Failure of carbon monoxide to induce myocardial infarction in cholesterol-fed cynomolgus monkeys (Macaca fascicularis)

The effect of prenatal administration of different doses of cortisone, corticosterone, dexamethasone, triamcinolone and prednisolone on the fetus and its palatal development was studied. All the glucocorticoids, except cortisone, produced cleft palate in the fetuses. Both the total frequency and morphologically different types of cleft palate were related to the dose of the teratogen. Triamcinolone appeared to be more potent than other glucocorticoid in inducing cleft palate. An association was noted between fetal growth inhibition, the dose of the teratogen and the frequency and type of cleft palate.     

Developmental toxicity of clarified slurry oil, syntower bottoms, and distillate aromatic extract administered as a single oral dose to pregnant rats

Clarified slurry oil (CSO), syntower bottoms (STB), and distillate aromatic extract (DAE) are refinery streams produced by processing crude oil. Each of these refinery streams is rich in both hydrocarbons having carbon numbers of C20 or greater and polycyclic aromatic compounds. Available data indicate that some refinery streams are developmentally toxic (manifested primarily as increased embryolethality and growth retardation) by the dermal route of exposure. However, there is no conclusive evidence for their being teratogenic. The present studies were designed to further explore the suspected teratogenic potency of refinery streams while at the same time limiting embryolethality. To profile teratogenic effects as a function of gestation day, pregnant rats received a single oral dose (2000 mg/kg) of CSO, STB, or DAE on one of gestation days (GD) 11-14; DAE and STB were also administered on GD 15. To profile effects as a dose response function, rats received a single oral dose of CSO, DAE, or STB on GD 12 at 125, 500, and 2000 mg/kg. Control animals were similarly treated but were administered tap water. On GD 20, dams were necropsied and the fetuses evaluated for normal development. In general, evidence of maternal toxicity (i.e., decreased body weight gain, decreased thymus weight) was observed at doses greater than or equal to 500 mg/kg. For each refinery stream tested, the incidence of resorption was greatest on GD 11. A common pattern of fetal malformations was observed for all of the refinery streams tested and included cleft palate, diaphragmatic hernia, and paw and tail defects. The incidence and type of malformation observed were influenced by the gestation day of exposure. The incidences of external and skeletal malformations were greatest on GD 11 and 12 for fetuses exposed to CSO; on GD 13 and 14, the incidence of malformation was comparable for CSO- and STB-exposed fetuses. The incidence of visceral anomalies was greatest on GD 11-13 for fetuses exposed to CSO and STB; on Gestation D 14, the incidence was comparable for each of the refinery streams tested. In general, the ability to produce adverse effects on development was greatest for CSO and least for DAE. Effects produced by STB were comparable to or less severe than those observed for CSO.     

Effects of glucocorticoids on pharmacokinetics and pharmacodynamics of midazolam in rats

We investigated the effect of dexamethasone (80 mg/kg per day for 2 days) and prednisolone (600 mg/kg per day for 2 days, equivalent to dexamethasone for glucocorticoid (GC) potency) on both pharmacokinetics and pharmacodynamics of midazolam (MDZ), a substrate for cytochrome P450 (CYP) 3A, in 8-week-old male Sprague-Dawley rats. Animals received a single injection of MDZ (pharmacokinetic study, 10 mg/kg; pharmacodynamic study, 55.5 mg/kg) in the tail vein 24 h after the last dose of GC or placebo. The elimination half-life (t(1/2)) and the area under the concentration-time curve of MDZ were significantly reduced by pretreatment with dexamethasone to 58.9% and 44.7% of the control value, respectively, and the clearance of MDZ was significantly increased by dexamethasone. Similar changes observed by prednisolone pretreatment did not reach significance. The t(1/2) of the dexamethasone pretreatment group (14.4+/-0.7 min) was significantly shorter than that of the prednisolone group (20.9+/-1.5 min). The amount of CYP3A2 protein and the activity of erythromycin N-demethylase were significantly increased by dexamethasone and prednisolone pretreatments, but dexamethasone showed a greater effect than prednisolone. Sleeping time was significantly shortened by dexamethasone and prednisolone pretreatment to 38.7% and 57.1% of control value, respectively. The current study demonstrates that the anesthetic effect of MDZ would be reduced in patients treated with dexamethasone or prednisolone, and that the CYP3A induction was greater by dexamethasone than by prednisolone, implying that the potency of CYP3A induction may differ among GCs even when GC activity is the same.     

