Biomedical subjects
Publications and source records attributed to W J Dougherty.
Surface analysis techniques and in vitro biologic assays were used to characterize sterilized commercially pure titanium surfaces. Significant surface alterations were observed following sterilization treatments. These alterations led to decreased fibroblast cell attachment and altered cellular spreading phenomena compared to nonsterilized control surfaces.
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The activity levels of serum acid phosphtase, aminopeptidase, and lysozyme in a Brazilian strain of Biomphalaria glabrata were ascertained at 1, 2, and 3 hr after mechanical wounding or injection with albumin on the 30th day postexposure to a compatible strain of Schistosoma mansoni miracidia and found to be elevated. Parallel transmission electron microscope studies on daughter sporocysts and developing cercariae at these time intervals revealed progressive disintegration of the parasites that was associated with increased numbers of host granulocytes abutting the sporocyst surfaces. Furthermore, host granulocytes were observed to have passed through eroded sporocyst walls and attacked developing cercarial embryos. It is proposed that the elevated levels of lysosomal hydrolases released from activated host granulocytes as a result of challenge altered the parasite's surfaces so that these were recognized as nonself. Consequently, additional host granulocytic response, which included additional release of lysosomal enzymes into serum as well as phagocytosis of remnants of both sporocysts and developing cercariae, was elicited.
Glucan administration in the rat induces a hyperplasia and hypertrophy of the reticuloendothelial system (RES) and a concomitant leukocytosis. Increased phagocytic function and lysozymal immunoreactivity of macrophages are also characteristic of the glucan effect. The potential role of arachidonic acid metabolites in mediating this hepatic inflammatory response induced by the RES stimulant glucan was assessed in the present study by two experimental approaches. In one study, rats were depleted of arachidonic acid by rendering them deficient in essential fatty acids (EFA). In another study, rats were pretreated with the fatty acid cyclooxygenase inhibitor indomethacin. Both treatment interventions markedly attenuated the hepatic Kupffer cell proliferative and granulomatous response to glucan and the associated leukocytosis. Lysozyme immunoreactivity of the Kupffer cells and rates of colloidal carbon clearance (T/2), however, were enhanced by the above treatments. Supplementation of EFA-deficient rats with ethyl arachidonate restored their glucan response to an extent that was not significantly different from nondeficient rats. Marked hepatic proliferative responses were apparent only in those treatment groups characterized by leukocytosis, which suggests that extrahepatic recruitment is an important component of the glucan response in normal, nutritionally adequate rats. Collectively these data suggest that arachidonic acid metabolites may play a role in modulating this extrahepatic recruitment and the associated cellular proliferative and granulomatous responses following glucan administration of the rat.
The effects of methyl mercury (CH3Hg) and selenium (Se) on renal ultrastructure were investigated and correlated to changes in renal gamma-glutamyl transpeptidase (gamma-GTPase) activity, mercury (Hg) accumulation, and renal function (serum creatinine and urea nitrogen). Three experimental protocols were used to investigate CH3Hg and Se interactions of both Se-sufficient and Se-deficient mice involving ip injection of the following administered alone or in combination: CH3Hg (4.0 mg/kg) and Se (0.16 mg/kg) daily for 7 days, CH3Hg (1.0 mg/kg) and Se (0.08 mg/kg) daily for 20 days, and a single acute dose of CH3Hg (8.0 mg/kg). Acivicin (12 to 50 mg/kg), an antitumor glutamine antagonist, was also used as a highly effective specific inhibitor of the gamma-GTPase. Our results show that CH3Hg administered to Se-deficient mice for 7 or 20 days resulted in significant (p less than or equal to 0.05) but only moderate inhibition (20%) of gamma-GTPase activity and extensive renal ultrastructural damage. Acivicin-treated mice had significant inhibition of gamma-GTPase activity (80%) following a single injection while ultrastructural damage was substantial only after several days of administration. These results may indicate different modes of action of acivicin and CH3Hg. Acivicin inhibited gamma-GTPase prior to renal damage while CH3Hg produced greater pathological effects with only moderate gamma-GTPase inhibition. Renal damage from acute and chronic CH3Hg toxicity occurred after distinct neurological signs were present. Selenium administered to Se-deficient mice ameliorated both the neurotoxic effects and