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Biomedical subjects

R D Simmons

Publications and source records attributed to R D Simmons.

At least 37 records · Page 2Linked to original sources
PubMed1988

Macrophage infiltration into experimental brain metastases: occurrence through an intact blood-brain barrier.

The purpose of this study was to examine the nature of the blood-brain barrier in experimental brain metastases. Syngeneic fibrosarcoma or melanoma cells were injected into the internal carotid arteries of mice. Several weeks later, once the experimental brain metastases were established, the mice were given injections iv of sodium fluorescein. The capillaries within the metastatic foci were enlarged and irregular, but there was no leakage of sodium fluorescein, showing that the blood-brain barrier was intact. The neoplastic lesions were infiltrated by mononuclear phagocytes, which were identified by immunohistochemical localization of the macrophage-specific antigen F4/80, class II major histocompatibility complex (MHC) antigens, and the macrophage product interleukin-1 (IL-1). The metastatic foci contained numerous stellate macrophages that expressed F4/80 and MHC class II antigens, but little IL-1. Round, monocyte-like F4/80 and MHC class II-positive cells were also observed within the tumor lesions and adhering to walls of the tumor microvasculature. Mice with fibrosarcoma brain metastases also had edematous lesions at sites remote from the metastatic foci that contained numerous astrocytes expressing class II MHC but not F4/80 antigens. In conclusion, the blood-brain barrier is intact within experimental brain metastases, yet macrophages of blood monocyte origin can infiltrate the lesions.

Animals↗
PubMed1988

An immunohistological study of autoimmune encephalomyelitis and neuritis in the rabbit. Observations in the dorsal root ganglion using the freeze-dried paraffin-embedded tissue technique.

Previous studies of experimental autoimmune encephalomyelitis have shown that, in the central nervous system, the emigration of T-lymphocytes precedes that of mononuclear phagocytes during inflammatory lesion formation. In the present report, the formation of analogous lesions of autoimmune neuritis (EAN) was investigated in the dorsal root ganglia of rabbits immunized with homologous spinal cord in Freund's adjuvant. The relative time course of emigration of T-lymphocytes and mononuclear phagocytes into the ganglia was examined using monoclonal antibody labeling of both types of cells in serial sections of freeze-dried paraffin-embedded tissue. Results indicate that, unlike in the central nervous system, in the rabbit dorsal root ganglion T-lymphocytes and mononuclear phagocytes appear to emigrate simultaneously, as revealed by their concomitant presence in the earliest detectable lesions of EAN. It was also found that the cortical region of the rabbit dorsal root ganglion was a preferential site of EAN lesion formation, and that such lesions correlated well with the onset of clinical signs of paralysis. These results are discussed within the context of known "blood-tissue barriers" and the possible local modulation of inflammatory cell entry into regions of the nervous system.

Animals↗
PubMed1988

Pharmacokinetics of ticarcillin and clavulanic acid given in combination to adult horses by intravenous and intramuscular routes.

The pharmacokinetics of ticarcillin and clavulanic acid following administration by the intravenous (i.v.) and intramuscular (i.m.) routes were investigated in six normal adult horses. Following i.v. administration, the ticarcillin disposition data conformed to a two-compartment model with an elimination half-life of 1.0 h. The disposition of clavulanic acid was described by a one-compartment model with an elimination half-life of 0.40 h. Following i.m. administration, the half-lives of both drugs were prolonged (ticarcillin 1.8 h, clavulanic acid 1.2 h). The bioavailability of ticarcillin was 84.4% and clavulanic acid 94.3%.

Animals↗
PubMed1988

Pharmacokinetics of intravenously and intramuscularly administered ticarcillin and clavulanic acid in foals.