Plasma integrated concentration of growth hormone after recombinant human growth hormone injection. Implications for determining an optimal dose

The length of the cervical spine in a series of 206 adult males with cleft lip and/or palate and 50 normal controls was measured. The patients were divided into five subgroups according to the type and extent of the cleft. The shortening of the spine was most marked in bilateral cleft lip and palate patients (complete), less marked in unilateral cleft lip and palate patients, and was slight in isolated cleft palate patients. Complete isolated cleft palate and cleft lip was not associated with a shortening of the spine. A shortening of the cervical spine in less extensive types of isolated cleft palate was suggestive of the participation of the spine in their development, while in cleft lip and palate a simultaneous exposure to a teratogenic agent or any other developmental error during early stages of embryogenesis could explain the concomitant occurrence of spine anomalies. Patients with cleft lip and palate associated with a short spine also had a shorter mandibular ramus, which could be suggestive of simultaneous damage to both structures during morphogenesis. This relationship was not demonstrated in isolated cleft palate that developed in later stages of embryogenesis. In these cases a short spine itself could not have impaired the growth potential of the mandible, yet it could have mechanically induced the development of cleft palate. These observations are in agreement with the present state of knowledge on the development of orofacial clefts as shown in experimental animals.     

Spinal cord limb motor neurons in dystrophia myotonica

Pregnant New Zealand White rabbits were treated on gestation day 12 with 19.2 mg/kg methotrexate (MTX), 750 mg/kg hydroxyurea (HU), or 1,500 mg/kg acetazolamide. Rabbits were killed either 2-32 hours posttreatment for histological analysis of embryos or at day 29 for gross and skeletal examination of fetuses. tmtx produced cleft palate, hydrocephalus, and fore- and hindlimb reduction defects. Histological analysis revealed pyknosis and edema in mesenchymal tissues at four to eight hours following treatment. The apical ectodermal ridges (AER) of treated embryos permanently lost their characteristic pseudostratified organization. By 32 hours the limb buds had regained their normal appearance except for the AER. HU affected all fetuses with skull and facial anomalies as well as severe reduction deformities of all limbs. Histologically HU-treated embryos had numerous, basophilic, intercellular granules (presumably cell debris) which appeared within two to four hours in the limb bud mesenchyme, neural tube, and dorsal root ganglion. The architecture of the AER was unchanged. Acetazolamide produced bilateral retarded ossification or possible aplasia of the first metacarpal and talus in nearly 80% of fetuses. Microscopic examination disclosed no apparent alterations in limb-bud morphology. Methyl green-pyronin Y staining called attention to green intracellular droplets within the endoderm of the trachea and bronchi at two hours posttreatment. It was concluded that the three drugs do not produce limb dysplasias by a common teratogenic mechanism.     

Induction of a receptor-mediated genomic DNA fragmentation in rat thymus following administration of glucocorticoids with different biopotencies: an approach by a cell-free system

To further understand a receptor-mediated apoptosis in rat thymus, we undertook experiments to examine the relationship between the induction of genomic DNA fragmentation and the depletion and the replenishment of cytosolic glucocorticoid receptor in rat thymus. Following administration of dexamethasone and prednisolone which had been known as synthetic glucocorticoids with different biological activities, we observed the fragmentation of thymus DNA in a dose-dependent manner. The time course and the extent of DNA fragmentation induced by these glucocorticoids were closely related to the degree of receptor depletion and the length of the depletion period. Relative biopotencies of dexamethasone and prednisolone estimated by their abilities to induce the DNA fragmentation were approximately 50:1. Administration of dexamethasone in combination with 2-deoxy-D-glucose, a potent inhibitor of the glycolytic pathway, significantly decreased the ability of dexamethasone to induce the DNA fragmentation, suggesting that a receptor-mediated DNA fragmentation by glucocorticoids is an ATP-dependent process. As an attempt to elucidate the molecular mechanism of DNA fragmentation in vivo, we reconstituted a cell-free system of thymus nuclei and cytosol fraction. Using the thymus cytosol fraction from dexamethasone-treated rats, we demonstrated for the first time an ATP-dependent fragmentation of nuclear DNA into nucleosomal units in vitro. Toward further understanding of the biochemical process of glucocorticoid-induced apoptosis in the thymocyte, the cell-free system reconstituted in the present study might provide a useful model system.     

