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Biomedical subjects

M Fabre

Publications and source records attributed to M Fabre.

At least 91 records · Page 5Linked to original sources
PubMed1998

Are hepatomas a good target for suicide gene therapy? An experimental study in rats using retroviral-mediated transfer of thymidine kinase gene.

BACKGROUND: Suicide gene transfer into tumor cells has been proposed for the treatment of various tumors. The most common suicide gene is coded for the herpes simplex type I thymidine kinase (HSV1-TK), which converts nontoxic nucleoside analogs such as ganciclovir into toxic triphosphated compounds. This study evaluated the potential of this treatment for gene therapy of liver tumors. METHODS: The sensitivity of different colon carcinoma and hepatoma cell lines to infection by recombinant retroviruses was evaluated. Next, HSV1-TK-expressing derivatives of these cells were generated to analyze their sensitivity to ganciclovir. Finally, these cells were used to generate experimental hepatomas in rats after injection under the liver capsule, and the efficacy and safety of a ganciclovir treatment on tumor growth and survival were evaluated. RESULTS: All the different cell lines analyzed were sensitive to retroviral-mediated gene transfer, although the susceptibility of individual cell lines to this transfer varied significantly. HSV1-TK derivatives were about 1000-fold more sensitive to the toxic effects of ganciclovir than parental cells. Tumors with HSV1-TK expressing MCA-RH8994 hepatoma cells were then generated. Intraperitoneal injection of 75 mg/kg ganciclovir twice daily for 5 days dramatically reduced the size of HSV1-TK-positive tumors compared with tumor size in untreated control rats (0.4 mm3 versus 65 mm3, p < 0.02). A long-term study demonstrated that this reduction of tumor volume was associated with a significant increase in survival (p < 0.01). Pathologic examination 26 days after the end of ganciclovir injections showed that complete tumor regression was observed in two of five rats. Most important, there was no toxicity associated with these tumors. CONCLUSIONS: In a clinical perspective the good tolerance to treatment and the significant clinical effect observed were encouraging. Gene transfer methods should be established to allow efficient targeting of the tumor cells in vivo.

3T3 Cells↗
PubMed1998

Intraoperative localization of neuroblastoma in children with 123I- or 125I-radiolabeled metaiodobenzylguanidine.

BACKGROUND: This study describes a novel method of intraoperative localization of neuroblastoma with a gamma-detecting probe, to detect in situ tumor binding of radiolabeled 123I- or 125I-metaiodobenzylguanidine (MIBG) and improve the quality of tumor resection. METHODS: Fifty-eight children underwent 66 surgical procedures with intraoperative detection of radiolabeled MIBG. All patients with positive MIBG scintiscans at diagnosis were included in the study. A tumor/background ratio exceeding 2:1 at the time of operation was considered positive, indicating a significant uptake of MIBG, compatible with the presence of malignant cells. The surgeons were requested to evaluate the contribution of the method to the surgical procedure. Sensitivity and specificity of the method with either 123I-labeled MIBG or 125I-labeled MIBG, on the basis of correlations between probe findings and pathologic analysis of 288 resected specimens, were determined. RESULTS: Intraoperative detection was helpful in 65% of surgical procedures, allowing a better definition of tumor limits and extension to locoregional nodes or detection of small and nonpalpable tumors in sites with difficult surgical access, especially during operation for relapse. The detection was not contributory in 35% of the procedures (well-localized tumors, thoracic neuroblastoma for technical reasons, highly differentiated tumors as ganglioneuroma, and tumors with mainly necrosis or fibrosis). The sensitivity of 123I and 125I was the same (91% and 92%), but the specificity of 125I (85%) was significantly higher than that of 123I (55%) (p < 0.005). CONCLUSIONS: First, this study demonstrates the feasibility of intraoperative detection, with radiolabeled MIBG, of neuroblastoma in children. We advocate the use of 125I rather than 123I. Second, the method is useful to improve the quality of macroscopic resection in widespread neuroblastoma with nodal involvement, in sites with difficult access, and in operations for relapse.

3-Iodobenzylguanidine↗
PubMed1998

[Large cell variant of small cell carcinoma of the ovary with hypercalcemia].

We describe an original distinct type of ovarian small cell carcinoma: large cell variant. The distinctive histologic features of tumor cells were the presence of large nuclei with prominent nucleoli and abundant eosinophilic cytoplasm. Immunohistochemistry revealed strong diffuse vimentin, smooth muscle actin positivity and slight reactivity with epithelial markers. Electron microscopy showed aggregates of intermediate filaments, intercellular attachments and no dense core granules. This tumor is associated with paraendocrine hypercalcemia in two thirds of cases. Parathyroid hormone-related protein was focally positive. This tumor is characterized as a very lethal neoplasm, occurring primarily in young women.

