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Biomedical subjects

S Norton

Publications and source records attributed to S Norton.

At least 55 records · Page 3Linked to original sources

Randomised trial of prophylactic daily aspirin in British male doctors.

A six year randomised trial was conducted among 5139 apparently healthy male doctors to see whether 500 mg aspirin daily would reduce the incidence of and mortality from stroke, myocardial infarction, or other vascular conditions. Though total mortality was 10% lower in the treated than control group, this difference was not statistically significant and chiefly involved diseases other than stroke or myocardial infarction. Likewise, there was no significant difference in the incidence of non-fatal myocardial infarction or stroke--indeed, disabling strokes were somewhat commoner among those allocated aspirin. The lower confidence limit for the effect of aspirin on non-fatal stroke or myocardial infarction, however, was a substantial 25% reduction. Migraine and certain types of musculoskeletal pain were reported significantly less often in the treated than control group, but as the control group was not given a placebo the relevance of these findings was difficult to assess. There was no apparent reduction in the incidence of cataract in the treated group. The lack of any apparent reduction in disabling stroke or vascular death contrasts with the established value of antiplatelet treatment after occlusive vascular disease.

Aspirin↗

Behavioral changes and structural defects in rats irradiated in utero.

Pregnant rats were irradiated with whole-body doses (0.25-1.25 Gy) of Cs-137 gamma-rays on gestational day 15, or with 1.0 Gy on gestational days 11, 13, 15, or 17. Postnatal growth (body weight) and several preweaning behaviors (righting reflex, negative geotaxis, reflex suspension, modified open field activity, spatial maze exploration, continuous corridor activity, and gait) of the offspring were monitored prior to sacrifice on post-parturition day 28. Brain (sensorimotor cortex) and pituitary tissues were processed for histological evaluation and morphometric analysis. For most behavioral endpoints, there were dose-dependent changes produced by irradiation on gestational day 15, with one endpoint (continuous corridor activity) demonstrating changes after 0.25 Gy that were significantly different from control values. The data indicate that the most sensitive organ showing radiation-induced alterations changes from the pituitary at gestational day 11 to the primitive cortex of the brain at days 13 to 17 with a peak of sensitivity at day 15. These results demonstrate that a spectrum of related functional and morphological deficits can be produced by even low-dose in utero irradiation, with the specific endpoint showing the greatest change being determined by the specific day of gestation on which irradiation occurs. Extrapolating from these experimental data with rats to the human situation, it is recommended that care be taken, when possible, to avoid exposure of the fetus, even after the early stages of organogenesis.

Animals↗

Early motor development and cerebral cortical morphology in rats exposed perinatally to alcohol.

Specific tests of early motor development and cerebral cortical morphology were studied in rats born from alcohol-fed mothers, pair-fed mothers, and ad libitum controls (either liquid or pellet diets). Liquid Bio-Serv diets were used. Alcohol feeding began on day 5 of pregnancy and ended on day 10 postpartum. The weight gain of the pups after birth was drastically reduced compared with pair-fed and other control groups; however, removal of the alcohol on day 10 postpartum resulted in an upswing of the growth curve that paralleled control groups. Between days 2 and 21 (postnatal) three behavioral tests of motor function were performed. Righting reflex (time for an animal to return to all four feet after being placed on its dorsum) was slightly delayed but the delay was not significant. Negative geotaxis (time for an animal to rotate 180 degrees from a head-down position on an inclined plane), and reflex suspension (time an animal maintained its grip on a crossbar) were significantly delayed (approximately 2 days) in offspring from alcohol-fed mothers. In the frontal cortex the offspring of alcohol-treated mothers, a marked decrease (approximately 25%) in thickness of Lamina VI was found while the other Lamina (I-V) were less altered. These results indicate that the effect of alcohol on the frontal cortex is related to a significant delay in motor development of reflex suspension and negative geotaxis since both of these require frontal integration.

