Biomedical subjects

C A Miller

Publications and source records attributed to C A Miller.

At least 37 records · Page 2Linked to original sources

PubMed2000

The neuronal response to electrical constant-amplitude pulse train stimulation: evoked compound action potential recordings.

The purpose of this study was to gain a greater understanding of the electrically evoked compound action potential (EAP) responses to pulse train stimulation. Analysis of EAP amplitude responses suggested that an alternating pattern varied depending upon stimulus level, interpulse interval (IPI), stimulus waveform, and stimulus polarity. Stimulus level-dependent recovery was seen in the cat and the guinea pig: higher stimulus level tended to provide faster recovery. Both polarity-dependent recovery and polarity-dependent adaptation were observed in the cat and these stimulus polarity effects were less consistent in the guinea pig. The polarity-dependent recovery effect supports the hypothesis that anodal and cathodal stimuli excite different sites along auditory nerve fibers. Amplitude differences between the response to the second pulse and the steady-state response at the same IPI are significantly greater for anodal stimuli than for cathodal stimuli in all cats. These data suggest that there is a cumulative refractory effect in the auditory nerve of cats, especially in response to anodal stimuli.

Action Potentials↗

PubMed2000

The neuronal response to electrical constant-amplitude pulse train stimulation: additive Gaussian noise.

Experimental results from humans and animals show that electrically evoked compound action potential (EAP) responses to constant-amplitude pulse train stimulation can demonstrate an alternating pattern, due to the combined effects of highly synchronized responses to electrical stimulation and refractory effects (Wilson et al., 1994). One way to improve signal representation is to reduce the level of across-fiber synchrony and hence, the level of the amplitude alternation. To accomplish this goal, we have examined EAP responses in the presence of Gaussian noise added to the pulse train stimulus. Addition of Gaussian noise at a level approximately -30 dB relative to EAP threshold to the pulse trains decreased the amount of alternation, indicating that stochastic resonance may be induced in the auditory nerve. The use of some type of conditioning stimulus such as Gaussian noise may provide a more 'normal' neural response pattern.

Action Potentials↗

PubMed2000

Mutation detection in an equivocal case of Friedreich's ataxia.

Compound heterozygosity at the Friedreich's ataxia locus accounts for approximately 2% of molecularly confirmed cases. Genotype-phenotype correlation in this subgroup of patients reveals a spectrum of clinical variability. This report describes the clinical and molecular findings in a 6-year-old patient with Friedreich's ataxia who carried a pathologic GAA expansion of approximately 1,000 repeats on one allele and a novel initiation codon point mutation (3G-->A) on the other.

Alleles↗

PubMed2000

Unintended pregnancy and preterm birth.

About one-third of all pregnancies that result in live births in the US are unintended. Despite the large number of these births, little is known about the outcomes of unintended pregnancies. The purpose of the current study was to evaluate the association between intendedness of pregnancy and preterm birth in a large prospective cohort of women who reported for prenatal care. Pregnant, black, low-income women were enrolled into this study at four hospital-based prenatal care clinics and one off-site hospital-affiliated prenatal clinic in Baltimore City. A self-administered questionnaire to assess demographic and psychosocial data was completed by each woman in the cohort at the time of enrolment in the study. The questionnaire contained an item to measure intendedness of the pregnancy. A total of 922 women comprised the final sample for analysis. For the analyses, intendedness was dichotomised as: intended (wanted now or sooner) vs. unintended (mistimed, unwanted or unsure). Overall, 13.7% of all births to women in the sample were preterm. In a logistic regression model, after controlling for potential confounding by clinical and behavioural predictors of preterm delivery, unintended pregnancy was significantly associated with preterm delivery (adjusted RR = 1.82, 95% confidence interval [1.08,3.08], P = 0.026). In this study of a cohort of urban, clinic-attending, low-income, pregnant black women, unintended pregnancy had a statistically significant association with preterm birth. After adjustment for behavioural and clinical risks, women with unintended pregnancies had almost twice the risk of a preterm delivery as women with intended pregnancies.

Adolescent↗

PubMed2000

CADASIL: the dermatologic diagnosis of a neurologic disease. Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an increasingly recognized neurologic disease characterized by pathognomonic changes to the small vessels, particularly in the brain and skin. Although much has recently been written about this disease in the neuropathology literature, to our knowledge nothing has appeared in the dermatology literature. We wish to call attention to the unique role dermatologists and dermatopathologists can play in the diagnosis of this disease. We review the condition's clinical, histologic, and ultrastructural features.

