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Biomedical subjects

S M Roberts

Publications and source records attributed to S M Roberts.

At least 91 records · Page 5Linked to original sources
PubMed1991

Examination of the role of catecholamines in hepatic glutathione suppression by cold-restraint in mice.

Cold-restraint stress was found to produce a depression in hepatic glutathione content and to elevate circulating catecholamine levels in four mouse strains--ICR, NIH, B6C3F1, and ND/4. Serum norepinephrine concentrations were significantly elevated after cold-restraint (2--3 h) in all strains, and serum epinephrine levels were increased in the B6C3F1 and ND/4 strains. In time-course studies conducted using ND/4 mice, the decline in hepatic glutathione concentrations was found to slightly precede increases in serum epinephrine and norepinephrine concentrations. Also, pretreatment with phentolamine, an alpha-adrenoreceptor antagonist compound shown in previous studies to block epinephrine-induced hepatic glutathione suppression, had no effect on glutathione losses from cold-restraint. These observations are inconsistent with catecholamines as sole mediators of cold-restraint induced hepatic glutathione depression. Two other endogenous substances elevated during stress, corticosteroids and glucagon, were found to diminish glutathione concentrations in the liver in ND/4 mice when administered exogenously. The effects of catecholamines (epinephrine), corticosteroids (hydrocortisone) and glucagon were not additive, i.e. the depression in glutathione when these agents were administered in combination was generally no greater than that induced when the most effective agent was administered alone. It is postulated that during cold-restraint stress multiple endogenous agents are released which are independently capable of causing a depression in hepatic glutathione content.

Animals↗
PubMed1991

Epidemiologic study of ocular/adnexal squamous cell carcinoma in horses.

Proportional hospital accession ratios for equine ocular/adnexal squamous cell carcinoma (SCC) were determined for 14 colleges of veterinary medicine participating in the Veterinary Medical Data Program between January 1978 and December 1986. Comparison of the ratios with their respective geographical, physical data has shown an increased prevalence of SCC with an increase in longitude, altitude, or mean annual solar radiation. In contrast, prevalence of SCC increased with a decrease in latitude. Between January 1978 and December 1988, 147 horses with ocular/adnexal SCC were admitted to the Colorado State University Veterinary Teaching Hospital. Diagnosis was confirmed by histologic examination of appropriate tissue specimens. Medical records provided information regarding month and year of admission and diagnosis, age at diagnosis, breed, gender, and hair color. Comparison with a randomly selected hospital control population revealed an increased prevalence of ocular/adnexal SCC with an increase in age (P less than 0.001). Compared with Quarter Horses, draft breeds (Belgian, Clydesdale, and Shire) and Appaloosas had a significantly (P less than 0.001) greater prevalence of ocular/adnexal SCC. Sexually intact males and females were significantly (P less than 0.001) less likely (5 and 2 times, respectively) to have ocular/adnexal SCC when compared with castrated males. The prevalence of ocular/adnexal SCC was significantly greater for all hair colors when compared with bay, brown, or black (P less than 0.01).

Age Factors↗
PubMed1991

Prognostic factors and survival of horses with ocular/adnexal squamous cell carcinoma: 147 cases (1978-1988).

