Cardioversion in the third trimester of pregnancy.
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Adult↗
Biomedical subjects
O Brown
Publications and source records attributed to O Brown.
Subcellular post-transcriptional targeting: delivery of an intracellular protein to the extracellular leaflet of the plasma membrane using a glycosyl-phosphatidylinositol (GPI) membrane anchor in neurons and polarised epithelial cells.
The effectiveness of viral vector-mediated gene transfer depends on the expression of therapeutic transgenes in the correct target cell types. So far, however, little attention has been given to targeted subcellular distribution of expressed transgenes. Targeting individual transgenes to particular subcellular compartments will provide various advantages in increasing the safety, efficacy, and specificity of viral vector-mediated gene delivery. Viruses normally hijack the cellular protein synthesis machinery for their own advantages. It is thus unknown whether cells infected with viral vectors will be able to target proteins to the correct subcellular organelles, or whether the subcellular targeting machinery would be selectively disrupted by viral infection. In this article we explored whether a herpes simplex virus type 1-derived vector could be used to deliver a transgene engineered to be targeted to the extracellular membrane of target cells. To do so we constructed a temperature-sensitive mutant HSV-1 vector, tsK-TT21 expressing a recombinant marker protein, tissue inhibitor of metalloproteinases (TIMP), linked to sequence encoding a signal for the addition of a glycosyl-phosphatidylinositol (GPI)-anchor within the endoplasmic reticulum. Our results demonstrate that HSV1-derived viral vectors can be used to target transgenes as GPI anchored proteins to the outside leaflet of plasma membranes, without disrupting the targeting machinery of host epithelial cells or neurons. This approach could then be used to target specific proteins to the cell membrane to modify cell-cell interactions, the function of specific plasma membrane proteins, or their interactions with other membrane proteins, and also to target a prodrug converting enzyme to the plasma membrane of target cells, therefore enhancing its cell killing effects.
Biotinylation↗
A twin pregnancy in a uterus didelphys.
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Journal Article↗
Twin pregnancy in a uterus didelphys, with unilateral placental abruption and onset of labour.
A dizygotic twin pregnancy with a fetus in each side of a uterus didelphys is described. An antepartum haemorrhage at 26 weeks' gestation, with subsequent onset of contractions in the right-sided uterus, precipitated delivery by Caesarean section.
Abruptio Placentae↗
Dihydropyrimidine dehydrogenase pharmacogenetics in patients with colorectal cancer.
Individuals with a deficiency in the enzyme dihydropyrimidine dehydrogenase (DPD) may experience severe life-threatening toxicity when treated with 5-fluorouracil (5-FU). As routine measurement of enzyme activity is not practical in many clinical centres, we have investigated the use of DNA mutation analysis to identify cancer patients with low enzyme levels. We have identified two new mutations at codons 534 and 543 in the DPD cDNA of a patient with low enzyme activity and screened the DNA from 75 colorectal cancer patients for these mutations and the previously reported splice site mutation (Vreken et al, 1996; Wei et al, 1996). In all cases, DPD enzyme activity was also measured. The splice site mutation was detected in a patient (1 out of 72) with low enzyme activity whereas mutations at codons 534 (2 out of 75) and 543 (11 out of 23) were not associated with low enzyme activity. These studies highlight the need to combine DPD genotype and phenotype analysis to identify mutations that result in reduced enzyme activity.
Adult↗
Dihydropyrimidine dehydrogenase pharmacogenetics in Caucasian subjects.