Effects of 5-fluorouracil on embryonic rat palate in vitro: fusion in the absence of proliferation

5-Fluorouracil (5-FU) inhibits the enzyme thymidylate synthetase (TS) which results in inhibition of DNA synthesis. 5-FU is teratogenic in many species, inducing cleft palate, limb, and tail defects. In the present study, gestation day (GD) 14 embryonic rat craniofacial explants were exposed to 5-FU in organ culture with increasing concentrations and durations of exposure. Palates exposed to 5-FU were morphologically abnormal and craniofacial shape, size, and palatal fusion pattern were affected with the severity of effects dependent on concentration and duration of exposure. Cleft palate was induced in vitro as opposing palates overlapped in a narrowed oral cavity. Palates exposed to higher levels of 5-FU were growth inhibited, but fused even though proliferation ceased and few cells were available to participate in elevation and fusion. This was demonstrated as a biphasic concentration-response profile for palatal fusion in which 0.05 to 0.15 micrograms 5-FU/ml produced decreasing rates of palatal fusion, while exposure to 0.15 to 3.0 micrograms/ml resulted in progressively increasing rates of fusion. The effects of 5-FU were detected biochemically as a reduction in TS activity which was concentration and time dependent during the first 12 hours, with a return to control levels by 24 hours. During the first day, 5-FU did not alter protein levels, but DNA levels significantly decreased at the high concentration, 2.0 micrograms/ml. After 5 days in culture, both DNA and protein decreased with increasing 5-FU concentration and duration of exposure. Also by the end of the culture period, 3H-TdR incorporation had decreased in a concentration dependent manner. It is concluded that progressive inhibition of proliferation and growth in organ culture results in two different morphological outcomes: cleft palate resulting from a narrowed oral cavity and increased incidence of anterior palatal fusion under conditions of strong growth reduction. This study demonstrates that elevation and fusion can occur in the absence of growth and proliferation. Based on these observations, severe inhibition of growth or proliferation would not necessarily be sufficient to induce cleft palate.     

Influence of abdominal aortic aneurysm size on the feasibility of endovascular repair

The specificity and potency of glucocorticoids to lower serum calcium (Ca) in rats after parathyroidectomy (PTX) and adrenalectomy (ADX) were examined. Rats fasted overnight were given sc injections of various steroids immediately after the operations. The fall in serum calcium 5 h after PTX-ADX in rats given hypocalcemic doses of corticosterone was compared to that after injection of a test steroid. At high doses, progesterone, estradiol, testosterone, and aldosterone were inactive, whereas glucocorticoids were consistently hypocalcemic. These results indicate that the Ca-lowering effect is specific for steroids with glucocorticoid activity. Potency estimates were made by comparing the dose-response of natural and synthetic glucocorticoids to that of corticosterone, the major glucocorticoid in rats. The mean potency of hydrocortisone was 8.2 times that of corticosterone. Prednisolone was about 9.6, triamcinolone 33, betamethasone 109, and dexamethasone 301 times as potent as corticosterone. Thus, the use of the calcium-lowering action as a bioassay has provides a specific and rapid in vivo method to compare potencies of glucocorticoids consistent with those obtained by anti-inflammatory and glycogen deposition assays. The importance of this interesting calcitonin-like action of glucocorticoids in normal physiology of calcium metabolism is not yet established.     

Psychiatry and bioethics. An exploration of the relationship

The purpose of this study was to determine glucocorticoid modulation of ocular pressure to epinephrine applied topically to rabbit eyes that were pretreated with dexamethasone. Rabbit eyes were pretreated with five applications of topical 0.07% dexamethasone (0.1% dexamethasone phosphate) or saline drops, administered at ten minute intervals. The eyes were then treated with epinephrine bitartrate drops at concentrations of free base epinephrine of 1.1%, 0.27%, 0.05%, 0.027%, 0.005% or 0.0005%. An additional group of rabbits received dexamethasone pretreatment only. Intraocular pressure (IOP) was measured for the next four hours. Enhanced lowering of intraocular pressure was observed with dexamethasone pretreatment. Rabbits receiving the smaller dose of epinephrine with dexamethasone had the largest decrease in IOP at 135 minutes after instillation of the epinephrine drops (0.005% epinephrine, mean difference +/- standard error of mean = 5.4 +/- 1.1 mmHg). Similarly, the duration of significant decrease of the IOP was prolonged in the groups receiving the lower concentrations of epinephrine (0.005% epinephrine, 255 minutes after administration of epinephrine). The synergism between glucocorticoids and adrenergic agonists in lowering IOP may be potentially useful in the therapy of ocular hypertension and glaucoma.     

