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Biomedical subjects

D H Gould

Publications and source records attributed to D H Gould.

At least 37 records · Page 2Linked to original sources
PubMed1991

The effect of glutathione depletion by buthionine sulphoximine on 1-cyano-3,4-epithiobutane toxicity.

The effect of glutathione (GSH) depletion by buthionine sulphoximine (BSO) on the nephrotoxicity and GSH-enhancing effect of the naturally occurring, crucifer-derived nitrile 1-cyano-3.4-epithiobutane (CEB), was investigated. Male Fischer 344 rats were administered 50 or 125 mg CEB/kg body weight by gavage with or without prior ip treatment with 550 mg/kg body weight L-BSO. One group of control animals was treated with water only by gavage, while another group was pretreated with BSO and then given water by gavage. Liver and kidney samples were taken 48 hr after CEB treatment for GSH determinations and histological examination. The high-dose CEB without BSO resulted in increased GSH in liver and kidney, marked karyomegaly in the pars recta of renal proximal tubules and tubular epithelial necrosis, which was limited to a few renal tubules. The low-dose CEB alone resulted in increased hepatic GSH and mild karyomegaly. Pretreatment with BSO abrogated the tubular necrosis and karyomegaly induced by either CEB dose. BSO pretreatment inhibited low-dose CEB-induced GSH enhancement in the liver. The combined BSO and high-dose CEB treatment still resulted in increased hepatic GSH, although the increase was less than that observed with high-dose CEB alone. In the kidney, BSO pretreatment abrogated the high-dose CEB-induced increase in GSH, but GSH content was not significantly different from that with high- or low-dose CEB alone. These results provide evidence that CEB conjugation may be a bioactivation reaction with the conjugate involved in nephrotoxicity. The conjugate may also be involved in increasing renal and hepatic GSH.

Animals↗
PubMed1991

Chronic cervical compressive myelopathy in horses: clinical correlations with spinal cord alterations.

Histological examination was performed on the cervical spinal cord from 13 horses with chronic cervical compressive myelopathy of 4 to 29 months duration. Structural alterations were correlated with clinical features. At the level of compression, the spinal cord was grossly deformed. Histological alterations included nerve fibre swelling and degeneration, occasional spheroids, astrocytic gliosis, increased macrophage activity and increased perivascular collagen. Myelin degeneration or loss at the level of the compressive lesion was greatest in the ventral and lateral funiculi and less consistently present in the dorsal funiculi. Asymmetry of lesions in the dorsal funiculi was associated with asymmetry of clinical signs in 5 horses. Histological alterations in areas of Wallerian degeneration were similar to that at the level of spinal cord compression, except that perivascular collagen was not increased. Wallerian degeneration was present cranial to the compressed site in the superficial portions of the lateral funiculi and in the middle of the dorsal funiculi. Caudal to the compressed site it was present in the ventral funiculi adjacent to the ventral median fissure and in the middle of the lateral funiculi. Deformation of the spinal cord did not correlate with the severity or duration of clinical signs but was positively correlated with the amount of perivascular collagen increase. The amount of nerve fibre swelling was not correlated with the severity of clinical signs but was negatively correlated with their duration. A rapid loss of nerve fibres apparently occurred early in the course of compression, since there was a marked decrease in the amount of nerve fibre swelling and Marchi stained degenerating myelin with increasing clinical duration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Chronic cervical compressive myelopathy in horses: patterns of astrocytosis in the spinal cord.

The distribution and morphology of fibrous astrocytes in the cervical spinal cord of normal horses and horses with chronic compressive myelopathy were demonstrated using immunohistochemical staining for glial fibrillary acidic protein. In the spinal cord from normal horses, astrocytes with stellate cell bodies and short processes were irregularly distributed in grey matter. In the white matter, their cell bodies were small and angular in areas adjacent to grey matter and larger and more stellate-shaped in the subpial area. Astrocyte processes were fine, and evenly distributed in a predominantly radial pattern in transverse sections of cord. Gliosis was marked in the spinal cords of horses with cervical compressive myelopathy. In the grey matter at the level of compression astrocytes were often enlarged and rounded, with short, blunt processes, but the gliosis was generally mild. In the white matter, gliosis was obvious in areas of nerve fibre swelling and degeneration at the level of compression and in areas of ascending and descending Wallerian degeneration. The fine radial pattern of astrocyte fibres was replaced by a dense, irregular arrangement. Gliosis persisted in the cords of chronically affected horses after active nerve fibre degeneration had subsided. The areas of gliosis coincided with the areas of Marchi staining for degenerating myelin and with areas of myelin loss in osmium tetroxide post-fixed tissue. Histological observations were consistent with astrocytes replacing areas of extracellular space that remained after nerve fibre degeneration. it is concluded that astrocytic gliosis is a prominent and persistent alteration of the spinal cord of horses with chronic cervical compressive myelopathy.