AIMS: Dihydropyrimidine dehydrogenase (DPD) catalyses the reduction of pyrimidines, including the anticancer agent 5-fluorouracil (5FU). Impaired 5FU degradation, through low DPD activity, has led to severe, life-threatening or fatal toxicity after administration of 5FU. Complete DPD deficiency is associated with the inherited metabolic disease thymine uraciluria. Several mutations in the gene encoding DPD have recently been identified, but the phenotype-genotype concordance of these alterations in the general population has not been reported. METHODS: Mononuclear cells were isolated from whole blood and DPD activity was determined after ex vivo incubation with 14C-5FU followed by h.p.1.c. analysis of 5FU metabolites. Analysis of mutations in the DPD gene at an exon splice site, codons 534, 543, and 732, and a deletion at base 1897 (deltaC1897) were performed in 30 subjects with the lowest and 30 subjects with the highest enzyme activity using PCR-RFLP. RESULTS: DPD activity was measured in 226 Caucasian subjects and was highly variable (range 19.1-401.4 pmol min(-1)mg(-1) protein). Mutations were frequently observed at codons 543 (allele frequency 28%), 732 (allele frequency 5.8%), and 534 (allele frequency 0.8%), but were not associated with low DPD activity. There were no splice site or deltaC1897 mutations found in this population. CONCLUSIONS: The five mutations analysed in this study are insufficient for identification of patients at risk for 5FU toxicity or thymine uraciluria. Both the splice site mutation and deltaC1897 are relatively rare in the general Caucasian population. Therefore, identification of further molecular alterations is required to facilitate the use of DPD analysis in genetic diagnosis and cancer therapeutics.
Alleles↗
Mutations at codon 974 of the DPYD gene are a rare event.
A mutation at codon 974 of the dihydropyrimidine dehydrogenase (DPD) gene was previously described in a cancer patient with undetectable DPD enzyme activity who experienced severe toxicity when treated with 5-fluorouracil. We have studied the frequency of this mutation in 29 Scottish subjects with low DPD enzyme activity and in 274 American subjects. We detected no mutations in the 606 alleles studied and conclude that mutations at codon 974 are a rare event.
Dihydrouracil Dehydrogenase (NADP)↗
Tympanometry and otoscopy prior to myringotomy: issues in diagnosis of otitis media.
Tympanometry and pneumatic otoscopy were compared to findings at myringotomy in 86 children (163 ears). Seventy percent of the ears (115) had effusion, as revealed by myringotomy. Sensitivity and specificity for tympanometry were 90% and 86%, respectively. Sensitivity and specificity for pneumatic otoscopy were 93% and 58%, respectively. A chi-square was performed to compare the sensitivity and specificity to tympanometry to otoscopy, revealing tympanometry significantly better at determining non-effusion states. Additionally, a combined otoscopy and tympanometry sensitivity and specificity were calculated for those otoscopy and tympanometry determinations in agreement, revealing both sensitivity and specificity above 90%. A Fisher's exact probability test revealed no significant differences for the accuracy of tympanometry over otoscopy when the determinations of each were not in agreement. Implications of these results are discussed.
Acoustic Impedance Tests↗
Specialized collagen mRNA and secreted collagens in human glomerular epithelial, mesangial, and tubular cells.
Isolated glomeruli and cultured cells were examined under nonmitogenic conditions by Northern hybridization of steady-state mRNA levels for procollagens alpha 1(I), alpha 1(III), alpha 1(IV), alpha 2(IV), beta-actin, and fibronectin. Procollagens concurrently secreted from these cells were characterized after limited pepsin digestion. Poly(A)-mRNA from freshly isolated whole porcine glomeruli was primarily type IV. For cultured glomerular and tubular epithelial cells, the collagen mRNA species were almost exclusively alpha 1(IV) and alpha 2(IV). Correspondingly, the secreted collagen was almost entirely type IV. The mRNA signals for collagens in glomerular mesangial cells included alpha 1(I), alpha 1(IV), alpha 2(IV), and less alpha 1(III). The secreted collagens were also types I and IV, with less types III and V. There were similar patterns of mRNA signal levels for the two type IV collagens and similar patterns of expression of alpha 1(I) and alpha 1(III). In situ hybridization showed the fibroblast and epithelial cell populations homogeneous in expressing the same mRNA signals seen by Northern hybridization. These findings establish the correlation of collagen mRNA and protein expression of collagens in differentiated glomerular cells in culture, under resting nonmitotic conditions.
