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Biomedical subjects

D B Miller

Publications and source records attributed to D B Miller.

At least 91 records · Page 5Linked to original sources

Effects of E2 levuglandins on the contractile activity of the rat uterus.

The effects of E2 levuglandins on the contractile activity of rat uterine horns were studied. LGE2, AnLGE2, delta 9-LGE2 and the synthetic epimer, 8-epi-delta 9-LGE2 all induced contractions in a dose-response fashion. AnLGE2 gave decreased responses with increased bath concentrations. Paired comparisons showed potent and selective inhibitory effects of AnLGE2 on the uterotonic activity of prostaglandins. AnLGE2 inhibited the uterotonic activity of PGE2 at a 0.1:1 ratio, of PGD2 at a 1:1 ratio, but did not inhibit the activity of PGF2 alpha. Exposure of spontaneously contracting uteri to high concentrations of AnLGE2, or prolonged exposure to lower concentrations, suppressed contractions.

Animals↗

Diethyldithiocarbamate increases distribution of cadmium to brain but prevents cadmium-induced neurotoxicity.

Dithiocarbamates exhibit potent metal-binding properties which have been exploited in a variety of applications, one of which is chelation therapy for heavy metal toxicity. Such therapy, however, promotes the accumulation of metals in the brain, a side effect which may result in neurotoxicity. To examine this possibility we used morphological and biochemical indices to assess the effects of diethyldithiocarbamate (DDC) on cadmium-induced neurotoxicity in the newborn rat. Co-administration of DDC prevented the neurotoxic effects of cadmium while causing a persistent increase in the distribution of cadmium to brain.

Animals↗

Alarm call responsivity of mallard ducklings: III. Acoustic features affecting behavioral inhibition.

Mallard ducklings (Anas platyrhynchos) inhibit their vocal and locomotor behavior upon hearing the maternal alarm call of their species. This study assesses the effects of varying acoustic features of alarm calls on the ducklings' freezing response (i.e., vocal and locomotor inhibition). Domestic mallard (Peking) ducklings were tested individually to alarm calls that varied either in note duration, frequency modulation, dominant frequency, repetition rate, or repetition rate in combination with these other features. The present study demonstrates that ducklings show a high degree of behavioral specificity to repetition rate (i.e., number of notes per second), relative to other acoustic features. This study also revealed that ducklings also exhibit some degree of behavioral specificity to note duration. Dominant frequency and frequency modulation play only a minor role in affecting behavioral inhibition. The behavioral specificity of mallard ducklings to slow repetition rates (that are typical of maternal alarm calls) provides a basis for the importance of their slow-rate perinatal vocalizations in the development of alarm call responsivity.

Animals↗

Hospital--nursing home collaboration.

In the present health care environment, the provision of quality care for the elderly depends on collaboration between hospitals and nursing homes. Nathan Miller Center for Nursing Care, Inc, a skilled nursing facility in White Plains, New York, and Montefiore Medical Center, a tertiary care hospital in Bronx, New York, developed a variety of joint educational programs in geriatrics for their staffs and for the local medical community. These programs not only helped improve patient care directly in such areas as development of care plans but also led to joint projects for research on geriatric care issues.

Aged↗

Behavioral perturbations in the vitamin K-deficient rat.

Anecdotal observations of the behavior of rats with a vitamin K-deficiency suggested that this deficiency was associated with hypoactivity, general malaise, and a lack of exploratory behavior. These observations were pursued by assessing locomotor activity in a circular photocell-monitored track, open-field activity, and radial-arm maze performance in rats rendered vitamin K-deficient by dietary depletion or by warfarin treatment. There was a significant reduction (approximately 25% at the median) in the locomotor activity of dietary vitamin K-deficient rats compared with rats fed a control diet. In the open-field, warfarin administration was associated with a significant shift from more exploratory behaviors to less exploratory behaviors. Consistent with these findings, radial-arm maze assessment showed a comparative reduction in locomotor activity in the dietary vitamin K-deficient rats with no alteration in performance, i.e., short-term memory. These animal behavioral studies suggest that sub-clinical and clinical vitamin K-deficiency may contribute to physical and psychiatric symptomatology.

