Search PubMed⌕ Search

Biomedical subjects

J Rosenbaum

Publications and source records attributed to J Rosenbaum.

At least 55 records · Page 3Linked to original sources
PubMed1997

Extracellular matrix composition and integrin expression in early hepatocarcinogenesis in human cirrhotic liver.

Extracellular matrix (ECM) plays a major role in cell differentiation, proliferation, and gene expression, both in physiological and in pathological conditions. Immunohistochemistry has been used to investigate modifications of ECM and related receptors, the integrins, in 26 small nodular lesions developed in human cirrhotic livers, on the basis that these lesions could represent sequential steps of hepatocarcinogenesis: the lesions were 16 macroregenerative nodules (MRNs), either of ordinary (n = 5) or atypical (n = 11) type, and ten small (< 15 mm) hepatocellular carcinomas (HCCs). Data were compared with those obtained in the surrounding cirrhotic tissue, in large HCCs, and in normal liver. The results indicate similarities between ordinary MRNs and cirrhosis, on the one hand, and between atypical MRNs and small HCCs, on the other. Strong and homogeneous deposition of collagen type IV and laminin in sinusoids and overexpression of alpha 6 integrin by sinusoidal cells and hepatocytes were especially noticeable in dysplastic areas characteristic of atypical MRNs, as in small HCCs. In addition, the staining of alpha 2 and alpha 6 integrins in MRNs revealed the presence of widespread atypical ductular proliferation expanding from periportal and perinodular areas, containing epithelial cells with transitional (hepato-biliary) phenotype. These findings suggest a transition from atypical MRNs to small HCCs and a possible role for liver epithelial precursor cells ('stem cells') in the development and evolution of MRNs.

Carcinoma, Hepatocellular↗
PubMed1997

Pentoxifylline inhibits growth and collagen synthesis of cultured human hepatic myofibroblast-like cells.

During the course of liver fibrogenesis, myofibroblast-like cells (MFLC), mostly derived from hepatic stellate cells, proliferate and synthesize excessive amounts of extracellular matrix components. Pentoxifylline (PTX) elicits antiproliferative and antifibrogenic effects in human dermal fibroblasts. The aim of this study was to test the effects of PTX on the proliferation and the synthesis of collagen and gelatinase A in cultured human hepatic MFLC. MFLC were obtained by outgrowth from human liver explants. PTX markedly reduced serum-driven cell proliferation, as assessed by nuclear autoradiography experiments and measurement of actual cell growth. Growth inhibition was totally reversed after removal of the drug. PTX also affected collagen synthesis, as measured by [3H]hydroxyproline incorporation into proteins. Synthesis of secreted collagen was reduced by 24% and 67% at concentrations of 100 microg/mL and 500 microg/mL, respectively. This was associated with a decrease in type I and III procollagen messenger RNA (mRNA), indicating an effect at a pretranslational level. In contrast, PTX did not affect either gelatinase A activity released in culture medium or the expression of its specific mRNA. In conclusion, PTX exhibits potent antiproliferative and antifibrogenic effects toward hepatic MFLC. These results suggest that PTX might have therapeutic implications in chronic liver disease.

Cell Division↗
PubMed1997

Tumor-dependent activation of rodent hepatic stellate cells during experimental melanoma metastasis.

In this work we report the presence of intrametastatic smooth-muscle iso-alpha-actin (SMA)-expressing cells which appeared from the early stages of the hepatic metastasis process of intrasplenically injected B16 melanoma (B16M) cells. They formed a network of stromal cells among B16M cells, a very low percentage of them expressing desmin. In contrast, those parts of liver tissue unaffected by metastasis had perisinusoidal desmin-expressing quiescent hepatic stellate cells (qHSC) which did not express SMA. Exposure of freshly isolated rat quiescent hepatic stellate cells (qHSC) to B16M cell-conditioned medium (B16M-CM) leads to a progressive increase (P < .01) in the number of SMA-expressing cells, which was accompanied by a parallel reduction in the number of desmin-expressing cells. In addition, B16M-CM also contained chemotactic factor(s) which significantly (P < .01) increased (50%) in vitro qHSC migration and stimulated both [3H]thymidine and [3H]glucosamine uptake in qHSC. Moreover, B16M-CM also significantly (P < .01) enhanced qHSC secretion of matrix metalloproteinase-2 (MMP-2), and unknown chemotactic factor(s) enhancing in vitro migration of B16M cells. The results suggest that B16 melanoma releases qHSC-activating factors, which induce the appearance of metastasis-infiltrating myofibroblasts by a paracrine mechanism. Such cells showed cytoskeletal alterations which are associated with enhanced proliferation, glycosaminoglycan synthesis, MMP-2 secretion, and tumor-chemotactic factor production. Thus, tumor-activated qHSC may play an important role in melanoma cell motility and invasion during hepatic metastasis progression.