nephrotoxic action of CH3Hg. While Se and CH3Hg treatments caused some of the same ultrastructural pathology as the treatment with CH3Hg alone (cytoplasmic vacuolation, increased lysosomal profile, mitochondrial swelling, and extrusion of cellular masses into the tubular lumen), degeneration was not as extensive. Although the total doses administered during both the 7- and the 20-day studies were similar, mice from the chronic 20-day study showed greater ultrastructural pathological effects from CH3Hg. The primary effects of CH3Hg appeared to be on the lysosomal system, while acivicin exerted its effects on the mitochondrial and endoplasmic reticulum systems. The accumulation studies on Hg suggest that dietary Se may have only an initial protective effect against Hg accumulation in the kidney while injected Se offers longer protection.(ABSTRACT TRUNCATED AT 400 WORDS)
American Cyanamid compound CL 115,574, a synthetic analog of prostaglandin E1, is active orally in inhibiting gastric acid secretion and in protecting against gastric ulcers induced by stress, ethanol, and nonsteroidal anti-inflammatory drugs. CL 115,574 was administered to rats for 6 months and to dogs for 1 year. Diarrhea occurred in both species and transient hyperthermia was observed in dogs. In rats, the only gross finding related to treatment was limited to the gastric mucosa and consisted of a dose-related widening of the cuticular ridge in the mid (2 mg/kg/day) and high (20 mg/kg/day) dose groups. Microscopically, there was a proliferation of the cuticular ridge stratified squamous epithelium. Morphologic findings in the dogs showed a multifocal proliferation of the foveolar epithelium in the pyloric antrum. Neither species had atypical cellular changes associated with the proliferative process. Furthermore, the changes in the dog consisted of well differentiated cells and occurred without pseudostratification of cells and increased mitotic activity. The "pseudoproliferative" character of these changes may be the result of a prolonged life span of most cell types of the gastric mucosa. These tissue adaptations reflect a true manifestation of the cytoprotective effect of prostaglandin E1 on the gastric mucosa.
Testes of the palaemonid shrimp Macrobrachium rosenbergii were prepared for study in the light, scanning and transmission electron microscopes and shown to be composed of solid, convoluted cords of tissue composed of two major sets of cells, spermatogenic and sustentacular cells. Among the spermatogenic cells, preleptotene spermatocytes and encysted spermatozoa were of most frequent occurrence. The sustentacular cells sent long, cytoplasmic extensions ramifying between and around tightly packed spermatocytes of the seminiferous cords and separated the spermatocytes from the basal lamina which surrounded the cords. Spermatocytes formed desmosome-like and short gap junctions with one another, while sustentacular cells formed intermediate-like junctions and gap junctions with spermatocytes. No special junctions between one sustentacular cell and another were encountered in the present study.
Electron microscopic study of tibial epiphyseal plates of young growing rats revealed amorphous-appearing electron dense deposits 5-35 nm in diameter, associated with the plasma membranes of more than 43% of the proliferative zone chondrocytes. Hypertrophic zone chondrocytes, however, revealed no plasma membrane-associated amorphous-appearing deposits. The membrane-associated densities were observable in unstained sections of tissues fixed in glutaraldehyde alone and in tissues double-fixed with glutaraldehyde and osmium tetroxide, and were extracted from ultrathin sections floated on neutral aqueous solutions of 4% ethyleneglycol bis-(beta-aminoethyl ether) N,N'-tetraacetic acid (EGTA) for one-half hour. Energy dispersive X-ray analysis of the densities in scanning transmission electron microscope (STEM) mode revealed the presence of Ca, suggesting that the membrane-associated amorphous-appearing deposits are Ca-enriched. Similar deposits were observed in the membrane of matrix vesicles present in the longitudinal cartilaginous septae in the hypertrophic zone. Four types of matrix vesicles were encountered in the longitudinal cartilaginous septae; one type with amorphous-appearing deposits, another with crystallites, a third type with both amorphous-appearing and crystalline-like deposits, and a fourth that is empty. These observations are interpreted to indicate that chondrocytes of the reserve and proliferative zones play a direct role in mineralization by elaborating amorphous mineral deposits along their plasma membranes. These deposits are incorporated into budding matrix vesicles, which then play a role in the initiation of mineralization by supporting the spontaneous phase transformation of amorphous-appearing mineral to crystalline mineral.
