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Biomedical subjects

R A Miller

Publications and source records attributed to R A Miller.

At least 145 records · Page 8Linked to original sources
PubMed1996

Toxicity of inhaled chloroprene (2-chloro-1,3-butadiene) in F344 rats and B6C3F(1) mice.

Chloroprene (2-chloro-1,3-butadiene) is a high production chemical used almost exclusively in the production of polychloroprene (neoprene) elastomer. Because of its structural similarity to isoprene (2-methyl-1,3-butadiene) and to 1,3-butadiene, a potent trans-species carcinogen, inhalation studies were performed on chloroprene to characterize its toxicological potential and to provide a basis for selecting exposure concentrations for chronic toxicity and carcinogenicity studies. Thirteen-week inhalation toxicology studies were conducted in male and female F344 rats and B6C3F(1) mice at exposure concentrations of 0, 5, 12, 32 or 80 ppm (6 h/day; 5 days/week). A 200 ppm exposure group was also included for rats only, because a previous study showed that this concentration of chloroprene is lethal to mice. In mice, exposure to 80 ppm chloroprene caused a marginal decrease in body weight gain in males and epithelial hyperplasia of the forestomach in males and females. This lesion has been observed in mice exposed to isoprene or 1,3-butadiene. In rats, exposure to 80 ppm chloroprene or higher concentrations caused degeneration and metaplasia of the olfactory epithelium and exposure to 200 ppm caused anemia, hepatocellular necrosis and reduced sperm motility. These lesions have not been observed in rats exposed to isoprene or 1,3-butadiene. The profile of toxic effects of chloroprene is considerably different from that of isoprene or 1,3-butadiene; this may be due to differences in exposure concentrations that were used in toxicology studies of these compounds and /or to the influence of the chlorine substitution on the toxicokinetics of these compounds, on their biotransformation, or on the reactivity of metabolic intermediates with tissue macromolecules.

Administration, Inhalation↗
PubMed1996

Analysis of cellular interactions in limiting dilution cultures.

Limiting dilution (LD) cultures are often used to study cellular heterogeneity in responses of murine splenocytes to specific or polyclonal activation. LD titration curves often reveal a nonlinear dependence of response on input cell dose. Although 'zigzag' shaped curves of this kind are often interpreted and analyzed as resulting from interactions among three distinct cell types, we observe that a more parsimonious two cell model, including a cell type that can generate both positive and negative effects, provides better fit to a wide range of experimental data. We have developed mathematical models for the accurate estimation of the frequencies of both interacting cell types and of the parameters for their multi-hit interaction. We show examples of LD cultures in which specific experimental manipulations alter the frequency of only one of the two cell types, or alter the interaction parameters without a change in responder frequency. We also provide a simplified method for approximation of the model parameters using graphical approaches and simple algebra. Lastly, we present an improved method for calculation of the effect generated per responder cell in microclonal cultures.

Animals↗
PubMed1996

Rhythmic auditory stimulation in gait training for Parkinson's disease patients.

Rhythmic auditory stimulation (RAS) was used as a pacemaker during a 3-week home-based gait-training program for Parkinson's disease (PD) patients (n = 15). Electromyogram (EMG) patterns and stride parameters were assessed before and after the test without RAS to evaluate changes in gait patterns. Data were compared with those of two control groups (n = 11), who either did not participate in any gait training or who participated in an internally self-paced training program. RAS consisted of audiotapes with metronome-pulse patterns embedded into the on/off beat structure of rhythmically accentuated instrumental music. Patients who trained with RAS significantly (p < 0.05) improved their gait velocity by 25%, stride length by 12%, and step cadence by 10% more than self-paced subjects who improved their velocity by 7% and no-training subjects whose velocity decreased by 7%. In the RAS-group, timing of EMG patterns changed significantly (p < 0.05) in the anterior tibialis and vastus lateralis muscles. Evidence for rhythmic entrainment of gait patterns was shown by the ability of the RAS group to reproduce the speed of the last training tape within a 2% margin of error without RAS.