Animals↗

Prenatal brain malformations following acute ethanol exposure in the rat.

Morphology of the cerebral cortex was studied in fetuses on gestational Day 21 following oral administration of several doses of ethanol (for total doses of 10, 15, or 18 g/kg) to pregnant rats on gestational Days 14 and 15, a critical period for the development of the cerebral cortex. All doses of ethanol were associated with a reduction in maternal weight gain, fetal body weight, and placental weight. Only the high dose of ethanol (total dose 18 g/kg) caused significant fetal cortical thinning. Acute exposure of pregnant rats to ethanol produced dose-dependent malformations of the cerebral cortex and hippocampus in fetuses. On gestational Day 21, the 18 g/kg group contained fetuses with severely disorganized cortical architecture, heterotopias of the cerebral cortex, pia and choroid plexus, and status verrucosus deformis. Fetuses from the 10 g/kg group had less severe malformations, such as disorganization of layers of cortical neurons and dentate granule cells while fetuses from the 15 g/kg group had a mixture of severe and minor malformations. This study demonstrates that acute ethanol exposure during a critical period of development in rats can result in brain malformations similar to those reported in human fetuses and neonates from alcoholic mothers.

Animals↗

Primary structure of an analog of crustacean pigment-dispersing hormone from the lubber grasshopper Romalea microptera.

An octadecapeptide capable of inducing pigment dispersion in the chromatophores of the fiddler crab Uca pugilator has been isolated from lyophilized heads of the lubber grasshopper Romalea microptera. This pigment-dispersing factor (PDF) was purified by gel filtration, ion-exchange chromatography, partition chromatography, and reversed-phase high performance liquid chromatography. Automated gas-phase sequencing, followed by the identification of the carboxyl-terminal amide, established the primary structure of this PDF as Asn-Ser-Glu-Ile-Ile-Asn-Ser-Leu-Leu-Gly-Leu-Pro-Lys-Leu-Leu-Asn-Asp-Ala- NH2. This structure was confirmed by chemical synthesis and by demonstrating that the synthetic and native PDF displayed identical chromatographic behavior and biological activity. The Romalea PDF is structurally related to the crustacean pigment-dispersing hormones (PDHs), which are also octadecapeptides. The sequence of grasshopper PDF shows 78% homology with beta-PDH (from the crabs U. pugilator and Cancer magister) and 50% homology with alpha-PDH (from the prawn Pandalus borealis). This study provides the first direct chemical evidence for the structural relatedness of insect PDF to the crustacean PDHs, thus identifying them as an authentic family of arthropod peptides.

Amino Acid Sequence↗

Gait analysis of chicks following treatment with tri-ortho-cresyl phosphate in ovo.

Chick embryos were treated during late embryonic development with tri-ortho-cresyl phosphate (TOCP), an organophosphate compound that causes delayed neurotoxicity in humans and some other species. Embryos were treated on incubation d 14 with either 62 or 250 microliters TOCP/kg egg. The higher dose reduced the number hatched, and signs of cholinergic toxicity were apparent in the newly hatched chick. All chicks that survived this dose were unable to stand. Recovery from the cholinergic effects occurred within a few days after hatching, but the chicks remained severely ataxic through 3 wk of observation. The mortality of embryos treated with 62 microliters TOCP/kg egg was not higher than that of controls, and young chicks showed no overt signs of cholinergic toxicity or ataxia. Motor impairment was detected by measuring gait parameters. These chicks had a short stride and walked with a more open angle of foot placement. These are adjustments in gait that provide a more steady base of support. The change in gait developed over a 3-wk period after hatching. The hindlimb motor impairment detected at both doses is consistent with neuropathy such as is seen in the adult chicken. The value of gait analysis is the ability to quantify effects that are not apparent by simple observation.

Animals↗

Behavioral changes in preweaning and adult rats exposed prenatally to low ionizing radiation.