Serum concentrations of ticarcillin and clavulanic acid were measured in healthy foals (2 to 6 months old) given the drugs in combination by intravenous and intramuscular routes of administration. Five foals were administered 50 mg of ticarcillin/kg of body weight and 1.67 mg of clavulanic acid/kg, IV. Five foals were administered 100 mg of ticarcillin/kg and 3.33 mg of clavulanic acid/kg, IV, and 4 of those 5 were given the same combined dose IM. The elimination half-life of ticarcillin for intravenous administration was 0.83 hour for the low dosage and 0.96 hour for the high dosage. After intramuscular administration, the half-life of elimination was 2.9 hours, with bioavailability of 54.6%. For IV administered clavulanic acid, the elimination half-life was 0.65 hour for the low dosage and 0.74 hour for the high dosage. After intramuscular administration, the elimination half-life was 0.92 hour, and bioavailability was 68.1%. A combined dosage, 50 mg of ticarcillin/kg and 1.67 mg of clavulanic acid/kg, given every 6 hours is recommended.

Animals↗
PubMed1987

Simultaneous visualization of vascular permeability change and leukocyte egress in the central nervous system during autoimmune encephalomyelitis.

An unresolved issue in the study of demyelinating disease is whether blood-brain barrier damage is dependent upon the migration of inflammatory cells into the central nervous system (CNS). In a study of experimental autoimmune encephalomyelitis (EAE) in rabbits, a freeze-dried, paraffin-embedded tissue technique was exploited to enable (1) the immobilization of intravenously injected sodium fluorescein tracer, as an index of vascular permeability; and (2) an effective labeling by monoclonal antibodies of both T-lymphocytes and mononuclear phagocytes in "unfixed" neural tissue. Using these newly combined methods, evidence was found that increased vascular permeability in the CNS during EAE occurs concomitantly with, and not prior to, infiltration by mononuclear phagocytes.

Animals↗
PubMed1987

A freeze-dried paraffin-embedded tissue technique for immunohistochemical studies requiring unfixed tissue from the nervous system.

Immunohistochemical studies using monoclonal antibodies against epitopes in neural tissues frequently require tissue which has not been fixed in formalin. In the past, such studies have been performed on frozen (cryostat) sections despite the general loss of morphological preservation compared with paraffin sections. In the present report, a detailed, versatile method for obtaining improved morphological preservation of "unfixed" neural tissue is described which utilizes freeze-dried paraffin-embedded sections (a modified Altmann-Gersh technique). The advantages of using mercury flotation of freeze-dried sections are particularly stressed.

Animals↗
PubMed1986

A simple 'free 3H-ligand' assay for rapid screening of hybridoma monoclonal antibodies against neurotransmitter analogs and anti-idiotype antibodies.

Effective, rapid screening of hybridoma supernatants for monoclonal antibodies against the dopaminergic antagonists pimozide and haloperidol, and the serotonergic antagonist ketanserin was performed using a 'free 3H-ligand' assay. Anti-mouse Ig-coated microtiter plates were incubated with hybridoma supernatants prior to incubation with excess 3H-ligand. After removal of free 3H-ligand, bound 3H-ligand was eluted with acid for liquid scintillation counting. With minor modification, the assay can be used to screen hybridomas for anti-anti-ligand (anti-idiotypic) antibodies.

Animals↗
PubMed1985

Concomitant detection of changes in myelin basic protein and permeability of blood-spinal cord barrier in acute experimental autoimmune encephalomyelitis by electroimmunoblotting.

An electroimmunoblotting technique was used with a monoclonal antibody to myelin basic protein (MBP) to assess demyelination in 3 defined regions of the spinal cord in rats with acute experimental autoimmune encephalomyelitis (EAE). A slight loss in MBP was detected only in the sacrococcygeal region of the spinal cord after the onset of clinical signs. In all 3 spinal cord regions studied, significantly elevated levels of albumin and IgG were detected during the course of EAE by the same technique. At the onset of clinical signs, the levels of IgG and albumin were highest in the more caudal regions of the spinal cord. As the clinical signs became more severe, IgG and albumin levels increased in the more cranial regions of the spinal cord. These changes thus correlated with the ascending progression of clinical signs typical of EAE in rats. These results provided added evidence that in rats affected with acute EAE, the clinical signs occur independently of demyelination and coincide with vasogenic edema.