Actins↗
PubMed1997

Human hepatic myofibroblasts increase invasiveness of hepatocellular carcinoma cells: evidence for a role of hepatocyte growth factor.

The stroma of hepatocellular carcinomas (HCC) is infiltrated with myofibroblasts (MFs). Preliminary in vivo data have suggested that liver MF express hepatocyte growth factor (HGF), a cytokine that has been implicated in several tumor models. Our aim was to investigate the role of MF and HGF in HCC. Cultured liver MF expressed HGF messenger RNA (mRNA) and secreted HGF in their medium, as shown by Western blot, immunoprecipitation, and enzyme-linked immunosorbent assay (ELISA). Addition of MF-conditioned medium to the HepG2 HCC cell line induced cell scattering. This was associated with a decrease in cell proliferation. MF also increased about 100-fold the ability of HepG2 to invade Matrigel. Increased invasiveness was also shown for HuH7 cells, but no scattering was observed and cell proliferation was stimulated. All the effects of MF on both tumor cell types were blocked by addition of an antibody to HGF and they all could be reproduced by adding recombinant HGF to the tumor cells. RT-PCR and Western blot analysis confirmed that both tumor cell lines expressed c-met, the receptor for HGF. The effects of MF-conditioned medium were not reproduced by acidic fibroblast growth factor, basic fibroblast growth factor, epidermal growth factor (EGF), transforming growth factor-beta1 (TGF-beta1), or platelet-derived growth factor (PDGF-BB). Reverse transcription-polymerase chain reaction (RT-PCR) analysis confirmed that HGF was expressed in human HCC. Our data show that human liver MF act on HCC cells to increase their invasiveness and suggest that MF-derived HGF could be involved in the pathogenesis of HCC.

Actins↗
PubMed1997

Double-blind comparison of sertraline, imipramine, and placebo in the treatment of dysthymia: psychosocial outcomes.

OBJECTIVE: The purpose of this study was to determine the effects of antidepressant pharmacotherapy on mood symptoms and psychosocial outcomes in dysthymia. METHOD: In a multicenter, double-blind, parallel-group trial, 416 patients with a diagnosis of early-onset primary dysthymia (DSM-III-R) of at least 5 years' duration without concurrent major depression were randomly assigned to 12 weeks of acute-phase therapy with sertraline, imipramine, or placebo. The psychosocial outcome measures used in the study were the Global Assessment of Functioning Scale, the Social Adjustment Scale, the Longitudinal Interval Follow-up Evaluation psychosocial ratings, and the Quality of Life Enjoyment and Satisfaction Questionnaire. RESULTS: Sertraline and imipramine were significantly better than placebo in improving psychosocial outcomes as measured by the first three instruments. The Quality of Life Enjoyment and Satisfaction Questionnaire scores demonstrated significant improvements from baseline, and both active treatments produced significantly greater improvements than placebo. Significantly fewer patients discontinued sertraline (6.0%) than discontinued imipramine (18.4%) because of adverse events. CONCLUSIONS: Pharmacotherapy is an effective treatment for dysthymia in terms of psychosocial functioning as well as depressive symptoms, even when the dysthymia is long-standing.

1-Naphthylamine↗
PubMed1997

Characterization of a new human liver myofibroblast cell line: transcriptional regulation of plasminogen activator inhibitor type I by transforming growth factor beta 1.