Acoustic Stimulation↗
PubMed1996

Components of EMG symmetry and variability in parkinsonian and healthy elderly gait.

Variability and bilateral symmetry of EMG gait-cycle profiles were studied in parkinsonian and healthy elderly subjects in the gastrocnemius, tibialis anterior, and vastus lateralis muscles. Components reflecting shape and timing were defined by the magnitude and phase of the cross-correlation function between individual stride profiles and the latency corrected ensemble average (LCEA) (variability), and between bilateral LCEAs (symmetry). Statistical significance was set at a confidence level of 0.01 reflecting a Bonferroni adjustment due to multiple measures. Parkinsonian gait was significantly different from the healthy elderly in several measures: increased shape variability and asymmetry in the gastrocnemius and tibialis anterior muscles, and reduced timing variability in the gastrocnemius. A portion of the parkinsonian group participated in a 3 week therapy program where they walked to rhythmic auditory stimulation. Gait parameters shifted toward healthy elderly values in each measure where population differences were found. Significant changes were observed in decreased tibialis anterior shape variability and asymmetry, and gastrocnemius shape variability. Strong trends were also observed in increased gastrocnemius timing variability and reduced bilateral asymmetry. In addition to the expected decreased in variability and asymmetry of healthy elderly, increased timing variability in the gastrocnemius was associated with a more normal gait, possibly reflecting feedback adaptability of muscle activity which may be useful in generating stable locomotion.

Aged↗
PubMed1996

Calcium signals in T lymphocytes from old mice.

Mitogen-induced increases in free calcium ion concentration ([Ca]i) are a key element of the process by which T lymphocytes are induced to proliferate and differentiate into effector cells. T cells from old mice exhibit lower average rises in calcium concentration than T cells from young donors when stimulated with either mitogenic lectins or antibodies to the CD3 chains of the antigen receptor. The decline with age in calcium signal generation is largely attributable to a shift from naïve to memory T cells, in that memory T cells, from mice of any age, are more resistant to mitogen-induced changes in [Ca]i. The decline in calcium signal generation is likely to be functionally significant, since T cells isolated on the basis of poor calcium signals show diminished ability to produce and to respond to the growth factor IL-2. Con A induces a transient increase in uptake of radiolabeled calcium from extracellular sources, and the extent of this increase declines with age. Alterations in production of inositol tris-phosphate (IP3) seem not to contribute to age-related changes in calcium signal generation. T cells from old mice, and memory T cells from mice of any age, are relatively resistant to increases in [Ca]i even when these are induced by receptor-independent stimuli such as the calcium ionophore ionomycin. The ionomycin-resistance of memory T cells suggests that these cells may have an augmented ability to buffer changes in [Ca]i, perhaps by increased activity of the ATP-dependent plasma membrane calcium pump. It seems likely that age-related declines in calcium signal generation contribute to the functional immunodeficiency of old age.

Aging↗
PubMed1996

Comparison of prostatic volume and dimensions by transrectal and transurethral ultrasonography.

OBJECTIVE: To compare the volumes and dimensions of the prostate gland as measured by transrectal and transurethral ultrasonography (TRUS and TUUS) and to study the prostatic changes that occur in the presence of an urethral instrument. PATIENTS AND METHODS: Twenty men (mean age 71 years, range 43-85) with symptoms of prostatic enlargement underwent TRUS and the dimensions and volumes of their prostates were obtained by the dimensional method and by step planimetry. Within 24 h, all the men were examined cystoscopically under sedoanalgesia and underwent TUUS. Their prostatic volumes and dimensions were again measured by the dimensional method and by step planimetry. Step planimetry was carried out using a specially designed indexer firmly attached to the examination couch or operating table. All the static images and planimetry slices were video recorded for later computer enhancement and to study the three-dimensional changes occurring in the prostate. The volumes and dimensions obtained by TRUS and TUUS were compared. RESULTS: Volumes obtained by transurethral step planimetry were 22% greater than those from transrectal planimetry. Although there was a good correlation (r = 0.984) between transurethral planimetry and the volumes derived using the transurethral dimensions with the prolate ellipsoid formula, the latter produced values 17% and 25% lower by the transurethral and transrectal routes, respectively. These volume estimates varied widely, indicating that the simple addition of a constant to the prolate ellipsoid formula would not correct the volume. Three-dimensional changes of the prostate occurred with TRUS and TUUS: with TUUS, the craniocaudal and anteroposterior diameters were significantly larger (by 7% and 18%, respectively) while the transverse diameter was smaller by 20%. CONCLUSION: The estimated volumes and dimensions of the prostate differed when measured by TRUS and TUUS and three-dimensional changes in the prostate occurred in the presence of an urethral instrument.