Animals↗
PubMed1991

High sulfide concentrations in rumen fluid associated with nutritionally induced polioencephalomalacia in calves.

Nine 115- to 180-kg, hay-adapted, Holstein steers were fed an experimental diet with added sodium sulfate that induces polioencephalomalacia (PEM). Five calves developed the disease. Thiamine concentrations in blood, CSF, brain, and liver were not indicative of thiamine deficiency. The odor of hydrogen sulfide in eructated rumen gas was associated with the onset of PEM. Sulfide concentrations in rumen fluid were measured 1 or 2 times a week by 2 techniques. Sulfide concentrations progressively increased in all 9 calves after the feeding of the PEM-inducing diet commenced. The highest concentrations coincided with the onset of clinical signs of PEM and were significantly higher in the calves that developed PEM than in those that did not. This suggests that PEM can result from sulfide toxicosis following excess production of sulfide in the rumen.

Animals↗
PubMed1991

Restoration of neutrophil and platelet function in feline Chediak-Higashi syndrome by bone marrow transplantation.

Allogeneic bone marrow transplantation (BMT) was successfully performed in four Chediak-Higashi (CHS) syndrome affected cats. Preparatory regimens included selective intestinal flora decontamination, fractionated total body irradiation for myeloablation, and prophylactic treatment for graft-versus-host disease with cyclosporin A. Neutrophil chemotaxis under-agarose and whole-blood platelet aggregation/secretion were characterized prior to BMT and after engraftment of donor-origin marrow cells. Liver and kidney biopsies were obtained and evaluated by light and electron microscopy before, and at 6 months post-BMT to determine what effect BMT might have on abnormal lysosome fusion in hepatocytes and renal tubule cells. The platelet storage pool defect was resolved by day 40 post-BMT. In vitro neutrophil migration in all cats appeared to improve with time after BMT and complete restoration was evident by day 175 post-BMT. No apparent differences were evident in either the liver or the kidney at 6 months post-BMT. One cat developed seizures and one developed posterior paresis 5 months post-BMT; neurologic impairment ultimately resulted in death of two cats at 6 and 8 months post-BMT, respectively. Neurologic lesions in both cats were characterized by non-suppurative encephalitis. Allogeneic BMT successfully corrected the neutrophil migration defect and platelet storage pool deficiency but had no effect on lysosome distribution in liver and kidney cells of CHS cats.

Adenosine Triphosphate↗
PubMed1990

Clinical and biochemical alterations in calves with nutritionally induced polioencephalomalacia.

Polioencephalomalacia (PEM) was induced in calves by feeding a semipurified, low-roughage diet of variable copper and molybdenum composition. Two formulations resulting in Cu-insufficient and Cu-sufficient forms of the diet were fed (n = 10 and 4 calves, respectively); both diets induced PEM. Clinical signs of disease developed as early as 15 days after transition to the experimental diets and included impaired vision, decreased response to external stimuli, and abnormal gait. Grossly evident cerebrocortical lesions consisted of laminar areas of cavitation and/or autofluorescence seen under UV illumination. Hepatic Cu concentration was decreased in calves fed the Cu-insufficient diet, but not below normal range. During the course of feeding either diet, rumen pH decreased, rumen volatile fatty acid concentrations increased, rumen and blood lactic acid concentrations increased, and rumen and plasma thiamine concentrations increased. The thiamine pyrophosphate effect on erythrocyte transketolase activity was unaltered in calves of either diet group. This nutritionally induced form of PEM does not appear to be related to Cu deficiency or reduction in plasma or rumen thiamine concentration.

