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Biomedical subjects

M T Smith

Publications and source records attributed to M T Smith.

At least 271 records · Page 15Linked to original sources
PubMed1984

Megadose corticosteroid therapy following experimental traumatic spinal injury.

Corticosteroids are frequently used in the treatment of spinal trauma, although neither experimental nor clinical evidence to support their use is persuasive. Recently there have been claims that extremely high doses ("megadoses") of corticosteroids (equivalent to 15 to 30 mg/kg of methylprednisolone) improve neurological recovery compared to results with traditional steroid doses. The authors have compared the effect of megadose dexamethasone and methylprednisolone therapy to that of saline treatment following traumatic cervical spinal injury in the cat. During 6 weeks postinjury, neurological recovery did not differ significantly in corticosteroid-treated and saline-treated animals. Moreover, histopathological changes in the spinal cord were similar in methylprednisolone- and saline-treated cats. Corticosteroid-treated animals had a higher mortality rate than did control animals, with the predominant cause of death being neurogenic pulmonary edema. It is concluded that megadose corticosteroid treatment does not improve neurological recovery in this experimental model of spinal injury, and is associated with increased mortality.

Animals↗
PubMed1984

Evaluation of the calcium channel antagonist nimodipine in experimental spinal cord ischemia.

The potent, centrally active, calcium channel antagonist, nimodipine, was utilized in a highly predictive "spinal stroke" model in order to investigate the potential pathophysiological effects of calcium flux in spinal injury, as well as to evaluate the potential therapeutic role of the newly developed dihydropyridine derivatives in ischemic central nervous system injury. Nimodipine, administered before or after ischemia, at doses shown to be effective in improving cerebral blood flow and in dilating central blood vessels, failed to improve either the histopathological changes or the functional deficit caused by temporary aortic occlusion in the unanesthetized rabbit.

Animals↗
PubMed1984

Bioavailability and pharmacokinetics of phenytoin during pregnancy.

Five epileptic women needing to commence phenytoin therapy during pregnancy received a single intravenous and a single oral dose of phenytoin several days apart before starting regular intake of the drug. Plasma phenytoin concentration - time data were analysed by three different pharmacokinetic techniques. However assessed, the mean oral bioavailability of the drug proved to be about 90% of the intravenous bioavailability. This finding makes it unlikely that impaired bioavailability accounts for the increase in oral phenytoin dosage necessary in pregnancy to maintain plasma phenytoin concentrations at pre-pregnancy values. Phenytoin clearance in the pregnant subjects was approximately double the published values for phenytoin clearance in non-pregnant persons. This suggests that increased (metabolic) clearance accounts for the increased phenytoin dosage requirement of pregnancy.

Aging↗
PubMed1984

Generation of anencephaly: 1. Aberrant neurulation and 2. Conversion of exencephaly to anencephaly.

An experimental model for anencephaly was used to focus on two important aspects of the development of anencephaly: neurulation and conversion of exencephaly to anencephaly. Vitamin A was administered to pregnant rats on gestational days nine and ten. The animals were killed on successive gestational days to allow study of the development of anencephaly. The scanning electron microscope revealed filopodia and lamellopodia as the predominant mode of initial neural fold contact in the controls. Intertwining and overlapping of filopodia and lamellopodia with fusion of the adjacent cutaneous ectoderm completed neurulation. In embryos developing anencephaly, filopodia and lamellopodia never made contact above the cervical region and exencephaly resulted. The first evidence of the conversion of exencephaly to anencephaly was profound, labyrinthine expansion of the extracellular space of the telencephalic mantle. In spite of normal vascular patency and intact vessel walls, the exencephalic malformation spontaneously disintegrated, converting the lesion to anencephaly. The causes for tissue disintegration other than infarction must be considered in reconstructing the pathogenesis of anencephaly.

Anencephaly↗
PubMed1983

Grading of oligodendrogliomas.

The purpose of this study was to determine the effectiveness of histologic grading of oligodendrogliomas in a retrospective study. 323 cases with adequate clinical information and confirmatory histological material were acquired from the files of the AFIP. A grading system was devised using the following criteria: endothelial proliferation, necrosis, nuclear/cytoplasmic ratio, cell density and pleomorphism. The grading system separated 23% of the cases into grade A, 49% into grade B, 22% into grade C and 6% into grade D. Statistical analysis showed that the grading system significantly correlated with survival (P less than or equal to 0.01). Median survival periods for each grade were as follows: grade A, 94 months; grade B, 51 months; grade C, 45 months; grade D, 17 months. Of the five factors comprising grade, only pleomorphism was significantly correlated with survival by itself (P less than or equal to 0.01). It is concluded that grading of this form of glioma can be an effective estimate of prognosis.

