury and repair. Therefore, we investigated these two cytokines in acute liver damage. Northern blots of RNA isolated from rats sacrificed at various time intervals after a single oral dose of CCl4 revealed that TNF-alpha mRNA levels were elevated within 6 hr of CCl4 administration and returned to control values by 24-32 hr. In contrast, TGF-beta 1 mRNA levels started to rise significantly at 24 hr, peaked at 48 hr, and approached baseline levels by 72 hr. Identical changes in TNF-alpha and TGF-beta 1 mRNA levels were also seen with D-galactosamine-induced hepatotoxicity. Immunohistochemical analysis using a TGF-beta 1 antibody demonstrated increased hepatic staining in CCl4-treated rats, at times corresponding to the increases in TGF-beta 1 gene expression. Therefore, there is a differential expression of these cytokines in acute CCl4 and galactosamine hepatotoxicity with an early rise in TNF-alpha, suggesting that this cytokine may affect inflammation and cell toxicity, while TGF-beta 1 peaks later, when it may regulate hepatocyte proliferation and extracellular matrix repair.

Acute Disease↗

PubMed1989

Terminal ileitis associated with cytomegalovirus and the acquired immune deficiency syndrome.

A 41-yr-old homosexual male had cytomegalovirus infection localized to the terminal ileum as his initial and sole evident opportunistic infection due to the acquired immune deficiency syndrome. The symptoms, signs, roentgenographic findings, and appearance at surgery were suggestive of Crohn's disease. The pathogen was identified only by microscopic examination of bowel resected during a second laparotomy. The terminal ileum had profound mucosal ulceration and transmural fibrosis without granulomas. This novel report suggests that cytomegalovirus infection should be carefully searched for in immunocompromised patients presenting with clinical features suggesting Crohn's disease.

Acquired Immunodeficiency Syndrome↗

PubMed1988

Insulinlike growth factor II expression and oval cell proliferation associated with hepatocarcinogenesis in woodchuck hepatitis virus carriers.

Insulinlike growth factor II (IGF-II) is a highly mitogenic fetal growth factor suspected of regulating the growth of a wide spectrum of tissues via an autocrine or paracrine mode of action or both. High steady-state levels of IGF-II RNA were detected in 45% of hepatocellular carcinomas (HCCs) arising from woodchuck livers with persistent woodchuck hepatitis virus (WHV) infection. Analysis of WHV RNA in the same HCCs revealed that HCCs with high levels of IGF-II RNA contained low or undetectable levels of WHV RNA and HCCs with low levels of IGF-II RNA contained high levels of WHV RNA. Integrated WHV DNA was present in HCCs from both groups, but viral DNA replicating forms were present, predominantly in HCCs with low levels of IGF-II. Several IGF-II RNAs, the most prominent of which were poly(A) species of approximately 3.75 and 1.1 to 1.3 kilobases, were detected only in precancerous nodules and HCCs. Levels of IGF-II were elevated two- to three-fold in the serum of woodchucks with chronic active hepatitis preceding the occurrence of HCC. Proliferation of a population of oval cells, which arise from portal tract regions in the liver, preceded the development of HCC and was a prominent feature of livers from which tumors with high levels of IGF-II occurred. The HCCs tended to have distinct histological features according to their growth factor status. Tumors with low levels of IGF-II were generally highly differentiated acinar-trabecular HCCs, whereas tumors with high levels of IGF-II were more anaplastic, with regions of fibrosis and fatty accumulation. A model to relate the pathology of WHV infection to oval cell proliferation and IGF-II expression in the development of these heterogeneous HCCs is presented.

Animals↗

PubMed1988

Morphologic and chemical studies on a murine mutation (toxic milk mice) resulting in hepatic copper toxicosis.

The accumulation of excessive amounts of copper in the livers of toxic milk mice results in gross morphologic, histologic, and ultrastructural changes that are progressive with age even though the concentrations of copper tend to decrease in mice older than 6 months. Striking differences in morphologic integrity between regenerative nodules and the intervening parenchyma were observed. Profound changes in mitochondria, endoplasmic reticulum, and nuclei as well as accumulation of microvesicular lipid droplets were observed in injured hepatocytes. By contrast, the hepatocytes of regenerative nodules appeared well preserved. Comparisons with other inherited mammalian disorders associated with hepatic copper toxicosis indicate that copper causes species specific organelle injury.

Animals↗

PubMed1987

Transcriptional and posttranscriptional effects of dexamethasone on albumin and procollagen messenger RNAs in murine schistosomiasis.

We have previously shown that dexamethasone increases albumin mRNA and decreases procollagen steady-state mRNA levels in rat hepatocyte cultures. These studies were extended by evaluating an in vivo model of fibrogenesis (murine schistosomiasis) and by determining a more precise level of gene expression responsible for these changes. Control mice and litter mates infected with Schistosomiasis mansoni were evaluated at 8 weeks postinfection when the livers of the infected mice had become fibrotic and their serum albumin levels significantly decreased. The addition of 4 micrograms/mL dexamethasone to the drinking water of half of the infected mice led to a 75% decrease in the liver collagen content as determined by high-performance liquid chromatography. RNA was extracted from the livers of mice under three conditions: control and infected +/- dexamethasone. This RNA was then hybridized with cDNA probes to determine steady-state levels of specific mRNAs. In the infected mice, albumin mRNA levels were decreased compared to control; however, infected mice treated with dexamethasone increased their albumin mRNA content by 3-fold at 8 weeks. Types I and IV procollagen steady-state mRNA levels in infected mice were increased compared to control while dexamethasone suppressed the mRNA level of collagen in infected mice by 50%. The level of gene expression responsible for these steady-state changes was evaluated by nuclear run-on analysis. While the effect of schistosomiasis on these genes was primarily at a transcriptional level, dexamethasone exerted its effect on different genes in the injured liver by diverse mechanisms, i.e., decreasing collagen synthesis at a transcriptional level and increasing albumin by posttranscriptional mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Transcriptional switch from albumin to alpha-fetoprotein and changes in transcription of other genes during carbon tetrachloride induced liver regeneration.