Biopsy, Needle↗

PubMed2000

Characterization of fine particulate matter produced by combustion of residual fuel oil.

Combustion experiments were carried out on four different residual fuel oils in a 732-kW boiler. PM emission samples were separated aerodynamically by a cyclone into fractions that were nominally less than and greater than 2.5 microns in diameter. However, examination of several of the samples by computer-controlled scanning electron microscopy (CCSEM) revealed that part of the PM2.5 fraction consists of carbonaceous cenospheres and vesicular particles that range up to 10 microns in diameter. X-ray absorption fine structure (XAFS) spectroscopy data were obtained at the S, V, Ni, Fe, Cu, Zn, and As K-edges and at the Pb L-edge. Deconvolution of the X-ray absorption near edge structure (XANES) region of the S spectra established that the dominant molecular forms of S present were sulfate (26-84% of total S) and thiophene (13-39% of total S). Sulfate was greater in the PM2.5 samples than in the PM2.5+ samples. Inorganic sulfides and elemental sulfur were present in lower percentages. The Ni XANES spectra from all of the samples agreed fairly well with that of NiSO4, while most of the V spectra closely resembled that of vanadyl sulfate (VO.SO4.xH2O). The other metals investigated (i.e., Fe, Cu, Zn, and Pb) also were present predominantly as sulfates. Arsenic was present as an arsenate (As+5). X-ray diffraction patterns of the PM2.5 fraction exhibit sharp lines due to sulfate compounds (Zn, V, Ni, Ca, etc.) superimposed on broad peaks due to amorphous carbons. All of the samples contain a significant organic component, with the loss on ignition (LOI) ranging from 64 to 87% for the PM2.5 fraction and from 88 to 97% for the PM2.5+ fraction. Based on 13C nuclear magnetic resonance (NMR) analysis, the carbon is predominantly condensed in graphitic structures. Aliphatic structure was detected in only one of seven samples examined.

Air Pollution↗

PubMed2000

Comparison of particle size distributions and elemental partitioning from the combustion of pulverized coal and residual fuel oil.

U.S. Environmental Protection Agency (EPA) research examining the characteristics of primary PM generated by the combustion of fossil fuels is being conducted in efforts to help determine mechanisms controlling associated adverse health effects. Transition metals are of particular interest, due to the results of studies that have shown cardiopulmonary damage associated with exposure to these elements and their presence in coal and residual fuel oils. Further, elemental speciation may influence this toxicity, as some species are significantly more water-soluble, and potentially more bio-available, than others. This paper presents results of experimental efforts in which three coals and a residual fuel oil were combusted in three different systems simulating process and utility boilers. Particle size distributions (PSDs) were determined using atmospheric and low-pressure impaction as well as electrical mobility, time-of-flight, and light-scattering techniques. Size-classified PM samples from this study are also being utilized by colleagues for animal instillation experiments. Experimental results on the mass and compositions of particles between 0.03 and > 20 microns in aerodynamic diameter show that PM from the combustion of these fuels produces distinctive bimodal and trimodal PSDs, with a fine mode dominated by vaporization, nucleation, and growth processes. Depending on the fuel and combustion equipment, the coarse mode is composed primarily of unburned carbon char and associated inherent trace elements (fuel oil) and fragments of inorganic (largely calcium-alumino-silicate) fly ash including trace elements (coal). The three coals also produced a central mode between 0.8- and 2.0-micron aerodynamic diameter. However, the origins of these particles are less clear because vapor-to-particle growth processes are unlikely to produce particles this large. Possible mechanisms include the liberation of micron-scale mineral inclusions during char fragmentation and burnout and indicates that refractory transition metals can contribute to PM < 2.5 microns without passing through a vapor phase. When burned most efficiently, the residual fuel oil produces a PSD composed almost exclusively of an ultrafine mode (approximately 0.1 micron). The transition metals associated with these emissions are composed of water-soluble metal sulfates. In contrast, the transition metals associated with coal combustion are not significantly enriched in PM < 2.5 microns and are significantly less soluble, likely because of their association with the mineral constituents. These results may have implications regarding health effects associated with exposure to these particles.

Air Pollution↗

PubMed2000

An improved method of reducing stimulus artifact in the electrically evoked whole-nerve potential.