Animals↗

Changes in in vitro brain and spinal cord protein phosphorylation after a single oral administration of tri-o-cresyl phosphate to hens.

The effect of a single oral 750 mg/kg dose of tri-o-cresyl phosphate (TOCP) on the endogenous phosphorylation of brain and spinal cord proteins was assessed in hens during the development of and recovery from delayed neurotoxicity. Crude membrane and cytosolic fractions were prepared from the brains and spinal cords of control and TOCP-treated hens at 1, 7, 14, 21, 35, and 55 days after treatment. Brain and spinal cord protein phosphorylation with [gamma-32P]ATP was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), autoradiography, and microdensitometry. TOCP administration conferred calcium and calmodulin dependence on the phosphorylation of a few brain cytosolic proteins and caused an increase in the phosphorylation of a number of other cytosolic and membrane proteins. This effect of TOCP was large in magnitude, and its time course reflected the onset of and recovery from the signs of ataxia and paralysis associated with delayed neurotoxicity in the hen. The molecular weights (Mr) and maximal phosphorylation (percent of control) for the most prominently affected bands were as follows: brain cytosol--50K (183%), 55K (575%), 60K (529%), 65K (273%), and 70K (548%); brain membranes--50K (622%) and 60K (697%); and spinal cord cytosol--20K (182%). The role of endogenous phosphorylation reactions in and their potential usefulness as biochemical indicators of delayed neurotoxicity are being explored further.

Administration, Oral↗

Interior design preferences of residents, families, and staff in two nursing homes.

The small number of respondents and the absence of specific demographic data concerning the three categories of respondents represented definite limitations. Further investigation in other long-term care facilities clearly is indicated. However, as a preliminary survey of preferences in nursing home interior design, several interesting findings have emerged: Patients, staff and families all emphasized patient safety and function over aesthetics. Yet, more residents than staff and families were concerned with appearance. Although experts advocate creating a home-like atmosphere in the nursing home, 50% or more of each group applied different criteria for specific design elements for private homes and for long-term care institutions. Design preferences for the three groups were similar, with an emphasis on modern furniture, painted walls, resilient tile rather than carpet, blinds, pastel and warm colors, and the use of paintings as accessories. Contrary to study assumptions, design features that promote patient individuality (e.g., patient artwork) received much greater emphasis from staff than from patients and families. Environmental change was considered an important aspect of interior design. Of the three constituencies, staff was most aware of periodic changes in decor and considered change as "very important" more often than did families or patients. As the nature of the nursing home patient population has changed--with residents presenting more disability and less rehabilitation potential and less likelihood of returning home--the ambiance of facilities has assumed even more importance. Clearly, the design preferences of residents who live in the facility are of paramount importance. However, it is also helpful to have an environment that is pleasing to family members who often experience difficulty in ongoing visitations, particularly to intellectually impaired relatives. Maintaining staff morale at a high level is a constant challenge in a long-term care facility because inevitably, in spite of the active rehabilitation efforts of the entire treatment team, the condition of patients eventually will worsen. Thus, an attractive lively setting can prove beneficial to those who visit and work in the nursing home. Effective long-term care, which includes attention to the physical environment, should be concerned with the triad of residents, their families, and staff. Awareness that interior design does indeed impact on overall quality of life should lead the nursing home administrator to collaborate with residents, staff, and families and to share their input with professional design consultants.

Attitude of Health Personnel↗

Cerebellar hypoplasia in the Gunn rat is associated with quantitative changes in neurotypic and gliotypic proteins.