Adolescent↗
PubMed1997

A "distant" bystander effect of suicide gene therapy: regression of nontransduced tumors together with a distant transduced tumor.

Antitumor gene therapy using herpes simplex type 1 thymidine kinase (TKh) and ganciclovir (GCV) treatment has revealed an important intratumoral bystander effect. A whole tumor can be eliminated when only a fraction of its tumor cells express TKh. We now report that the bystander effect not only acts within a tumor, but also between distant tumors. One TKh+ tumor was generated simultaneously with one or multiple TKh- tumors in different rat liver lobes such that there was no contact between the resulting tumors. Both the TKh+ and the TKh- tumors regressed after GCV treatment and showed infiltration with macrophages and T lymphocytes. This distant bystander effect, which is likely immune mediated, should be of major importance for gene therapy of disseminated tumors.

3T3 Cells↗
PubMed1997

Primary sequence of the human, lysine-rich, ribosomal protein RPL38 and detection of an unusual RPL38 processed pseudogene in the promoter region of the type-1 angiotensin II receptor gene.

We have isolated a cDNA clone encoding the human ribosomal protein L38 (HSRPL38). The longest ORF of the cDNA predicts a lysine-rich small polypeptide identical to the rat RPL38 protein (100% identity), and sharing a 84% of identity to the tomato RPL38 protein sequence. Northern blot analysis of a number of epithelial cell lines showed that the HSRPL38 is encoded by a mRNA ubiquitously expressed. Southern blot analysis of human genomic DNA suggested that the RPL38 does not constitute a multigene family but it is encoded by a reduced set of active genes, among which we have also found a RPL38 processed pseudogene located in the promoter region of the human type-1 angiotensin II receptor gene. This RPL38 pseudogene is very unusual among processed pseudogenes in that the poly A tail and the entire 5'-UTR of the original RPL38 mRNA were deleted during the retrotransposition process.

Amino Acid Sequence↗
PubMed1997

Posterior lumbar epidural fat as a functional structure? Histologic specificities.

STUDY DESIGN: A topographic and histologic study was done to describe the location of the lumbar epidural fat and to find potential tissular specificities. OBJECTIVES: To search for possible histologic characteristics of posterior lumbar epidural fat, which so far has been described as semifluid tissue, and to determine whether posterior lumbar epidural fat is not a simple incidental tissue. SUMMARY OF BACKGROUND DATA: The lumbar epidural fat on two fetuses was studied. In adults, subcutaneous fat and posterior lumbar epidural fat were taken from seven corpses. The authors obtained 13 posterior lumbar epidural fat pads (two at L1-L2, three at L2-L3, six at L3-L4, and two at L4-L5) and four subcutaneous fat pads. METHODS: The authors studied abdominal axial histologic sections in two fetuses, histologic multiplanar sections in seven adults, and semithin sections in four adults of posterior lumbar epidural fat and subcutaneous fat. RESULTS: Fetal distribution of epidural fat was circumferential. Adult epidural fat distribution was limited to the posterior part of the vertebral canal and located at the disc level. Fascicles of connective tissue were less numerous and thinner in posterior lumbar epidural fat than in subcutaneous fat. Organized sliding spaces were found in the posterior epidural fat ped. CONCLUSIONS: Posterior lumbar epidural fat is not a simple incidental tissue and shows specific histologic features: sliding spaces and rarefaction of connective tissue that could explain semifluid features of the tissue. These characteristics suggest a functional role of posterior epidural fat in the lumbar spinal unit.

Adipose Tissue↗
PubMed1997

Tertiary hepatic syphilis. A treatable cause of multinodular liver.

Although the incidence of syphilis is increasing, liver involvement in tertiary syphilis remains exceptional. We report a case of tertiary syphilis revealed by liver localization. The clinical picture was misleading, mimicking multinodular hepatic metastasis. The final diagnosis was suspected following a fine-needle ultrasound-guided biopsy of a liver nodule showing granulomas as well as acellular necrosis and confirmed by positive serum syphilitic reactions and the presence of spirochetes in the liver. The outcome was uneventful following antibiotic treatment. It is important to be aware of the misleading picture of the disease, which has a favorable prognosis provided that simple treatment is rapidly initiated.