Myofibroblasts (MF) are a major effector cell type in liver fibrogenesis, where they are thought to derive from the activation of hepatic stellate cells. Cultured human MF, grown from liver explants, retain most of the in vivo characteristics of liver MF but are in limited supply. A continuous MF cell line would therefore be valuable in studying human liver fibrogenesis. For this purpose, we sought to immortalize human liver MF with polyoma virus large T antigen. MF were obtained from explants of human liver and transfected with a plasmid containing the coding sequence of polyoma virus large T antigen. This procedure yielded an activity growing cell line, designated GREF-X, which did not express large T antigen. Nevertheless, this cell line has been passaged repeatedly for almost 1 year and is thus likely immortalized. The morphology of GREF-X resembles that of primary liver MF. These cells have a doubling time of approximately 72 hours and are density-inhibited, and their growth is serum-dependent. Moreover, GREF-X cells do not grow in soft agar or induce tumors in nude mice, suggesting that they are not transformed. They stain positively for MF markers, such as smooth muscle alpha-actin and vimentin; express collagens type I, IV, V, and VI, fibronectin, and laminin: and secrete matrix-metalloproteinase-2. In addition, GREF-X cells are able to take up and esterify [3H]retinol, suggesting that they actually derive from hepatic stellate cells. Finally, these cells respond to transforming growth factor-beta 1, a major mediator of liver fibrogenesis, by increasing secretion of fibronectin and plasminogen activator-inhibitor type 1. Transient transfection experiments showed that plasminogen activator-inhibitor type 1 regulation, by transforming growth factor-beta 1, was transcriptional. We believe, therefore, that GREF-X would be a useful tool for studying the pathophysiology and pharmacology of liver fibrogenesis.

Actins↗
PubMed1997

Osteonectin (SPARC) expression in human liver and in cultured human liver myofibroblasts.

Osteonectin/SPARC is a glycoprotein involved in the regulation of cell shape, adhesion, migration, and proliferation. It also has complex effects on extracellular matrix synthesis and turnover. We found that osteonectin mRNA was very abundant in a human liver myofibroblast library. Using Northern and Western blot, immunoprecipitation, and radioimmunoassay, we found that cultured liver myofibroblasts actively secreted osteonectin. Myofibroblasts are very rare in normal liver but proliferate during liver fibrosis where they synthesize extracellular matrix components. Thus, we studied the distribution of osteonectin in normal and fibrotic human liver using in situ hybridization. Osteonectin mRNA expression was weak in normal liver but very high in fibrotic liver within fibrous septae and scattered sinusoidal cells. Serial sectioning and double staining experiments with an antibody to smooth muscle alpha-actin showed that osteonectin transcripts were mostly co-localized with myofibroblasts. In conclusion, osteonectin is highly expressed in human liver myofibroblasts in culture as well as in human liver fibrosis in vivo. The many biological properties of osteonectin make it a candidate effector of human liver fibrogenesis.

Actins↗
PubMed1996

TRH stimulation test as a predictor of acute and long-term antidepressant response in major depression.

We assessed the prognostic utility of the TRH stimulation test by examining (a) the relationship between pre-treatment delta TSH and acute response to fluoxetine treatment, and (b) the relationship between the change in delta TSH (delta delta TSH value) after repeated TRH testing at 6 weeks of fluoxetine treatment and long-term outcome during maintenance fluoxetine or placebo therapy. 43 MDD patients were studied with sequential TRH tests at 6-week intervals. Fluoxetine 'responders' were defined as patients with a Hamilton Depression Rating Scale score < or = 7 by week 9 of treatment and who remained in remission at least 3 additional weeks. These subjects were then randomized to one of four fluoxetine/placebo treatment groups and long-term outcome assessed. Overall, there was no difference in the mean pre-treatment delta TSH values between acute fluoxetine responders and nonresponders. Moreover, we observed similar delta delta TSH values in patients who maintained long-term remission compared to those who relapsed during maintenance with either fluoxetine or placebo. In contrast to prior reports of an higher delta delta TSH value in long-term remitters, the present observation of similar mean delta delta TSH values patients with long-term remission compared to those who relapsed suggest a limited prognostic utility for the TRH stimulation test in MDD.

