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Biomedical subjects

D B Miller

Publications and source records attributed to D B Miller.

At least 55 records · Page 3Linked to original sources
PubMed1995

Restraint-induced stress in pregnant mice--degree of immobilization affects maternal indices of stress and developmental outcome in offspring.

Maternal stress on gestational day 8 (GD8) in the CD-1 mouse can induce a syndrome of fetal anomalies, including encephalocele, supernumerary ribs, fused ribs and vertebral anomalies. Two forms of restraint were compared for their ability to induce these defects. The two types of restraint differed in the degree of mobility afforded the dam during confinement, either total restraint in a supine position or a less confining restraint in which restrained dams could move from a supine to a non-supine position, but could not turn from front to back. Dams were exposed to either form of restraint for 12 h on GD8 and their near-term fetuses examined for external and skeletal abnormalities. As both types of restraint precluded normal eating and drinking, an additional control group deprived of food/water was included for evaluation. Cohorts of dams were restrained for 3, 6 or 12 h on GD8 and end points commonly used to gauge the degree of stress evaluated. These included serum corticosterone level and the weight of body, spleen and thymus. Stress-induced analgesia, as measured by the tail-flick procedure, was monitored in these same dams as an additional non-invasive measure of stress. Both types of restraint induced greater and longer-lasting weight loss than food/water deprivation. Both also produced more fetal anomalies than observed in the offspring of caged controls or food/water deprived dams. Both forms of restraint equally elevated serum corticosterone levels above the increase exhibited by the food/water deprived dams. The most pronounced difference between the two types of restraint concerned the degree of analgesia. The type limiting mobility the most, caused much greater analgesia after 6 and 12 h of restraint although the dams subjected to the other form of restraint were significantly more analgesic than the food/water deprived dams by 12 h. Dams restrained in the supine position exhibited slightly greater weight loss, more analgesia and produced significantly more offspring with anomalies.

Analysis of Variance↗
PubMed1995

Temperature regulation and metabolism in rats exposed perinatally to dioxin: permanent change in regulated body temperature?

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been shown to lower thyroxine levels and cause hypothermia in the adult rat; however, there is little known regarding the perinatal effects of TCDD on metabolism and temperature regulation of the offspring. To address this issue, thermoregulatory responses were assessed in adult male rat offspring exposed perinatally to 1.0 micrograms TCDD/kg body wt by gavage on Gestational Day 15. Individual castrated offspring were placed in a gradient-layer calorimeter for 5 hr during their nocturnal period while ambient temperature (Ta) was maintained at 10, 16, 24, or 28 degrees C. Metabolic rate (M), as measured from the total heat loss in the calorimeter, was determined along with evaporative heat loss (EHL), dry thermal conductance, and body core temperature (Tc). Animals exposed to TCDD had a significantly lower body temperature at TaS of 10, 16, and 24 degrees C and a higher thermal conductance. M was unaffected by TCDD, indicating that TCDD did not impair the effector to regulate Tc during cold exposure. EHL was also unaffected by TCDD. Skin blood flow of the interscapular area was measured in anesthetized rats with laser Doppler velocimetry and found to be the same in control and TCDD groups. The reduction in body temperature over a wide range of TaS concomitant with normal thermoregulatory effector function suggests that perinatal exposure to TCDD results in a reduction in the regulated body temperature (i.e., decrease in set-point).

Adipose Tissue, Brown↗
PubMed1995

Quantitative aspects of drug and toxicant-induced astrogliosis.