Seven behavioral tests were used to evaluate the postnatal behavior of rats after exposure on gestational Day 15 to 0, 25, 50, 75, or 125 r, whole body irradiation of the pregnant rat. Three tests were administered in the first 2 postnatal weeks (righting reflex, negative geotaxis, and reflex suspension); three tests were administered on postnatal Day 21 (modified open field, spatial maze, and continuous corridor). As adults, the rats were retested with the same tests as at 21 days and also in the running wheel. Dose-response decreases in body weight were greater in the younger rats. Some behavioral tests were not altered by irradiation, while others showed clear dose-response relationships, starting as low as 25 r. The early changes were characterized by light body weight, delays in behavioral development and hypoactivity, followed by recovery of some parameters with maturation. Eventually hyperactivity developed in adult rats after gestational irradiation. However, it cannot be concluded that either morphological or behavioral tests are more sensitive than neonatal body weight change for detection of damage from gestational irradiation.

Animals↗

Primary structure of Mucor miehei aspartyl protease: evidence for a zymogen intermediate.

The gene encoding the aspartyl protease of the filamentous fungus Mucor miehei has been cloned in Escherichia coli and the DNA sequenced. The deduced primary translation product contains an N-terminal region of 69 amino acid (aa) residues not present in the mature protein. By analogy to the evolutionarily related mammalian gastric aspartyl proteases it is inferred that the primary secreted product is a zymogen containing a 47-aa propeptide. This propeptide is presumably removed in the later steps of the secretion process or upon secretion into the medium. To study the effects of modifications of the protease structure on its maturation by enzyme-engineering methods, an efficient expression system was sought. In E. coli, transcription of the preproenzyme coding sequence from a bacterial promoter results primarily in the accumulation of unsecreted, enzymatically inactive polypeptides, immunologically related to the authentic protease. In Aspergillus nidulans expression of the cloned gene, probably from its own promoter, results in the secretion into the culture medium of polypeptides which, compared to the authentic protease, are similar in specific activity, but differ in the character of their asparagine-linked oligosaccharides.

Amino Acid Sequence↗

Morphologic alterations in leg muscles of chicks treated with triorthocresyl phosphate in ovo.

Chick embryos were injected on incubation Day 14 with 62 microliter of triorthocresyl phosphate (TOCP)/kg egg. Muscles of the leg were examined from 5 to 25 days after hatching. The sartorius from the thigh and the external gastrocnemius and peroneus longus from the tibial leg region were compared for muscle fiber size and end-plate length over this period. Treated chicks showed no acute toxic effects or overt ataxia and were equal in body weight to controls. At 5, 15, and 25 days after hatching, morphologic alterations consistent with denervation were detected. Muscle fibers were smaller than controls on Day 5 and were hypertrophic on Days 15 and 25. On Day 5 growth of fibers was retarded, an effect consistent with denervation, and the subsequent hypertrophy is predicted as compensation for denervated fibers. Small end plates were seen on Day 15, characteristic of end plates that were delayed in development by denervation. Each of these differences was greater in the tibial muscles than in the more proximally located sartorius. This is consistent with a distal neuropathy, such as that caused by TOCP in adult hens. Some recovery was apparent at the low dose 25 days after hatching. It is suggested that this resulted from reinnervation by repaired axons. This study of the myoneural apparatus and muscle fiber response to TOCP adds evidence to the possibility that the developing chick embryo may develop delayed neuropathy from organophosphorus compounds which produce this effect in adult hens.

Animals↗

Forebrain damage following prenatal exposure to low-dose X-irradiation.