Animals↗
Direct CO2 laser "revascularization" of the myocardium.
Evidence of regional myocardial perfusion and contractile function after direct CO2 laser myocardial revascularization (DLR) is lacking. We examined myocardial segment shortening, adenine nucleotide concentrations, and regional blood flow after DLR of the left anterior descending coronary artery (LAD) distribution before and after its proximal ligation in seven anesthetized conditioned dogs. Sonomicrometry assessed myocardial fiber shortening and radioactive microspheres were used to estimate baseline regional blood flows. Cardiopulmonary bypass was followed by cardioplegia arrest. Laser channels (1 mm diameter) were made every 3 to 5 mm in the LAD region with an 80 watt Laser-sonics CO2 unit. Bypass was terminated, the LAD occluded, and parameters reassessed. Core samples of myocardium from the lased LAD and control circumflex area were taken to assess adenine nucleotides. After occlusion, LAD distribution blood flow and myocardial shortening were reduced to pre-lasting ischemic controls. Adenine nucleotides were reduced in the LAD region relative to the control CMX area. DLR cannot be relied upon to acutely revascularize the ischemic myocardium.
Acidosis↗
Loracarbef concentrations in middle ear fluid.
Loracarbef concentrations in plasma and middle ear fluid (MEF) were measured in specimens obtained approximately 2 h after doses of 7.5 or 15 mg/kg. The mean +/- standard deviation concentrations in MEF were 2.0 +/- 2.6 mg/liter (48% of the concentration in plasma) after the smaller dose and 3.9 +/- 2.6 mg/liter (42% of the concentration in plasma) after the larger dose. With the larger dose, the concentrations in MEF were greater than the MIC for 90% of strains of the usual pathogens of acute otitis media tested in 16 of 17 specimens.
Body Fluids↗
Otitis media. Incidence, duration, and hearing status.
The middle ear status and hearing sensitivity in 483 normal infants have been closely monitored as part of the Dallas Cooperative Project, University of Texas at Dallas, effort to assess the effect of early otitis media with effusion on speech and language development. At least one episode of otitis media with effusion occurred in 73.5% of the children between the ages of 6 and 18 months. Almost a quarter of these were discovered at "well-baby" checkups and were appropriately classified as "silent." The hearing levels, the methods of hearing assessment, and the implications of these data are described.
Hearing Loss, Conductive↗
Hypothalamic serotonin in the control of meal patterns and macronutrient selection.
Serotonin (5-HT) is believed to have an inhibitory influence over feeding behavior. The present experiments were designed to investigate the effects of hypothalamic 5-HT on spontaneously motivated feeding and appetite regulation. Freely-feeding rats were injected with 5-HT or norfenfluramine (NORFENF) directly into the paraventricular hypothalamus (PVN), and precise changes in feeding behavior were monitored by a computer. Following PVN 5-HT or NORFENF injection, animals exhibited a marked suppression in food intake, associated with a decrease in meal size, duration and eating rate, and no change in the frequency of meals consumed. This suggests that brain 5-HT may influence primarily the induction of satiety rather than the suppression of hunger. The effect of drugs presumed to affect brain 5-HT transmission on diet selection was also investigated in groups of rats injected centrally with 5-HT or NORFENF or peripherally with either fenfluramine, quipazine or cyproheptadine. In a series of 2-diet tests, rats centrally injected with 5-HT or NORFENF exhibited a selective suppression of the carbohydrate-rich diets. In animals provided with three pure macronutrient diets, protein, carbohydrate, and fat, systemic administration of serotonergic agents had its greatest impact on fat and carbohydrate ingestion, as compared to protein consumption. These findings support a role for hypothalamic 5-HT in modulating meal patterns and appetite for particular macronutrients.
Animals↗
Dominantly inherited craniodiaphyseal dysplasia: a new craniotubular dysplasia.
