Biomedical subjects

Peter A Hardy

Publications and source records attributed to Peter A Hardy.

13 recordsLinked to original sources

PubMed2006

Assessing nigrostriatal dysfunctions by pharmacological MRI in parkinsonian rhesus macaques.

New imaging techniques are needed to longitudinally monitor the development, progression and treatment of Parkinson's disease. The present study was designed to test whether the blood oxygenation level-dependent (BOLD) response to dopaminergic stimulation as measured by pharmacological MRI (phMRI) correlated to specific histological and behavioral features of the parkinsonian state. Nine adult rhesus monkeys were rendered hemiparkinsonian by intracarotid administration of MPTP. Three months after MPTP treatment, the trained, MRI-adapted awake animals were scanned with a phMRI technique while being administered a presynaptic (D-amphetamine) or postsynaptic (apomorphine) dopamine stimulating agents. The primary findings were (1) the putamen and substantia nigra (SN) but not the caudate nucleus displayed significant BOLD responses to these dopaminergic drugs; (2) a significant relationship was found between amphetamine-evoked activation and the number of surviving dopamine neurons in the SN, which was also correlated with bradykinesia; and (3) inverse relationships were seen in response to apomorphine and amphetamine stimulation between the MPTP-lesioned and unlesioned putamen and SN. The results suggest that phMRI may prove useful for longitudinally monitoring the progression and treatment of PD.

Animals↗

PubMed2006

fMRI in alert, behaving monkeys: an adaptation of the human infant familiarization novelty preference procedure.

Functional magnetic resonance imaging (fMRI) is increasingly used in non-human primate research. In the present study, we adapt the familiarization-novelty preference (FNP) procedure used in human infant research to examine visual behavior in alert, unanaesthetized rhesus monkeys that were acclimated to the fMRI environment, but did not undergo behavioral training. In keeping with the typical FNP paradigm, we recorded eye movements (looking time and number of fixations) while monkeys viewed a series of four identical pictures (familiarization phase) followed by two different pictures (novelty phase). Number of fixations and looking time both increased during the novelty phase, thereby demonstrating visual discrimination of the new from the old picture. Importantly, discrimination did not occur on catch trials in which six identical pictures were presented. Moreover, brain activation in the amygdala was more strongly associated with the novelty phase than with the familiarization phase. In addition, magnitude of brain activation in the amygdala was correlated with the behavioral effect of visual discrimination. These findings demonstrate the feasibility of using eye movements as an index of visual discrimination in untrained monkeys during fMRI scanning. This methodological approach helps to extend the repertoire of research tools for fMRI in non-human primates.

Adaptation, Physiological↗

PubMed2006

Iron accumulation in the striatum predicts aging-related decline in motor function in rhesus monkeys.

Changes in the nigrostriatal system may be involved with the motor abnormalities seen in aging. These perturbations include alterations in dopamine (DA) release, regulation and transport in the striatum and substantia nigra, striatal atrophy and elevated iron levels in the basal ganglia. However, the relative contribution of these changes to the motor deficits seen in aging is unclear. Thus, using the rhesus monkey as a model, the present study was designed to examine several of these key alterations in the basal ganglia in order to help elucidate the mechanisms contributing to age-related motor decline. First, 32 female rhesus monkeys ranging from 4 to 32 years old were evaluated for their motor capabilities using an automated hand-retrieval task. Second, non-invasive MRI methods were used to estimate brain composition and to indirectly measure relative iron content in the striatum and substantia nigra. Third, in vivo microdialysis was used to evaluate basal and stimulus-evoked levels of DA and its metabolites in the striatum and substantia nigra of the same monkeys. Our results demonstrated significant decreases in motor performance, decreases in striatal DA release, and increases in striatal iron levels in rhesus monkeys as they age from young adulthood. A comprehensive statistical analysis relating age, motor performance, DA release, and iron content indicated that the best predictor of decreases in motor ability, above and beyond levels of performance that could be explained by age alone, was iron accumulation in the striatum. This suggests that striatal iron levels may be a biomarker of motor dysfunction in aging; and as such, can be monitored non-invasively by longitudinal brain MRI scans. The results also suggest that treatments aimed at reducing accumulation of excess iron in the striatum during normal aging may have beneficial effects on age-related deterioration of motor performance.

Aging↗

PubMed2006

Three-dimensional in vivo motion of adult hind foot bones.