We are characterizing toxicant-induced injury to the nervous system by measuring nervous system, cell-type specific proteins together with accompanying changes in morphology and behavior. In the present study, cerebellar neurotoxicity was assessed in the Gunn rat, an autosomal recessive mutant that exhibits degeneration of Purkinje cells due to hereditary hyperbilirubinemia. Five proteins associated with neuronal or glial cell types were chosen for evaluation as follows: G-substrate, a Purkinje cell-specific phosphoprotein that serves as the endogenous substrate of cyclic GMP-dependent protein kinase; PCPP-260, a Purkinje cell-specific phosphoprotein that serves as an endogenous substrate of cyclic AMP-dependent protein kinase; synapsin I, a synapse-specific phosphoprotein present in all neurons; glial fibrillary acidic protein, an astrocyte-specific protein; and myelin basic protein, a protein unique to myelin. In comparison to heterozygote (Jj) controls, homozygous (jj) rats showed alterations in the amounts of neurotypic and gliotypic proteins in cerebellum that were consistent with the neuropathological effects associated with development of hyperbilirubinemia in the Gunn rat. Decreased cerebellar cyclic GMP, but not cyclic AMP, alterations in indices of motoric competence and increased responsiveness to a nociceptive stimulus also were observed in jj rats. In general, the degree of cerebellar hypoplasia was predictive of the degree of biochemical, morphological or behavioral change observed. The results indicate that neurotypic and gliotyic proteins may be used as biochemical indicators of neurotoxicity.

Animals↗

Pre- and postweaning indices of neurotoxicity in rats: effects of triethyltin (TET).

Pre- and postweaning measures of learning and locomotor activity were used as indices of CNS function after early perinatal neurotoxic insult. Triethyltin (0.0, 3.0, or 6.0 mg/kg, ip) administered on Postnatal Day 5 (PND5) was used as the neurotoxicant. Learning deficits and alterations in locomotor activity were observed during both the pre- and postweaning periods. Preweaning learning ability was evaluated with an appetitive alleyway paradigm, while an automated radial-arm maze (RAM) was used to assess juvenile learning. Preweaning open-field locomotion was evaluated in the presence and absence of homecage litter while postweaning activity was measured in an automated device, the Motron, or as a component of performance in the RAM. The 6.0-mg/kg TET-exposed animals required more trials to acquire the alleyway task. RAM subjects receiving 6.0 mg/kg of TET were less accurate than those given 3.0 mg/kg or vehicle control. TET did not affect open-field activity on PND10; low levels of spontaneous locomotion occurred regardless of treatment. On PND13, there was a dose-related decrease in locomotion over home-cage litter while all groups exhibited equivalent low rates of locomotion in the absence of home-cage cues. All treatment groups were more active when tested over litter than over no litter. In contrast, on PND21 and throughout the RAM testing period, TET-exposed subjects exhibited dose-related increases in activity. TET produced treatment-related decreases in wet weight of whole brain, hippocampus, and cerebellum in both developing (PND23) and adult (PND200) animals with the hippocampus being most affected on a percentage basis. In contrast, no treatment-related body weight differences were observed at these times. The neurotoxicity of TET can be demonstrated during the preweaning period whether a commonly used endpoint in assessing CNS function (locomotor activity) is monitored or a more complex endpoint (learning) is evaluated provied (1) the method used to monitor locomotor activity incorporates both the normally low levels of preweaning locomotion and the more elevated levels induced by home-cage cues and (2) the learning paradigms utilized are appropriate for the capabilities of the animal.

Animals↗

Neuron-specific phosphoproteins as biochemical indicators of neurotoxicity: effects of acute administration of trimethyltin to the adult rat.