Adult↗
PubMed1996

Transrectal ultrasonography: why are estimates of prostate volume and dimension so inaccurate?

OBJECTIVES: To determine why there are variations in the volumes of the prostate obtained by step planimetry and those calculated from the prolate ellipsoid formula using the measured maximum gland dimensions, to assess the reproducibility of estimates of prostate volume from transrectal ultrasonography (TRUS) and to determine the effect of the angle of the transrectal probe, the human error in the clinical setting and the benefit of computer enhancement of the ultrasonograms. PATIENTS AND METHODS: Forty-five men (mean age 72 years, range 43-89) with symptoms of prostatic enlargement were divided randomly into three groups; those in group 1 had their prostate volume estimated three times by measuring the maximal gland dimensions and calculating the volume using the prolate ellipsoid formula (dimensional method) and by step planimetry, to assess the reproducibility of TRUS; men in group 2 had their prostate volume estimated using the dimensional method and by step planimetry with the probe in the optimal axis, and then from scans repeated after deflecting the transrectal probe 5 degrees anteriorly and posteriorly; men in group 3 had their prostate volume estimated once by the dimensional method and by step planimetry. Step planimetry was carried out using a specially designed indexer firmly attached to the examination couch. All 'frozen' images and planimetry slices were videotaped for later computer enhancement. The volumes and dimensions obtained by each method were compared. RESULTS: The volumes obtained by step planimetry were 17% greater than those obtained by the dimensional method because the craniocaudal, anteroposterior and transverse diameters were underestimated significantly by the latter (by 13%, 2% and 7%, respectively). The largest anteroposterior and transverse diameters were included in the same axial scan in only 44%, while the largest craniocaudal diameter was in the midline in only 38%, of the patients. The human error in the clinic was negligible (2%) with a good correlation between the dimensions and volumes obtained in the clinic and those from computer-enhanced images (r = 0.94). There were no advantages in computer enhancing the TRUS images. Volumes calculated from the dimensional method using the maximum dimensions obtained from planimetric contours correlated well with planimetric volumes (r = 0.93). The reproducibility of TRUS showed a mean error of 8% by the dimensional method and 1% by step planimetry. Anterior deflection of the transrectal probe reduced the estimated volume by 2% and posterior deflection increased the volume by 4%, using the dimensional method, while there were no significant volume changes when estimated by step planimetry. CONCLUSION: This study confirms that to estimate accurately the volume of the prostate using the prolate ellipsoid formula, the current methodology needs to be changed. The largest anteroposterior and transverse diameters may need to be measured in different transverse scan slices and the largest craniocaudal diameter in a sagittal scan away from the midline. If volume estimation is to be repeated then step planimetry is reliable and TRUS using the prolate ellipsoid formula is not.

Adult↗
PubMed1996

Phototherapy of cancer and atheromatous plaque with texaphyrins.

Cancer and cardiovascular disease are the leading causes of death in the western world. Photodynamic therapy (PDT) has demonstrated activity in the treatment of superficial cancerous lesions and as an intraoperative adjunct during surgical debulking. Texaphyrins are pure, synthetic water-soluble macrocycles that localize in both cancerous lesions and atheromatous plaque. Lutetium texaphyrin (PCI-0123) is activated by tissue-penetrating far red light (720-760 nm). Patient diagnosis and treatment planning is possible via magnetic resonance imaging (MRI) with the paramagnetic gadolinium texaphyrin (PCI-0120) or via fluorescence imaging using the diamagnetic PCI-0123. In this study it is shown that texaphyrins localize selectively in cancer and atheromatous plaque. PDT with PCI-0123 is found to cause selective photodamage to the diseased tissue. Specifically, PCI-0123 acts to eradicate the SMT-F murine mammary tumors and diet-induced atheromatous plaque in rabbits.