Animals↗
PubMed1989

The relationship of vehicle to target organ toxicology induced by the naturally occurring nitrile 1-cyano-2-hydroxy-3-butene.

The effects of gavage vehicle on the acute toxicity of the naturally occurring nitrile 1-cyano-2-hydroxy-3-butene (CHB) were investigated by oral administration of 200 mg/kg body wt/day CHB to male CDF (F-344/Crl BR) rats for 2 days. The vehicles studied here were distilled water, 5% aqueous Tween 20, and corn oil. Liver, kidney, and pancreas were examined histologically and the differences in lesion incidence and severity were assessed. The effects of gavage vehicle on nitrile-induced elevations of daily urinary thiocyanate excretion and tissue glutathione concentrations were also assessed. The pancreatotoxicity of CHB was present regardless of vehicle and consisted of apoptosis of pancreatic acinar cells, infiltration of pancreatic lobules by macrophages, and acinar atrophy and disorganization. CHB in water alone was associated with the least pancreatotoxic effect, whereas the aqueous Tween vehicle was associated with more severe CHB-induced pancreatic lesions. CHB-induced elevations of tissue nonprotein thiol and glutathione concentrations occurred in all treatment groups, but the values were elevated significantly less in the pancreata of CHB/Tween-treated rats than in those of rats given CHB in water or corn oil. By contrast, the greatest elevation in daily urinary thiocyanate excretion occurred in rats given CHB in aqueous Tween, indicating increased biotransformation of CHB to cyanide when Tween 20 was used as a vehicle. These results illustrate the difficulty of identifying suitable vehicles for administration of lipophilic compounds in toxicology studies.

Alkenes↗
PubMed1989

Sequential changes in hepatic and renal glutathione and development of renal karyomegaly in 1-cyano-3,4-epithiobutane toxicity in rats.

The effect of 1-cyano-3,4-epithiobutane (CEB) on glutathione (GSH) metabolism was investigated in rat liver, kidney and pancreas. Male Fischer 344 rats were gavaged with a single dose (125 mg/kg body weight or 50 mg/kg body weight) of CEB. Tissue samples were taken for histological examination, determination of GSH and oxidized glutathione (GSSG) concentrations and gamma-glutamyl transpeptidase (GGT) and glutathione S-transferase (GST) activities. Urine samples were analysed for non-protein thiol (NP-RSH) content. The high dose of CEB induced hepatic GSH depletion followed by increased GSH. The low dose of CEB induced elevated hepatic GSH by 12 hr without depletion. Renal GSH was increased with both doses without an observed depletion phase. Renal tubule epithelial cell death was observed only with the high dose of CEB, but both doses caused renal proximal tubule karyomegaly. Pancreatic GSH content was unaffected. No alterations of GSSG were observed. GST activity was unaffected in any tissue. Renal GGT activity was decreased at 12 hr with both doses and at 24 and 48 hr with the high dose. Urinary NP-RSH excretion was increased with both doses. Depletion of hepatic GSH concurrent with increased urinary NP-RSH excretion suggests that conjugation with GSH is a significant pathway in CEB metabolism.

Animals↗
PubMed1988

Selective pancreato-toxicity in the rat induced by the naturally occurring plant nitrile 1-cyano-2-hydroxy-3-butene.

The acute toxicity of 1-cyano-2-hydroxy-3-butene (CHB), a nitrile derived from many cruciferous plants, was investigated. Young male CDF (F-344/CrlBr) rats were treated by gavage once daily with 200 mg (2.1 mmol) CHB/kg body weight for 0-4 days and killed 24 hr after the final dose. Lesions were confined to the exocrine pancreas and characterized by individual acinar cell death, inflammation and acinar atrophy and disorganization. Ultrastructural alterations included dilation of cisternae of the acinar cell endoplasmic reticulum, acinar cell death resembling apoptosis, macrophage phagocytosis of acinar cell debris and regenerative changes in remaining acinar cells. Pancreatic, hepatic and renal non-protein thiol concentrations were elevated, suggesting an enhancement of tissue glutathione concentrations and an alteration in glutathione metabolism. Urinary thiocyanate (SCN-) excretion was modestly elevated, indicating some in vivo cyanide release from this nitrile. The results of this study indicate that CHB is a selective pancreatotoxin, inducing changes consistent with apoptosis. CHB is also a possible inducer of tissue glutathione in the liver and kidneys as well as in the pancreas, even at toxic doses.

