Search PubMed⌕ Search

Biomedical subjects

D L Hill

Publications and source records attributed to D L Hill.

At least 37 records · Page 2Linked to original sources
PubMed2000

Celecoxib inhibits N-butyl-N-(4-hydroxybutyl)-nitrosamine-induced urinary bladder cancers in male B6D2F1 mice and female Fischer-344 rats.

Epidemiological studies have shown that nonsteroidal anti-inflammatory drugs (NSAIDs) may have a role in the prevention of human cancers. A number of preclinical studies have also suggested that inhibition of cyclooxygenase (COX) with NSAIDs has an anticancer effect in animal models of colon, urinary bladder, skin, and breast. In these studies, we evaluated the COX-2 inhibitor celecoxib in two rodent models of urinary bladder cancer. Male B6D2F1 mice treated with N-butyl-N-(4-hydroxybutyl)-nitrosamine (OH-BBN) developed transitional and squamous cell urinary bladder cancers, many of which grew rapidly and caused substantial morbidity that required sacrifice of the mice. Groups of mice received various daily doses of celecoxib in the diet (1250, 500, or 200 mg/kg of diet) beginning 7 days before the initiation of 12 weekly doses of OH-BBN. Mice were checked weekly for the presence of palpable urinary bladder masses. The study was terminated at 8 months following the initial treatment with OH-BBN. The percentage of mice with large palpable bladder lesions, which necessitated sacrifice of the mice, was 40% in the OH-BBN control group. In contrast, only 10% of all celecoxib-treated mice required sacrifice before the scheduled termination of the experiment, implying that all three doses of celecoxib inhibited the formation of large palpable lesions. Celecoxib did not significantly alter the incidence of preneoplastic bladder lesions, but did dose-dependently decrease the total number of urinary bladder cancers/mouse, palpable plus microscopic, by 77, 57, and 43% at dosages of 1250, 500, and 200 mg of celecoxib/kg of diet, respectively. In the second model, female Fischer-344 rats were administered OH-BBN twice/week for a period of 8 weeks. After 8 months, all rats developed preneoplastic lesions, whereas roughly 60% of the rats developed relatively small urinary bladder cancers. Rats were treated continually with celecoxib in the diet (500 or 1000 mg/kg of diet) beginning either 1 week prior to the initial OH-BBN treatment or beginning 1 week following the last OH-BBN treatment. Neither celecoxib treatment regimen significantly altered the number of preneoplastic lesions. Whereas celecoxib treatment initiated prior to OH-BBN administration decreased cancer incidence roughly 65%, celecoxib treatment initiated beginning 1 week after the last dose of OH-BBN profoundly decreased cancer incidence (>95%). Celecoxib did not alter the body weights of the mice or rats, or cause other signs of toxicity at any of the doses studied. Taken together these results demonstrate that: (a) celecoxib effectively inhibits tumor growth and enhances survival in the mouse model of urinary bladder cancer; and (b) celecoxib profoundly inhibits development of urinary bladder cancers in the rat model even when administered following the last dose of OH-BBN. Clinical trials will be necessary to determine whether COX-2 inhibitors will provide a clinical benefit in human bladder cancer.

Animals↗
PubMed2000

Sampling and reconstruction effects due to motion in diffusion-weighted interleaved echo planar imaging.

Subject motion during diffusion-weighted interleaved echo-planar imaging causes k-space offsets which lead to irregular sampling in the phase-encode direction. For each image, the k-space shifts are monitored using 2D navigator echoes, and are shown to lead to a frequent violation of the Nyquist condition when an ungated sequence is used on seven subjects. Combining data from four repeat acquisitions allows the Nyquist condition to be satisfied in all but 1% of images. Reconstruction of the irregularly-sampled data can be performed using a matrix inversion technique. The repeated acquisitions make the inversion more stable and additionally improve the signal-to-noise ratio. The resultant isotropic diffusion-weighted images and average apparent diffusion coefficient (ADC) maps show high resolution and enable clear localization of a stroke lesion. Residual ADC artifacts with a slow spatial variation are observed and assumed to originate from non-rigid pulsatile brain motion. Magn Reson Med 44:101-109, 2000.

Artifacts↗
PubMed2000

Lack of functional and morphological susceptibility of the greater superficial petrosal nerve to developmental dietary sodium restriction.

Restriction of dietary sodium during gestation has major effects on taste function and anatomy in the offspring. The chorda tympani nerve of offspring that are maintained on sodium-reduced chow throughout life (NaDep) has reduced neurophysiological responses to sodium and altered morphology of its terminal field in the nucleus of the solitary tract. There are many anatomical and physiological similarities between the chorda tympani nerve that innervates taste buds on the anterior tongue and the greater superficial petrosal nerve (GSP) that innervates taste buds on the palate. To determine if the GSP is similarly susceptible to the effects of dietary sodium restriction, the present study examined neurophysiological responses and the terminal field of the GSP in NaDep and control rats. Neurophysiological responses of the GSP to a variety of sodium and non-sodium stimuli did not differ between NaDep and control rats. Furthermore, the volume and shape of the GSP terminal field in the nucleus of the solitary tract did not differ between the groups. Therefore, despite the high degree of functional and anatomical correspondence between the chorda tympani nerve and the GSP, the GSP does not appear to be susceptible to the effects of lifelong dietary sodium restriction.