Authoritarianism in Queensland: a reply to Ray

To examine the hypothesis that the teratogenic effects of the phenothiazine derivative T-82 are due to its causing a riboflavin deficiency day 11 or 12 pregnant CB Wistar rats were each given 2,000 mg/kg T-82 po plus 100 mg/kg riboflavin ip, 12.4 mg/kg ATP ip, or both. The rates of fetal mortality and external malformations were significantly decreased in all supplementation experiments. The frequencies of cleft palate, micrognathia, and micromelia were unchanged but those of ectopic testis and hydrops fetalis were significantly increased in the group treated with T-82 and ATP on day 12.     

Hypervitaminosis A and matrix alterations in maxillary explants from 16-day rat embryos

Hypervitaminosis A in treated pregnant rats has been shown to interfere with normal palatal closure and fusion, as demonstrated by the presence of cleft palates in offspring. The observation that palatal shelves of excess vitamin A exposed fetuses are stunted and delayed in rotation suggests that vitamin A may inhibit a biochemical event crucial to the successful contact of the palatal shelves. Maxillary explants from 16 day Wistar rat embryos cultured in the presence or absence of 30 IU/ml retinyl palmitate were analyzed for DNA, glycosaminoglycan, and collagen synthesis. Maxillary explants cultured in vitamin A-containing medium showed an inhibition in DNA, GAG, and collagen synthesis in comparison to control explants. Excess vitamin A in the culture medium of maxillary explants also resulted in a reduction of intermolecular cross-links in collagen. The possible significance of the results in terms of cleft palate and normal secondary palate formation is discussed.     

Axial ultrasonographic imaging of the fetal maxilla for accurate characterization of facial clefts

The purpose of this study was to determine whether scanning of the fetal midface in the axial plane allows accurate characterization of facial clefts. During fetal anatomic survey, facial clefts were identified in six fetuses. The midface anatomy was evaluated with ultrasonography in the coronal and axial planes, and the clefts were characterized prospectively as unilateral or bilateral and as involving the lip alone or both the lip and the palate. The integrity of the upper lip was assessed in the coronal and axial planes. The continuity of the normal C-shaped curve of the tooth-bearing alveolar ridge and the anterior six tooth sockets was assessed in the axial plane. The prospective prenatal diagnosis was correlated with postnatal findings in all cases. The clefts where characterized prospectively as unilateral cleft lip (one case), unilateral cleft lip and cleft palate (four cases), and bilateral cleft lip and cleft palate (one case). The prenatal characterization was confirmed to be correct postnatally in all cases. Prenatal sonographic evaluation of the axial view of the tooth-bearing alveolar ridge of the maxilla allows accurate determination of whether a cleft is confined to the lip or involves both the lip and the palate.     

Maternal hyperoxia greatly reduces the incidence of phenytoin-induced cleft lip and palate in A/J mice

The A/J mouse has been used to study the teratogenic affects of phenytoin. The developmental abnormalities produced in offspring of this model are similar to some of the malformations observed in cases of human "fetal hydantoin syndrome." Placing pregnant A/J mice in a hyperoxic chamber after phenytoin injection greatly reduces the incidence of phenytoin-induced cleft lip and palate. These results suggest that phenytoin may affect embryonic development indirectly by altering maternal physiology. This maternally mediated mechanism, and the protection against it afforded by hyperoxia, has general implications for the effects of maternal toxicity on teratogenesis.     

Rhinolith in a patient with cleft palate: a case report

Dental anomalies are well documented in patients with cleft palate, although reports of intranasal teeth in these patients are extremely rare. This paper discusses the case of a rhinolith associated with tooth-like structures in a patient with a treated cleft palate.     

Antineurofilament and antiretinal antibodies in AIDS patients with cytomegalovirus retinitis

Approximately 5% of children with neural tube defects (NTDs) have a congenital heart defect and/or cleft lip and palate. The cause of isolated meningomyelocele, congenital heart defects, or cleft lip and palate has been largely thought to be multifactorial. However, chromosomal, teratogenic, and single gene causes of combinations of NTDs with congenital heart defects and/or cleft lip and palate have been reported. We report on 3 patients with meningomyelocele, congenital heart defects, and 22q11 deletions. Two of the children had the clinical diagnosis of velo-cardio-facial syndrome (VCFS); both also have bifid uvula. The third child had DiGeorge sequence (DGS). The association of NTDs with 22q11 deletions has not been reported previously. An accurate diagnosis of the 22q11 deletion is critical as this micro-deletion and its associated clinical problems is transmitted as an autosomal dominant trait due to the inheritance of the deletion-bearing chromosome. We recommend that all children with NTDs and congenital heart defects, with or without cleft palate, have cytogenetic and molecular studies performed to detect 22q11 deletions.     