Between January 1978 and December 1988, 147 horses with ocular/adnexal squamous cell carcinoma (SCC) were admitted to the Colorado State University Veterinary Teaching Hospital (CSU-VTH). Diagnosis was confirmed by histologic examination of appropriate tissue specimens. Medical records and communication with owners, referring veterinarians, or both provided information regarding initial examination, treatment at the CSU-VTH, and final outcome. At initial examination, 123 (83.7%) horses had unilateral involvement and 24 (16.3%) horses had bilateral involvement. The nictitating membrane, nasal canthus, or both (28.1%); limbus (27.5%); and eyelid (22.8%) were most commonly affected. In addition to the ocular/adnexal location, SCC was found elsewhere in 14 (9.5%) horses at initial examination. Adequate follow-up (greater than or equal to 4 months) for examination of tumor recurrence and survival analysis was obtained for 125 (85.0%) cases. After treatment at the CSU-VTH, tumor recurred in 30.4% of the cases. Tumor location, multiple vs single tumors at initial diagnosis, and CSU-VTH treatment modality influenced the recurrence of tumors. Survival analysis revealed a good prognosis for horses with ocular/adnexal SCC. Although undefined, a conservative estimate of the median survival time was 47 months. Six factors (treatment prior to referral, tumor location, tumor size, single or multiple tumors, treatment modality at the CSU-VTH, and recurrence or nonrecurrence) were analyzed to determine their relation with survival. Treatment prior to referral, multiple vs single tumors at initial examination, and treatment modality used at the CSU-VTH did not influence survival. Tumor location influenced survival; SCC involving the eyelid or orbit was associated with the poorest prognosis. Tumor stage (maximal dimension) was inversely related with survival.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Potentiation of carbon tetrachloride hepatotoxicity by phenylpropanolamine.

Hepatic necrosis produced by carbon tetrachloride (0.02, 0.06, or 0.20 ml/kg, ip) in mice was found to be potentiated by simultaneous cotreatment with phenylpropanolamine (200 mg/kg, ip), a drug with catecholamine-like pharmacologic effects. The ability to potentiate carbon tetrachloride-induced hepatic necrosis was shared by a compound with agonist effects relatively selective for alpha 2-adrenoreceptors (clonidine, 5 mg/kg, ip), but not by specific alpha 1-adrenoreceptor agonists (phenylephrine, up to 100 mg/kg, ip and methoxamine, up to 50 mg/kg, ip) or by the beta-adrenoreceptor agonist isoproterenol (up to 100 mg/kg, ip). Yohimbine (5 mg/kg, ip), a selective alpha 2-adrenoreceptor antagonist, completely blocked the potentiating effect of phenylpropanolamine on carbon tetrachloride hepatotoxicity, providing further evidence that the increased hepatotoxic response with phenylpropanolamine cotreatment was mediated through alpha 2-adrenoreceptor stimulation. Four potential mechanisms for phenylpropanolamine potentiation of liver injury from carbon tetrachloride were examined: (1) increased concentrations of carbon tetrachloride in the liver from greater absorption or altered distribution; (2) diminished food consumption leading to a starvation-like increase in responsiveness to carbon tetrachloride; (3) impaired detoxification through a depletion of hepatic glutathione content; and (4) enhanced toxicity produced by elevated core body temperature. None of these potential mechanisms was supported by the experimental results. It is concluded that phenylpropanolamine and related compounds potentiate carbon tetrachloride hepatotoxicity through a mechanism involving alpha 2-adrenoreceptor stimulation that has yet to be identified.

Animals↗
PubMed1991

Hepatic glutathione suppression by the alpha-adrenoreceptor stimulating agents phenylephrine and clonidine.

The effects of alpha-adrenoreceptor stimulation on hepatic glutathione content were examined in ICR male mice using a selective alpha 1-adrenoreceptor stimulating agent, phenylephrine, and a selective alpha 2-adrenoreceptor stimulating drug, clonidine. Phenylephrine produced a dose-dependent depression in hepatic glutathione levels when administered by the intraperitoneal (i.p.) route, with a maximum extent of depression of approximately 30% occurring in both male and female mice. Phenylephrine was ineffective by the intracerebroventricular route, indicating a peripheral site of action which would be consistent with the mechanism(s) suggested by earlier in vitro studies using rat liver. Clonidine, an alpha 2-adrenoreceptor stimulating agent, also depressed hepatic glutathione concentrations in a dose-dependent manner. The maximum extent of depression (approx. 45%) from clonidine administered by the i.p. route was somewhat greater than that from phenylephrine, and the apparent potency was about 10-fold greater. Unlike phenylephrine, clonidine was effective when administered by the intracerebroventricular route. Pretreatment of mice with phenylephrine (100 mg/kg, i.p.) resulted in a potentiation of hepatic necrosis from a mildly hepatotoxic dose of acetaminophen (400 mg/kg, i.p.). The results of these experiments suggest that the changes in glutathione homeostasis produced by alpha-adrenoreceptor stimulation may be sufficient to impair detoxification mechanisms.