Adult↗
PubMed1996

A placebo-controlled, randomized clinical trial comparing sertraline and imipramine for the treatment of dysthymia.

BACKGROUND: Despite the high prevalence of dysthymia and its associated morbidity, few controlled trials have evaluated the efficacy of antidepressant medication for this disorder. A 12-week, double-blind, placebo-controlled, randomized, multicenter trial was performed to evaluate the safety and efficacy of sertraline hydrochloride and imipramine hydrochloride in treating dysthymia. METHODS: A total of 416 outpatients (271 women and 145 men) aged 25 to 65 years with DSM-III-R-defined, early-onset, primary dysthymia without concurrent major depression were randomized to 12 weeks of treatment with sertraline, imipramine, or placebo. RESULTS: Both active treatments resulted in significantly reduced scores on the 17-item Hamilton Rating Scale for Depression (P = .04 and P = .01 for sertraline and imipramine vs placebo, respectively), the Montgomery-Asberg Depression Rating Scale (P = .01 and P = .003 vs placebo, respectively), Hopkins Symptom Checklist (P < .05), and the self-rated version of the Inventory of Depressive Symptoms (P < .05). With the use of a Clinical Global impressions improvement score of 1 or 2 (very much or much improved) to define response, response rates were 59% for sertraline, 64% for imipramine, and 44% for placebo (P = .02 for sertraline vs placebo and P < .001 for imipramine vs placebo). A significantly greater proportion of patients receiving imipramine than those receiving sertraline or placebo discontinued treatment because of adverse events (P = .001 and P < .001, respectively). CONCLUSIONS: Pharmacotherapy provides considerable relief from the symptoms of dysthymia in patients suffering from this chronic affective disorder, with both sertraline and imipramine being more effective than placebo. The greater tolerability of sertraline is an important consideration because of the chronicity of dysthymia, which may require prolonged treatment with antidepressant medication.

1-Naphthylamine↗
PubMed1996

Heparan sulfate proteoglycan expression in chronic cholestatic human liver diseases.

The mechanism of bile ductular reaction and accompanying fibrogenesis depends on interactions of ductular cells with the matrix and growth factors. Heparan sulfate proteoglycans (HSPGs) are essential cofactors in cell-matrix adhesion processes, in cell-cell recognition systems, and in receptor-growth factor interactions. We used monoclonal antibodies specific for the cell surface HSPGs (syndecans, glypican), for matrix HSPG (perlecan), and for heparan sulfate carbohydrate (HS) to investigate their immunohistochemical expression in 20 specimens with chronic cholestatic liver disease and in five normal human liver specimens. Because activated hepatic stellate cells (HSC are a major source of fibrosis in the liver, we also examined HSPG expression in primary cultures of human activated HSC using immunocytochemistry and Western blotting and for syndecan-1 also Northern blotting. In comparison with bile ductular cells of normal liver, reactive ductules in chronic cholestasis were marked by an elevated expression of syndecan-1, surrounded by an increased perlecan expression. In acinar zone 1, large stimulated macrophages and HSC, present in increased numbers, were strongly positive for syndecan-3. Cultured HSC showed a membranous staining pattern for syndecan-1, syndecan-3, and heparan sulfate, and in addition intracellular staining for syndecan-2, -3, and 4. Perlecan immunoreactivity was detected as intercellular strings. Western blotting revealed positive bands with all antibodies and Northern blotting for syndecan-1 was also positive. These results show that cultured human HSC can synthesize all four syndecans, glypican, and perlecan. These data reveal changes in the expression of syndecan-1, syndecan-3, and perlecan in human chronic cholestatic liver disease, that may be important in the deposition of matrix components and activation of growth factors that support ductular reaction and accompanying fibrogenesis.

Antibodies, Monoclonal↗
PubMed1996

The use of theory based semistructured elicitation questionnaires: formative research for CDC's Prevention Marketing Initiative.