Animals↗
PubMed1996

Reciprocal expression of P-glycoprotein and TAP1 accompanied by higher expression of MHC class I antigens in T cells of old mice.

We have shown previously that (a) aging leads to an increase in the proportion of murine splenic T cells that express high activity of P-glycoprotein (PGP), the ATP-dependent plasma membrane pump that mediates multiple drug resistance, and (b) PGPhi CD4 memory cells from mice of any age do not proliferate or secrete IL-4 after activation with anti-CD3 and IL2. We now report that the age-associated increase in expression of MHC Class I molecules is limited to the subset of T cells that overexpress PGP and thus extrude the fluorochrome R123 (the "R123lo" subset). Although H-2 levels increase on T cells of old mice, the levels of TAP1, a component of the polypeptide pump responsible for assembly and internal transport of Class I MHC molecules, decline, unexpectedly, by about fourfold in T cells from old donors. Thus, aging leads to reciprocal changes in the level of T-cell expression of PGP and TAP1, two closely related members of the ABC superfamily of peptide transport proteins.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

An objective measurement of the anchoring strength of anagen hair in an adult with the loose anagen hair syndrome.

A 21-year-old male presented with the life-long symptom of slowly growing, easily extractable hair lacking sheath remnants. The distribution and density of all his hair regions appeared normal and there was no alopecia. A hair-pull test was painless and resulted in all hairs being removed, all in keeping with a diagnosis of loose anagen hair syndrome (LAHS). The trichogram was normal. Electronically measured epilation revealed values which were significantly lower than controls. His hair follicles were remarkable for this syndrome in that they looked perfectly normal with light microscopy; however, the segment of the follicle with the keratogenous zone was significantly shorter than normal. It is postulated that a subtle intercellular defect must reside in the line of shear proximal to the level of cuticular differentiation to account for the weak anchoring of the root in the follicle. A consequence of a genetic error probably causes both the weak anchoring and the slow hair growth.

Adult↗
PubMed1996

Lutetium texaphyrin (PCI-0123): a near-infrared, water-soluble photosensitizer.

Lutetium texaphyrin, PCI-0123, is a pure, water-soluble photosensitizer with a large broad absorption band centered at 732 nm. The compound was tested for photodynamic therapy (PDT) effectiveness in a murine mammary cancer model. The texaphyrin macrocycle as illustrated by magnetic resonance imaging and 14C-radiolabeled texaphyrin studies was shown to be tumor selective; a tumor-to-muscle ratio of 10.55 was seen after 5 h. Lutetium texaphyrin, at a drug dose of 20 mumol/kg with irradiation 5 h postinjection at 150 J/cm2 and 150 mW/cm2, had significant efficacy (P < 0.0001) in treating neoplasms of moderate size (40 +/- 14 mm3) and also had significant efficacy (P < 0.0001) in treating larger neoplasms (147 +/- 68 mm3). The PDT efficacy was correlated with the time interval between PCI-0123 administration and light exposure. A 100% cure rate was achieved when photoirradiation took place 3 h postinjection compared to 50% for 5 h using 10 mumol/kg and 150 J/cm2 at 150 mW/cm2. The PDT efficacy was attributable to the selective uptake/retention of the texaphyrin photosensitizer in addition to the depth of light penetration achievable at the 732 nm laser irradiation.

Animals↗
PubMed1996

Protease cleavage of iron-transferrin augments pyocyanin-mediated endothelial cell injury via promotion of hydroxyl radical formation.

