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Does mesna prevent the embryotoxic manifestations of cyclophosphamide?
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Reproductive Toxicology
A computer-assisted estimation of risk in monogene hereditary diseases B. Kobrinsky, L. Kazantseva, R. Uvarov Institute of Paediatrics and Child Surgery, Moscow, Russia
A procedure based on a method presented by E.A. Murphy and G.A. Chase (1975) and realized on IBM PC/AT has been applied to calculate recurrence risk of monogene diseases in families: at the 1st step--moving from proband up the pedigree--probability estimates of his ancestors' genotypes are calculated; at the 2nd step--moving down the pedigree--probability estimates of his offspring genotypes are calculated in accordance with Bayesian procedure in the case of autosomal-dominant, autosomal-recessive, and Xlinked recessive modes of inheritance. As a preliminary, a coefficient of relationship is calculated automatically for each member of the pedigree. The character of disease inheritance, its penetrance and gene mutation frequency (for isolated case of autosomal-dominant pathology) are determined automatically according to Catalogue of hereditary diseases in man (V.A. Mc Kusick, 1988), or in case of its absence in this catalogue, are asked of the clinician addressing the system. Restrictions are connected with the impossibility of accounting for consanguinity marriages in the pedigree, and the number of generations may not exceed 10. Work is being carried out to combine the given system with a programme for graphic visualization of pedigrees.
The occurrence of some uncommon congenital defects J. Kocova, T. Kohoutek Faculty of Medicine, Charles University, Pilsen, Czechoslovakia
There is a long tradition of teratologic studies in our Department of Histology and Embryology. All abortions from the Pilsen region are systematically studied and autopsied. This cooperation with clinical practice allows us to intercept both frequent and uncommon congenital malformations. In our set of more than 500 cases, the defects of the lymphatic system form about 6% of all anomalies. They are connected with cardiac defects and with angiodysplasia. We observed an increase of these anomalies. We observed some exceptional defects in the cranial region, including total aplasia of the head (acardius acephalus) and partial twinning in the case of dicephalous. We describe the formal pathogenesis of these defects. Acardius can develop in monochorial twins only by asymmetrically divided embryoblast and with disturbance defect in the mesenchymal differentiation of angioblasts and capillary plexuses in the region of joint embryonic stalks. Thus, the umbilical artery joined the umbilical vessels of the other fetus with resultant reverse circulation and hypoxia. The general frequency of this so-called "Twin Reversed Arterial Perfusion Sequence" has been estimated to be 1:35,000 in newborns. A double monster dicephalous dibrachius dipus can be explained as incomplete separation of embryoblast and twinning of the cranial part of the embryonic disc. Conjoined twinning occurs rarely, with a frequency variably reported at 1:50,000 to 1:100,000 live births. Our case possesses two spinal cords situated in one vertebral column
Volume 6, Number 2, 1992 canal. The grey matter is present only in lateral halves of both cords, the medial spinal ganglions are degenerated. Does mesna prevent the embryotoxic manifestations of cyclophosphamide? K. Kosar, V. Mueller Department of Biological and Medical Sciences, Faculty of Pharmacy, Charles University, Hradec Kralove, Czechoslovakia
Cyclophosphamide (CP) is an effective antitumour agent with considerable side effects such as urotoxicity, carcinogenicity, and embryotoxicity. The two manifestations mentioned formerly can be reduced by a simultaneous treatment with mesna (sodium 2-mercaptoethane sulfonate). The latter phenomenon of CP has not been shown yet to be affected by mesna. Hence, the present study was aimed at the determination of the basic embryotoxic parameters of both drugs at separate and, especially, combination administrations. The direct embryotoxicity was assessed by the CHEST (Chick Embryotoxicity Screening Test). The results of various combined dose administrations are presented. It seems from our preliminary results that mesna administered 1 hour prior to the treatment of chick embryos with CP could prevent or at least decrease the embryotoxic potential of CP depending on the ontogenetic stage and dosing. The incidence of embryolethality and malformations induced by CP was reduced from day 2 to day 4 of embryogenesis in an increasing rate. This finding is related to the limited dose spectrum of mesna only. Hazards result in risk, risks indicate hazards: A 30-yearexperience of the Czech Surveillance System of Congenital Malformations Jiri Ku~era Institute for Care of Mother and Child, Prague, Czechoslovakia
After introducing the Czech Surveillance System of Congenital malformations--the oldest nationwide system in Europe--the terms "risk" and "hazard" are confronted, and their mutual relation expounded. Main findings of projects using both descriptive and analytic epidemiology designs undertaken between 1956 and 1986 are demonstrated. In the very beginning, elementary patterns of the population background in teratogenesis were identified. A further set of programmes focused on some specific, well-defined questions. Some of them are briefly mentioned. While analyzing abnormal behaviour of congenital malformations (CM) in time and space--mostly clusters, nestings, outbreaks, accumulations, and/or drops of occurrence of C M - - w e always tried to identify a teratogenic potential, that is, a "hazard" causing the increased "risk" of abnormal cell division and, thus, the failure ofembryogenesis and/or organogenesis. In evaluating data, our own scale of validity and/or reliability of findings was used. It must be stated that, except for a few events, no teratogenic potential was found: cotton dust, fat solvents, and hair dyes of high pH can be considered the positive findings--all verified and confirmed by CHEST. A poor harvest after 30 years of work.
