Studies on adrenal steroid hydroxylases. Extrinsic properties of the optical activity in adrenal iron-sulfur protein (adrenodoxin).
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Adrenal Glands↗
Biomedical subjects
R Padmanabhan
Publications and source records attributed to R Padmanabhan.
Extrinsic properties of optical activity in adrenal iron-sulfur protein (adrenodoxin).
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Adrenal Glands↗
Studies on steroid hydroxylase. Molecular properties of adrenal iron-sulfur protein.
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Adrenal Glands↗
Nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate-linked succinic semialdehyde dehydrogenases in a Pseudonomas species.
A Pseudomonas species grown on polyamines was found to have the following enzymes that can dehydrogenate succinic semialdehyde: a constitutive nicotinamide adenine dinucleotide phosphate (NADP)-linked dehydrogenase, an inducible NAD-linked dehydrogenase specific for succinic semialdehyde (EC 1.2.lb), and more than one inducible NAD-linked aminoaldehyde dehydrogenase which can act on succinic semialdehyde, 3-aminopropanal, and 4-aminobutanal. These enzymes have been separated from each other by ammonium sulfate precipitation, column chromatography on diethylaminoethyl-Sephadex, and electrophoresis on polyacrylamide gel. The level of NAD-linked succinic semialdehyde dehydrogenase in cells grown on various C and N sources has been determined and found to be as expected of an inducible enzyme with, however, two slight variations: the basal level of the enzyme in cells grown on Casamino Acids is relatively high and readily detectable, and the level of this enzyme is the same when the cells are grown on gamma-aminobutyrate with or without glucose and is, therefore, not subject to the classical glucose effect.
Aldehydes↗
Experimental induction of cranioschisis aperta and exencephaly after neural tube closure. A rat model.
Administration of single doses of cyclophosphamide to pregnant rats on days 12-14 of gestation (i.e. well after closure of the neural tube) resulted in cranioschisis and exencephaly in 100% of fetuses observed at term. In these fetuses the brain was covered by atrophic epidermis devoid of skin appendages and a highly vascular loose mesoderm without the osseous skull vault and the meninges. There were obvious hemorrhages in the brain tissue and in the ventricles. The thin walls of the distended ventricles showed breaks through which the ventricles communicated with the exterior and with the cavities in the brain. The choroid plexus had hypertrophied and denuded neuroepithelium could be found in the ventricles. Associated anomalies included edema, hemorrhage, exophthalmia, micrognathia, defects of the skull base, an increase in the basiocranio vertebral angle, reduction deformities of the limbs, etc. Chronological observations indicated a progressive distension of the ventricular system of the brain. A very high incidence of cranioschisis and exencephaly and the consistency of associated pathology validate the point that this is an excellent experimental model for investigating the pathogenetic mechanisms of these serious malformations.
Anencephaly↗
Congenital malformations and intrauterine growth retardation in streptozotocin induced diabetes during gestation in the rat.
Diabetes was induced in Wistar rats by single intraperitoneal injections of streptozotocin (STZ) (50 mg/kg, in citrate buffer pH 4.7) at both preimplantation and organogenetic stages. The controls were either buffer treated or, following STZ administration, injected intraperitoneally with 2 to 6 IU of insulin daily until term. Fetuses collected on day 20 were found to have several malformations. Major abnormalities included gastroschisis and evisceration, maxillary hypoplasia and interatrial, and interventricular septal defects. Intrauterine growth retardation was present in most of the diabetic groups. Heavier placentae and shorter umbilical cords were also observed. Malformations and intrauterine growth retardation were numerous and severe in the preimplantation treatment groups. Insulin administration significantly improved the fetal body weight but did not change the malformation rate in the group made diabetic during organogenesis. It appears that the duration of hyperglycemic state plays a crucial role in malformation and growth retardation, and meticulous control of blood sugar from early stages has significant beneficial effects on fetal development.
Animals↗
Sodium valproate augments spontaneous neural tube defects and axial skeletal malformations in TO mouse fetuses [corrected].