Alkenes↗
PubMed1988

Comparative toxicities of the naturally occurring nitrile 1-cyano-3,4-epithiobutane and the synthetic nitrile n-valeronitrile in rats: differences in target organs, metabolism and toxic mechanisms.

Toxic but sublethal oral doses of 125 mg/kg (1.1 mmol/kg) of the cruciferous nitrile, 1-cyano-3,4-epithiobutane (CEB), or 175 mg/kg (2.1 mmol/kg) of its synthetic saturated analogue, n-valeronitrile (VN), were given by gavage to male CDF (F-344/CrlBr) rats once daily for 1, 2 or 3 days, in order to compare target tissues and to observe structure-activity relationships between the nitriles. CEB-induced changes included degeneration and necrosis of the pars recta of the renal proximal tubules, ulceration and necrosis in the forestomach, a mild increase (4.5-fold) in daily urinary thiocyanate (SCN-) excretion (only in rats treated for 3 days) and 1.5- to 2.4-fold increases in hepatic and pancreatic non-protein thiol (RSH) concentrations (in all CEB-treated groups). In VN-treated rats, there were no consistent histological changes but 95- to 170-fold increases in daily urinary SCN- excretion, delayed clinical signs of cyanide toxicity and minimal effects on tissue RSH concentrations. These results indicate different toxic mechanisms for VN and CEB. The nephrotoxic effects of CEB were very similar to those of 1-cyano-2-hydroxy-3,4-epithiobutane, suggesting a role for the epithio group in the nephrotoxicity of these nitriles. The relatively low SCN- excretion in CEB-treated rats also suggested that cyanide played only a minimal role in CEB toxicity, while the high SCN- excretion, clinical signs of cyanide poisoning and lack of histological changes imply a greater role for metabolically-derived cyanide in VN toxicity. The enhancement of tissue RSH by CEB treatment with indications of enhanced tissue glutathione concentrations suggested the involvement of glutathione in the detoxication of CEB and/or its reactive metabolites.

Animals↗
PubMed1988

Functional and structural alterations of the nervous system induced by avian retrovirus RAV-7.

Chickens infected as embryos with RAV-7 developed neurological signs including ataxia, lethargy, and imbalance. Evoked spinal cord potentials for RAV-7 infected SC chickens were considerably slower (64.8 m/s) than for uninfected SC (103.4 m/s), genetically hypothyroid (OS) (93.9 m/s) or special C (95.1 m/s) chickens. Conduction velocity measurements of sciatic nerves showed normal values for all the chickens examined in this study. Histopathological studies revealed non-suppurative meningoencephalomyelitis in RAV-7 infected SC chickens. The inflammatory infiltrate consisted of lymphocytes, macrophages, and occasional plasma cells. The cells in the infiltrate reacted with mouse monoclonal antibodies directed against la and T-cell antigens. Astrocytic hypertrophy and hyperplasia, demonstrated by the use of monoclonal antibody specific for glial fibrillary acidic protein (GFAP), was associated with the CNS lesions. The results of this investigation indicate that RAV-7 causes significant central nervous system lesions and functional impairment in the infected chicken. This system may serve as a useful model for studying retrovirus-induced neurological dysfunction.

Animals↗
PubMed1988

Chronic flunixin meglumine therapy in foals.

Effects of a therapeutic dose of flunixin meglumine on gastric mucosa of horse foals were determined by endoscopy, double-contrast radiography, and gross and histologic examinations. Foals were administered 1.1 mg of flunixin meglumine/kg of body weight, PO/day for 30 days in an encapsulated form that was divided into 2 doses/day (group 1; n = 3) or by IM injection once a day (group 2; n = 7). Three control foals (group 3; n = 3) were administered capsules (n = 1) containing dextrose powder or IM injections (n = 2) of vehicle solution without flunixin meglumine. All 3 groups-1 foals given flunixin meglumine PO developed oral ulcers. Group-2 foals given flunixin meglumine IM did not develop oral ulcers. One control foal (group 3) developed 1 oral ulcer that healed during the study. Endoscopic examination revealed linear crease-like mucosal lesions in the glandular portion of the stomach in 2 group-2 foals. Radiographic evidence of gastric ulcers was observed in only 1 gastrogram of a group-1 foal. Foals were euthanatized, and necropsy revealed erosions and/or ulcers of the glandular portion of the stomach. Oral ulcers were observed in all 3 group-1 foals. Erosions of the glandular portion of the stomach developed in all 10 foals given flunixin meglumine, but did not develop in group-3 foals. Ulceration of the glandular portion of the stomach was present in 1 group-2 foal.