A universal cellular reaction to damage of the CNS is hypertrophy of astrocytes. The hallmark of this response, often termed 'reactive gliosis', is the enhanced expression of the major intermediate filament protein of astrocytes, glial fibrillary acidic protein (GFAP). This latter observation suggests that increased synthesis of GFAP would occur in response to diverse neurotoxic insults. To investigate this possibility, prototype neurotoxicants were administered to experimental animals and the effects of these agents on the tissue content of GFAP was determined by immunoassay. Assays of GFAP were found to reveal dose-, time- and region-dependent patterns of neurotoxicity at toxicant dosages below those that cause light microscopic evidence of cell loss or damage. Moreover, the temporal and regional increments in GFAP correspond to the temporal and regional patterns of argyrophilia, as revealed by the cupric silver degeneration stain of de Olmos. Our findings indicate that assays of GFAP represent a sensitive, simple and quantitative approach for evaluation of nervous system damage. Combining this indirect yet quantitative indicator of neurotoxicity with more traditional neuroanatomical endpoints, should augment the armamentarium of techniques useful for detection and characterization of neurotoxicity.

Animals↗
PubMed1995

Identification, molecular characterization, and cellular studies of an apolipoprotein E mutant (E1) in three unrelated families with hyperlipidemia.

Remnants of triglyceride-rich lipoproteins accumulate in plasma of subjects with type III hyperlipoproteinemia (HLP) due to defective clearance by hepatic receptors. Although most subjects with type III HLP are homozygous for apolipoprotein (apo) E2 (arg158-->cys, R158C), a variant that binds defectively to cell surface receptors, some individuals with type III HLP have rare mutations of apo E. We identified six subjects from three families with type III HLP who had either an apo E3/1 or E4/1 phenotype by isoelectric focusing. Using DNA restriction isotyping with HhaI, all six subjects were determined to have only one apo E allele encoding cys158 and the other encoding arg158. Subsequently, digestion of polymerase chain reaction-amplified portions of exon 4 of the apo E gene with endonucleases HaeIII, TaqI, and Sau3AI demonstrated a second DNA variant that encoded a single amino acid substitution (gly127-->asp, G127D) due to a guanosine-to-adenosine nucleotide change resulting in the apo E1 isoform (G127D, R158C), which had arisen from a parent apo E2 allele. This mutation was confirmed with direct DNA sequencing. Incubation of very low density lipoprotein (VLDL) isolated from hyperlipidemic apo E1 subjects with J774 macrophages resulted in a 7- to 12-fold increase in cellular cholesterol ester compared with VLDL from apo E2/2 subjects. Although heterozygosity for apo E1 alone did not impair the interaction of VLDL with cellular receptors in vitro, its presence in subjects with type III HLP suggests that apo E1, perhaps in combination with secondary factors, may be causative for the dyslipidemia.

Adolescent↗
PubMed1994

The heterologous expression and characterization of human prostaglandin G/H synthase-2 (COX-2).

The open reading frame of human cyclooxygenase-2 was cloned by pcr amplification of IL-1 beta stimulated human dermal fibroblast cDNA. The coding region was used to construct a recombinant baculovirus which when used to infect Sf9 cells directed the expression of recombinant human cyclooxygenase-2. The heterologously expressed enzyme was characterized and found to display all salient features of cyclooxygenase. Large-scale microsomal preparations of infected cells yielded more than 20 units of enzyme with a specific activity of 240 nmoles prostaglandin product/mg protein.

Animals↗
PubMed1994

Prenatal cocaine eliminates the sex-dependent differences in activation observed in adult rats after cocaine challenge.

In the adult rat, acute administration of cocaine results in enhanced expression of certain behaviors. This activation is often referred to as "stereotypy" because of its repetitive nature. Repeated exposure to the same dose of cocaine does not result in tolerance or a dimunition of these behavioral responses. Rather, an increased responsiveness to cocaine, termed "sensitization," is observed. Female rats, in comparison to male rats, display greater activation to a given dose of cocaine and greater sensitization with repeated exposure. As prenatal cocaine exposure can involve repeated exposure to the drug, we examined the behavioral activation induced by an acute dose of cocaine. Young adult rats of both sexes received a challenge dose of cocaine to determine the long-term effects of repeated in utero exposure to cocaine (30 mg/kg daily, SC) given between gestational days 8-20. As expected, female offspring of dams exposed to saline in utero displayed greater activation to a 20 mg/kg SC dosage of cocaine than their male counterparts. However, these sex differences were completely eliminated by prenatal exposure to cocaine. That is, female rats receiving cocaine during the prenatal period showed no more activation to an acute dose of cocaine as young adults than either control males or those males receiving cocaine in utero. Males exposed in utero to cocaine showed activation to cocaine challenge equivalent to that displayed by males exposed to saline in utero. Prenatal exposure to cocaine may alter sexual differentiation of the brain.