OBJECTIVE: Recording a compound action potential in response to electrical stimulation requires attention to minimize contamination due to electrical stimulus artifact. In patients implanted with the Nucleus 24 device, the electrically evoked whole-nerve potential (EAP) is recorded using a neural response telemetry (NRT) system. This system employs a forward-masking technique that greatly reduces stimulus artifact. However, theoretical considerations and experimental animal data suggest that the technique may distort the acquired EAP waveform under some situations. We proposed and evaluated a modification to the forward-masking technique that addresses this concern, particularly during collection of refractory recovery data. DESIGN: We first examined neural responses of the electrically stimulated auditory nerve using cat preparations. Through single-fiber recordings from cats, we demonstrated underlying physiological limitations likely encountered with the "standard" forward masking technique. We then recorded feline EAP waveforms using both the standard technique and our proposed, modified, technique. Finally, we collected EAP data from human cochlear implant patients using both artifact reduction methods. These comparisons allowed us to evaluate the effectiveness of our modification. RESULTS: The cat EAP data demonstrated that the standard forward-masking technique currently in use in the Nucleus NRT system can distort the EAP waveform when the nerve is partially refractory. In the cat, this distortion resulted in forward-masking recovery curves with artifactually prolonged recovery times and inaccurate latency trends. Similar effects were observed in the comparison of human recovery curves obtained using both the standard and modified techniques. In some cases, the modified technique produced EAP waveforms with more clearly defined peaks than were obtainable with the standard method. CONCLUSIONS: Consideration should be given to implementing our modified forward-masking artifact reduction scheme, because it introduces less distortion of the EAP waveform and accordingly provides for more accurate assessment of the refractory properties of the electrically stimulated nerve.

Action Potentials↗

PubMed2000

Temporal lobe epilepsy presenting as panic attacks: detection of interictal hypometabolism with positron emission tomography.

Cerebral glucose metabolism was studied using positron emission tomography (PET) in a 13-year-old girl with a history of panic attacks that were thought to be of psychiatric origin. Positron emission tomography imaging revealed marked right temporal lobe hypometabolism and magnetic resonance imaging (MRI) detected T2 changes consistent with right mesial temporal sclerosis. Electroencephalogram (EEG) studies 3 years later confirmed a primary diagnosis of right temporal lobe epilepsy. As shown by this case and one other, PET and MRI imaging of patients with panic disorder who are thought to have epilepsy may be helpful in leading to definitive electrographic studies that confirm temporal lobe epilepsy as the primary diagnosis.

Adolescent↗

PubMed2000

Clearance of Alzheimer's amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier.

Elimination of amyloid-ss peptide (Ass) from the brain is poorly understood. After intracerebral microinjections in young mice, (125)I-Ass(1-40) was rapidly removed from the brain (t(1/2) </= 25 minutes), mainly by vascular transport across the blood-brain barrier (BBB). The efflux transport system for Ass(1-40) at the BBB was half saturated at 15.3 nM, and the maximal transport capacity was reached between 70 nM and 100 nM. Ass(1-40) clearance was substantially inhibited by the receptor-associated protein, and by antibodies against LDL receptor-related protein-1 (LRP-1) and alpha(2)-macroglobulin (alpha(2)M). As compared to adult wild-type mice, clearance was significantly reduced in young and old apolipoprotein E (apoE) knockout mice, and in old wild-type mice. There was no evidence that Ass was metabolized in brain interstitial fluid and degraded to smaller peptide fragments and amino acids before its transport across the BBB into the circulation. LRP-1, although abundant in brain microvessels in young mice, was downregulated in older animals, and this downregulation correlated with regional Ass accumulation in brains of Alzheimer's disease (AD) patients. We conclude that the BBB removes Ass from the brain largely via age-dependent, LRP-1-mediated transport that is influenced by alpha(2)M and/or apoE, and may be impaired in AD.

Aging↗

PubMed2000

A newly emerging toxic dinoflagellate, Pfiesteria piscicida: natural ecology and toxicosis to fish and other species.

Pfiesteria, a toxic dinoflagellate, recently has emerged as a cause of fish kills near the East Coast. Recent research into one species. Pfiesteria piscicida, has revealed a complex life cycle of at least 24 stages. Metamorphosis of one stage to another often depends on presence or absence of fish. Growth of P piscicida is promoted both directly and indirectly by nutrients such as inorganic phosphate and nitrate, as well as organic phosphate, and may be related to effluent-induced blooms. Sewage and agricultural runoff flowing into estuaries often provide these nutrients and may be correlated with the majority of fish kills in the Atlantic coastal region of the US (5). P piscicida is extremely toxic, with a low density capable of killing fish within 3 minutes (1,3,12). Fish exposed to sublethal doses of the toxin have prominent lesions. The syndrome leads to population level death losses and associated economic losses in local fisheries.

Animals↗

PubMed1999

A human aryl hydrocarbon receptor signaling pathway constructed in yeast displays additive responses to ligand mixtures.