Albumins↗
PubMed1985

Preparation and characterization of antisera and monoclonal antibodies to haloperidol.

For the first time a library, of monoclonal antibodies (MoAbs) to the butyrophenone haloperidol (D-2 antagonist) has been prepared. Synthesis of a haloperidol derivative suitable for chemical coupling to a protein carrier via oxobutyric acid produced an immunogen which was used to develop two polyclonal antisera and twelve MoAbs specific for the hapten. Our library of MoAbs can be grouped into three classes; 1) high affinity and specificity for free 3H-haloperidol, 2) moderate affinity with significant cross-reactivity to other butyrophenone ligands, and 3) a group which binds poorly to free 3H-haloperidol but instead recognizes the ligand only when it is coupled to carrier protein. Clone (189(2)-6) was found to have the highest equilibrium binding affinity (Kd = 4 nM) and is far more specific than the currently available antisera to haloperidol. This MoAb has significantly lower affinity for all of the common metabolites of haloperidol. This capability makes 189(2)-6 a candidate for further development with regard to use in clinical radioimmuno-assays of therapeutic drug levels. In addition, one of the anti-haloperidol Moabs (190(2)-6) binds more tightly to spiperone than to haloperidol and displays a qualitative correlation in the rank order of neuroleptic binding affinity for a limited series of analogs when compared to membrane bound D-2 receptor binding.

Animals↗
PubMed1984

Prenatal exposure to diazepam alters central and peripheral responses to stress in adult rat offspring.

Central and peripheral responses to restraint stress were evaluated in 90-day-old rats exposed prenatally to diazepam (1.0, 2.5, or 10.0 mg/kg/day) over gestational days 13-20. As a measure of a central response to stress, the utilization of norepinephrine (NE) by hypothalamic NE neurons was assessed by determining the effect of stress on the loss of NE after synthesis inhibition. The stress-induced changes in plasma corticosterone and prolactin levels were evaluated as a physiologic index of stress. While stress increased the loss of NE after synthesis inhibition in the non-exposed control animals, it totally prevented any loss of NE after synthesis inhibition in offspring prenatally exposed to DZ. Additionally, the stress-induced change in plasma corticosterone was attenuated in a dose-related manner by prenatal exposure to DZ. The stress-induced change in plasma prolactin was also altered in a dose-related manner by the prenatal exposure. Both the altered response to stress within hypothalamic NE neurons and the attenuated change in plasma corticosterone induced by prenatal exposure to DZ (2.5 mg/kg) were prevented by concurrent administration of the centrally acting benzodiazepine antagonist Ro15-1788 to the pregnant dam, indicating that the effects of DZ were mediated via binding of the drug to central sites during gestation. These results indicate that activation of specific binding sites during early development can induce neural alterations in the adult offspring which can be reflected in functional changes which may compromise the organism.

Animals↗
PubMed1984

Prenatal diazepam exposure in rats: long-lasting, receptor-mediated effects on hypothalamic norepinephrine-containing neurons.

The concentration and turnover of catecholamines (CAs) were measured in the cortex, hippocampus, and hypothalamus of rats exposed in utero to diazepam (DZ, 1.0, 2.5, or 10.0 mg/kg/day) over gestational days 13-20. Prenatal DZ induced a regionally specific, dose-related decrease in the level of norepinephrine (NE) (maximum decrease, 65%) and turnover rate of NE (maximum decrease, 85%) in the hypothalamus of 90-day-old adult rats. Dopamine levels were not altered in this region and neither of the CAs were altered in the other regions. Dividing the prenatal exposure period into two shorter periods revealed that late gestation (days 17-20) was the period when factors influencing NE function in the hypothalamus were most sensitive to DZ. Analysis of the development of the CA in the hypothalamus demonstrated that the effect of the prenatal exposure on NE levels did not become apparent until after 28 days of age. However, at 28 days, there was a dose-related increase in turnover rate of NE (maximum increase, 52%). Concurrent administration of the specific benzodiazepine (BZ) antagonist RO15-1788 with DZ (2.5 mg/kg) to pregnant rats effectively reversed the effects of DZ in the hypothalamus of the adult offspring, suggesting that the effects were mediated via the BZ receptor. These data have provided insight into the intricate processes of neuronal development; in particular the importance of target cell-nerve terminal interactions and the role of early developing receptors.