The cytoarchitecture of the adult central nervous system is expressed by proteins specific to individual cell types. In this investigation, a subclass of these proteins, the neuron-specific phosphoproteins, was examined after the administration of trimethyltin (TMT), a neurotoxicant which preferentially damages neurons in limbic structures. After acute administration of TMT (0.0-9.0 mg/kg i.v.), effects on neuronal phosphoproteins were examined by three separate techniques: endogenous phosphorylation of total synaptic membrane proteins; radiometric assay of synapsin I, a neuron-specific phosphoprotein associated with synaptic vesicles; and radioimmunoassay of synapsin I and protein III, another synapse specific, synaptic vesicle-localized phosphoprotein. All three procedures gave similar results. TMT caused dose- and time-dependent decreases in hippocampal phosphoproteins. These effects were large in magnitude and were still evident 14 weeks after exposure to TMT. Microdissection of slices of dorsal hippocampus did not reveal significant regional differences in the extent to which TMT affected synapsin I. Phosphoproteins in frontal cortex, unlike those in hippocampus, were not affected by TMT. Our findings are consistent with the neuropathological effects of this compound and suggest that neuron-specific phosphoproteins may be useful biochemical indicators of neurotoxicity.

Animals↗

Biochemical, functional and morphological indicators of neurotoxicity: effects of acute administration of trimethyltin to the developing rat.

The neurotoxic organometal, trimethyltin (TMT), was administered to rats on postnatal day (PND)5. Neurotoxicity was assessed throughout subsequent development using morphological, biochemical and functional endpoints. These consisted of brain weight measures and histology (morphology), assays of nervous system-specific proteins (biochemistry) and neurobehavioral indices of activity and learning (function). All three indices were affected. TMT caused dose-related decreases in brain weights at all ages examined, PND13, 22 and 66, with the hippocampus being the most severely reduced. Histological examination of the hippocampus revealed loss of pyramidal neurons in CA3 to CA4. Exposure to TMT was followed by dose- and age-dependent reductions in synapsin I, a neuron-specific phosphoprotein associated with synaptic vesicles; these effects of TMT were greater in hippocampus than in forebrain. TMT did not alter the concentration or protein composition of isolated myelin. The ontogeny of locomotion was altered in a dose- and time-dependent manner; TMT induced hypoactivity early in development (PND13) and hyperactivity by weaning (PND21); hyperactivity was also observed in the adult. Finally, TMT also affected learning ability throughout development. Deficits were observed in: acquisition and retention of an instrumental alleyway response; acquisition of a step-through passive avoidance response; and radial-arm maze performance. These results demonstrate the use of a multi-endpoint, multi-timepoint strategy for the detection and characterization of neurotoxicity.

Animals↗

Alarm call responsivity of mallard ducklings: I. The acoustical boundary between behavioral inhibition and excitation.

Mallard (Anas platyrhychos) maternal assembly calls have fast repetition rates (notes/sec), which promote behavioral excitation in ducklings (i.e., vocalizing, approaching). On the other hand, maternal alarm calls have slow repetition rates, which promote behavioral inhibition (i.e., cessation of vocalizations, "freezing"). This study assesses the nature of the acoustical boundary separating these 2 behavioral states. Maternally naive ducklings were tested to 1 of 2 series of altered alarm calls that either increased or decreased in repetition rate every minute by 2/10 sec. Ducklings in control groups were exposed to a constant repetition rate for comparable periods of time. The inhibitory and disinhibitory responses of ducklings revealed that a relatively sharp acoustical boundary between inhibitory and excitatory repetition rates exists around 2.6 to 2.8 notes/sec. This transitional region happens to coincide with the range within which neither maternal assembly nor maternal alarm calls occur. Thus, there is a genuine match along this acoustical dimension between auditory perception of ducklings and the 2 major species-typical vocalizations of mallards.

Animals↗

Alarm call responsivity of mallard ducklings: II. Perceptual specificity along an acoustical dimension affecting behavioral inhibition.