Administration, Oral↗
PubMed1987

Correlation of morphologic brain lesions with physiologic alterations and blood-brain barrier impairment in 3-nitropropionic acid toxicity in rats.

3-Nitropropionic acid (NPA), a toxin which irreversibly inhibits the Krebs cycle enzyme succinate dehydrogenase, causes severe neurologic disease and a specific pattern of morphologic brain damage when given subcutaneously to rats. To determine whether hypotension or hypoxemia were necessary for development of morphologic brain lesions in NPA neurotoxicity, systemic blood pressure and arterial blood gases were measured in NPA-intoxicated rats. The extent and distribution of albumin extravasation was examined by immunohistochemistry, and was compared to the extent and severity of morphological injury in the caudate-putamen. Neither hypotension nor hypoxemia were necessary for the development of morphologic injury in the brains of NPA-intoxicated rats. In fact, intoxicated rats had significantly higher systolic blood pressure and arterial blood oxygen than did controls. Arterial bicarbonate and pH were significantly lower in intoxicated rats than controls, however, suggesting that acidosis may be involved in the pathogenesis of NPA toxicity. When morphologic injury was severe, albumin extravasation was extensive occupying approximately 30%-80% of the lesion area in the caudate-putamen of NPA-intoxicated rats. When morphologic injury was mild, albumin extravasation was absent, or limited to small cuffs around individual capillaries (less than 1% of the lesion area). There was no leakage of albumin in the cerebral cortex, which was resistant to morphologic injury. It was concluded that leakage of protein-rich fluid into cerebral parenchyma from blood-brain barrier impairment is not responsible for the initiation of morphologic injury in NPA toxicity, but may contribute to the severity of injury later in the evolution of brain lesions.

Albumins↗
PubMed1987

Nature and distribution of brain lesions in rats intoxicated with 3-nitropropionic acid: a type of hypoxic (energy deficient) brain damage.

The clinical signs and morphological brain lesions associated with histotoxic hypoxia induced by subcutaneous injection of 3-nitropropionic acid (NPA) in rats are described, and compared to hypoxic brain damage from other causes including ischemia and hypoglycemia. The brains were perfusion-fixed with paraformaldehyde/glutaraldehyde fixative, and examined by light and electron microscopy. Intoxicated rats developed severe neurological disease characterized by somnolence, uncoordinated gait with stereotypical paddling movements, and ventral or lateral recumbency. Recumbent rats had a selective, bilaterally symmetrical pattern of severe morphological injury in the caudate-putamen, hippocampus, and thalamus. Recumbency was a consistent indicator of the development of morphological brain lesions. In contrast to reports describing rat models of ischemia and hypoglycemia, morphological injury was not seen in the cerebral and cerebellar cortices of NPA-intoxicated rats. Ultrastructurally, neuronal alterations ranged from chromatin clumping with increased cytoplasmic lucency to severe cellular shrinkage or swelling with marked mitochondrial swelling (high amplitude swelling). White matter alterations included axonal swelling and adaxonal splitting of myelin lamellae. Vascular changes included perivascular deposits of proteinaceous material presumably from leakage of serum proteins, variable electron lucency of endothelial cell cytoplasm, an apparent increase in pinocytotic vesicles, rare platelet thrombosis of capillaries, and rare intravascular blebs of luminal plasma membrane. As a model of brain damage following energy deficiency, NPA intoxication has the advantages of producing morphological brain injury in a highly predictable anatomical pattern, and at a time paralleling the onset of clinical recumbency.

Animals↗
PubMed1986

Conduction velocities and reflexes of the proximal and distal parts of the saphenous nerve of the dog.