Exposure of fetal rats to X-irradiation on gestational day 15 resulted postnatally in dose-related effects on body weight, growth of forebrain structures, and branching of dendrites of caudate neurons. Rats were followed for 4 months postnatally after 125, 75, 50, or 25 R whole-body irradiation to the dam. Significant decreases in body weight were present at birth after the three high doses and continued as long as 4 months after 125 or 75 R. Decreased thickness of the cerebral cortex and decreased area of the caudate nucleus were also seen. Cortical thickness was reduced by 125 R to half the size of the control cortex and the caudate nucleus to two-thirds of the control. Significant decreases were present to 50 R. Dendritic branching was reduced in caudate neurons by 125 R but not in the basilar dendrites of cortical pyramidal cells. No reduction in number of cortical synapses was seen from electron micrographs of cortical layers 1 or 5. The effect on the cerebral cortex was interpreted as a loss of neurons with retention of branching and synaptogenesis of remaining neurons. In contrast, the caudate nucleus, which develops somewhat before the cerebral cortex, showed effects as a consequence either of direct damage to caudate neurons or of reduced neuropil from reduced afferent input.

Animals↗

Peripheral nerve damage in chicks following treatment with organophosphorus compounds in ovo.

Chick embryos were treated with tri-o-cresyl phosphate (TOCP) or leptophos, organophosphorus compounds that cause delayed neurotoxicity. Embryos received either TOCP (62 or 250 microliter/kg egg) or leptophos (125 to 750 mg/kg egg) Day 14 of incubation and were examined after hatching for nerve damage. The high doses caused high embryo mortality. Chicks which survived the high doses were grossly ataxic from hatching until the study was ended at 3 weeks posthatching. On Posthatching Day 2, many degenerating nerve fibers were observed in the profundus/superficialis peroneus nerve in chicks surviving the high doses. TOCP-treated chicks were followed in detail for neuromuscular changes. Twenty days after hatching there were fewer large nerve fibers in the distal ischiadic nerve compared with controls and the largest nerve fibers were absent in the peroneus profundus nerve. Consistent with the evidence of denervation there was increased terminal branching of motor axons in femoral (sartorius) and tibial (external gastrocnemius and peroneus longus) leg muscles. The leg nerves of chicks treated with the low dose of TOCP did not show either an excessive number of degenerating nerve fibers or a detectable loss of large nerve fibers. However, terminal branching of motor axons was increased in the external gastrocnemius and peroneus longus muscles of 5- and 15-day-old chicks, followed by recovery by Day 25. The evidence is interpreted as a distal axonopathy in chicks treated with TOCP during late embryonic development.

Animals↗

Behavioral consequences of perinatal hypothyroidism in postnatal and adult rats.

The long-term effects of perinatal hypothyroidism on spontaneous locomotor behaviors were assessed after exposure to the antithyroid drug, methimazole. Perseveration was observed in methimazole-treated rats in a spatial maze. Locomotor activity in residential mazes was examined at 6 weeks, 4 months, and 6 months of age. Treated rats were hypoactive at some intervals compared with controls and were hyperactive at others. These paradoxical differences resulted from changes in exploratory, diurnal, and nocturnal locomotor activity in control rats both with increasing age and on repeated exposures to residential mazes; rats after perinatal hypothyroidism had relatively constant levels of activity on repeated days of exposure to residential mazes and at different ages. These results may be related to perseveration noted in the spatial maze. In an analysis of walking patterns, treated rats tended to have a more pronounced asymmetry in gait than controls.

Animals↗

Characterization of a pigment-dispersing hormone in eyestalks of the fiddler crab Uca pugilator.