Knowledge of hind foot bone motion is important for understanding gait as well as various foot pathologies, but the three-dimensional (3D) motion of these bones remains incompletely understood. The purpose of this study was to quantify the motion of the talus, calcaneus, navicular, and cuboid in normal adult feet during open chain quasi-static uniplanar plantar flexion motion. Magnetic resonance images of the right feet of six normal young adult males were taken from which 3D virtual models were made of each hind foot bone. The 3D motion of these models was analyzed. Each hind foot bone rotated in the same plane about half as much as the foot (mean 0.54 degrees of bone rotation per degree of foot motion, range 0.40-0.73 degrees per degree of foot motion as measured relative to the fixed tibia). Talar motion was primarily uniaxial, but the calcaneus, navicular, and cuboid bones exhibited biplanar (sometimes triplanar) translation in addition to biaxial rotation. Net translational motions of these bones averaged 0.39 mm of bone translation per degree of foot motion (range 0.06-0.62 mm per degree of foot motion). These data reflect the functional anatomy of the foot, extend the findings of prior studies, provide a standard for comparison to patients with congenital or acquired foot deformities, and establish an objective reference for quantitatively assessing the efficacy of various hind foot therapies.

Adolescent↗

PubMed2006

Biocompatible nanotemplate-engineered nanoparticles containing gadolinium: stability and relaxivity of a potential MRI contrast agent.

In this article, we use a nanotemplate engineering approach to prepare biodegradable nanoparticles composed of FDA-approved materials and possessing accessible gadolinium (Gd) atoms and demonstrate their potential as a Magnetic Resonance Imaging (MRI) contrast agent. Nanoparticles containing dimyristoyl phosphoethanolamine diethylene triamine penta acetate (PE-DTPA) were prepared using 3.5 mg of Brij 78, 2.0 mg of emulsifying wax and 0.5 mg of PE-DTPA/ml from a microemulsion precursor. After the addition of GdCl3, the presence of Gd on the surface of nanoparticles was characterized using inductively coupled plasma atomic emission spectroscopy and Scanning Transmission Electron Microscopy (STEM). The in vitro relaxivities of the PE-DTPA-Gd nanoparticles in different media were assessed at different field strengths. The conditional stability constant of Gd binding to the nanoparticles was determined using competitive spectrophotometric titration. Transmetallation kinetics of the gadolinium ion from PE-DTPA-Gd nanoparticles with zinc as the competing ionic was measured using the relaxivity evolution method. Nanoparticles with a diameter of approximately 130 nm possessing surface chelating functions were made from GRAS (Generally Regarded As Safe) materials. STEM demonstrated the uniform distribution of Gd3+ on the surface of the nanoparticles. The thermodynamic binding constant for Gd3+ to the nanoparticles was approximately 10(18) M(-1) and transmetallation studies with Zn2+ yielded kinetic constants K1 and K(-1) of 0.033 and 0.022 1/h, respectively, with an equilibrium constant of 1.5. A payload of approximately 10(5) Gd/nanoparticle was achieved; enhanced relaxivities were observed, including a pH dependence of the transverse relaxivity (r2). Nanoparticles composed of materials that have been demonstrated to be hemocompatible and enzymatically metabolized and possessing accessible Gd ions on their surface induce relaxivities in the bulk water signal that make them potentially useful as next-generation MRI tumor contrast enhancement agents.

Binding Sites↗

PubMed2005

Correlation of R2 with total iron concentration in the brains of rhesus monkeys.

PURPOSE: To estimate the relationship between R2 = 1/T2 as measured with a double echo spin echo sequence and total iron concentration in gray matter structures in the brains of aging rhesus monkeys. MATERIALS AND METHODS: Using a 1.5-T magnetic resonance (MR) imager, we collected double echo spin echo images of the brains of 12 female rhesus monkeys aged between 9 and 23 years. From the double echo images, the transverse relaxation rate R2 = 1/T2 was calculated in selected gray matter regions. After the animals were euthanized, their brains were excised and tissue punches were taken of the substantia nigra, globus pallidus, and gray matter regions of the cerebellum. Some of the tissue punches were assayed for total iron using atomic absorption spectroscopy. RESULTS: The range of tissue iron concentration spanned from 15 to 450 microg/g wet weight, with the highest levels in the globus pallidus and the lowest levels in the cerebellum. The results show that R2 was highly correlated with the total iron concentration and that the relationship between R2 and tissue iron concentration appeared to depend upon the iron concentration. For concentrations above approximately 150 microg/g wet weight, R2 increased with a sensitivity of 0.0484 +/- 0.0023 second(-1)(microg/g)(-1). In contrast, where the iron concentration was below 150 microg/g, R2 increased at 0.0013 +/- 0.0073 second(-1)(microg/g)(-1). The bilinear behavior may reflect changes with age in the relative amounts of iron distributed diffusely and in granular form in the globus pallidus and substantia nigra. Histological sections of the tissues stained for iron and ferritin support this hypothesis and indicate that the distribution of ferritin is similar to the distribution of iron. CONCLUSION: This study reaffirms the value of measuring the MR relaxation rate R2 for a noninvasive estimate of iron content in the brain and identified limitations in the relationship at low tissue iron concentrations.