Adolescent↗
PubMed1983

Inhibition of ATP-dependent microsomal Ca2+ sequestration during oxidative stress and its prevention by glutathione.

The metallochromic indicator arsenazo III was used to study the effect of oxidative stress on ATP-dependent Ca2+ uptake by rat liver microsomes. Addition of ATP caused a rapid increase in ionophore A23187-releasable Ca2+ which stabilized in 2-3 min and provided a rapid and very sensitive assay for ATP-dependent Ca2+ sequestration. Quantitatively, this fraction was sufficient to account for virtually all of the nonmitochondrial ionophore-releasable Ca2+ of rat hepatocytes. Incubation with t-butyl hydroperoxide caused a rapid loss in the ability of microsomes to sequester Ca2+ in the presence of ATP. Addition of dithiothreitol or a physiological concentration of GSH to these incubations provided effective protection against the oxidative damage. ATP-dependent microsomal Ca2+ sequestration is therefore sensitive to oxidative damage and may be a primary site of injury leading to disturbed Ca2+ homeostasis during the early stages of drug hepatotoxicity. Intracellular thiols, notably GSH, may prevent these changes by protecting the microsomal Ca2+ pump from oxidative damage.

Adenosine Triphosphate↗
PubMed1983

Chronic propranolol administration during pregnancy. Maternal pharmacokinetics.

The pharmacokinetics of propranolol (P) and its major metabolites, propranolol glucuronide (PGLUC), 4-hydroxypropranolol (4OHP), 4-hydroxypropranolol glucuronide (4OHPGLUC) and naphthoxylactic acid (NLA), (Walle et al. 1972) were determined, whenever possible, in the first, second and third trimesters of pregnancy in thirteen patients and also when these patients were at least three months post-partum. No correlations were found between the mean arterial blood pressure (post-therapy) or the fall in blood pressure as a result of the P therapy (p much greater than 0.05) and P dose, peak P plasma concentrations, peak 4-hydroxypropranolol (4OHP) plasma concentrations or peak (P plus 4OHP) plasma concentrations. However, a positive nonlinear relationship was found between the daily P dose (independent variable) and peak P plasma concentrations over the daily dose range 30-160 mg/day. The elimination half-lives of NLA for patients in the third trimester of pregnancy were significantly shorter (p = 0.072, df = 13) than those when the patients were at least three months post-partum. Also, the areas under the plasma level-time curves of NLA were significantly less (p less than 0.05, df = 13) for patients in the third trimester of pregnancy than when these patients were at least three months post-partum. The results of this study indicate that the pharmacokinetics of P, PGLUC, 4OHP and 4OHPGLUC are not significantly altered by pregnancy. However, the kinetics of NLA do appear to be altered. The formation of NLA by N-dealkylation of P and further oxidation, appears to be competitively inhibited by unidentified substances, perhaps endogenous steroids, especially in the third trimester when compared to at least three months post-partum.

Adult↗
PubMed1983

Metabolism of propranolol in the human maternal-placental-foetal unit.

Propranolol (P) and all of its major known metabolites were found in maternal plasma, cord plasma and neonatal plasma in 10 women at term, irrespective of the P doses administered and the time elapsed (up to 15 h) between administration of the last P dose and delivery. The ratios of cord plasma to simultaneous maternal plasma levels for propranolol and its major metabolites (mean +/- SD) were: propranolol 0.32 +/- 0.17, propranolol glucuronide 0.86 +/- 0.36, 4-hydroxypropranolol 1.4 +/- 1.0, 4-hydroxypropranolol glucuronide 0.71 +/- 0.45 and naphthoxylactic acid 3.0 +/- 1.6. P binding in cord plasma at delivery was 67.2 +/- 3.9% (mean +/- SD) which was significantly less ('t' = 13.4, df = 13, p less than 0.001) than the P binding in maternal plasma at delivery (87.5 +/- 1.6%, mean +/- SD). The plasma protein binding (mean +/- SD) of naphthoxylactic acid in cord plasma (98.6 +/- 0.2%) was significantly greater ('t' = 3.808, df = 4, p less than 0.02) than the naphthoxylactic acid binding in maternal plasma at delivery (97.6 +/- 0.4%). When the simultaneous concentrations of P and naphthoxylactic acid in maternal and cord plasma are compared in conjunction with protein binding and ionic effects, it would seem that metabolism of P does occur in the placental/foetal unit.

Blood Proteins↗
PubMed1983

Cloning DNA from the replication terminus region of the Bacillus subtilis chromosome.