Female↗
PubMed1997

In situ detection of lipid peroxidation by-products in chronic liver diseases.

Lipid peroxidation is an autocatalytic mechanism leading to oxidative destruction of cellular membranes. The deleterious consequences of this mechanism are related in part to the formation of reactive aldehydic products that bind to intra- or extracellular molecules to form adducts. Specific antibodies directed against malondialdehyde (MDA) and 4-hydroxynonenal (HNE) adducts, major aldehydic metabolites of lipid peroxidation, allowed us to investigate in situ, with an immunohistochemical procedure, the occurrence of lipid peroxidation in a panel of different chronic liver diseases. Intracellular HNE and MDA adducts were detected respectively in 24 of 39 cases (62%) and in 12 of 34 cases investigated (35%). They were localized mainly in the cytoplasm of hepatocytes, with the strongest staining observed in hemochromatosis, Wilson's disease, and in areas of acute alcoholic hepatitis in cases of alcoholic liver diseases. A peculiar pattern of immunostaining was observed in primary biliary cirrhosis where biliary cells of destroyed but also intact bile ducts strongly expressed HNE adducts. The liver extracellular matrix also displayed MDA adducts (30 of 34 cases, 88%) and HNE adducts (23 of 39 cases, 59%). While HNE adducts were specifically localized on large bundles of collagen fibers, MDA adducts were detected in a thin reticular network and in sinusoidal cells around portal tracts or fibrous septa. In conclusion, lipid peroxidation by-products are detectable in chronic liver diseases. Immunohistochemical results suggest that this mechanism is implicated very early in the pathogenesis of some of these diseases.

Adolescent↗
PubMed1997

Liver failure in children with hepatitis A.

There have been very few reports dealing with liver failure related to hepatitis A in children. Moreover, the criteria usually used for selecting patients with fulminant hepatitis A for liver transplantation have not been evaluated in children. Therefore, the current study was conducted retrospectively in a single French urban pediatric liver transplantation center to serve as a reminder of the potential severity of hepatitis A in children and to identify predictors of outcome. Children were selected by chart review using a data base system and were grouped according to outcome for analyses purposes. Over a 15-year period, 24 children with hepatitis A showed evidence of liver failure, including 6 children who did not develop hepatic encephalopathy, 7 children in whom encephalopathy occurred but resolved spontaneously, and 11 children in whom death or liver transplantation was the outcome. The mean age at onset was 6.5 years. Those with the most rapid onset of liver failure from onset of jaundice had the best chance of recovery without developing encephalopathy. Otherwise, no predictive factors of outcome were found at onset of liver failure. Among the 18 children who developed encephalopathy, the best early prognostic indicator of a poor outcome irrespective of the grade of encephalopathy, appeared to be a prothrombin time level below 21% of normal combined with a serum bilirubin level above 400 micromol/L. Therefore, these two prognostic indicators may be helpful in deciding liver transplantation in children with hepatitis A-induced fulminant liver failure.

Adolescent↗
PubMed1997

[Guided fine needle puncture in the diagnosis of pancreatic disorders].

Fine-needle aspiration (FNA) of pancreatic disorders with ultrasound or computed tomographic, and recently echo-endocopic guidance has become commonplace to diagnose the nature of a pancreatic lesion. It is specially usefull in diagnosing solid neoplasms. Most often, FNA is performed to confirm a diagnosis of ductal adenocarcinoma. The aspirate shows cellular clusters with high nuclear-to cytoplasmic ratio, overlapping nuclei and prominant macronucleoli. The cytologic features that permit a diagnosis of neuroendocrin neoplasm are loose cellular aggregates with round nuclei, evently dispersed nuclear chromatin, a moderate amount of amphophilic cytoplasm and rosette formation. Immunocytochemistry can provide additional confirmatory information. Difficulties are encountered in diagnosing cystic neoplasms. The major cytologic differences between serous and mucinous tumors are the absence of mucin and presence of low cuboidal glycogen-containing cells in the microcystic adenoma vs the presence of goblet cells in the mucinous tumors. Except for the presence of necrotic debris, and in the absence of obvious malignant cytologic features, it is impossible to predict the behaviour of mucinous neoplasms. The lower accuracy for cystic neoplasm can be attributed to predominantly bloody specimens and limited cellularity. These problems illustrate the importance of knowing the clinical and radiological features of pancreatic cystic neoplasms.

Biopsy, Needle↗
PubMed1996

p120-catenin expression in human colorectal cancer.