During liver regeneration induced by CCl4 administration to rats, changes in the relative transcription rates of albumin and alpha-fetoprotein genes have been measured in conjunction with other liver-specific and general cellular function genes. Within 24 h following CCl4 administration, albumin gene transcription decreases by 85%, whereas alpha-fetoprotein transcription increases from undetectable levels to 50% of that observed for albumin. These changes precede maximal [3H]thymidine incorporation into DNA which peaks at 48 h. Other genes related to liver-specific functions, such as ligandin, alpha 1-antitrypsin, and cytochrome P-450's, as well as general cellular genes pro alpha 1- and pro alpha 2-collagen, beta-actin, and alpha-tubulin, respond in kinetic patterns often distinct from each other and from albumin and alpha-fetoprotein. Changes in the steady-state levels of albumin and alpha-fetoprotein mRNA correlate with changes in transcription, but there is a lag in alpha-fetoprotein mRNA accumulation, which peaks at 72 h following CCl4 administration. These studies indicate that reciprocal changes in albumin and alpha-fetoprotein gene transcription occur during CCl4-induced liver regeneration, leading to changes in the level of these specific mRNAs. These changes precede DNA synthesis and would appear to represent an alteration in differentiated function of hepatocytes in conjunction with the liver regenerative process.

Actins↗

PubMed1986

Collagenase and elastase production by mouse mammary adenocarcinoma primary cultures and cloned cells.

We have shown previously that an increase in tumor invasion and metastases occurred concurrently with a decrease in collagen content of the extracellular matrix surrounding the C3H mouse mammary adenocarcinoma borne by C3H/HeJ mice. In this paper we report the production of collagenase and elastase activities by the primary tumor cultures and three types of cloned C3H mouse mammary adenocarcinoma cell cultures. The primary tumor cell cultures and tumor-associated stromal cultures produced large amounts of collagenase and elastase activities. On the other hand, the primary tumor capsule cultures produced little or no collagenase and elastase activities even though they produced type I collagen. The production of proteases by the primary tumor cultures decreased along with time and with an alteration in the morphology of cell populations and/or passage of the cultures. The three clones of tumor cell cultures produced variable amounts of collagenase in response to induction by phorbol myristate acetate, an agent that stimulates maximal collagenase production. In contrast, all three cloned cultures elaborated significant amounts of elastase that degraded insoluble ligamental elastin, and most of the elastase production was increased further in response to induction by phorbol myristate acetate. Each cloned cell population exhibited differences in their production of collagenase and elastase in parallel with their difference in growth kinetics, yet these cells still possess the distinctive properties of the tumor. However, a unit amount of collagenase produced by each of the cloned cultures, with or without induction by phorbol myristate acetate, was less than that of the primary tumor cultures. Results suggest that some cell types or combination of cell types in the heterogeneous cell population of the tumor and/or their products appear to be responsible for the increased production of collagenase and elastase activities and for the invasiveness of a malignant tumor.

Adenocarcinoma↗

PubMed1985

Effects of vitamin A and dexamethasone on collagen degradation in mouse mammary adenocarcinoma.

Collagenases and other neutral proteases in tumors may facilitate tumor extension, invasion, and subsequent metastasis. We report the effects of vitamin A and dexamethasone, known inhibitors of collagenase production in vitro, on the collagen metabolism of mouse mammary adenocarcinoma and its capsule, borne by C3H/HeJ mice. The weight of the capsule was about 4% of the tumor, yet the total collagen content of the capsule was about 10-fold greater than that of the tumor tissue; tumor cells had no detectable collagen. With tumor growth, the collagenase and other neutral protease activities were increased in the tumor tissue; a negative correlation existed between collagenase activity and collagen content of the capsule. The protease activities of the tumor borne by vitamin A-treated hosts were about 50% lower than those of the controls; this coincided with a slight increase in the collagen content of the capsule. In contrast, the collagen content of the capsule borne by dexamethasone-treated hosts was 50% less than that of the controls; the protease activities were similar to the controls and occurred with tumor invasion and metastasis. Results suggest that the collagen metabolism of the capsule may be an indicator of proteolytic events within the tumor and the metastatic potential of the tumor that, in turn, suggests the possibility of preventing metastasis by inhibiting the production of collagenases and other neutral proteases, thereby localizing the tumor cells within the capsule. Vitamin A could be used for that purpose.

Adenocarcinoma↗

PubMed1985

Bile duct carcinoma in an adolescent.

Bile duct carcinoma is a relatively uncommon lesion that usually presents in the 6th to 7th decade. The only prior reported cases under the age of 20 were two patients with diseases known to predispose to the development of this tumor. We report a case of a 17-year-old girl with a bile duct tumor without any known predisposing factors.

Adenocarcinoma↗