Through one of its many HIV prevention programs, the Prevention Marketing Initiative, the Centers for Disease Control and Prevention promotes a multifaceted strategy for preventing the sexual transmission of HIV/AIDS among people less than 25 years of age. The Prevention Marketing Initiative is an application of marketing and consumer-oriented technologies that rely heavily on behavioral research and behavior change theories to bring the behavioral and social sciences to bear on practical program planning decisions. One objective of the Prevention Marketing Initiative is to encourage consistent and correct condom use among sexually active young adults. Qualitative formative research is being conducted in several segments of the population of heterosexually active, unmarried young adults between 18 and 25 using a semistructured elicitation procedure to identify and understand underlying behavioral determinants of consistent condom use. The purpose of this paper is to illustrate the use of this type of qualitative research methodology in designing effective theory-based behavior change interventions. Issues of research design and data collection and analysis are discussed. To illustrate the methodology, results of content analyses of selected responses to open-ended questions on consistent condom use are presented by gender (male, female), ethnic group (white, African American), and consistency of condom use (always, sometimes). This type of formative research can be applied immediately to designing programs and is invaluable for valid and relevant larger-scale quantitative research.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Morphology of hepatic stellate cells in patients with fulminant or subfulminant hepatitis requiring liver transplantation.

Hepatic stellate cells were studied by immuno-cytochemistry with anti smooth muscle alpha-actin antibody (an activation marker for these cells) and electron microscopy, in eleven patients transplanted for fulminant or subfulminant hepatitis. Numerous smooth muscle alpha-actin positive cells were found in necrotic areas. In both fulminant and subfulminant hepatitis, hepatic stellate cells appeared enlarged, often irregular, with spikes. There were numerous signs of activation and many contained numerous small lipid droplets. In the cases of fulminant hepatitis, hepatic stellate cells presented, at times, some subcellular damage. Hepatic stellate cells processes, often in several layers, displayed numerous cytoplasmic microfilaments with conspicuous dense plaques below the plasma membrane. Hepatic stellate cells were never surrounded by a basement membrane. The extracellular matrix was loose and granulofibrillar. In areas of multiacinar nodules (in cases of map-like pattern), hepatic stellate cells were grossly normal. These results are in agreement with in vitro data showing that acutely damaged hepatocytes activate hepatic stellate cells but do not fully transform them into myofibroblasts.

Acetaminophen↗
PubMed1995

Fibroblast growth factor 2 and transforming growth factor beta 1 interactions in human liver myofibroblasts.

BACKGROUND & AIMS: During liver fibrogenesis, myofibroblastic liver cells proliferate and synthesize components of fibrosis. Fibroblast growth factor 2 (FGF-2) is expressed in vivo in myofibroblastic liver cells (MFLCs) during fibrogenesis, and exogenous FGF-2 is mitogenic for MFLCs. The aim of this study was to study the expression and role of endogenous FGF-2 in cultured human MFLCs. METHODS: FGF-2 and FGF-2 receptors were studied using immunoblotting. All RNA studies used ribonuclease protection. Growth of MFLCs was studied using [3H]thymidine incorporation and direct cell counting. RESULTS: MFLCs expressed FGF-2 and its receptors FGF receptor 1 and FGF receptor 2. An antibody to FGF-2 blocked the mitogenic effect of transforming growth factor beta 1 (TGF-beta 1) for MFLCs but not TGF-beta 1-induced increase in cellular fibronectin messenger RNA (mRNA). TGF-beta 1 increased levels of FGF-2 and FGF receptor mRNAs in MFLCs. We have previously shown that TGF-beta 1 also increased platelet-derived growth factor (PDGF) A chain mRNA in these cells and that anti-PDGF antibody blunted the mitogenic effect of TGF-beta 1. The present results show that anti-FGF-2 and anti-PDGF-AA are not additive and that FGF-2 and PDGF-AA are not sequentially induced by TGF-beta 1. CONCLUSIONS: FGF-2 mediates the mitogenic but not the profibrogenic effect of TGF-beta 1 for human MFLCs, and autocrine FGF-2 and PDGF-A interact in the mediation of the mitogenic effect of TGF-beta 1.