Recent data suggest that p120-catenin plays a role in the regulation of functionality of E-cadherin, a protein essential for the establishment and maintenance of cell-cell contacts. Since dysfunction of intercellular adhesiveness is an alteration frequently observed in colon cancer we have studied the expression and distribution of p120-catenin in human colorectal tumors. In normal colon, p120-catenin was observed in the crypt and surface epithelium; the cells showed reactivity both in the membrane and in the cytosol. Thirteen primary tumors were examined for p120-catenin expression: they were graded as uniformly positives (+) (4); heterogeneous (+/-) (6), with a diminished expression, detected mainly in the cytosol; and negatives (-) (3). Although the number of tumors was low, the reduction in p120-catenin correlated with a larger size of the tumors (p = 0.038). Association of p120-catenin to the cytoskeleton was also determined in 5 tumors by detergent extraction and Western blot; this analysis shows that lack of reactivity in the membrane was accompanied by absence of p120-catenin in the cytoskeleton-associated fraction. Analysis of E-cadherin was performed in order to compare the distribution of this protein and p120-catenin. Although no complete correlation was found between the expression of both proteins (p = 0.077), our results showed that alterations in the level or distribution of p120-catenin were accompanied by lack of E-cadherin reactivity in the membrane, whereas absence of p120-catenin in the cytoskeleton fraction was associated with important decreases in the amount of E-cadherin in this same fraction. These results show that alterations in p120-catenin levels are a common event in colorectal tumors, and suggest that the distribution of this protein and E-cadherin is coordinately regulated.

Antibodies, Monoclonal↗
PubMed1996

Assessment of hyperacute rejection in a rat-to-primate cardiac xenograft model.

We studied a rat-to-cynomolgous monkey model for xenotransplantation of vascularized organs and found that a rat heart was rejected in 5.5 +/- 1.4 min (n = 10). This hyperacute rejection (HAR) was consistent with kinetic experiments in vitro that showed damage to rat endothelial cells (ECs) after 3 min of incubation with primate serum. Histopathology and ultrastructural analysis of rejected hearts showed marked EC damage and early adherence of platelets and polymorphonuclear leukocytes to the endothelium. Immunohistochemical analysis revealed deposition along endothelial surfaces of IgG, IgM, and complement (C) components of the classical but not the alternative pathway, suggesting that, as in the pig-to-primate model, HAR is mediated by the binding of recipient xenogeneic natural antibodies and C activation. The effect of C depletion on xenograft survival was evaluated in two recipients that were treated with cobra venom factor (CVF). CVF caused complete C inactivation, demonstrated by lack of serum hemolytic activity and C-dependent EC cytotoxicity at engraftment and until the animals died. The rat cardiac transplants survived for at least 9 hr and 77 hr. Histology showed massive interstitial hemorrhage, edema, and cellular infiltration with scanty fibrin deposits. These results in CVF-treated recipient monkeys indicate that C activation mediates the development of HAR in this rat-to-primate model. We suggest that the model may be of interest as an alternative to the more expensive and time-consuming pig-to-primate model for testing the efficacy of transgenic modification of donor organs to prolong xenograft survival and for studying mechanisms of discordant xenograft rejection.

Animals↗
PubMed1996

Evidence for a role of conventional protein kinase-C alpha in the control of homotypic contacts and cell scattering of HT-29 human intestinal cells.

Incubation of HT-29 M6 cells with the phorbol ester phorbol 12-myristate 13-acetate (PMA) induces cell scattering, loss of cellular contacts and inactivation of E-cadherin. We have investigated the involvement of different protein kinase C (PK-C) isoforms in these processes using specific activators. Thymeleatoxin, a derivative of mezerein that activates conventional PK-Cs (cPK-Cs) but not novel PK-Cs (nPK-Cs), promoted effects that were similar to those of PMA, i.e. at concentrations of 200 nM it induced scattering of HT-29 M6 colonies, loss of homotypic contacts and dissociation of E-cadherin from the cytoskeleton. Among the isoforms activated by this compound, only cPK-C alpha was detected in HT-29 M6 cells by Western blot. The specificity of this compound with respect to the rest of the PK-C isoforms present in these cells was determined; thymeleatoxin induced, as did PMA, the translocation of cPK-C alpha from the cytosol to the membrane and the cytoskeleton, and its partial down-regulation. On the other hand, thymeleatoxin did not modify the cellular levels or localization of nPK-C epsilon or atypical PK-C zeta. "In vitro' assays also showed that thymeleatoxin did not activate nPK-C epsilon at the concentrations added to the cell cultures. These results indicate that thymeleatoxin is selective for cPK-C alpha over nPK-C epsilon and show a role for the former enzyme in the regulation of cell-cell contacts and the inactivation of E-cadherin in HT-29 M6 cells.