Acetaminophen↗
PubMed1991

Fluorocarbocyclic nucleosides: synthesis and antiviral activity of 2'- and 6'-fluorocarbocyclic 2'-deoxy guanosines.

A series of four isomeric 2'- and 6'-fluorocarbocyclic guanosine analogues have been prepared and evaluated as potential anti-herpes agents. The racemic 2' beta-fluoro isomer 2-amino-1,9-dihydro- 9-[(1 alpha, 2 alpha, 3 beta, 4 alpha)-2-fluoro-3-hydroxy-4- (hydroxymethyl)cyclopentyl]-6H-purin-6-one (11a, C-AFG) and its 2' alpha-fluoro epimer 11b plus the chiral 6' beta-fluoro isomer 2-amino-1,9-dihydro-9-[[1S-(1 alpha, 2 alpha, 3 alpha, 4 beta)]- 2-fluoro-4-hydroxy-3-(hydroxymethyl)cyclopentyl]-6H-purine-6-one (11c) and its 6' alpha-fluoro epimer 11d were prepared from their respective fluoro amino diol hydrochlorides (6a,d). For comparison, the furanosyl compound 9-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)guanine (17, AFG) was prepared by coupling 2-amino-6-chloropurine with 2-deoxy-2-fluoro-3,5-di-O-benzoyl-alpha- D-arabinofuranosyl bromide followed by base hydrolysis. The 6' alpha-fluoro derivative 11d exhibited comparable activity to that of acyclovir (ACV) against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in vitro but was greater than 30-fold more active than ACV against HSV-1 and HSV-2 in vivo in the mouse systemic model. The 2' beta-fluoro derivative (11a, C-AFG) was extremely potent in vitro against HSV-1 and HSV-2 (ID50 0.006 and 0.05 micrograms/mL) and in vivo it was greater than 2 orders of magnitude more potent than ACV against HSV-1 and 70-fold more potent against HSV-2. The 2' alpha-fluoro 11b and 6' beta-fluoro 11c isomers were much less active.

Antiviral Agents↗
PubMed1991

Utility of the PRECEDE model in differentiating users and nonusers of smokeless tobacco.

The utility of the PRECEDE model in identifying factors associated with smokeless tobacco use among male adolescents was investigated. Users and triers were more likely than nonusers to be white, older than average age for their grade, receive below average grades in school, and have had no classroom instruction on adverse effects of smokeless tobacco use. The standard score means of users, triers, and nonusers differed significantly on six of seven PRECEDE model components: attitudes, beliefs, values, perceptions, reinforcing factors, and enabling factors. The standard score means of triers and nonusers, only, differed significantly for the knowledge component. A stepwise multiple regression analysis using all seven model components as predictor variables of smokeless tobacco use accounted for 47.9% of explained variance among users, triers, and nonusers. The values component was the most powerful predictor of smokeless tobacco use (35% of the explained variance). Discriminant function analysis demonstrated the seven components of the PRECEDE mode instrument accurately classified 93.1% of users and nonusers.

Adolescent↗
PubMed1991

Comparison of three antismoking interventions among pregnant women in an urban setting: a randomized trial.

This study examined smoking cessation and cigarette reduction of indigent inner city pregnant women (n = 193) who completed one of three interventions: a special video program based on their perceptions of the effects of smoking during pregnancy, the American Lung Association's "Freedom From Smoking For You and Your Baby" program, or the usual physician's advice. Six percent of the women quit smoking, and 43% reduced the number of cigarettes they smoked. There were no significant differences among the three groups for either the number who quit smoking or who reduced the number of cigarettes smoked.