The TO mouse exhibits a low incidence (3.65%) of spontaneous exencephaly at birth. The objectives of this study were to determine if sodium valproate (VPA) would augment this background frequency of exencephaly and to characterize its gross and histologic bases. Single doses of 200, 400, or 600 mg/kg of VPA were administered on one of gestation days (GD) 7 to 10 and fetuses were collected on GD 18. Significant augmentation of the background incidence of exencephaly was observed in the GD 7 and 8 treatment groups. Absence of the skull vault, hemorrhage, and degeneration of the exposed brain, polyhydramnios, and a female excess characterized the abnormality. Exencephalic embryos were markedly growth retarded. In addition to craniofacial and urogenital anomalies, severe axial skeletal malformations were found to be consistently associated with exencephaly. Morphometric evaluation of the alizarin red-stained skeleton confirmed significant skeletal growth inhibition. Histologic sections of GD 10 embryos revealed early onset of treatment-related growth retardation. Arrest of closure appeared to affect intermittent segments of the neural tube. The closure defect sometimes only involved the surface ectoderm of the dorsal midline. The unclosed neural tube was at times covered by a continuous layer of surface ectoderm. Cell death per se was not pronounced in the neuroepithelium. The mesenchyme was generally sparse and edema was obvious in embryos with partial closure. Growth inhibition of the optic and otic primordia was marked by pronounced cell death in these structures as well as in the otic and trigeminal ganglia and in the pharyngeal arch mesenchyme. Evidence for neural crest cell migration was also recorded. These data indicate that VPA interacts with genetic susceptibility, augments the frequency of exencephaly, and also induces other malformations in the TO mouse. The widespread malformations of the cranifacial structures are suggestive of the preferential effect of VPA on the neural crest or its derivatives.
Analysis of Variance↗
Folic acid awareness and intake survey in the United Arab Emirates.
OBJECTIVE: The aim of this study was to determine the level of knowledge and use of periconceptional folic acid supplementation in a sample of postpartum women recruited from three hospitals. DESIGN: Cross-sectional survey in which a structured questionnaire was used in a face-to-face encounter between the subject and a trained nurse. SETTINGS: Two teaching hospitals associated with Faculty of Medicine and Health Sciences and one private hospital. SUBJECTS: Postpartum women in the three hospitals were recruited during a 40-day period in November 1999. Women who did not agree to participate, had complicated labor, delivered babies with congenital malformations, or were too exhausted or difficult to examine, were excluded. RESULTS: Univariate analyses showed that overall 46.4% of the respondents had heard about folic acid and only 8.7% knew that it prevented birth defects. 45.5% of respondents took folic acid in the first trimester. The percentage of women who had ever heard about folic acid was higher in those with higher education, and those who were not UAE nationals. Use of folic acid was associated with non-UAE nationality. CONCLUSION: Awareness of the value of periconceptional folic acid was very low and use of folic acid was less prevalent among women of UAE nationality.
Adult↗
Effect of Rhazya stricta on the developing rat fetus.
Rhazya stricta is a medicinal plant traditionally used in the treatment of diabetes mellitus, inflammation, and helminthiasis. Our objective was to determine if the plant extract has any effect on fetal development in the rat. A lyophilized extract of the plant was administered daily on three consecutive gestation days (GD) covering the period of preimplantation and organogenesis. The fetuses were examined on GD 20. Higher doses (5.0 or 8.0 g/kg) of R. stricta generally caused a reduction in maternal weight gain, compared to controls, whereas the lower doses (0.5 to 2.0 g/kg) did not. Treatment on GD 1, 2, 3, or 7, 8, 9 had no effect on the fetal weight. Treatment on later days GD 8, 9, 10, or 10, 11, 12, or 13, 14, 15 reduced both the number of live fetuses and their weight. Pronounced intrauterine growth retardation (IUGR) was observed in groups treated at later stages, particularly in the high dose groups. Extreme resorption characterized R. stricta treatment on GD 10, 11, and 12. Examination of the conceptus 24 h after R. stricta treatment indicated retarded placental development associated with hypovascularity, which possibly contributed to the IUGR and fetal death. The incidence of malformations such as micromelia, adactyly, maxillary-mandibular hypoplasia, protruding tongue, and edema, did not reach statistical significance. Except perhaps for a generalized growth retardation, no skeletal malformations were obvious. These observations are suggestive of potential fetal toxicity of R. stricta if taken during pregnancy.
Animals↗
Retinoic acid-induced asymmetric craniofacial growth and cleft palate in the TO mouse fetus.