Analysis of Variance↗
PubMed1995

Gender differences in hostility among depressed and medical outpatients.

We assessed possible gender differences in state and trait hostility in a large sample of depressed outpatients and in a group of medical outpatients. We administered the Cook and Medley Hostility Scale, measuring trait hostility and aggressiveness, and the Symptom Questionnaire, including a state measure of irritability and hostility, to 218 depressed outpatients and 51 medical outpatients. There was a statistically significant positive correlation between severity of depression and our state measure of hostility, and a weak, although statistically significant, relationship between severity of depression and total score of our trait measure of hostility. Among depressed outpatients, trait hostility was greater in men than in women, while no significant gender difference was observed in state hostility. Among medical outpatients, the state hostility scale scores were significantly higher in men than in women. These gender differences in both groups remained significant even after adjusting for severity of depression. Thus, it appears that men with depression tend to have higher scores than women on state and trait measures of hostility, suggesting that men may be at greater risk than women of developing patterns of pathologic aggression and hostile behavior.

Adult↗
PubMed1995

Growth inhibitory properties of endothelin-1 in human hepatic myofibroblastic Ito cells. An endothelin B receptor-mediated pathway.

Ito cells play a pivotal role in the development of liver fibrosis associated with chronic liver diseases. During this process, Ito cells acquire myofibroblastic features, proliferate, and synthesize fibrosis components. Considering the reported mitogenic properties of endothelin-1 (ET-1), we investigated its effects on the proliferation of human Ito cells in their myofibroblastic phenotype. Both ET receptor A (ETA: 20%) and ET receptor B (ETB: 80%) binding sites were identified, using a selective ETA antagonist, BQ 123, and a selective ETB agonist, sarafotoxin S6C (SRTX-C). ET-1 did not stimulate proliferation of myofibroblastic Ito cells. In contrast, ET-1 inhibited by 60% DNA synthesis and proliferation of cells stimulated with either human serum or platelet-derived growth factor -BB (PDGF-BB). PD 142893, a nonselective ETA/ETB antagonist totally blunted this effect. SRTX-C was as potent as ET-1, while BQ 123 did not affect ET-1-induced growth inhibition. Analysis of the intermediate steps leading to growth-inhibition by ET-1 revealed that activation of mitogen-activated protein kinase by serum or PDGF-BB was decreased by 50% in the presence of SRTX-C. In serum-stimulated cells, SRTX-C reduced c-jun mRNA expression by 50% whereas c-fos or krox 24 mRNA expression were not affected. We conclude that ET-1 binding to ETB receptors causes a potent growth inhibition of human myofibroblastic Ito cells, which suggests that this peptide could play a key role in the negative control of liver fibrogenesis. Our results also point out that, in addition to its well known promitogenic effects, ET-1 may also exert negative control of growth on specific cells.

Adipocytes↗
PubMed1995

Community participation in dengue prevention and control: a survey of knowledge, attitudes, and practice in Trinidad and Tobago.

The priorities of public health planners are often at variance with the community's own environmental sanitation priorities and perspectives. Public opinion about individual, collective, and governmental responsibilities in addressing these issues and priorities is of particular importance when designing community-based programs. In a study conducted in Trinidad and Tobago on knowledge, attitudes, and practice regarding dengue, its prevention and control, a high level of awareness about dengue and its etiology was evident, but there was poor understanding of the symptoms and hence little concern about the health risks associated with it. The most important household pest problem identified by the respondents was related to mosquito nuisance, particularly from night-biting mosquitoes. Rodents were also a major concern perceived as being responsible for economic losses, ruined food, and a health hazard. Unreliable water supply, a factor associated with Aedes aegypti abundance, was an environmental sanitation issue of major importance to householders in rural areas. No correlation was found between knowledge of dengue and levels of Ae. aegypti abundance as measured by larval surveys of the respondents' premises. The study gave a clear indication of the need for broad-based environmental sanitation strategies when planning community-based vector control initiatives for the prevention and control of dengue in Trinidad and Tobago.

Aedes↗