Animals↗
PubMed1994

New nonionic triiodinated x-ray contrast media containing the N-(2-hydroxyethyl)aminopropane-2,3-diol side chain.

We have found the amino alcohol (HE)APD to be an effective solubilizing and detoxifying agent for triiodinated benzene XRCM. Most of the compounds containing the (HE)APD moiety displayed good solution properties (low osmolality and viscosity) and relatively low toxicities. A general trend was observed in which compounds with low hydrophilicity were more toxic. High hydrophilicity was found to be necessary for low intracisternal toxicity, but is not the only criterion. Use of the 5-glycolamido group provides compounds with high hydrophilicity. When all the properties were compared, the best compounds in this study were found to be the three asymmetrically substituted isophthalamides containing the (HE)APD and APD side chains (4a-c: MP-1556, MP-1683, and MP-1689). These compounds have excellent solution properties (low osmolality and viscosity) and low intravenous and intracisternal toxicities, and compare favorably to current clinical agents.

Animals↗
PubMed1994

Neurotoxicity profiles of substituted amphetamines in the C57BL/6J mouse.

Dopaminergic (DA) and serotonergic (5-HT) projections to striatum and cortex have been implicated as the primary targets of substituted amphetamine (AMP)-induced neurotoxicity, largely on the basis of the propensity of these compounds to cause protracted decrements in DA and 5-HT rather than on the basis of AMP-induced alterations of indices linked to neural damage. Moreover, most studies of AMP-induced neurotoxicity, regardless of the endpoints assessed, have been conducted using a rat model; relatively little attention has been focused on the effects of these compounds in the mouse. Here, we evaluated the potential neurotoxic effects of d-methamphetamine (d-METH), d-methylenedioxyamphetamine (d-MDA), d-methylene-dioxymethamphetamine (d-MDMA) and d-fenfluramine (d-FEN) in the C57BL6/J mouse. Astrogliosis, assessed by quantification of glial fibrillary acidic protein (GFAP), was taken as the main index of AMP-induced neural damage. A silver degeneration stain also was used to obtain direct evidence of AMP-induced neuronal damage. Assays of tyrosine hydroxylase (TH), DA and 5-HT were used to assess effects on DA and 5-HT systems. Mice received d-METH (10 mg/kg), d-MDA (20 mg/kg), d-MDMA (20 mg/kg) or d-FEN (25 mg/kg) every 2 hr for a total of four s.c. injections. d-METH, d-MDA and d-MDMA caused a large (300%) increase in striatal GFAP that resolved by 3 weeks and a 50 to 75% decrease in TH and DA that did not resolve. d-METH, d-MDA and d-MDMA also caused fiber and terminal degeneration in striatum as revealed by silver staining. d-FEN did not affect any parameters in striatum. d-METH, d-MDA and d-MDMA also increased GFAP in cortex, effects that were associated with small (10-25%) and transient decrements in cortical 5-HT. d-FEN caused prolonged (weeks) decrements (20%) in cortical 5-HT but did not affect cortical GFAP. The effects of d-METH, d-MDA and d-MDMA were stereoselective and were blocked by pretreatment with MK-801. Core temperature was slightly elevated by d-METH, d-MDA and d-MDMA but was dramatically lowered by d-FEN. The data suggest that d-METH, d-MDA and d-MDMA, but not d-FEN, produce damage to neural elements of mouse striatum and cortex.