Adult↗
PubMed1990

Depression of glutathione by cold-restraint in mice.

The effects of cold-restraint as a physiological stressor on the glutathione (GSH) content of the liver and other tissues were examined in male mice. Mice of the ICR, NIH, ND/4, and B6C3F1 strains subjected to cold-restraint for 2 or 3 h experienced a loss of hepatic GSH concentrations ranging from approximately 15 to 50%. Though 3 of these strains (ICR, NIH, and B6C3F1) experienced hypothermia as result of the cold-restraint treatment, with average decreases in core body temperature ranging from 3.3 to 9.8 degrees C, hepatic GSH levels were depressed in the ND/4 mouse in the absence of changes in core body temperature. The ability of cold-restraint as a stressor to diminish hepatic GSH therefore could not be attributed simply to hypothermia. The decrease in hepatic GSH from cold-restraint in ND/4 mice was paralleled by a decrease in non-protein sulfhydryl (NPSH) content of the liver. In addition to its effects on liver GSH and NPSH concentrations, 1.5 h of cold-restraint stress significantly depressed plasma, heart, kidney, and lung NPSH concentrations. The extent of NPSH depression was equivalent to the GSH depression in the liver, heart, and kidney, despite the observation that the normal contribution of GSH to total NPSH content in these tissues ranged from a high of 89% (liver) to a low of 49% (heart). These results with cold-restraint in the ND/4 mouse suggest that other stressors may significantly depress cellular concentrations of GSH and other thiols, and may thereby render the affected tissues more susceptible to the toxicity of free radicals, electrophilic xenobiotic metabolites, or reactive oxygen species.

Animals↗
PubMed1990

Effects of procainamide hydroxylamine on generation of reactive oxygen species by macrophages and production of cytokines.

A series of experiments was conducted to examine the effects of the N-oxidized metabolite of procainamide, procainamide hydroxylamine (PAHA), on reactive oxygen species (ROS) production by macrophages in vitro, as well as on the release of the cytokine interleukin-1 (IL-1). Results with PAHA were compared with those from the parent compound, procainamide, and in some cases with other procainamide metabolites such as N-acetylprocainamide or nitrosoprocainamide. The effects of PAHA on ROS production by mouse and rat macrophages were complex, resulting in both stimulatory and inhibitory activity depending upon the PAHA concentration and whether macrophages were resting or elicited. The primary effect of PAHA appeared to be a stimulation of ROS production. Monocytes pretreated with PAHA (20 microM) depressed the responsiveness of lymphocytes in co-culture to a T-cell mitogen (conconavalin A) but not a B-cell mitogen (lipopolysaccharide). This effect was inhibited when monocyte pretreatment with PAHA was accompanied by the antioxidants, catalase or superoxide dismutase. IL-1 production by rat adherent splenocytes was unaffected by PAHA in concentrations that were not cytotoxic. These observations suggest that the oxidative metabolism of procainamide to PAHA may result in enhanced production of ROS by macrophages contributing its toxicity to lymphocytes.

Animals↗
PubMed1990

Radiation-induced ocular injury in the dog: a histological study.

