The main goal of the present study was to investigate the response of the human skin equivalent A... more The main goal of the present study was to investigate the response of the human skin equivalent Apligraf in vitro to the application of irritant substances and its predictivity as a screening tool for cumulative skin irritant potential in humans. Vaseline, calcipotriol, trans-retinoic acid, and sodium lauryl sulfate were applied to Apligraf in vitro for 24 h. Cell viability (lactate dehydrogenase leakage), release and mRNA expression of the proinflammatory cytokines IL-1alpha and IL-8, and morphological changes were assessed. The same products were applied to 30 healthy volunteers in a double-blind, randomized, vehicle-controlled within-subject study. The skin reactions after repeated 24-h applications over 3 weeks under Finn chamber patches were monitored by visual scoring and biophysical methods (trans-epidermal water loss, chromametry, and blood flow). Sodium lauryl sulfate was cytotoxic to Apligraf, and increased the release and expression of cytokines at low (0.2%, 0. 4%), but not at high (0.8%, 1%) concentrations. It induced severe irritancy in vivo. Trans-retinoic acid increased the expression and release of cytokines with no detectable cytotoxicity and showed moderate irritancy in humans. Although calcipotriol did neither affect cell viability nor the production of cytokines, it induced morphological signs of irritation and was mildly irritant for healthy volunteers. Vaseline was innocuous in vivo and induced no changes in Apligraf. In conclusion, the cumulative skin irritation potential of the tested products could be predicted with Apligraf in a sensitive and specific manner, by monitoring cytotoxicity, proinflammatory cytokines, and morphological changes.
Today's stringent requirements for new drugs make it necessary to prove their safety by the u... more Today's stringent requirements for new drugs make it necessary to prove their safety by the use of ever more refined techniques, in particular methods to quantify morphologic findings to determine accurately, for example, the highest non-toxic dose in animal studies or to correlate morphological effects with other parameters. Increased cell proliferation due to subtle cytotoxicity can lead to epigenetic tumorigenicity, which can be recognized early by cytokinetic investigations using bromodeoxyuridine (BrdU) incorporation and/or proliferating cell nuclear antigen (PCNA) expression, or by malignancy-associated nuclear texture changes. Morphometric criteria are also used to increase diagnostic accuracy in experimental animal pathology. The various applications of morphometry in toxicopathology are reviewed, and examples illustrating these applications are presented, most of them unpublished.
The main goal of the present study was to investigate the response of the human skin equivalent A... more The main goal of the present study was to investigate the response of the human skin equivalent Apligraf in vitro to the application of irritant substances and its predictivity as a screening tool for cumulative skin irritant potential in humans. Vaseline, calcipotriol, trans-retinoic acid, and sodium lauryl sulfate were applied to Apligraf in vitro for 24 h. Cell viability (lactate dehydrogenase leakage), release and mRNA expression of the proinflammatory cytokines IL-1alpha and IL-8, and morphological changes were assessed. The same products were applied to 30 healthy volunteers in a double-blind, randomized, vehicle-controlled within-subject study. The skin reactions after repeated 24-h applications over 3 weeks under Finn chamber patches were monitored by visual scoring and biophysical methods (trans-epidermal water loss, chromametry, and blood flow). Sodium lauryl sulfate was cytotoxic to Apligraf, and increased the release and expression of cytokines at low (0.2%, 0. 4%), but not at high (0.8%, 1%) concentrations. It induced severe irritancy in vivo. Trans-retinoic acid increased the expression and release of cytokines with no detectable cytotoxicity and showed moderate irritancy in humans. Although calcipotriol did neither affect cell viability nor the production of cytokines, it induced morphological signs of irritation and was mildly irritant for healthy volunteers. Vaseline was innocuous in vivo and induced no changes in Apligraf. In conclusion, the cumulative skin irritation potential of the tested products could be predicted with Apligraf in a sensitive and specific manner, by monitoring cytotoxicity, proinflammatory cytokines, and morphological changes.
Estimation of age at death from human bones in legal medicine or in anthropology and archaeology ... more Estimation of age at death from human bones in legal medicine or in anthropology and archaeology is hampered by controversial results from the various macroscopic and histological techniques. This study attempted an estimation of age at death by histomorphometric analysis, from the fourth left rib adjacent to the costochondral joint in 80 forensic cases. Use of the picrosirius dye provided a reliable staining of the decalcified paraffin-embedded ribs. The total bone cortical area, the major and minor diameter as well as the area of the Haversian canals, the osteon areas of intact and remodelled secondary osteons, the area of non-Haversian canals were evaluated by means of image analysis, and derived parameters were calculated on both the internal and external sides of the rib. Most of the variables exhibited consistency between three different observers. Noteworthy, morphometric measurements in the internal cortex of the rib showed less variability than in the external cortex. Finally, discriminant statistical analysis from the 80 cases in this study indicated that the osteon population density was virtually sufficient to significantly discriminate between three groups of age: 20-39 (adulthood), 40-59 (middle age) and a group superior to 60. A subsequent blind evaluation of ten new subjects satisfactorily classified seven subjects out of ten within the three age groups. These results make feasible a larger study aimed at characterization of the practical relationships between bone tissue histomorphometry in ribs and chronological age in forensic cases.