DNA from the Bacillus subtilis 168 prototroph, SB19, was partially cleaved with MboI and cloned into the BamHI site of the Escherichia coli cosmid vector, pHC79. [3H]thymine-labelled DNA from the replication terminus region of the B. subtilis dna-1 chromosome was used to identify, by hybridization, clones harboring recombinant cosmids carrying inserts from the terminus region. Restriction maps have been constructed for two such cosmids carrying overlapping DNA inserts that cover or extend into four of the previously identified five SalI fragments which are replicated last. The composite map of the cloned region, together with the available data on the replication order of fragments within it, is consistent with its replication being achieved by the unidirectional movement of a fork through it and towards the late replicating 16.2-kb SalI fragment. Most, if not all, of the terminus sequences in at least one of the recombinant cosmids are missing from a viable strain of B. subtilis that carries a deletion in the SP beta-gltA region of the chromosome.

Bacillus subtilis↗
PubMed1983

Propranolol, propranolol glucuronide, and naphthoxylactic acid in breast milk and plasma.

High-performance liquid chromatographic assays for propranolol and its major metabolites in plasma and breast milk are described. The breast milk/whole plasma ratios of propranolol in three lactating women were in the range of 0.33 to 1.65. The half-life of elimination of propranolol from breast milk was 6.5 +/- 3.4 h (mean +/- SD), which was significantly longer (t = 1.844, df = 4, p less than 0.01) than the half-life of elimination of propranolol from plasma, which was 2.6 +/- 1.2 h (mean +/- SD). The half-life of elimination of the propranolol metabolite naphthoxylactic acid from breast milk was 4.2 +/- 0.9 h (mean +/- SD), which was not significantly different (t = 0.042, df = 4, p greater than 0.05) from the mean half-life of elimination from plasma, which was 4.2 +/- 1.2 h (mean +/- SD). The penetration of propranolol glucuronide into breast milk was slower and to a lesser extent than that of propranolol and naphthoxylactic acid. The maximum dose, calculated from the results presented in this paper, ingested as either propranolol or as propranolol glucuronide in breast milk by the neonate would be less than 0.1% of the maternal dose.

Female↗
PubMed1983

Quantitative immunohistochemistry: a comparison of microdensitometric analysis of unlabeled antibody peroxidase-antiperoxidase staining and of microfluorometric analysis of indirect fluorescent antibody staining for nicotinamide adenosine dinucleotide phosphate (NADPH)-cytochrome c (P-450) reductase in rat liver.

The intralobular distribution of nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome c (P-450) reductase (NADPH:ferricytochrome oxidoreductase, EC 1.6.2.4) in rat liver has been investigated by means of two quantitative immunohistochemical techniques: microdensitometric quantitation of unlabeled antibody peroxidase-antiperoxidase staining and microfluorometric analysis of indirect fluorescent antibody staining. Utilizing sheep antiserum elicited against NADPH-cytochrome c (P-450) reductase that had been isolated and purified to apparent homogeneity from rat liver microsomes, the reductase was detected within hepatocytes throughout the liver. However, differences in the intensity of staining of hepatocytes within different regions of the liver lobule were readily apparent after completion of both immunohistochemical staining procedures. These visual findings were verified by microdensitometric and microfluorometric analyses of immunohistochemical staining, both of which revealed that approximately the same degree of staining for NADPH-cytochrome c (P-450) reductase was produced within the centrilobular and midzonal regions of the liver lobule, whereas periportal hepatocytes were stained with significantly less intensity. These results demonstrate that the application of either microdensitometry in conjunction with unlabeled antibody peroxidase-antiperoxidase staining or microfluorometry after indirect fluorescent antibody staining can be used to quantitatively determine the intratissue distributions of antigens.

Animals↗
PubMed1983

Comparison of thyrotropin-releasing hormone (TRH), naloxone, and dexamethasone treatments in experimental spinal injury.

We have shown that early treatment with either naloxone or thyrotropin-releasing hormone (TRH) significantly improves neurologic outcome after experimental spinal injury. Because these previous studies used different injury variables, no conclusion could be made about the relative effectiveness of the two drugs. In the present study naloxone and TRH treatment (each 2 mg per kilogram bolus, 2 mg per kilogram per hour for 4 hours) were directly compared; other cats received either dexamethasone (0.5 mg per kilogram bolus, 0.5 mg per kilogram per hour) or saline. The spinal cord was traumatized at C-7, using the Allen method; treatment was begun 1 hour after injury. Neurologic function was graded between 0 and 10, using an ordinal rating scale. Both TRH- and naloxone-treated animals had significantly better functional scores than saline controls at 6 weeks postinjury. Moreover, TRH-treated cats also showed significantly better neurologic recovery than either naloxone- or dexamethasone-treated animals. These findings confirm the therapeutic benefit of TRH and naloxone in experimental spinal injury and indicate that TRH treatment is most effective. In contrast, corticosteroid treatment was of no benefit in the present model.