Animals↗
PubMed1983

Prenatal diazepam: distribution and metabolism in perinatal rats.

Previous investigations have revealed that prenatal exposure to diazepam (DZ) alters brain development and behavior in the offspring of rats and mice. In order to understand how DZ may affect the developing nervous system it is necessary to examine its metabolic fate in the neonate. It is therefore the aim of this study to investigate the disposition, metabolism, and persistence of DZ in the neonate. Dams were injected s.c. with 2.5 mg/kg of 14C DZ (10 muCi/day) on days 13-20 of gestation and their litters were fostered at birth. Dams killed within 24 hours postpartum and neonates killed at postnatal days 0, 10, and 20 were analyzed for 14C activity. Brain levels (pmoles DZ and metabolites/100 mg tissue SE) were 3.4 +/- 0.3 in the dam and in the neonates were 3.2 +/- 0.3 (day 0), 3.4 +/- 0.3 (day 10), and undetectable at day 20. Neonatal peripheral tissue 14C activity was undetectable by day 10. Brain regional analysis indicates 14C is highest in the colliculi at day 0, but not at day 10. Brain levels of DZ, oxazepam (OXA), N-desmethyldiazepam (NDZ), and the glucuronide (GLU) determined by high-performance liquid chromatography (HPLC), were GLU (49%), DZ (28%), and NDZ (24%) in the dam; GLU (52%), DZ (24%), and NDZ (25%) in the day 0 neonate; and GLU (32%), DZ (12%), NDZ (39%), and OXA (19%) at day 10. The distribution and metabolism of 14C DZ that persists in the neonate following prenatal exposure differs from that which occurs in the dam.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Experimental autoimmune encephalomyelitis. An anatomically-based explanation of clinical progression in rodents.

Lactate accumulation was measured soon after decapitation in three adjacent lower spinal cord regions of rats with EAE. Results indicate that during EAE, and in correlation with the onset of clinical signs of both initial attack and short-term relapse, a differential focal increase in lactate accumulation occurs in rat spinal cord compared to Freund's Complete Adjuvant controls, with greater increase occurring in more caudal segments. A [14C]antipyrine method of estimating relative spinal cord blood flow failed to find evidence that the lactate accumulations were due to focal ischemia. Subsequent measurement of isotopic water and total protein increases in the same cord regions indicated that a slight but significant increase in vasogenic edema occurs in correlation with the increase in lactate accumulation and the onset of EAE clinical signs. The data are interpreted as lending support to a speculative theory of paralysis induced by edema during EAE, in which nerve root endoneurium is postulated as the functionally vulnerable site. More specifically, it is hypothesized that the ascending progression of clinical signs of EAE in rodents can be explained on an anatomical basis by progressive disturbance of the nodes of Ranvier in nerve root myelinated fibers.

Animals↗
PubMed1981

Hind-limb motor ability in Lewis rats during the onset and recovery phases of experimental autoimmune encephalomyelitis.

Hind-limb motor function in adult female Lewis rats with experimental autoimmune encephalomyelitis (EAE) was investigated using an objective behavioral measurement of motor ability. Rats were pretrained to avoid falling from the external surface of a power-driven running wheel. The performance of EAE-group rats on the wheel was then compared with that of saline and adjuvant controls immediately prior to the onset of clinical signs of EAE, and within 3 days of apparent recovery from EAE. Results indicate no apparent hind-limb motor deficit in the absence of overt clinical signs of EAE, despite histological evidence of severe inflammatory lesions persisting in the central nervous system (CNS) at the time of the post-recovery test. The remarkably transient nature of motor impairment is discussed within the context of a continuing search for the underlying cause(s) of clinical signs of EAE.

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