A pigment-dispersing hormone (PDH) from eyestalks of the fiddler crab Uca pugilator has been purified by gel filtration, ion-exchange chromatography, partition chromatography, and reversed-phase liquid chromatography. Based on automated gas-phase sequencing and subsequent identification of carboxyl-terminal amide, we have assigned the primary structure of this peptide as Asn-Ser-Glu-Leu-Ile-Asn-Ser-Ile-Leu-Gly-Leu-Pro-Lys-Val-Met-Asn-Asp-Ala-NH (2). We have confirmed the sequence by synthesizing this peptide and demonstrating that the synthetic PDH and the native PDH display identical chromatographic behavior and biological activity. This hormone is a member of a family of invertebrate neuropeptides that includes a light-adapting/pigment-dispersing octadecapeptide hormone from the prawn Pandalus borealis. In assays for melanophore pigment dispersion in destalked fiddler crabs, Uca PDH was 21-fold more potent than Pandalus PDH. These two hormones share a hexapeptide core sequence (residues 5-10: -Ile-Asn-Ser-Ile-Leu-Gly-) as well as the amino- and carboxyl-terminal residues but differ at positions 3, 4, 11, 13, 16, and 17. These results point to speciesrelated or group-specific structural differences among crustacean PDHs.

Journal Article↗

Early development in the caudate and thyroid of methimazole-treated rats.

Rat pups were made hypothyroid by administration of the antithyroid agent, methimazole, to pregnant and lactating dams from gestational day 17 to postnatal day 10. Dendritic branching of caudate neurons in methimazole-treated pups was decreased 30 to 40 percent between 1 and 28 days of age. Perinatal methimazole treatment produced a pattern of developmental deficit or prolonged delay in the growth of dendrites of caudate interneurons. The antithyroid effect was also apparent in morphometric changes in the thyroid gland of methimazole-treated rats. Functional tissue was present at all ages examined. Colloid storage in the thyroid was decreased during methimazole administration compared with colloid storage after methimazole was discontinued. Both during and after methimazole administration the size of thyroid follicular cell nuclei in methimazole-treated pups was significantly greater than that of thyroid nuclei in control animals. Changes in dendritic branching, body weight and thyroxine levels lasted into adult life but recovery toward control levels was seen in adults. These changes in offspring following maternal administration of a goitrogen were demonstrated at an exposure level well below complete thyroid suppression.

Animals↗

Rabies virus glycoprotein analogs: biosynthesis in Escherichia coli.

The surface of rabies virus is composed of an approximately 60,000 dalton glycoprotein, in which most of the antigenic and immunogenic determinants of the virus reside. We have constructed plasmids for the direct expression in Escherichia coli of the mature full length rabies glycoprotein gene and also for the expression of a glycoprotein gene which has been truncated to exclude the coding region for a hydrophobic, possibly transmembrane, domain of the protein. Escherichia coli harboring the plasmids synthesize analog proteins which conform by several biochemical and antigenic criteria to rabies glycoprotein.

Amino Acid Sequence↗

Forebrain damage in chick embryos exposed to carbon monoxide.

The consequences of CO-induced hypoxia to the forebrain of seven-day-old chick embryos were investigated. Exposure of embryos to CO for three hours caused hemorrhages in developing forebrain areas. Carboxyhemoglobin levels reached about 50% in the embryos. Two weeks later, about one day prior to hatching, morphology of large neurons in the paleostriatum primitivum was evaluated. In Golgi-stained sections examined under the light microscope, the CO-exposed chicks were found to have reduced branching of the dendritic tree. In addition, the nuclear size of the paleostriatum primitivum neurons was reduced in the CO-exposed chicks. These findings in chick embryos are comparable to results in previous experiments with fetal rats.

Animals↗

Caudate morphology and behavior of rats exposed to carbon monoxide in utero.

Postnatal morphologic damage was found in the caudate nucleus of rats exposed 2 or 3 h to carbon monoxide on gestational day 15. There were gross abnormalities in the form of ecotopic swellings of caudate tissue into the lateral ventricles. The incidence of caudate ectopias was about 20% in rats exposed 2 h as fetuses and 70% from 3 h of exposure. In addition, in the body of the caudate the number of dendritic branches was reduced in Golgi type II neurons. Postnatal behavior of the exposed rats was not significantly altered in a series of behavioral tests of motor function. Growth rate was not retarded. The failure to detect behavioral changes may be due to insensitivity of these tests detecting functional damage or to compensation by the developing brain, resulting in normal function.

Animals↗