Although a number of bacterium- and host-derived factors have been suggested to contribute to the pathogenesis of Pseudomonas aeruginosa-associated tissue injury, the mechanism remains unclear. We have previously shown that protease modification of iron (Fe)-transferrin generates new iron chelates capable of catalyzing hydroxyl radical (.OH) formation from superoxide and hydrogen peroxide. The latter two oxidants are generated during redox cycling of another P. aeruginosa secretory product, pyocyanin. The lung is a major site of P. aeruginosa infection, with damage to local endothelial cells contributing to the pathogenesis of such infections. Endothelial cells are highly susceptible to oxidant-mediated injury. Therefore, we examined whether pseudomonas elastase-cleaved Fe-transferrin and pyocyanin synergistically enhance pulmonary artery endothelial cell injury via .OH formation. By measuring 51Cr release from cultured endothelial cell monolayers, pseudomonas elastase-cleaved Fe-transferrin significantly augmented cell injury resulting from cellular exposure to sublethal concentrations of pyocyanin. This enhancement in injury was not protease specific, as similar results were obtained with pyocyanin in combination with trypsin- or porcine pancreatic elastase-cleaved Fe-transferrin. The association of iron with the transferrin appeared to be necessary in this process. Supporting the involvement of .OH generation via the Haber-Weiss reaction in augmenting cell injury, catalase, dimethyl thiourea, superoxide dismutase, deferoxamine, and dimethyl sulfoxide significantly inhibited cell injury resulting from exposure to pyocyanin and protease-cleaved Fe-transferrin. Furthermore, spin trapping demonstrated the production of .OH in this cellular system. We conclude that .OH formation resulting from the interaction of protease-cleaved Fe-transferrin and endothelial cell redox cycling of pyocyanin may contribute to P. aeruginosa-associated tissue injury via endothelial cell injury.

Animals↗
PubMed1996

Lifespan and lesions in genetically heterogeneous (four-way cross) mice: a new model for aging research.

Genetically heterogeneous animal models provide many advantages for research on aging but have been used infrequently. We present here lifespan and lesion data from a study of mice bred as a cross between (AKR/J x DBA/2J)F1 females and (C57BL/6J x SJL/J)F1 males. In such a four-way cross population, each mouse is genetically unique, but replicate populations of essentially similar genetic structure can be generated quickly, at low cost, and of arbitrary size from commercially available, genetically stable hybrid parents. We employed a protocol in which mice judged to be severely ill were euthanatized to obtain tissue in optimal condition for necropsy, and we were able to infer a likely cause of illness in 42 of 44 animals. Malignant lymphoma, including at least four histopathologically distinct subtypes, was the most common cause and was also a frequent incidental finding in mice dying of other causes. Neoplastic disease, benign or malignant, was the sole or a contributing cause of illness in 90% of the mice for which a cause could plausibly be assigned. A wide range of lethal and nonlethal degenerative lesions was also noted. The coefficient of variation for lifespan in these genetically heterogeneous mice was 26%, similar to that seen in analyses of recombinant inbred mouse lines. Baseline lifespan and pathology data on four-way cross mice is a useful prelude to the exploitation of this rodent model in tests of genetic and mechanistic hypotheses about aging.

Adenocarcinoma↗
PubMed1996

Origin and course of the dorsomedial cutaneous nerve to the great toe.

The purpose of this study was to describe the course of the dorsomedial cutaneous nerve (DMCN) to the great toe. The DMCN is a branch of the medial dorsal cutaneous nerve, which originates from the superficial peroneal nerve. Injury to the DMCN may result in a painful neuroma. Identifying and protecting the DMCN to the great toe during surgical procedures near these areas may decrease the rate of painful neuroma formation.

Cadaver↗
PubMed1996

Heterotopic ossification.

Heterotopic ossification is a well-recognized condition frequently encountered by the orthopedic surgeon. Although typically asymptomatic, heterotopic ossification can be a complication of extreme severity. This article is a review of literature and attempts to clarify the definition, and delineates the etiology, incidence, risk factors, and current modes of prophylaxis and treatment of various types of heterotopic ossification.

Aged↗