Radiation-induced ocular injury secondary to treatment of nasal cancer occurs in humans and animals. Dogs with nasal carcinomas were randomized to receive 36 to 67.5 Gy in fractionated doses given in 4 weeks using a 6 MV linear accelerator. Ophthalmic examinations were performed according to a predetermined protocol and eyes were removed for histologic examination when dogs were euthanatized. The eye in the radiation field exhibited greater injury than the contralateral eye with nasal areas of the globe having more severe lesions than temporal areas. Lesions occurred in all dogs and at all doses. At 1 month or less postirradiation treatment, all dogs had blepharitis, keratoconjunctivitis and corneal epithelial atrophy. Surface lesions persisted in all eyes, becoming less severe and more chronic with time. At 3-6 months postirradiation treatment, degenerative angiopathy of retinal vessels appeared with multifocal retinal hemorrhage and mild diffuse retinal degeneration which affected outer layers first and progressed inwardly with time. At 6 months postirradiation treatment, there were cataracts, fibrosis of retinal vessel walls with loss of vascular smooth muscle, retinal hemorrhage, and mild to moderate retinal degeneration. At 1 year postirradiation treatment, retinal vessels remained sclerotic, retinal hemorrhage was less frequent, and there was moderate retinal degeneration with swelling and loss of ganglion cells. By 2 years or more postirradiation treatment, optic nerve axonal degeneration secondary to retinal changes had appeared. Tapetal and choroidal atrophy were inconsistently seen. Thus, ocular lesions at the doses received developed along a relatively predictable time course and recovery was not seen. Structures of the canine eye appear sufficiently sensitive that even relatively low total doses given in small doses per fraction cause significant long-term injury.

Animals↗
PubMed1990

Cocaine toxicity in cultured rat hepatocytes.

Cocaine hydrochloride was added to primary cultures of hepatocytes isolated from naive and phenobarbital-induced (80 mg/kg i.p. for 3 d) Sprague-Dawley rats. Cocaine was cytotoxic, as measured by lactate dehydrogenase release, to cells from naive rats in concentrations of 1 mM or greater. Phenobarbital induction greatly increased the cytotoxic potency of cocaine in vitro, with nearly complete loss of cell viability at cocaine concentrations in culture as low as 0.01 mM. The addition of 10 microM SK&F-525-A to the cultures blocked cocaine cytotoxicity in cells from both naive and phenobarbital-induced rats. These results suggest that the metabolic pathways leading to cocaine hepatotoxicity identified in the mouse also exist in the rat hepatocyte.

Animals↗
PubMed1990

Fluoro carbocyclic nucleosides: synthesis and antiviral activity of 2'- and 6'-fluoro carbocyclic pyrimidine nucleosides including carbocyclic 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-methyluracil and carbocyclic 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodouracil.

The racemic carbocyclic 2'-fluoroarabinosyl pyrimidine nucleosides 8, 9 (C-FIAU), 12, and 13 (C-FMAU) and the 2'-fluororibosyl pyrimidine nucleosides 17, 20, and 21 were prepared from their respective protected 2'-fluoro amino diols 5 and 14. The carbocyclic 2'-2'-difluorothymidine analogue 27 was obtained from the protected difluoro amino diol 24 which was prepared from the ketone 23 and (diethylamino)sulfur trifluoride (DAST). The chiral carbocyclic 2'-deoxy-6'-fluorouridines 33, 34, 38, and 39 were synthesized from the protected 6'-fluoro amino diols 30 and 36, which were prepared by reduction of the azides 28 and 35. C-FMAU (13) and C-FIAU (9) were active in vitro against HSV-1 with ID50 values of 4.4 and 11 micrograms/mL, respectively, but they were inactive against HSV-2. The cytidine analogues 12 and 20 displayed modest activity in vitro against HSV-1 and HSV-2 but were inactive against human influenza A virus.

Animals↗
PubMed1990

Recent advances in the generation of chiral intermediates using enzymes.

Different types of enzyme-catalyzed processes are reviewed, with particular regard to those procedures leading to the generation of chiral compounds of high optical purity. The main body of the review deals with hydrolyses and esterification as well as the reduction and oxidation of organic substrates. Other biotransformations of current and/or future importance in the synthesis of homochiral fine chemicals (such as the formation of carbon-carbon bonds using aldolases) are also discussed in some detail. Attention is drawn to current trends in the area and, to this end, a majority of the references are taken from journals published during the period April 1987 to September 1988.

Alcohols↗
PubMed1989

The pharmacokinetics of 2,2',5,5'-tetrachlorobiphenyl and 3,3',4,4'-tetrachlorobiphenyl and its relationship to toxicity.