Aging↗

PubMed2005

Imaging articular cartilage under compression--cartilage elastography.

We constructed a device to compress small samples of articular cartilage while the samples were imaged in a 1.5 T imager. With the use of a piezoelectric piston, the device compressed 1-cm-diameter cylindrical samples of articular cartilage (200 microm) at a rate of 2 Hz. Simultaneously, we imaged the samples with a displacement-sensitive stimulated-echo acquisition mode (STEAM) sequence. We validated the technique using tissue that mimicked silicone samples. We compared the results from the same cartilage samples before and after they were degraded by digestion in trypsin. The extent of degradation was visualized from T(1)-weighted images of the samples after they were soaked in 0.5 mmolar of GdDTPA. The resulting elastographic images show compression and differential strain in directions both parallel and perpendicular to the surface of the cartilage. The static elastographic images that depict compression made before digestion and after 5 and 15 hr of trypsin digestion show that the elastic modulus of the samples decreased with a spatial variation consistent with the enzymatic digestion as revealed by the T(1) images. We believe this technique will be useful in studies of the mechanical properties of articular cartilage and other tissues, and may in the future be extended to the clinical setting.

Animals↗

PubMed2003

Kinetic comparison of different acute dialysis therapies.

Recent clinical data indicate both ultrafiltration rate (Qf) and timing of treatment initiation in continuous renal replacement therapy (CRRT) and therapy frequency in intermittent hemodialysis (HD) influence survival in critically ill patients with acute renal failure (ARF). In this study, kinetic modeling is used to compare effective dose delivery by three acute dialysis therapies: continuous venovenous hemofiltration (CVVH), daily HD, and sustained low-efficiency dialysis (SLED). A modified equivalent renal clearance (EKR) approach to account for the initial unsteady-state stage during dialysis is employed. Effective small solute clearance in CVVH is found to be 8% and 60% higher than in SLED and daily HD, respectively. Differences are more pronounced for middle and large solute categories, and EKR in CVVH is approximately 2-fold and 4-fold greater than the corresponding values in daily HD and SLED, respectively. The superior middle and large solute removal for CVVH is due to the powerful combination of convection and continuous operation. In CVVH, a decrease in the initial BUN from 150 to 50 mg/dL is predicted to decrease TAC and, therefore, increase EKR by approximately 35%. After clinical validation, the quantification method presented in this article could be a useful tool to assist in the dialytic management of critically ill ARF patients.

Acute Kidney Injury↗

PubMed2003

A numerical and experimental study of mass transfer in the artificial kidney.

To develop a more efficient and optimal artificial kidney, many experimental approaches have been used to study mass transfer inside, outside, and cross hollow fiber membranes with different kinds of membranes, solutes, and flow rates as parameters. However, these experimental approaches are expensive and time consuming. Numerical calculation and computer simulation is an effective way to study mass transfer in the artificial kidney, which can save substantial time and reduce experimental cost. This paper presents a new model to simulate mass transfer in artificial kidney by coupling together shell-side, lumen-side, and transmembrane flows. Darcy's equations were employed to simulate shell-side flow, Navier-Stokes equations were employed to simulate lumen-side flow, and Kedem-Katchalsky equations were used to compute transmembrane flow. Numerical results agreed well with experimental results within 10% error. Numerical results showed the nonuniform distribution of flow and solute concentration in shell-side flow due to the entry/exit effect and Darcy permeability. In the shell side, the axial velocity in the periphery is higher than that in the center. This numerical model presented a clear insight view of mass transfer in an artificial kidney and may be used to help design an optimal artificial kidney and its operation conditions to improve hemodialysis.

Biological Transport↗

PubMed2003

Effect of flow baffles on the dialysate flow distribution of hollow-fiber hemodialyzers: a nonintrusive experimental study using MRI.