The etiology and pathogenetic mechanisms of cleft palate (CP) are rather uncertain. Both genetic and environmental factors are known to cause failure of horizontalization and/or failure of fusion of the palatal shelves resulting in CP. Retinoic acid (RA)-induced CP in the mouse is reported to exhibit two peaks of incidence separated by a less sensitive window. The morphologic bases of the differential sensitivity are not known. The objectives of this study were to determine whether the TO mouse had similar peaks of sensitivity to RA-induced CP, and if it did, to evaluate the morphologic and histologic bases of CP induced at an early [Gestation Day (GD) 8] and at a late (GD 12) stage of embryonic development. Single doses of all-trans-RA were administered to groups of mice on one of GD 8 to 15. On GD 18, fetuses were evaluated for the presence of CP, and the developmental stage of the palatal shelves was determined. All doses of RA were found to induce a high incidence of CP in the GD 8 to 13 treatment groups. GD 14 and 15 were not susceptible. There were no stage-dependent peaks or less sensitive windows, indicating that RA-induced CP in this strain is a continuum from GD 8 through 13. Morphologically clefting in the GD 8-RA treatment group was characterized by extreme hypoplasia (65% to 100%, depending on the dose) or agenesis (35% in the 200 mg/kg group) of the palatal shelves and associated with astomia, microstomia, aglossia, microglossia, and micrognathia with fusion of mandible, maxilla, and zygoma. Treatment on subsequent days of gestation resulted in CP with the shelves reaching progressively higher levels of maturity in terms of developmental staging. There was no case of CP with horizontalized shelves apposing but failing to fuse with each other. The facial skeleton of GD 12-RA group was hypoplastic but not malformed. Reduction in all dimensions of the cranium and mandible was highly significant (P < 0.001) in the GD 8-RA group, whereas there was a clear imbalance between the vertical growth and that in other directions in the GD 12-RA group. The CR length, head and body weights, and the protein content of heads of GD 8-RA-treated embryos were significantly reduced. Histologic studies showed that both the intrinsic and extrinsic muscles of the tongue and face, growth of the Meckel's cartilage, and ossification of the mandible were severely affected in the GD 8 treatment group, whereas these tissues were only moderately affected in the embryos of the GD 12-RA group. However, the quality of cytodifferentiation of the muscles was not affected in either group. These data provide evidence for the susceptibility continuum of CP in this strain. They also indicate that agenesis and hypoplasia of the palatal shelves and primordia of craniofacial skeleton and musculature contribute to CP, the relative involvement of the components depending on the stage of drug administration. In the absence of pronounced cell death, it appears that RA possibly produces its deleterious effects on the precursors of craniofacial primordia, such as the neural crest, by misexpression of developmentally important genes.
Animals↗
Retinoic acid-induced caudal regression syndrome in the mouse fetus.
Caudal regression syndrome (CRS) comprises developmental anomalies of the caudal vertebrae, neural tube, urogenital and digestive organs, and hind limbs, the precursors of all of which are derived from the caudal eminence. Although the syndrome is well recognized, the etiology and pathogenetic mechanisms are poorly understood. Genetic and experimental models may provide some important clues to the early events that precede the dysmorphogenesis in CRS. The objectives of this study were to determine the susceptible stages for induction of CRS and to ascertain the early events that precede the development of this syndrome in a mouse model. Single oral doses of 100, 150, or 200 mg/kg retinoic acid (RA) were administered to TO mice on one of Gestation Days (GD) 8 to 12, and fetuses were observed on GD 18. All doses administered on GD 8 or 9 resulted in CRS in a large number of survivors. Agenesis of the tail, caudal vertebral defects, spina bifida occulta/aperta, imperforate anus, rectovesicle or rectourethral fistula, renal malformations, cryptorchidism, gastroschisis, and limb malformations, including the classical mermaid syndrome (sirenomelia), were characteristic features of this animal model. Several craniofacial malformations accompanied CRS in the GD 8 treatment group. Chronologic examination of treated embryos at early stages revealed pronounced cell death in the caudal median axis, hindgut, and neural tube and consequently, failure of development of the tail bud in the high-dose groups. In the 100 mg/kg RA group, patches of hemorrhage occurred initially that subsequently coalesced into large hematomas and the tail progressively regressed. Histologic examination revealed the onset and progression of hemorrhage, edema, and cell death in these embryos. Transillumination and histologic preparations also revealed dilation of the caudal neural tube in the prospective CRS embryos. Thus, a combination of cell death, vascular disruption, and tissue deficiency appears to be the highlight of caudal regression in this model. Symmelia appeared to be due to failure of fission or due to the merger of limb fields rather than a result of fusion of two limb buds. The data are also indicative of caudal agenesis in the high-dose RA groups and caudal regression due to a combination of vascular disruption, edema, and cell death in the lower dose groups of TO mouse embryos.
Abnormalities, Drug-Induced↗
Chlorambucil-induced postclosure exencephaly and axial skeletal abnormalities in rat fetuses.