During a routine long-term drug safety study, lasting approximately 2½ yr, male Wistar rats, trea... more During a routine long-term drug safety study, lasting approximately 2½ yr, male Wistar rats, treated with a prolactin-inhibiting compound, developed an excess of Leydig cell tumors (LCTs). Most tumors were typical for the rat but a small number showed an unusual variation and some appeared malignant. The variation consisted of glandular and/or tubular structures within the tumor mass which occasionally anastomosed and contained an eosinophilic periodic-acid Schiff (PAS) positive material. In a few of these variants, malignant features such as cellular atypia, capsular, and lymphatic invasion and necrosis were seen. No metastases were detected. Detailed morphological and immunohistochemical investigations were conducted in order to establish the cell of origin of these variants. Glandular/tubular structures were found to stain with varying intensity for vimentin and cytokeratin, but were always negative for β-tubulin. The results indicated that the cell of origin of these LCT variant...
L'autopsie est une methode d'investigation des causes d'un deces. Elle est realisee p... more L'autopsie est une methode d'investigation des causes d'un deces. Elle est realisee par une equipe de technicien(s) et de medecin(s). A cette equipe s'ajoutent des enqueteurs s'il s'agit d'une autopsie medico-legale. La technique autopsique reste la meme, mais le deroulement de l'autopsie medicale et medico-legale est different car il repond a des preoccupations specifiques. Le but premier de l'autopsie medicale est d'etablir la verite du diagnostic clinique car environ 25% des diagnostics portes du vivant du patient sont partiellement ou totalement errones. Certains diagnostics sont insoupconnes malgre les progres notamment des techniques d'investigation clinique et radiologique (cancer de decouverte fortuite). Ceci est rendu possible par l'examen macroscopique, voire histologique de tous les visceres. Les regles administratives regissant l'autopsie medicale ont ete changees le 31 juillet 1998 avec l'introduction du Registre N...
L'autopsie constitue une methode d'investigation des causes et des circonstances du deces... more L'autopsie constitue une methode d'investigation des causes et des circonstances du deces chez l'homme et l'animal. L'autopsie medicale permet un diagnostic de cause de la mort, le plus souvent apres examen macroscopique. Les prelevements, histologiques ou biologiques, sont realises par interet clinique (decouverte fortuite d'un cancer non connu par exemple). Ils sont conserves dans le service de pathologie pour une duree variable, a la discretion du pathologiste. Les regles regissant l'autorisation des autopsies et des prelevements ont ete modifiees le 31 juillet 1998, avec la mise en place d'un registre national automatise des refus de prelevements. L'autopsie medico-legale permet egalement un diagnostic macroscopique de la cause de la mort. Les prelevements histologiques, biologiques et toxicologiques sont realises afin de confirmer la cause du deces et afin de permettre des expertises ou contre-expertises ordonnees par un juge d'instruction. Ces prelevements, mis sous scelles et conserves pour une duree variable a la discretion du Magistrat, sont sous la dependance d'articles du Code de procedure Penale. L'autopsie toxicologique des animaux sacrifies a la fin d'une experience apporte des renseignements sur l'effet pharmacologique et surtout toxique d'une substance. L'examen des liquides biologique et l'etude histologique de tous les organes sont de regle afin d'evaluer l'effet toxique, l'effet en fonction de la dose et la reversibilite de l'effet de la substance testee. Ces prelevements sont regis par les Principes de l'OCDE relatifs aux Bonnes Pratiques de Laboratoire (BPL) en cours depuis le 12 mai 1981.