Reproductive Toxicology
A computer-assisted estimation of risk in monogene hereditary diseases B. Kobrinsky, L. Kazantseva, R. Uvarov Institute of Paediatrics and Child Surgery, Moscow, Russia
A procedure based on a method presented by E.A. Murphy and G.A. Chase (1975) and realized on IBM PC/AT has been applied to calculate recurrence risk of monogene diseases in families: at the 1st step--moving from proband up the pedigree--probability estimates of his ancestors' genotypes are calculated; at the 2nd step--moving down the pedigree--probability estimates of his offspring genotypes are calculated in accordance with Bayesian procedure in the case of autosomal-dominant, autosomal-recessive, and Xlinked recessive modes of inheritance. As a preliminary, a coefficient of relationship is calculated automatically for each member of the pedigree. The character of disease inheritance, its penetrance and gene mutation frequency (for isolated case of autosomal-dominant pathology) are determined automatically according to Catalogue of hereditary diseases in man (V.A. Mc Kusick, 1988), or in case of its absence in this catalogue, are asked of the clinician addressing the system. Restrictions are connected with the impossibility of accounting for consanguinity marriages in the pedigree, and the number of generations may not exceed 10. Work is being carried out to combine the given system with a programme for graphic visualization of pedigrees.
The occurrence of some uncommon congenital defects J. Kocova, T. Kohoutek Faculty of Medicine, Charles University, Pilsen, Czechoslovakia
There is a long tradition of teratologic studies in our Department of Histology and Embryology. All abortions from the Pilsen region are systematically studied and autopsied. This cooperation with clinical practice allows us to intercept both frequent and uncommon congenital malformations. In our set of more than 500 cases, the defects of the lymphatic system form about 6% of all anomalies. They are connected with cardiac defects and with angiodysplasia. We observed an increase of these anomalies. We observed some exceptional defects in the cranial region, including total aplasia of the head (acardius acephalus) and partial twinning in the case of dicephalous. We describe the formal pathogenesis of these defects. Acardius can develop in monochorial twins only by asymmetrically divided embryoblast and with disturbance defect in the mesenchymal differentiation of angioblasts and capillary plexuses in the region of joint embryonic stalks. Thus, the umbilical artery joined the umbilical vessels of the other fetus with resultant reverse circulation and hypoxia. The general frequency of this so-called "Twin Reversed Arterial Perfusion Sequence" has been estimated to be 1:35,000 in newborns. A double monster dicephalous dibrachius dipus can be explained as incomplete separation of embryoblast and twinning of the cranial part of the embryonic disc. Conjoined twinning occurs rarely, with a frequency variably reported at 1:50,000 to 1:100,000 live births. Our case possesses two spinal cords situated in one vertebral column
Volume 6, Number 2, 1992 canal. The grey matter is present only in lateral halves of both cords, the medial spinal ganglions are degenerated. Does mesna prevent the embryotoxic manifestations of cyclophosphamide? K. Kosar, V. Mueller Department of Biological and Medical Sciences, Faculty of Pharmacy, Charles University, Hradec Kralove, Czechoslovakia
Cyclophosphamide (CP) is an effective antitumour agent with considerable side effects such as urotoxicity, carcinogenicity, and embryotoxicity. The two manifestations mentioned formerly can be reduced by a simultaneous treatment with mesna (sodium 2-mercaptoethane sulfonate). The latter phenomenon of CP has not been shown yet to be affected by mesna. Hence, the present study was aimed at the determination of the basic embryotoxic parameters of both drugs at separate and, especially, combination administrations. The direct embryotoxicity was assessed by the CHEST (Chick Embryotoxicity Screening Test). The results of various combined dose administrations are presented. It seems from our preliminary results that mesna administered 1 hour prior to the treatment of chick embryos with CP could prevent or at least decrease the embryotoxic potential of CP depending on the ontogenetic stage and dosing. The incidence of embryolethality and malformations induced by CP was reduced from day 2 to day 4 of embryogenesis in an increasing rate. This finding is related to the limited dose spectrum of mesna only. Hazards result in risk, risks indicate hazards: A 30-yearexperience of the Czech Surveillance System of Congenital Malformations Jiri Ku~era Institute for Care of Mother and Child, Prague, Czechoslovakia
After introducing the Czech Surveillance System of Congenital malformations--the oldest nationwide system in Europe--the terms "risk" and "hazard" are confronted, and their mutual relation expounded. Main findings of projects using both descriptive and analytic epidemiology designs undertaken between 1956 and 1986 are demonstrated. In the very beginning, elementary patterns of the population background in teratogenesis were identified. A further set of programmes focused on some specific, well-defined questions. Some of them are briefly mentioned. While analyzing abnormal behaviour of congenital malformations (CM) in time and space--mostly clusters, nestings, outbreaks, accumulations, and/or drops of occurrence of C M - - w e always tried to identify a teratogenic potential, that is, a "hazard" causing the increased "risk" of abnormal cell division and, thus, the failure ofembryogenesis and/or organogenesis. In evaluating data, our own scale of validity and/or reliability of findings was used. It must be stated that, except for a few events, no teratogenic potential was found: cotton dust, fat solvents, and hair dyes of high pH can be considered the positive findings--all verified and confirmed by CHEST. A poor harvest after 30 years of work.