Amphetamines↗
PubMed1994

Environment-, drug- and stress-induced alterations in body temperature affect the neurotoxicity of substituted amphetamines in the C57BL/6J mouse.

In the companion paper we demonstrated that d-methamphetamine (d-METH), d-methylenedioxyamphetamine (d-MDA) and d-methylenedioxymethamephetamine (d-MDMA), but not d-fenfluramine (d-FEN), appear to damage dopaminergic projections to the striatum of the mouse. An elevation in core temperature also was associated with exposure to d-METH, d-MDA and d-MDMA, whereas exposure to d-FEN lowered core temperature. Given these findings, we examined the effects of temperature on substituted amphetamine (AMP)-induced neurotoxicity in the C57BL/6J mouse. Levels of striatal dopamine (DA) and glial fibrillary acidic protein (GFAP) were taken as indicators of neurotoxicity. Alterations in ambient temperature, pretreatment with drugs reported to cause hypothermia in the mouse and hypothermia induced by restraint stress were used to affect AMP-induced neurotoxicity. Mice received d-METH (10 mg/kg), d-MDA (20 mg/kg) or d-MDMA (20 mg/kg) every 2 hr for a total of four s.c. injections. All three AMPs increased core temperature and caused large (> 75%) decreases in striatal dopamine and large (> 300%) increases in striatal glial fibrillary acidic protein 72 hr after the last injection. Lowering ambient temperature from 22 degrees C to 15 degrees C blocked (d-MDA and d-MDMA) or severely attenuated (d-METH) these effects. Pretreatment with MK-801 lowered core temperature and blocked AMP-induced neurotoxicity; elevation of ambient temperature during this regimen elevated core temperature and markedly attenuated the neuroprotective effects of MK-801. Pretreatment with MK-801 also lowered core temperature in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice but did not block 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamines↗
PubMed1993

Repeated exposure to the polychlorinated biphenyl (Aroclor 1254) elevates the basal serum levels of corticosterone but does not affect the stress-induced rise.

Previous studies indicate that repeated exposure of weanling male Fischer 344 rats to Aroclor can cause immune system alterations but the pattern of effects suggested the release of corticosteroids may have played a role. Rats were exposed daily by gastric intubation to the polychlorinated biphenyl (PCB) Aroclor 1254 at 0.1, 1.0, 10, or 25 mg/kg for exposure durations of 5, 10 or 15 weeks. By the 15th week of dosing all groups displayed an elevation in the basal level of serum corticosterone but no change in adrenal weight. Further, rats exposed to Aroclor 1254 for 15 weeks and subjected to stress prior to serum collection displayed elevations in corticosterone levels equivalent to stressed control rats. The failure to observe altered adrenal structure indicative of hyperactivity in the presence of increased serum levels of corticosterone suggest these basal increases may be indirect rather than direct effects of Aroclor 1254.

Animals↗
PubMed1992

Interactions of parents and nurses with high-risk preterm infants.

The interactions of preterm infants with parents were compared with their interactions with nurses. Twenty-nine high-risk preterm infants who were a part of a larger longitudinal study of behavioral development were observed once weekly from 7 p.m. to 11 p.m. A single observation for each infant that contained a minimum of 2 min of parental care and 2 min of nursing care was selected for analysis. Results showed that nurses and parents provided different types of stimulation with nurses more likely to engage in procedural care and parents more likely to hold, talk to, move, and touch the infants affectionately. Infants showed more sleep-wake transition, large body movements, and jitters when with nurses and more active sleep and more smiles when with parents. Similar differences were found when parents and nurses were just holding or touching the infants, but no differences in infant responses were seen during feeding or changing. Thus, the different infant behavioral responses appeared to result primarily from the different stimulation provided by parents and nurses. Implications of these findings for research and clinical practice are discussed.

Caregivers↗
PubMed1992

Attenuation of alcohol consumption by MDMA (ecstasy) in two strains of alcohol-preferring rats.