The maximal conduction velocities of compound-action potentials in the proximal and distal parts of the saphenous nerve were determined by averaging potentials evoked and recorded through needle electrodes. Antidromic, triphasic compound-action potentials unipolarly recorded from the distal part of the saphenous nerve were of the same minimal latency as potentials having 4 phases which were recorded bipolarly from the same site. However, the unipolarly recorded potentials were of greater amplitude. Monophasic compound-action potentials were recorded through bipolar chlorided silver electrodes from the surface of fascicles of the distal part of the saphenous nerve. The maximal conduction velocity of these potentials was in agreement with the conduction velocity of compound-action potentials of the distal part of the saphenous nerve which were evoked and recorded through subcutaneous needle electrodes. The specificities of the stimulating and recording sites were verified by recording before and after the saphenous nerve was cut between the stimulating and recording sites. Mean conduction velocities were 62.3 +/- 2.0 m/s for the distal part of the saphenous nerve and 66.3 +/- 2.2 m/s for the proximal part of the saphenous nerve. Reflex-evoked muscle activity was elicited in the ipsilateral tensor muscle of the fascia lata and semimembranous muscle after electrical stimulation of the saphenous nerve through subcutaneous needle electrodes. The effects of various stimulus intensities on the latency and duration of these reflex-evoked muscle potentials were determined.

Animals↗
PubMed1986

Immunohistochemical staining patterns of canine eyes affected with chronic superficial keratitis.

Fourteen limbal biopsy specimens from 11 dogs with chronic superficial keratitis (CSK) were examined histologically and immunohistochemically. Ten of the 14 specimens had corneal epithelial hyperplasia and/or atrophy. Eleven of the 14 specimens had thickened epithelial basement membranes. Each specimen had cellular infiltration and lamellar disruption of the stroma. An avidin-biotin immunoperoxidase complex stain was used to detect immunoglobulin (Ig) deposition. Twelve of the 14 specimens stained positive for Ig. The staining pattern was consistent and characterized by diffuse deposition of stain in the superficial conjunctival stroma near the limbus. Four of the 12 Ig-positive specimens also stained positive in the superficial corneal stroma with 1 of these 4 also staining positive along the epithelial cell basement membrane. The diffuse pattern of stain deposition and the absence of staining of specific epithelial structures indicated that CSK is not a classical autoimmune disease similar to any disease in the pemphigus group or similar to systemic lupus erythematosus. Although the results may implicate CSK as an immune-mediated disease, nonspecific factors could not be ruled out.

Animals↗
PubMed1985

Functional and structural alterations of the rat kidney induced by the naturally occurring organonitrile 2S-1-cyano-2-hydroxy-3,4-epithiobutane.

The organonitriles, 2S-1-Cyano-2-hydroxy-3,4-epithiobutane (erythro and threo) (CHEB), isolated from the seed of Crambe abyssinica were administered by gavage to male Fischer-344 rats. Rats given 50 mg/kg/day were killed at 24, 48, and 72 hr. The rats given 100 mg/kg/day were killed at 48 and 72 hr. Serum urea nitrogen and creatinine were increased by 48 hr and further elevated by 72 hr. Glomerular filtration rate (GFR) of the 50 mg/kg CHEB rats was elevated at 24 hr but fell to subnormal values by 72 hr. The GFR of the 100-mg/kg group was decreased at 48 and 72 hr. Urine output of the 50-mg/kg group increased continuously through 72 hr, while urine output of the 100-mg/kg group was increased to a lesser degree. Urinary N-acetyl-beta-D-glucosaminidase (NAG) activity (nmol/hr/mg creatinine) was significantly elevated in both groups by 48 hr, and further increased by 72 hr. Twenty-four hours after administration of 50 mg/kg, renal proximal tubular epithelial cells of some rats had fine cytoplasmic vacuolation. At 48 and 72 hr, necrosis and coarse vacuolation of proximal tubular epithelial cells occurred in both dose groups. The necrosis was most severe at the apexes of the medullary rays and the coarse vacuolation extended deeply toward the outer stripe of the outer zone of the medulla. Higher doses and/or longer times of CHEB administration resulted in a more extensive lesion distribution. It is concluded that CHEB induces nephrotoxicity in rats characterized by nonoliguric, acute renal failure, and morphological lesions preferentially involving the pars recta of the proximal tubules.

Acetylglucosaminidase↗