Calcium folinate diminishes the teratogenic effects of all-trans retinoic acid in the developing craniofacial region and neural tube of the rat

This study tests the hypothesis that calcium folinate diminishes, or ameliorates, the teratogenic effects of all-trans retinoic acid during craniofacial and neural tube development. Four experimental groups were used; two were treated with three doses of 30mg/k.b.w all-trans retinoic acid (on gestational days 9, 10, and 11), with one of these groups having additional doses of calcium folinate (5mg/k.b.w.). The other two groups were given higher doses of all-trans retinoic acid (50mg/k.b.w), with again one of these groups having additional doses of calcium folinate (5mg/k.b.w.). Retinoic acid was administered by gastric intubation and calcium folinate by peritoneal injection. Two further control groups were used where the pregnant rats were exposed to neither all-trans retinoic acid nor calcium folinate. All rats were sacrificed on gestational day 18. Standard histological techniques were employed to assess the extent of abnormal development of the craniofacial region (including the palate) and the brain. The fetuses treated with all-trans retinoic acid alone showed varying degrees of neural tube defects (including excencephaly, myelomeningocele and spina bifida), eye malformations and clefting of the face and palate. However, fetuses treated with calcium folinate showed no neural tube and eye defects and only occasionally minor clefting in the presumptive hard palate. In addition, although many fetal absorptions and teratomas were seen within the litters of rats treated only with all-trans retinoic acid, there were no absorptions (and few teratomas) seen with calcium folinate supplements. The findings support our initial hypothesis concerning the beneficial effects of calcium folinate on craniofacial development (AU)

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The legal and ethical frameworkgoverning Body Donation in Europe - Areview of current practice andrecommendations for good practice

Discussions at the inaugural meeting of aTrans-European Pedagogic Research Group forAnatomical Sciences highlighted the fact thatthere exist considerable variations in the legaland ethical frameworks throughout Europeconcerning body bequests for anatomicalexamination. Such differences appear to reflectcultural and religious variations as well as differentlegal and constitutional frameworks. Forexample, there are different views concerningthe “ownership” of cadavers and concerningthe need (perceived by different societies andnational politicians) for legislation specificallyrelated to anatomical dissection. Furthermore,there are different views concerning the acceptabilityof using unclaimed bodies that have notgiven informed consent. Given that in Europe (AU)

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Histological examination of major craniofacial abnormalities produced in rat foetuses with a variety of retinoids

Retinoic acid is a vitamin-A derived compoundthat plays an important role in craniofacialdevelopment. However, numerousstudies have shown that exogenously administeredretinoic acid analogues have teratogeniceffects both in humans and in experimentalanimals. This paper presents the results of astudy where exogenous administration ofretinoic acid analogues to pregnant Wistarrats resulted in major craniofacial malformationsof most of the foetuses. Seven groups ofpregnant rats were exposed to a variety ofretinoic acid analogues, administered in differentdoses on different gestational days. Afurther control group was not exposed to thesecompounds. All the rats were impregnatedand sacrificed on the same gestational days(GD 0 and GD 18 respectively). Followingexamination of the 34 foetuses obtained fromthe retinoic acid-treated litters, 5 were chosenfor histological investigation to describe themajor, external craniofacial malformationsresulting from exposure to the teratogens.These malformations included exophthalmos,anophthalmos, exencephaly, craniofacial asymmetryand facial tags. Also reported here arethe incidences of teratomas and absorptions inthese litters. Previously, we have reported theincidence of cleft lip and palate in rats subjectedto an identical experimental regimen. Ourdata provide further evidence that retinoicacid analogues, all-trans-retinoic acid in particular,disturb normal craniofacial developmentin such a way that a spectrum ofcraniofacial malformations can be induced byembryonic exposure to these compounds (AU)

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Palatal abnormalities in the developing rat induced by retinoic acid