"Synaptic" ribbon (SR) populations in the rat pineal gland were analyzed morphometrically at various ages from birth to early adulthood. The rats were born and raised in continuous light or continuous darkness. SR numbers were high irrespective of the presence or absence of light during the early neonatal period. However, SR numbers decreased substantially during the second neonatal week of continuous light, remaining low at subsequent ages, including early adulthood. In contrast, SR numbers apparently remained elevated during continuous darkness at various ages from the early neonatal period to early adulthood. Stimulation of pineal adrenergic receptors with L-isoproterenol during continuous light resulted in an acute, reversible increase in SR numbers; blockade of these receptors with L-propranolol during continuous darkness resulted in an acute decrease in SR numbers. These results indicate that light-mediated changes in SR populations were 1) age related and 2) related to some component of the pineal beta-adrenergic receptor mechanism. A hypothesis that SR formation may be related to beta-adrenergic receptor-associated membrane turnover is presented.
The formation of pineal 'synaptic' ribbons (SR) may be directly related to the adrenergic innervation of the gland. In order to clarify this relationship, SR populations at various times from 12 h to 14 days after pineal denervation were morphometrically analysed by electron microscopy. Pineal denervation was accomplished by bilateral superior cervical ganglionectomy. A decrease in nocturnal pineal SR numbers, indicating a reduction in SR formation, was demonstrated 12 to 24 h after pineal denervation. Seventy-two hours after ganglionectomy SR numbers were comparable with those in nocturnal intact and sham-operated controls. Thereafter, 7 and 14 days after ganglionectomy, SR numbers exceeded nocturnal intact and sham-operated controls. Administration of isoproterenol, a beta-adrenergic receptor agonist, 24 h after denervation significantly increased SR numbers over those in untreated rats denervated 24 h earlier. Thus SR formation remained responsive to adrenergic receptor stimulation in the absence of an intact adrenergic innervation. Further, the increase in SR numbers following subacute (7 to 14 days) denervation indicated that SR formation was not dependent on an intact innervation or the presence of endogenous (pineal) norepinephrine. On the basis of these results, we suggest that SR formation may be related structurally as well as functionally to adrenergic receptors on the rat pinealocyte.
The effect of pre- or posttreatment with glucan, a reticuloendothelial stimulant, on the course of Leishmania donovani infection was assessed in highly susceptible hamsters. Intravenous administration of glucan before or after L. donovani infection significantly suppressed proliferation of amastigote-stage parasites in liver and spleen. Glucan-activated peritoneal macrophages in vitro also significantly reduced multiplication of the intracellular parasite. Ultrastructural studies revealed a well-defined hepatic granulomatous response to glucan, with hypertrophic Kupffer cells and reduced numbers of intracellular parasites compared to the control group. In additional studies, groups of hamsters were immunized by intravenous injections of glucan with Formalin-killed promastigote-stage L. donovani cells and challenged 60 days after the last immunizing injection. This treatment regimen significantly prolonged the mean survival time of those hamsters which died after infection, relative to untreated control groups. Hamsters stimulated with the glucan-killed promastigote preparation also exhibited significant reductions in splenic amastigotes on days 10 and 21 postinfection compared with all other control groups, but on day 35, splenic amastigotes did not differ significantly from those of control animals. Our composite observations provide evidence for glucan-enhanced nonspecific resistance of hamsters to visceral leishmaniasis.
Twenty-four adult beagle dogs were divided into four groups of three males and three females and received iv infusions of doxorubicin (36.05 mg/m2), mitoxantrone (2.58 or 5.15 mg/m2), or the vehicle (0.9% normal saline). All animals were given a single dose once every 3 weeks. The duration of the study was 30 weeks. Animals were observed for toxicologic and cardiotoxic signs. The methods used to evaluate the cardiotoxic potential of both mitoxantrone and doxorubicin were sequential endomyocardial biopsies, ECGs, blood pressure, and serum levels of the cardiospecific isoenzyme CPK-MB (MB band of CPK). Animals given mitoxantrone had signs of gastrointestinal toxicity and fluctuating decreases in wbc counts. Animals given doxorubicin had signs of gastrointestinal toxicity and cardiotoxicity, as well as alopecia, fluctuating decreases in wbc counts, and diffuse erythema. All three male animals given doxorubicin died during the study from apparent congestive heart failure. All dogs treated with doxorubicin had positive CPK isoenzyme elevation, ECG changes, or progressive cardiomyopathy prior to administration of the last dose. None of these signs was observed in dogs treated with mitoxantrone. One male dog given mitoxantrone died during the course of the study.