An optimized signal transduction pathway that reproduces the response of human aryl hydrocarbon (Ah) receptor to ligands has been established in Saccharomyces cerevisiae. Ligand treatment induced a 50-fold increase in beta-galactosidase activity from a reporter plasmid in yeast engineered to express human Ah receptor and Ah nuclear translocator (Arnt) proteins. The archetypal Ah receptor ligand, 2,3,7,8-tetrachlorodibenzo(p)dioxin, activated Ah receptor and induced lacZ reporter activity at concentrations of >/=0.3 nM. Mixtures of halogenated and nonhalogenated Ah receptor ligands produced additive signaling responses in this yeast bioassay. These results were consistent with the existence of a common binding site and mechanism of ligand-mediated Ah receptor activation. Although yeast have no natural counterpart to the Ah receptor pathway, expression of human Ah receptor and Arnt under the appropriate conditions provides a functional model system for studying Ah receptor activation and signal transduction.

Aryl Hydrocarbon Receptor Nuclear Translocator↗

PubMed1999

The inefficient replication origin from yeast ribosomal DNA is naturally impaired in the ARS consensus sequence and in DNA unwinding.

Ribosomal DNA (rDNA) replication origins of Saccharomyces cerevisiae are known to function inefficiently, both in the context of the tandem rDNA repeats in the chromosome and as single copy autonomously replicating sequences (ARSs) in plasmids. Here we examined components of the rDNA ARS that might contribute to inefficient extrachromosomal replication. Like the efficient H4 ARS, the rDNA ARS requires a match to the 11 bp ARS consensus sequence (ACS) and a broad non-conserved region that may contain multiple elements, including a DNA unwinding element (DUE). Using a single-strand-specific nuclease hypersensitivity assay and by determining the superhelical density required for stable DNA unwinding, we found that the DNA of the rDNA ARS is not as easily unwound as the H4 ARS. Unwinding of the rDNA ARS required additional energy, similar to the unwinding of mutations in the H4 ARS that stabilize the double helix in the DUE region and impair replication. In vivo extrachromosomal replication of the rDNA ARS was cold sensitive, like H4 ARS mutants that require additional energy to unwind the DUE region but unlike the easily unwound, wild-type H4 ARS. Impairment of replication function at reduced temperature suggests that the elevated energy requirement for DNA unwinding inherent in the wild-type rDNA ARS contributes to inefficient replication function. We also examined the essential ACS match in the rDNA ARS, which is known to be imperfect at one position. A point mutation in the essential ACS that corrects the imperfect match increased the efficiency of extrachromosomal replication. Our results reveal that the essential ACS element and DNA unwinding in the rDNA ARS are naturally impaired, suggesting that inefficient function of the rDNA replication origin has a biological purpose.

Cold Temperature↗

PubMed1999

Human c-Jun N-terminal kinase expression and activation in the nervous system.

Differential expression and localization of c-Jun N-terminal kinases (JNKs) in the human brain may reflect transduction of a variety of extracellular stimuli to selective cellular responses. Of the three JNKs, JNK1 and 2 are widely distributed in tissues and JNK3 is predominantly restricted to brain where it is expressed in neurons. Although there is considerable molecular conservation among all three JNKs, we distinguished expression of each by in situ hybridization, immunoblot analysis with a panel of antibodies, and stress-activation using c-Jun as substrate. In the human central nervous system (CNS), there are at least 10 isoforms: JNK3alpha1 and JNK1alpha1 were the major JNK isoforms expressed; JNK2 was not detected. On immunoblots of brain homogenates, antibody selectivity identified JNK3alpha1 as a 45-kDa protein, JNK1alpha1, a slightly lower band at 44 kDa, and a 50-kDa band of unknown specificity. Recombinant human JNK3alpha1, transfected either into CHO, COS-1, or Neuro2A (N2A) cells, was strongly expressed as a 45-kDa protein in each. Transfected JNK3alpha1, and endogenous JNK1, each immunoprecipitated from N2A cells, phosphorylated recombinant forms of human c-Jun. Kinase activity of each JNK was modestly stimulated in N2A cells by anisomycin but not by ceramide, UV irradiation, or heat shock. Endogenous JNK activation, especially at a low level, may reflect a chronic and cumulative stress process that contributes to hyperphosphorylation of cytoskeletal proteins such as those found in Alzheimer's disease (AD), and ultimately, induction of apoptosis.

Animals↗

PubMed1999

Tuberculin skin testing among economically disadvantaged youth in a federally funded job training program.