The degradation and drug carrier properties of poly(ethylene carbonate) (PEC) were investigated i... more The degradation and drug carrier properties of poly(ethylene carbonate) (PEC) were investigated in vitro and in rats and rabbits. PEC was found to be specifically degraded in vivo and in vitro by superoxide radical anions O2−·, which are, in vivo, mostly produced by inflammatory cells. No degradation of PEC was observed in the presence of hydrolases, serum or blood. PEC
The main goal of the present study was to investigate the response of the human skin equivalent A... more The main goal of the present study was to investigate the response of the human skin equivalent Apligraf in vitro to the application of irritant substances and its predictivity as a screening tool for cumulative skin irritant potential in humans. Vaseline, calcipotriol, trans-retinoic acid, and sodium lauryl sulfate were applied to Apligraf in vitro for 24 h. Cell viability (lactate dehydrogenase leakage), release and mRNA expression of the proinflammatory cytokines IL-1alpha and IL-8, and morphological changes were assessed. The same products were applied to 30 healthy volunteers in a double-blind, randomized, vehicle-controlled within-subject study. The skin reactions after repeated 24-h applications over 3 weeks under Finn chamber patches were monitored by visual scoring and biophysical methods (trans-epidermal water loss, chromametry, and blood flow). Sodium lauryl sulfate was cytotoxic to Apligraf, and increased the release and expression of cytokines at low (0.2%, 0. 4%), but not at high (0.8%, 1%) concentrations. It induced severe irritancy in vivo. Trans-retinoic acid increased the expression and release of cytokines with no detectable cytotoxicity and showed moderate irritancy in humans. Although calcipotriol did neither affect cell viability nor the production of cytokines, it induced morphological signs of irritation and was mildly irritant for healthy volunteers. Vaseline was innocuous in vivo and induced no changes in Apligraf. In conclusion, the cumulative skin irritation potential of the tested products could be predicted with Apligraf in a sensitive and specific manner, by monitoring cytotoxicity, proinflammatory cytokines, and morphological changes.
Today's stringent requirements for new drugs make it necessary to prove their safety by the u... more Today's stringent requirements for new drugs make it necessary to prove their safety by the use of ever more refined techniques, in particular methods to quantify morphologic findings to determine accurately, for example, the highest non-toxic dose in animal studies or to correlate morphological effects with other parameters. Increased cell proliferation due to subtle cytotoxicity can lead to epigenetic tumorigenicity, which can be recognized early by cytokinetic investigations using bromodeoxyuridine (BrdU) incorporation and/or proliferating cell nuclear antigen (PCNA) expression, or by malignancy-associated nuclear texture changes. Morphometric criteria are also used to increase diagnostic accuracy in experimental animal pathology. The various applications of morphometry in toxicopathology are reviewed, and examples illustrating these applications are presented, most of them unpublished.
The main goal of the present study was to investigate the response of the human skin equivalent A... more The main goal of the present study was to investigate the response of the human skin equivalent Apligraf in vitro to the application of irritant substances and its predictivity as a screening tool for cumulative skin irritant potential in humans. Vaseline, calcipotriol, trans-retinoic acid, and sodium lauryl sulfate were applied to Apligraf in vitro for 24 h. Cell viability (lactate dehydrogenase leakage), release and mRNA expression of the proinflammatory cytokines IL-1alpha and IL-8, and morphological changes were assessed. The same products were applied to 30 healthy volunteers in a double-blind, randomized, vehicle-controlled within-subject study. The skin reactions after repeated 24-h applications over 3 weeks under Finn chamber patches were monitored by visual scoring and biophysical methods (trans-epidermal water loss, chromametry, and blood flow). Sodium lauryl sulfate was cytotoxic to Apligraf, and increased the release and expression of cytokines at low (0.2%, 0. 4%), but not at high (0.8%, 1%) concentrations. It induced severe irritancy in vivo. Trans-retinoic acid increased the expression and release of cytokines with no detectable cytotoxicity and showed moderate irritancy in humans. Although calcipotriol did neither affect cell viability nor the production of cytokines, it induced morphological signs of irritation and was mildly irritant for healthy volunteers. Vaseline was innocuous in vivo and induced no changes in Apligraf. In conclusion, the cumulative skin irritation potential of the tested products could be predicted with Apligraf in a sensitive and specific manner, by monitoring cytotoxicity, proinflammatory cytokines, and morphological changes.
Estimation of age at death from human bones in legal medicine or in anthropology and archaeology ... more Estimation of age at death from human bones in legal medicine or in anthropology and archaeology is hampered by controversial results from the various macroscopic and histological techniques. This study attempted an estimation of age at death by histomorphometric analysis, from the fourth left rib adjacent to the costochondral joint in 80 forensic cases. Use of the picrosirius dye provided a reliable staining of the decalcified paraffin-embedded ribs. The total bone cortical area, the major and minor diameter as well as the area of the Haversian canals, the osteon areas of intact and remodelled secondary osteons, the area of non-Haversian canals were evaluated by means of image analysis, and derived parameters were calculated on both the internal and external sides of the rib. Most of the variables exhibited consistency between three different observers. Noteworthy, morphometric measurements in the internal cortex of the rib showed less variability than in the external cortex. Finally, discriminant statistical analysis from the 80 cases in this study indicated that the osteon population density was virtually sufficient to significantly discriminate between three groups of age: 20-39 (adulthood), 40-59 (middle age) and a group superior to 60. A subsequent blind evaluation of ten new subjects satisfactorily classified seven subjects out of ten within the three age groups. These results make feasible a larger study aimed at characterization of the practical relationships between bone tissue histomorphometry in ribs and chronological age in forensic cases.