Amino Acid Sequence↗
PubMed1996

[Nosocomial infections in a burns unit. Results of a prospective study over a year].

OBJECTIVES: To assess nosocomial infections in a burn care centre, to identify patients' infection risk factors at the time of admission and factors of monthly variations of infection incidence. STUDY DESIGN: Prospective survey, from October 1992 to September 1993. PATIENTS AND METHOD: The study included 140 patients staying for more than two days in a 22-bed burn unit. Nosocomial infection criteria were derived from the 1988 CDC criteria. Incidence rates of infection were calculated. Infected and noninfected patients were compared. Each monthly infection incidence was compared with six unit activity indicators. RESULTS: Fifty-six patients developed 132 infections. The overall incidence was 94%. Incidence density was 25 infections per 1,000 days of care. The distribution of infected sites was: skin (30%), intravascular catheters (25%), blood (22%), urinary tract (18%), respiratory tract (5%). The most frequent pathogens were Pseudomonas sp (49%), Staphylococcus sp (18%), Escherichia coli (18%), and Streptococcus faecalis (10%). They were characterized by a good antibiotic sensitivity. Each common burn severity index was predictive of nosocomial infections. Facial, perineal and respiratory lesions were also linked to infection. There was a positive correlation between the peak of nosocomial infections in the unit during a month and the peak of activity during the foregoing one. CONCLUSION: Incidence rates of infection were high, as 40% of the population was concerned. Choosing reliable infection criteria was the most difficult problem to solve.

Adult↗
PubMed1996

[Serotonin syndrome in acute poisoning with antidepressive agents].

We report a case of severe serotonin syndrome after self-poisoning with two antidepressant drugs, paroxetine (a selective inhibitor of serotonin reuptake) and moclobemide (a reversible inhibitor of MAO-A). The serotonin syndrome is characterized by neuromuscular, behavioural, and autonomic changes. It occurs with the use of drugs able to increase serotonergic transmission in brain by acting on biosynthesis, reuptake, catabolism or release of serotonin. Treatment is symptomatic. The incidence of severe cases seems to have increased, probably due to the use of new antidepressant "specific" inhibitors of the serotonin reuptake.

Adult↗
PubMed1996

[Sarcoidosis with hematologic involvement and hypogammaglobulinemia].

BACKGROUND: Hematological changes are uncommon in childhood sarcoidosis. CASE REPORT: Case 1. This patient developed severe hemolytic anemia associated with splenomegaly at the age of 11 months. A second episode of hemolysis was seen at the age of 6 years; it was associated with thrombocytopenia and hypogammaglobulinemia. A partial splenectomy permitted histological diagnosis of sarcoidosis that was confirmed by elevated angiotensin-converting enzyme level, and subsequently developement of pulmonary involvement. Case 2. This boy suffered from autoimmune hemolytic anemia and thrombocytopenia associated with splenomegaly at the age of 3 years. At the age of 7 years, he had splenomegaly, enlarged cervical and lomboaortic lymph nodes and hypogammaglobulinemia. Diagnosis of sarcoidosis was made from lymph nodes and spleen biopsies after splenectomy; the patient had increased angiotensin-converting enzyme concentration, and subsequently developed specific renal involvement. CONCLUSION: Association of hemolytic anemia, thrombocytopenia, hypogammaglobulinemia and splenomegaly should suggest the diagnosis of sarcoidosis and could be considered as part of the disease spectrum.

Agammaglobulinemia↗
PubMed1996

Bcl-2 protects from lethal hepatic apoptosis induced by an anti-Fas antibody in mice.

Fas is an apoptosis-signalling cell surface antigen that has been shown to trigger cell death upon specific ligand or antibody binding. Treatment of mice with an anti-Fas antibody causes fulminant hepatic failure due to massive apoptosis. To test a putative protective effect of the anti-apoptotic Bcl-2 protein, transgenic mice were generated to express the human bcl-2 gene product in hepatocytes. Early onset of massive hepatic apoptosis leading to death was observed in all nontransgenic mice treated with an anti-Fas antibody. By contrast, hepatic apoptosis was delayed and dramatically reduced in transgenic animals, yielding a 93% survival rate. These results demonstrate that Bcl-2 is able to protect from in vivo Fas-mediated cytotoxicity, and could be of significance for preventing fulminant hepatic failure due to viral hepatitis in humans.

Animals↗