We used an innovative, nonintrusive MRI technique called the two-dimensional (2D) Phase-Contrast (2DPC) velocity-imaging technique to investigate the effect of flow baffles on the dialysate-side flow distribution in two different hollow-fiber hemodialyzers (A and B); each with flow rates between 200 and 1000 mL/min (3.33 x 10(-6) and 1.67 x 10(-5) m3/s). Our experimental results show that (1) the dialysate-side flow distribution was nonuniform with channeling flow occurred at the peripheral cross section of these hollow-fiber hemodialyzers, and (2) the existing designs of flow baffles failed to promote uniform dialysate-side flow distribution for all flow rates studies.

Blood Flow Velocity↗

PubMedDate not supplied

Three-dimensional hindfoot motion in adolescents with surgically treated unilateral clubfoot.

Advances in imaging and computerized analyses have enabled three-dimensional bone motion in the treated clubfoot to be measured precisely. Three-dimensional translations and rotations of the talus, calcaneus, navicular, and cuboid of surgically treated clubfeet were less in magnitude and sometimes different in direction (or without motion in a specific plane) compared with the contralateral normal feet. Surgical techniques used for clubfoot treatment do not restore normal hindfoot bone motion when examined with high-resolution magnetic resonance imaging, computer reconstruction, and image analysis techniques. These data advance the knowledge of hindfoot bone motion and establish a new and quantitative objective.

Adolescent↗

PubMedDate not supplied

Tarsal shape, size, and articulating surface morphology in adolescent surgically treated clubfoot and their contralateral normal foot.

Despite the inability of radiographic measurements to quantify the 3-dimensional (3D) shape and size of the hindfoot bones affected by the clubfoot pathology, radiographs continue to be used to evaluate treatment efficacy. Advancements in imaging and image analysis allow new quantitative insights to be obtained into bone shape and size. Therefore, this study sought to quantify and compare the 3D size, shape, and articulating surface morphology of the tibia, talus, calcaneus, navicular, and cuboid bones in the adolescent surgically treated unilateral clubfoot and the contralateral normal foot. Anatomic measurements were obtained by geometrically modeling 3D reconstructed magnetic resonance images of the hindfoot tarsals in the feet of 7 adolescents (mean age, 13.0+/-2.8 years). The results showed that the tarsal bones in the surgically treated clubfoot were smaller in volume (20%-36%) and smaller in surface area (16%-28%) than those in the contralateral normal foot. Correspondingly, the size and shape of the articulating surfaces of these bones in the surgically treated clubfoot were also smaller and flatter than those in the contralateral normal foot. Specifically, the mean talar articular surface area was 25% to 40% smaller, the mean talar-tibiotalar articular surface length was 26% smaller, the mean tibiotalar articular surface length difference was 78% smaller, and the mean navicular "flattening index" was 86% larger in the surgically treated clubfoot. These data offer an objective standard that will advance the knowledge of the clubfoot pathology and aid treatment efficacy evaluation.

Adolescent↗

PubMedDate not supplied

Effect of spacer yarns on the dialysate flow distribution of hemodialyzers: a magnetic resonance imaging study.

Blood side and dialysate side flow distributions play an important role in determining the optimal use of dialysis membrane in hemodialyzers for the removal of uremic solutes. In this article, we used two nonintrusive magnetic resonance imaging (MRI) techniques called the two-dimensional phase contrast (2DPC) and two-dimensional Fourier transform (2DFT) velocity imaging techniques to (1) study the effect of space yarns on the dialysate side flow distribution, (2) investigate the effect of flow baffle on the dialysate side flow distribution, and (3) characterize the blood side and dialysate side flow profiles of hemodialyzers with flow rates ranging from 200 to 1000 ml/min. We investigated two types of hollow fiber hemodialyzers: hemodialyzers A (with spacer yarns) and B (without spacer yarns). We used a 3 mmol cupric sulfate solution as the compartmental fluid and imaged five transverse cross sections of these hemodialyzers. The hemodialyzer with spacer yarns had a more uniform dialysate side spatial flow distribution than that without spacer yarns. In addition, the design of flow baffle in these hemodialyzers can be further improved to promote uniform dialysate side flow distribution, and the blood side flow had a fully developed laminar flow profile. Our experimental results showed that these velocity imaging techniques provide an innovative, nonintrusive tool for characterizing flow distribution in hemodialyzers.

Blood Flow Velocity↗