The pharmacokinetics of two toxicologically diverse tetrachlorobiphenyls (TCBs) were measured in mice. After dosing to apparent steady-state conditions, 2,2',5,5'-TCB was found to have a tissue elimination half-life of between 1.64 and 2.90 days. The half-life of 3,3',4,4'-TCB was similar, ranging from 1.07 to 2.60 days. Systemic clearance and volume of distribution estimates were also similar for the two TCB isomers. The 3,3',4,4'-isomer had a substantially greater partitioning from serum into adipose, liver, and thymic tissues. With dosing regimens developed using these measured pharmacokinetic parameters, experiments were undertaken to compare toxic potency of these two TCBs when similar tissue concentrations of the two isomers were achieved in target and storage tissues. These studies demonstrated that thymic atrophy occurs at lower 3,3',4,4'-TCB doses and tissue concentrations than those required to produce hepatotoxicity. These two organ toxicities were produced only by 3,3',4,4'-TCB despite the fact that equivalent or higher tissue concentrations of 2,2',5,5'-TCB were achieved in vivo in all tissues. We conclude that the in vivo difference in the toxic potency of these two TCB isomers does not result from the significant differences in their tissue disposition, elimination, and ultimate bioaccumulation.

Adipose Tissue↗
PubMed1989

Depression of hepatic glutathione by opioid analgesic drugs in mice.

The ability of morphine and other opioid analgesic drugs to diminish hepatocellular glutathione (GSH) concentrations was examined in ICR mice. When administered intraperitoneally, morphine, hydromorphone, ethylmorphine, l-alpha-acetylmethadol (LAAM), and meperidine all caused a significant decrease in hepatic GSH concentrations in male mice while codeine, methadone, butorphanol, nalbuphine, and pentazocine were without effect even at doses up to those approaching acute lethality. Depression of hepatic GSH equivalent to that observed after ip administration could be elicited by icv administration of small doses of morphine, ethylmorphine, and hydromorphone. LAAM and meperidine were ineffective following icv administration in these experiments. The discrepancy between results following ip versus icv administration of LAAM and meperidine suggests that hepatic metabolism of some opioids may be important for their activity in the CNS, as both norLAAM and normeperidine diminished hepatic GSH when administered by the icv route. The opioid-induced lowering of hepatic GSH does not appear to be sex-dependent since morphine and LAAM produced qualitatively and quantitatively similar effects on hepatic GSH in female mice. Morphine administered icv produced a substantial increase in the hepatotoxicity of two compounds dependent upon GSH for detoxification, acetaminophen and cocaine, as measured by serum alanine aminotransferase activities. These observations indicate that a number of opioid analgesic drugs have the potential to diminish hepatic GSH. Further, these results support earlier studies which indicate that central opioid effects on hepatic GSH are mediated through mu-opioid receptor stimulation. Last, these studies suggest that a centrally initiated opioid action on hepatic GSH may significantly influence the susceptibility of the liver to the effects of some hepatotoxic agents.

Alanine Transaminase↗
PubMed1989

Ocular manifestations of Rocky Mountain spotted fever in dogs.

Dogs were examined ophthalmoscopically to determine the prevalence and type of ocular lesions associated with naturally acquired Rocky Mountain spotted fever (RMSF). In a consecutive series of 11 dogs with serologically confirmed RMSF, 9 had ocular involvement reflecting various degrees of vascular damage, including subconjunctival hemorrhage, hyphema, anterior uveitis, iris stromal hemorrhage, retinal petechiae, and focal areas of retinal edema and perivascular inflammatory cell infiltrate. The ophthalmic lesions generally were mild, and most resolved without complication after systemic administration of appropriate antibiotics. The high prevalence of ocular lesions in these dogs suggested that critical ophthalmologic evaluation is a useful diagnostic tool for the early detection and management of RMSF in dogs.

Animals↗