Low income, medically underserved communities are at increased risk for tuberculosis. Limited population-based national data are available about tuberculous infection in young people from such backgrounds. To determine the prevalence of a positive tuberculin skin test among economically disadvantaged youth in a federally funded job training program during 1995 and 1996, the authors evaluated data from medical records of 22,565 randomly selected students from over 100 job training centers throughout the United States. An estimated 5.6% of students had a documented positive skin test or history of active tuberculosis. Rates were highest among those who were racial/ethnic minorities, foreign born, and (among foreign-born students) older in age (p < 0.001). Weighted rates (adjusting for sampling) were 1.3% for white, 2.2% for Native American, 4.0% for black, 9.6% for Hispanic, and 40.7% for Asian/Pacific Islander students; rates were 2.4% for US-born and 32.7% for foreign-born students. Differences by geographic region of residence were not significant after adjusting for other demographic factors. Tuberculin screening of socioeconomically disadvantaged youth such as evaluated in this study provides important sentinel surveillance data concerning groups at risk for tuberculous infection and allows recommended public health interventions to be offered.

Adolescent↗

PubMed1999

Electrically evoked single-fiber action potentials from cat: responses to monopolar, monophasic stimulation.

We recorded action potentials from single auditory-nerve fibers of cats using monophasic current pulses delivered by a monopolar intracochlear electrode. These simple stimuli provided a means of investigating basic properties and hypotheses of electrical excitation. Standard micropipette recording techniques were used. Responses to anodic (positive) and cathodic (negative) stimulus pulses were recorded separately to evaluate stimulus polarity effects. Mean spike (action potential) latency was polarity dependent, with greater latencies for cathodic stimulation. Threshold stimulus level was also polarity dependent, with relatively lower cathodic thresholds. Both effects are consistent with trends reported in the compound action potential. Variability in single-fiber latency (i.e., jitter) was dependent upon stimulus polarity. In contrast, the slope of single-fiber input-output functions failed to show a clear polarity dependence, although such trends have been seen in the compound action potential data. We also observed a relatively greater degree of adaptation over time with anodic stimulation. Bimodal post-stimulus-time histograms were recorded in a small number (2%) of fibers, supporting the hypothesis that both the peripheral (dendritic) and central axonal processes are excitable with the same stimulus polarity, in a limited number of cases. This observation, together with analyses of interactions among measures of latency, threshold, and jitter, is consistent with the hypothesis that, with monopolar intracochlear stimulation, most fibers are stimulated at axonal (modiolar) sites and a minority of fibers nearest the electrode are stimulable at their peripheral processes.

Action Potentials↗

PubMed1999

An empirically based model of the electrically evoked compound action potential.

The relationship between electrically evoked single-fiber action potentials and the electrically evoked compound action potential of the auditory nerve is of interest to those attempting to model such responses with computational techniques. It also relates to efforts to exploit the gross potentials that can now be recorded by some implantable cochlear prostheses. In this paper, we develop a computational model of the auditory nerve response to single, pulsatile, electrical stimuli based upon the response characteristics obtained from 230 single fibers of 13 cats. These fibers were stimulated by brief (39s) monophasic cathodic stimuli delivered by a monopolar intracochlear electrode. The data were pooled to obtain an estimate of the distribution of fiber thresholds. Post-stimulus time histograms were modeled using Poisson functions and adjusted to account for empirically determined latency and jitter characteristics. The probabilistic nature of single-fiber input-output functions (i.e. Verveen's (1961) 'relative spread') was also modelled. PST histograms from 5000 modelled fibers were then summed and convolved with an estimated 'unit potential' following the method of Goldstein and Kiang (1958). This convolution produced modelled compound action potentials, which were then compared with experimentally obtained data. Manipulations of model parameters affecting threshold, jitter, and relative spread suggest that the most important determinant of the shape of the EAP amplitude-level function is the threshold distribution. A model based solely on threshold distribution produces an EAP input-output function similar to one that accounts for probabilistic single-fiber input-output functions. Discrepancies between these two models do occur if the threshold distribution function is compressed significantly, as might be the case in pathological cochleae with altered distributions or numbers of nerve fibers.

Algorithms↗

PubMed1999

How do cochlear prostheses work?

The past two decades have witnessed a revolution in the treatment of sensorineural hearing loss. Cochlear prostheses have evolved from laboratory experiment to a commercial technology that has benefited over 20,000 people. Paralleling this phenomenal development has been a substantial increase in our understanding of the biophysical, physiological and psychophysical mechanisms underlying the function of these devices.

Animals↗