Open neural tube defects (NTD) are reported to arise from failure of the embryonic neural folds to close or rupture of a previously closed neural tube. The critical period for dysmorphogenesis of the neural tube by either mechanism is of clinical importance. We had previously reported that single doses of cyclophosphamide (CPA), administered to pregnant rats resulted in reopening of the closed neural tube. The objective of the present study was to determine if other antineoplastic drugs also had similar ability to cause rupture of the closed neural tube. Therefore, single doses of chlorambucil dissolved in bicarbonate buffer were administered to Wistar rats on one of gestation days (GD) 11 through 14 (i.e., well after closure of the neural tube) and fetuses were examined on GD 20. It was observed that the window of susceptibility extended from GD 11 through 14 and that a single dose of 10 mg/kg of the drug was most effective. The affected fetuses had the prosencephalon and mesencephalon parts of the brain protruding through a wide opening of the cranial roof. The exposed brain tissue was hemorrhagic and covered by a thin, transparent and often porous membrane. The cranial vault was missing. Numerous malformations of the axial skeleton and of several nonneural organs were found to accompany the brain defect. Electron microscopic and light microscopic studies revealed extensive cell death, fragmentation, and phagocytosis of dead cells and vacuolization of the neuroepithelium (NE) within 12 h of the drug treatment. Cell death per se was not pronounced in the cranial mesenchyme (ME). The vacuoles in the NE coalesced into small cavities. The ME failed to proliferate adequately and organize itself into the cranial vault primordium. Hemorrhage and disorganization of the NE was progressive. The fluid that escaped into the interstitium seemed to extend into the cysts that developed in the ME externally and into the ventricular system internally. The edema of the ME thus might have contributed to disruption of precursor mesenchymal tissue and consequently to malformation of the cranial bones. Large hematomas and cysts also developed on the basal aspect of the crumbling brain vesicles and appeared to lift the neural tissue out of the shallow cranial cavity. As previously reported for CPA, these data provide evidence for the ability of chlorambucil to cause postclosure exencephaly in rat fetuses for a susceptible period that is considerably long.
Abnormalities, Drug-Induced↗
Atypical ductal hyperplasia in stereotactic breast biopsies: enhanced accuracy of diagnosis with the mammotome.
There is little literature assessing the incidence of subsequent carcinoma in patients diagnosed with atypical ductal hyperplasia (ADH) by mammotome. We reviewed 216 stereotactic mammotome biopsies (SMBs) and compared the results to the 121 automated tru-cut biopsies (ATC) performed at our breast care center from June 1994 to July 1998. The median age in the mammotome series was 57 years, compared to 56 years in the ATC group. An increase in biopsies for microcalcifications (49% versus 41%) was noted in the SMB series. This was accompanied by an increase in the number of cases with a diagnosis of pure ductal carcinoma in situ (DCIS) (10% versus 4%). Compared to the tru-cut, in which 38% (3 of 8) of the cases diagnosed as atypical hyperplasia (AH) showed DCIS and/or invasive carcinoma on open biopsy, none of the cases diagnosed as AH on mammotome revealed carcinoma on open biopsy. ADH is more accurately diagnosed with SMB than by the ATC method and may not be an indication for subsequent open biopsy.
Adult↗
Exencephaly and axial skeletal malformations induced by maternal administration of sodium valproate in the MF1 mouse.
Clinical and epidemiological studies indicate that maternal use of valproic acid (VPA) during pregnancy causes an increased risk for spina bifida in the fetus. A proportion of infants exposed to VPA in utero exhibit a characteristic pattern of facial malformations. Despite the developmental interdependence of the neural plate and paraxial mesoderm during normal morphogenesis, the possible involvement of the axial skeleton in VPA-induced NTD has not been clearly documented. So the objective of this investigation was to determine the nature and extent of involvement of the axial skeleton in VPA-induced exencephaly in the mouse. A single dose of 600 mg/kg of sodium valproate was administered (IP) to MF1 mouse on day 8 of gestation. This treatment resulted in significant increase in resorption, reduction in mean fetal weight, and exencephaly (25%) of live fetuses. Several craniofacial malformations and subcutaneous haematomas were associated with exencephaly. Alizarin red-stained skeletal preparations revealed maxillary-, mandibular hypoplasia, absence of skull vault, hypoplasia and/or agenesis of basicranial bones, and obtuse angulation of the craniovertebral junction. Hemivertebrae, longitudinal fusion of the vertebral arches and bodies, accessory ribs (cervical and lumbar), fusion of thoracic ribs, and several patterns of sternal variations were observed. Nonexencephalic VPA-treated embryos exhibited mandibular, maxillary hypoplasia, arched and cleft palates, cleft lip, kinky tail, and vertebral and sternal anomalies. Treated embryos at early stages of development revealed delay in elevation and fusion of neural folds, distended IVth ventricle, kinky spinal cord, incomplete separation of somites and growth retardation. When viewed in light of the published work on VPA action on embryonic systems, these observations suggest that abnormalities associated with VPA-induced exencephaly may be due to either a direct action of VPA on the precursors of these organs or secondary to its action on neural tube. A significantly high incidence of NTD and their consistent association with defective development of the axial skeleton suggest that this is an excellent experimental model for investigating the pathogenetic mechanism(s) of VPA induced NTD.
Abnormalities, Drug-Induced↗