Animals↗
PubMed1983

Propranolol in pregnancy three year prospective study.

We compared propranolol with methyldopa in a randomized prospective study of 28 women with pregnancy associated hypertension. Both drugs were equally effective in controlling maternal hypertension. There was no significant difference in the birthweights of the babies in each group. However one infant born to a mother receiving propranolol had symptomatic hypoglycaemia. The mean peak levels of propranolol, propranolol glucuronide, 4-hydroxypropranolol, and 4-hydroxypropranolol glucuronide were not significantly different in the first, second, third trimesters and at least 3 months post partum. The mean peak plasma level of naphthoxylactic acid however was significantly less in the third trimester compared with post partum levels. Propranolol and its metabolites were found to cross into breast milk with the maximum dose likely to be ingested by the infant as either propranolol or propranolol glucuronide being 7 micrograms of propranolol per 100 g of breast milk, being approximately 0.1% of the maternal dose.

Blood Pressure↗
PubMed1982

The metabolism of menadione (2-methyl-1,4-naphthoquinone) by isolated hepatocytes. A study of the implications of oxidative stress in intact cells.

The cytotoxic effects of many quinones are thought to be mediated through their one-electron reduction to semiquinone radicals, which subsequently enter redox cycles with molecular oxygen to produce active oxygen species and oxidative stress. The two-electron reduction of quinones to diols, mediated by DT-diaphorase (NAD(P)H: (quinone-acceptor) oxidoreductase), may therefore represent a detoxifying pathway which protects the cell from the formation of these reactive intermediates. By using menadione (2-methyl-1,4-naphthoquinone) and isolated hepatocytes, the relative contribution of the two pathways to quinone metabolism has been studied and a protective role for DT-diaphorase demonstrated. Moreover, in the presence of cytotoxic concentrations of menadione rapid changes in intracellular thiol and Ca2+ homeostasis were observed. These were associated with alterations in the surface structure of the hepatocytes which may be an early indication of cytotoxicity.

Animals↗
PubMed1982

Possible enhancement of vincristine neuropathy by VP-16.

Eleven consecutive patients with small cell carcinoma of the lung treated intensively with a combination chemotherapy regimen cyclophosphamide, Adriamycin, VP-16, and vincristine experienced peripheral neuropathy. Four of the 11 patients had severe (Grade III) neuropathy, leaving them virtually bedridden; the remaining seven patients had mild to moderate neuropathy. Only 8 of the 14 patients treated less intensively with vincristine and VP-16 had Grade I and II neuropathy. Predisposing factors for severe neuropathy included advanced age and preexisting peripheral neuropathy. All patients' performance status declined and all lost much weight before developing neuropathy. From accumulated treatment experience of small cell carcinoma with vincristine alone or with vincristine, Adriamycin, cyclophosphamide combinations, the authors feel that the severe neuropathy observed was due to an interaction of vincristine and VP-16. This conclusion is supported by electron microscopic observation of electronopaque granular degeneration of the myelin lamellae of affected nerve fibers.

Aged↗
PubMed1982

The measurement of lipid peroxidation in isolated hepatocytes.

Different techniques for the measurement of lipid peroxidation in isolated hepatocytes have been compared. Measurements of ethane production, chemiluminescence and fluorescent products correlated extremely well with those of malondialdehyde formation. Of the five different techniques studied, measurements of ethane production and chemiluminescence were found to the the most sensitive indices of lipid peroxidation. Incubation of hepatocytes for up to 4 hr in the presence of ethylmorphine and aminopyrine, at concentrations known to stimulate H2O2 production, completely failed to increase the amount of chemiluminescence, malondialdehyde or ethane produced in these cells, indicating that the drug-stimulated production of H2O2 did not lead to an increased rate of lipid peroxidation, as cells under the experimental conditions employed. The relationship between lipid peroxidation, as measured by chemiluminescence and ethane production, and the cytotoxic effects of bromobenzene and carbon tetrachloride has also been studied. The results obrained further indicate that lipid peroxidation is an important even in carbon tetrachloride hepatotoxicity, but that it appears to be only a subsequent event in bromobenzene toxicity, possibly occurring only as a result of glutathione depletion and cell death.

Animals↗