During a routine long-term drug safety study, lasting approximately 2½ yr, male Wistar rats, trea... more During a routine long-term drug safety study, lasting approximately 2½ yr, male Wistar rats, treated with a prolactin-inhibiting compound, developed an excess of Leydig cell tumors (LCTs). Most tumors were typical for the rat but a small number showed an unusual variation and some appeared malignant. The variation consisted of glandular and/or tubular structures within the tumor mass which occasionally anastomosed and contained an eosinophilic periodic-acid Schiff (PAS) positive material. In a few of these variants, malignant features such as cellular atypia, capsular, and lymphatic invasion and necrosis were seen. No metastases were detected. Detailed morphological and immunohistochemical investigations were conducted in order to establish the cell of origin of these variants. Glandular/tubular structures were found to stain with varying intensity for vimentin and cytokeratin, but were always negative for β-tubulin. The results indicated that the cell of origin of these LCT variant...
L'autopsie est une methode d'investigation des causes d'un deces. Elle est realisee p... more L'autopsie est une methode d'investigation des causes d'un deces. Elle est realisee par une equipe de technicien(s) et de medecin(s). A cette equipe s'ajoutent des enqueteurs s'il s'agit d'une autopsie medico-legale. La technique autopsique reste la meme, mais le deroulement de l'autopsie medicale et medico-legale est different car il repond a des preoccupations specifiques. Le but premier de l'autopsie medicale est d'etablir la verite du diagnostic clinique car environ 25% des diagnostics portes du vivant du patient sont partiellement ou totalement errones. Certains diagnostics sont insoupconnes malgre les progres notamment des techniques d'investigation clinique et radiologique (cancer de decouverte fortuite). Ceci est rendu possible par l'examen macroscopique, voire histologique de tous les visceres. Les regles administratives regissant l'autopsie medicale ont ete changees le 31 juillet 1998 avec l'introduction du Registre N...
L'autopsie constitue une methode d'investigation des causes et des circonstances du deces... more L'autopsie constitue une methode d'investigation des causes et des circonstances du deces chez l'homme et l'animal. L'autopsie medicale permet un diagnostic de cause de la mort, le plus souvent apres examen macroscopique. Les prelevements, histologiques ou biologiques, sont realises par interet clinique (decouverte fortuite d'un cancer non connu par exemple). Ils sont conserves dans le service de pathologie pour une duree variable, a la discretion du pathologiste. Les regles regissant l'autorisation des autopsies et des prelevements ont ete modifiees le 31 juillet 1998, avec la mise en place d'un registre national automatise des refus de prelevements. L'autopsie medico-legale permet egalement un diagnostic macroscopique de la cause de la mort. Les prelevements histologiques, biologiques et toxicologiques sont realises afin de confirmer la cause du deces et afin de permettre des expertises ou contre-expertises ordonnees par un juge d'instruction. Ces prelevements, mis sous scelles et conserves pour une duree variable a la discretion du Magistrat, sont sous la dependance d'articles du Code de procedure Penale. L'autopsie toxicologique des animaux sacrifies a la fin d'une experience apporte des renseignements sur l'effet pharmacologique et surtout toxique d'une substance. L'examen des liquides biologique et l'etude histologique de tous les organes sont de regle afin d'evaluer l'effet toxique, l'effet en fonction de la dose et la reversibilite de l'effet de la substance testee. Ces prelevements sont regis par les Principes de l'OCDE relatifs aux Bonnes Pratiques de Laboratoire (BPL) en cours depuis le 12 mai 1981.
The degradation and drug carrier properties of poly(ethylene carbonate) (PEC) were investigated i... more The degradation and drug carrier properties of poly(ethylene carbonate) (PEC) were investigated in vitro and in rats and rabbits. PEC was found to be specifically degraded in vivo and in vitro by superoxide radical anions O2−·, which are, in vivo, mostly produced by inflammatory cells. No degradation of PEC was observed in the presence of hydrolases, serum or blood. PEC
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