Dexamethasone treatment of the guinea pig fetus: its effects on the incorporation of 3H-thymidine into deoxyribonucleic acid

Pregnant guinea pigs of 50 to 53 days' gestation (term 63 days) were anesthetized with ether, and their fetuses were injected intramuscularly with 30 mg of dexamethasone or sterile saline. One week later, the fetuses were injected with 3H-thymidine intramuscularly under direct vision at laparotomy; after one hour, the incorporation of thymidine into deoxyribonucleic acid (DNA was analyzed in various fetal tissues. The relative labeling of DNA was significantly depressed in the cerebral hemispheres, cerebellum, medulla oblongata, and midbrain of the treated fetuses compared to their littermate controls. The relative labeling of the DNA of lungs, kidneys, heart, and adrenals was also significantly reduced. Increasing the dose of dexamethasone produced a progressive inhibition of the incorporation of 3H-thymidine into DNA. A variable recovery from the inhibition became apparent by 14 days following exposure to dexamethasone. The evidence suggests that exposure of the fetus to dexamethasone may exert a potentially deleterious effect on fetal tissues.     

Dextromethorphan and dextrorphan in rats: common antitussives--different behavioural profiles

Patients with complete unilateral cleft lip and palate present difficult growth problems. Their anteroposterior discrepancies in jaw and dentition are frequently so severe that some epidemiologic studies report the necessity of orthognathic surgery in 25% of their sample. The aims of this study were three-fold: (1) to delineate diagnostic measures in borderline surgical cases of unilateral cleft lip and palate, (2) to verify the significance of negative overjet as a measure of anteroposterior discrepancy, and (3) to compare these diagnostic measures with those of borderline surgical cases of noncleft Class III malocclusions. The sample consisted of 29 patients with unilateral cleft lip and palate and 25 noncleft Class III Korean patients (mean age, 18.69 years); all had crossbites of all four incisors. Each of their pretreatment study casts and cephalograms were analyzed. The group with unilateral cleft lip and palate was divided into two subgroups on the basis of the method of their anterior crossbite resolution; 18 subjects were treated with orthodontics alone (Cleft-NS) and 11 subjects with orthognathic surgery (Cleft-Surg). The noncleft Class III group was divided into two subgroups; 6 of the subjects were orthodontically treated (Cl III-NS), and 19 were surgically treated (Cl III-Surg). The group with unilateral cleft lip and palate showed smaller SNA and SNB angles than the noncleft Class III group, but the ANB angles and the amount of anterior crossbites showed no statistical differences. When the Cleft-NS and the Cleft-Surg groups were compared, the ANB angle and the Wits measurements were significantly different. When the Cl III-NS and Cl III-Surg groups were compared, the SNB, ANB, L1GoGn, Wits, and the crossbite showed significant differences. For borderline surgical Class III unilateral cleft lip and palate cases, ANB angle, Wits appraisal, and ABGoGn angle were critical diagnostic parameters. On the other hand, the magnitude of anterior crossbite, the negative overjet, was shown not to be a significant measure of anteroposterior discrepancy.     

Acceptability of BCG vaccination

Exposure of Syrian hamsters for two twenty-minute periods at 40 degrees C on a single day of pregnancy (ranging from day 6 to day 13) resulted in differing teratogenic effects. Maximum resorption (52.6%) was seen with treatment on day 7 whereas the highest rate of malformation (51.9%) was observed with treatment on day 9. Cranial defects predominated with treatment early in pregnancy (highest incidence of day 9) while limb defects were not observed with any treatment administered before day 9. Exencephaly occurred with treatments on day 6 and 8, with a single case after treatment on day 10. Cleft lip and cleft palate were observed with treatment on days 9 and 10. These studies illustrate the usefulness of the Syrian hamsters in teratological studies and characterize some of effects exerted after mild heat treatment at varying stages of pregnancy.     

Diclofenac analgesia following cleft palate surgery

OBJECTIVE: This prospective study looked at the postoperative hemorrhage risk associated with the use of diclofenac following cleft palate repair. PATIENTS: Twenty consecutive children (6 months to 9 years of age) requiring repair of the hard or soft palate were included. DESIGN AND METHODS: Single per rectum doses of diclofenac were given at 1 mg/kg following cleft palate repair, with additional doses every 12 hours. RESULTS AND CONCLUSIONS: The use of the nonsteroidal anti-inflammatory drug, diclofenac, for postoperative analgesia is well established for many types of surgery. The authors find that twice daily diclofenac rectal suppositories provide very good analgesia postcleft palate repair. This, combined with supplemental oral paracetamol, obviates the need for opiates, resulting in alert infants who feed well and are suitable for early discharge.