Palatogenesis is a complex developmental processthat requires two main events: elevation andthen fusion of the palatal shelves. These processesare disrupted by teratogens such as retinoicacid (RA) and genetic defects, resulting in variousmalformations (including cleft palate). Usinghistological and immunohistochemical techniques,the effects of different isomers of RA, administeredin various concentrations to pregnantrats on different gestational days (GD), were assessedfrom observations of the state of palataldevelopment on GD 18 in foetuses without exencephaly.Varying degrees of clefting of thepalate were observed, from failure of elevationof the palatal shelves to failure of fusion in themidline. This study shows that all-trans-RA isthe most teratogenic RA isomer in terms of ratpalatal abnormalities. It also supports previousfindings that the timing of administration of alltrans-RA is more critical than the concentration,with treatment between GD 10 and 10.5 havingthe most severe effects. Previous histologicalstudies also suggested that RA is associatedwith the appearance of ectopic cartilages withinthe developing palate of foetuses showing exencephaly.In this investigation, immunohistochemicallabelling of the foetal material with antibodiesthat recognise epitopes present in linkproteins 1, 2, and 3 (8A4), chondroitin-4-sulphatestubs (2B6), and G1 and chondroitin sulphateattachments (7D1) present in aggrecan (associatedwith hyaluronan in cartilage) showedno signs of ectopic cartilage formation within the palate at GD18. Internal controls of the cartilagesof the nasal septum, vomeronasal cartilage, andMerkel’s cartilage labelled intensely and appearedmorphologically normal (AU)

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The development of the palate. A brief review / El desarrollo del paladar. Una breve revisión

Palatogenesis is a complex developmental process that requires two main events: elevation and then fusion of the palatal shelves. There remains controversy concerning the mechanism(s) responsible for palatal shelf elevation, it being proposed that an intrinsic shelf elevation force might be produced either by the generation of a turgor pressure following hydration of the extracellular matrix via its glycoconjugate molecules or by proliferation, migration and/or contraction of the palatal shelf mesenchymal cells. Recent evidence indicates that the shelf elevation force is related to the presence of hyaluronan in the extracellular matrix, to an as yet unknown molecule that is packaged in the mesenchymal cells' Golgi complex, and to CD44 receptor functioning. For fusion of the palatal shelves to occur, the breakdown of the midline epithelial seam relates to apoptosis and redifferentiation of the epithelial cells and this appears to be signalled by the synthesis of type IX collagen just prior to the breakdown of the basement membrane around the midline epithelial seam. The events associated with palatogenesis are controlled by the palatal shelf mesenchyme, under the influence of a variety of homeobox genes and transcription factors and and of several growth factors (particularly TGF-?s) (AU)

La palatogénesis es un proceso complejo del desarrollo embrionario que requiere dos hechos principales: la elevación y después la fusión de las apófisis palatinas. Existe una controversia respecto al(los) mecanismo(s) responsables de la elevación de la apófisis palatina, habiéndose propuesto que una fuerza intrínseca de elevación de esta apófisis podía ser producida bien por la generación de una presión turgente por hidratación de la matriz extracelular a través de sus moléculas glicoconjugadas o bien por proliferación, migración y/o contracción de las células mesenquimatosas de las apófisis palatinas. Evidencias recientes indican que esta fuerza de elevación está relacionada con la presencia de hialuronan en la matriz extracelular, con una molécula desconocida hasta ahora que es empaquetada en el complejo de Golgi de las células mesenquimatosas y con un receptor CD44 funcional. Para que ocurra la fusión de las apófisis palatinas, la ruptura de la sutura epitelial de la línea media se relaciona con apoptosis y rediferenciación de las células epiteliales y esto parece estar señalado por la síntesis de colágeno tipo IX justo previa a la ruptura de la membrana basal en torno a la sutura epitelial de la línea media. Los hechos asociados con la palatogénesis están controlados por el mesénquima de las apófisis palatinas bajo la influencia de una variedad de genes homeobox y factores de transcripción y de varios factores de crecimiento (particularmente TGF-Betas) (AU)