Alcohol preference and manifestation of alcoholism are thought by many to be associated with serotonin (5-HT) dysfunction in the brain. Thus, experiments were performed to determine the effect of acute and subchronic administration of (+/-) 3,4-methylenedioxymethamphetamine (MDMA), an amphetamine analog that stimulates 5-HT release, on alcohol preference in two strains of alcohol-preferring rats, the Fawn-Hooded (FH) and alcohol-preferring (P) rats. Rats were individually housed and provided free access to a solution of 10% ethanol, food, and water. Ethanol, food, and water intakes were measured daily. After establishing a stable baseline for ethanol and water intake, each rat was injected SC with a dose of 5.0 mg/kg MDMA or an equal volume of saline for 1 or 3 consecutive days. Body temperature was recorded immediately before and 120, 240, and 360 min after MDMA treatment. Ethanol, food, and water intake were measured for the preceding 24 h. Further, to determine the effect of MDMA on alcohol metabolism rats were injected with 5.0 mg/kg MDMA or saline and 15 min later with 2.5 g/kg alcohol. Then, blood alcohol levels were determined at 1, 3, and 5 h after alcohol administration. Our results show that a single administration of 5.0 mg/kg MDMA significantly decreased ethanol intake in both FH and P rats and increased water intake. Subchronic administration of 5.0 mg/kg MDMA for 3 consecutive days significantly attenuated alcohol intake in both strains but only increased water intake in P rats. Administration of MDMA induced hyper- and hypothermia in FH and P rats, respectively. This drug failed to exert any significant effect on the pharmacokinetics of alcohol, indicating a central effect.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Methylenedioxyamphetamine↗
PubMed1991

Effects of 3,4-methylenedioxymethamphetamine on autonomic thermoregulatory responses of the rat.

3,4-Methylenedioxymethamphetamine (MDMA), a substituted amphetamine analogue which stimulates serotonin release in the CNS, has been shown to induce near lethal elevations in core temperature in the rat. To characterize the effects of MDMA on temperature regulation, we measured metabolic rate (MR), evaporative water loss (EWL), motor activity (MA), and colonic temperature (Tc) in male, Long-Evans rats at 60 min following 30 mg/kg (SC) MDMA or saline at ambient temperature (Ta) of 10, 20 and 30 degrees C. MDMA caused an elevation in MR at Ta's of 20 and 30 degrees C but had no effect at 10 degrees C. At a Ta of 30 degrees C, MR of the MDMA group was double that of the saline group. EWL was elevated by MDMA, an effect which was potentiated with increasing Ta. MDMA also elicited an increase in MA at all three Ta's. MDMA led to a 3.2 degrees C increase in Tc at 30 degrees C, no change in Tc at 20 degrees C, and a 2.0 degrees C decrease in Tc at 10 degrees C. A second study found that treatment with 20 mg/kg MDMA failed to elicit an increase in blood flow to the tail in spite of a hyperthermic core temperature of 41.4 degrees C. Preliminary studies using radiotelemetry methodology suggested that MDMA lethality is preceded by precipitous elevations in heart rate and core temperature. The data suggest that, at relatively warm Ta's. MDMA-induced stimulation of serotonergic pathways causes an elevation in MR and peripheral vasoconstriction, thus producing life-threatening elevations in Tc.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Methylenedioxyamphetamine↗
PubMed1991

The role of the matrix metalloproteinase stromelysin in the progression of squamous cell carcinomas.

The expression of the metalloproteinase stromelysin correlates with the progression of chemically induced squamous cell carcinomas. We demonstrate that the expression of activated stromelysin in papilloma-derived cells enhances in vitro cell invasion. We also demonstrate that the Ha-ras oncogene induces the transcription of the stromelysin gene through an AP-1 dependent pathway. The hypothesis is that alterations in oncogenes and suppressor genes influence stromelysin expression and thus influence subsequent steps of tumor invasion and metastasis.

Carcinoma, Squamous Cell↗