Mallard ducklings (Anas platyrhynchos) inhibit their vocal and locomotor behavior upon hearing the maternal alarm call. An important acoustic feature of the call that affects such inhibition is the slow repetition rate of the notes. This study assesses the range of repetition rates that affect behavioral inhibition in 1-day-old domestic mallard (Peking) ducklings. Four hundred and fifty maternally naive ducklings were tested in groups of 30 to repetition rates ranging from .2 to 3.0 notes/sec in 2/10-sec increments. Various behavioral measures (i.e., incidence of inhibition, latency and duration of inhibition) revealed that the optimal range of repetition rates affecting inhibition extends from .8 to 1.8 notes/sec. Within this range, 1.0 and 1.6 notes/sec are particularly effective. The efficacy of these particular 2 rates may reflect their correspondence with the rates of the modal alarm call and certain kinds of self-produced embryonic vocalizations, respectively. Unexpectedly, very slow repetition rates (.2 and .4 notes/sec) are not as effective as faster rates in promoting inhibition. Thus, the inhibitory response exhibited by ducklings upon hearing the alarm call reflects auditory perceptual specificity to a range of moderately slow repetition rates that are characteristic of normally occurring sounds of the perinatal environment.

Animals↗

Bupropion, d-amphetamine, and amitriptyline-induced conditioned taste aversion in rats: dose effects.

Nine groups of rats (n = 6 per group) were adapted to a daily one-half hour period of water availability. When intake had stabilized, they were allowed access to a 0.1% (w/v) solution of saccharin, and immediately afterward were given IP injections of isotonic saline; bupropion HCl (10.0, 20.0, or 40.0 mg/kg); d-amphetamine-sulfate (0.5, 1.0, 2.0 mg/kg); or amitriptyline HCl (5.0, 10.0, or 20.0 mg/kg) in a volume of 1 ml. The lowest dose of each compound as chosen to be equipotent in screening tests used to identify potential antidepressants. Following 2 days of access to water alone, all groups were given a choice between water and saccharin for 3 consecutive days. All compounds induced taste aversions in a dose-related manner, but amitriptyline induced greater and longer-lasting aversions than either bupropion or d-amphetamine which were equipotent over the dose range studied. As such, this is the first demonstration that bupropion and amitriptyline, two clinically effective antidepressants, can induce taste aversions and replicates as well the common finding that d-amphetamine has substantial taste aversion-inducing properties. The ability of these compounds to induce taste aversions could be mediated through their effects on central catecholaminergic processes although amitriptyline has significant peripheral anticholinergic effects.

Amitriptyline↗

Fine structure analysis and nucleotide sequence of the vaccinia virus thymidine kinase gene.

The thymidine kinase (ATP:thymidine 5'-phosphotransferase, EC 2.7.1.21) gene of vaccinia virus has previously been mapped near the middle of the viral DNA, within the 4.85-kilobase HindIII J fragment, and shown to encode a Mr 19,000 polypeptide [Hruby, D. E. & Ball, L. A. (1982) J. Virol. 43, 403-409]. To locate the gene more precisely and to determine the structure of the basic transcriptional unit, the positions of cleavage sites for several restriction endonucleases were mapped within the HindIII J DNA fragment. Four appropriate subfragments of HindIII J DNA were inserted into plasmid pBR322 derivatives and cloned in Escherichia coli. These recombinant plasmid DNAs were tested for their ability to inhibit the cell-free synthesis of active thymidine kinase and to retain the mRNA for this enzyme when immobilized on nitrocellulose filters. The data showed that the gene spanned an EcoRI cleavage site that lies 850 base pairs from the left-hand end of the HindIII J fragment (the HindIII L-J boundary). Because hybridization of vaccinia virus DNA to partially purified thymidine kinase mRNA detected only a single 670-nucleotide RNA species capable of hybridizing to this region of the genome, nuclease S1 mapping experiments were carried out with thymidine kinase mRNA to protect DNA fragments that were terminally labeled at this EcoRI site. The results indicated that the gene extended from about 550 to 1,150 base pairs from the left end of HindIII J, was transcribed in a rightward direction, and contained no intervening sequences. Hence, a 1.04-kilobase Ava II-Hpa II restriction fragment containing this region of DNA was isolated and subjected to nucleotide sequence analysis. An examination of this nucleotide sequence revealed the presence of an open reading frame of 531 nucleotides capable of encoding a protein of 177 amino acids with a Mr of 20,077.

Amino Acid Sequence↗