We describe a mother and her male infant affected with a craniotubular dysplasia characterized by severe craniofacial hyperostosis and sclerosis with obliteration of paranasal sinuses and foramina of the skull base. Subsequent severe bilateral hearing loss and facial diplegia with relative sparing of the optic nerves were noted. The long bones show extreme asymmetric hyperostosis and sclerosis of the diaphyses and evidence of a modelling defect in the metaphyses. The spine, ribs, clavicles, and pelvis all show some degree of sclerosis and defective modelling, but are less severely involved. According to the definition by Gorlin, this disorder would best be classified as craniodiaphyseal dysplasia. Distinguishing features in these two patients as contrasted to previously described cases include a greater degree of hyperostosis and sclerosis than that described for other patients with craniodiaphyseal dysplasia, apparent dominant transmission, and significant metaphyseal involvement.
Adult↗
Norepinephrine, clonidine, and tricyclic antidepressants selectively stimulate carbohydrate ingestion through noradrenergic system of the paraventricular nucleus.
Using a self-selection feeding procedure, the present experiments examined the impact of central and peripheral injection of the alpha-adrenergic agonist clonidine (CLON) and the tricyclic antidepressant drugs amitriptyline (AMIT) and chlorimipramine (CIMIP) on nutrient selection in the adult male rat. In tests with mixed diets or with separate sources of the 3 macronutrients (carbohydrate, protein, and fat) simultaneously available, the following results were obtained: Peripheral and paraventricular nucleus (PVN) injection of CLON stimulated total food intake and preferentially increased ingestion of carbohydrate. Little or no change in protein or fat intake was observed. This pattern of response is similar to that observed with norepinephrine. PVN injection of AMIT and peripheral injection of CIMIP also selectively enhanced carbohydrate intake. These drug effects on carbohydrate selection occurred under a variety of conditions, including with mixed diets and pure dietary nutrients; under ad lib and restricted feeding conditions; in short (1 hr) as well as long (6 hr) test intervals; and in the absence or presence of a change in total calorie intake. Based on this and other evidence, it is proposed that noradrenergic neurons innervating the PVN in the rat play a role in regulating carbohydrate selection, and that this neurochemical system mediates the stimulating action of CLON and antidepressants on carbohydrate ingestion.
Amitriptyline↗
Dorsolateral pontine inhibition of dorsal horn cell responses to cutaneous stimulation: lack of dependence on catecholaminergic systems in cat.
The effect of stimulating the dorsolateral pons (DLP) in the region of locus ceruleus (LC) on lumbar dorsal horn cell responses to innocuous and noxious cutaneous stimuli was assessed and the dependence of these effects on intact pontospinal catecholaminergic systems was tested in chloralose-anesthetized cats. DLP stimulation inhibited the responses of dorsal horn cells to both noxious and innocuous skin stimuli. The inhibitory effect was most prominent when the responses to noxious stimuli were tested. The thresholds for eliciting DLP-spinal inhibition were lowest (less than 30 microA) in the region of LC. The inhibitory effect was found in both ipsilateral and contralateral dorsal horns. The DLP-spinal inhibition was unaltered by depletion of spinal catecholamines brought about by repeated lumbar intrathecal administration of 6-hydroxydopamine or systemic administration of reserpine. We conclude that the DLP-dorsal horn inhibition is not related to a catecholaminergic ceruleospinal system in the cat and that the dependence of pain modulation by catecholamine systems is a reflection of other descending pathways.
Animals↗
Goodpasture's syndrome with normal renal function.
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Adult↗
Craniovertebral anomalies.
We have tried to clarify this confusing area by demonstrating the common relationships of these abnormalities. The development of the craniovertebral junction was present in order to understand the formation of the anomalies discussed. The radiologic lines and measurements that have been described are actually to measure the degree of compromise of the functional size of the foramen magnum. This mechanical compromise, either from direct neural compression and/or from a secondary vascular impairment (arterial or venous), leads to the signs and symptoms of cervicomedullary compression.
Adult↗