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Populations of "synaptic" ribbons (SR) in pinealocytes of the rat pineal gland at various ages from the neonatal period through early adulthood were analyzed morphometrically. Diurnal and nocturnal numbers of SR were small on day one but had increased dramatically by the end of the first week and beginning of the second week. By day 10, numbers of SR had peaked. Thereafter nocturnal numbers of SR demonstrated no significant increases or decreases. However, between days 10 and 19, diurnal numbers of SR decreased precipitously, appearing to have leveled off the onset of puberty to levels observed in adults. SR were never scarce or absent in any age group studied. The neonatal appearance of large numbers of SR coincides developmentally with the initial sympathetic innervation of pineal parenchyma. Circadian rhythm in numbers of SR begins shortly thereafter. It is suggested 1) that circadian rhythm in numbers of SR is initiated and regulated or modified by sympathetic innervation of pinealocytes containing SR, and 2) that SR formation may be related to the intracellular flow of membrane relative to the transport and release of specific pineal products.
Pretreatment of rats with the RES stimulant, glucan, markedly increases their sensitivity to endotoxic shock. Intravenous administration of S. enteritidis endotoxin (10 micrograms/100 gm B.W.) produced a more severe shock in glucan-pretreated rats than IV injection of 1 mg/100 gm B.W. of endotoxin in normal rats. Endotoxic shock in glucan-sensitized rats was associated with a precipitous increase in serum activity of lysosomal enzymes and a more severe hypoglycemic response. The shocked glucan-pretreated rats died before marked increases in plasma hepatocyte enzyme activity were apparent. Assessment of RE-phagocytic function with the 131I RE test-lipid emulsion revealed a rapid clearance and hepatic uptake of the emulsion in nonshocked glucan-control animals. This hyperphagocytic function, however, was abolished at two hours after injection of endotoxin. Hepatic ultrastructure in shocked glucan and normal rats revealed extensive sinusoidal changes. Hepatocytes, with the exception of a depletion of glycogen granules, were comparatively intact in the shocked-glucan group as opposed to the shocked control group. Pretreatment with methylprednisolone (60 mg/kg) protected the glucan-treated rats from endotoxin and was relatively more effective in diminishing the hypoglycemic response than preventing a loss of lysosomal integrity. Thus, despite the absence of overt ultrastructural changes in hepatocytes, altered glucoregulation appears to be a significant factor in the enhanced sensitivity of glucan-pretreated rats to endotoxin.
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Young and preodontoblasts and matrix vesicles which occur in the presecretory region of incisor teeth of growing rats were examined in stained and unstained ultrathin sections in order to characterize sites involved in the initial mineralization of dentin. Common to pre- and young odontoblasts in the presecretory region were hemispherical membrane-associated amorphous densities, measuring 5-35 nm in diameter after fixation in glutaraldehyde-osmium tetroxide or glutaraldehyde only. Amorphous densities were associated also with the limiting membranes of some vesicles in the extracellular matrix. Other vesicles in the extracellular matrix contained needle-like crystalline deposits typical of dentinal matrix vesicles. Fully differentiated odontoblasts in more incisal regions of the tooth lacked plasma membrane-associated amorphous densities. Neither amorphous nor crystalline densities were associated with any other cellular or subcellular structures in cells of the presecretory region. Flotation of ultrathin sections on solutions of EDTA or EGTA removed the amorphous densities from the plasma membranes, suggesting that the amorphous densities are calcium-containing mineral deposits. Amorphous deposits were associated with the membrane of vesicular structures protruding from the surfaces of pre- and young odontoblasts, suggesting that vesicles found in the extracellular matrix arise by budding from the plasma membranes of pre- and young odontoblasts. The occurrence of amorphous mineral deposits in association with the limiting membrane of some vesicles in the extracellular matrix, and the occurrence of needle-like mineral crystals within other matrix vesicles, suggest that an amorphous-to-crystalline phase transformation of mineral takes place within the matrix vesicle. The results of this study suggest that calcium-binding sites associated with plasma membranes of pre- and young odontoblasts act as nucleating centers for primary mineral deposition in tooth dentin.
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