Amiloride↗
PubMed2000

Voxel similarity measures for 3-D serial MR brain image registration.

We have evaluated eight different similarity measures used for rigid body registration of serial magnetic resonance (MR) brain scans. To assess their accuracy we used 33 clinical three-dimensional (3-D) serial MR images, with deformable extradural tissue excluded by manual segmentation and simulated 3-D MR images with added intensity distortion. For each measure we determined the consistency of registration transformations for both sets of segmented and unsegmented data. We have shown that of the eight measures tested, the ones based on joint entropy produced the best consistency. In particular, these measures seemed to be least sensitive to the presence of extradural tissue. For these data the difference in accuracy of these joint entropy measures, with or without brain segmentation, was within the threshold of visually detectable change in the difference images.

Adult↗
PubMed2000

Design and evaluation of a system for microscope-assisted guided interventions (MAGI).

The problem of providing surgical navigation using image overlays on the operative scene can be split into four main tasks--calibration of the optical system; registration of preoperative images to the patient; system and patient tracking, and display using a suitable visualization scheme. To achieve a convincing result in the magnified microscope view a very high alignment accuracy is required. We have simulated an entire image overlay system to establish the most significant sources of error and improved each of the stages involved. The microscope calibration process has been automated. We have introduced bone-implanted markers for registration and incorporated a locking acrylic dental stent (LADS) for patient tracking. The LADS can also provide a less-invasive registration device with mean target error of 0.7 mm in volunteer experiments. These improvements have significantly increased the alignment accuracy of our overlays. Phantom accuracy is 0.3-0.5 mm and clinical overlay errors were 0.5-1.0 mm on the bone fiducials and 0.5-4 mm on target structures. We have improved the graphical representation of the stereo overlays. The resulting system provides three-dimensional surgical navigation for microscope-assisted guided interventions (MAGI).

Computer Simulation↗
PubMed2000

Development of rat chorda tympani sodium responses: evidence for age-dependent changes in global amiloride-sensitive Na(+) channel kinetics.

In rat, chorda tympani nerve taste responses to Na(+) salts increase between roughly 10 and 45 days of age to reach stable, mature magnitudes. Previous evidence from in vitro preparations and from taste nerve responses using Na(+) channel blockers suggests that the physiological basis for this developmental increase in gustatory Na(+) sensitivity is the progressive addition of functional, Na(+) transduction elements (i.e., amiloride-sensitive Na(+) channels) to the apical membranes of fungiform papilla taste receptor cells. To avoid potential confounding effects of pharmacological interventions and to permit quantification of aggregate Na(+) channel behavior using a kinetic model, we obtained chorda tympani nerve responses to NaCl and sodium gluconate (NaGlu) during receptive field voltage clamp in rats aged from 12-14 to 60 days and older (60+ days). Significant, age-dependent increases in chorda tympani responses to these stimuli occurred as expected. Importantly, apical Na(+) channel density, estimated from an apical Na(+) channel kinetic model, increased monotonically with age. The maximum rate of Na(+) response increase occurred between postnatal days 12-14 and 29-31. In addition, estimated Na(+) channel affinity increased between 12-14 and 19-23 days of age, i.e., on a time course distinct from that of the maximum rate of Na(+) response increase. Finally, estimates of the fraction of clamp voltage dropped across taste receptor apical membranes decreased between 19-23 and 29-31 days of age for NaCl but remained stable for NaGlu. The stimulus dependence of this change is consistent with a developmental increase in taste bud tight junctional Cl(-) ion permeability that lags behind the developmental increase in apical Na(+) channel density. A significant, indirect anion influence on apical Na(+) channel properties was present at all ages tested. This influence was evident in the higher apparent apical Na(+) channel affinities obtained for NaCl relative to NaGlu. This stimulus-dependent modulation of apical Na(+) channel apparent affinity relies on differences in the transepithelial potentials between NaCl and NaGlu. These originate from differences in paracellular anion permeability but act also on the driving force for Na(+) through apical Na(+) channels. Detection of such an influence on taste depends fundamentally on the preservation of taste bud polarity and on a direct measure of sensory function, such as the response of primary afferents.

Aging↗
PubMed2000

Sources of error in comparing functional magnetic resonance imaging and invasive electrophysiological recordings.

OBJECT: Several authors have recently reported studies in which they aim to validate functional magnetic resonance (fMR) imaging against the accepted gold standard of invasive electrophysiological monitoring. The authors have conducted a similar study, and in this paper they identify and quantify two characteristics of these data that can make such a comparison problematic. METHODS: Eight patients in whom surgery for epilepsy was performed and five healthy volunteers underwent fMR imaging to localize the part of the sensorimotor cortex responsible for hand movement. In the patient group subdural electrode mats were subsequently implanted to identify eloquent regions of the brain and the epileptogenic zone. The fMR imaging data were processed to correct for motion during the study and then registered with a postimplantation computerized tomography (CT) scan on which the electrodes were visible. The motion during imaging in the two groups studied, and the deformation of the brain between the preoperative images and postoperative scans were measured. The patients who underwent epilepsy surgery moved significantly more during fMR imaging experiments than healthy volunteers performing the same motor task. This motion had a particularly increased out-of-plane component and was significantly more correlated with the stimulus than in the volunteers. This motion was especially increased when the patients were performing a task on the side affected by the lesion. The additional motion is hard to correct and substantially degrades the quality of the resulting fMR images, making it a much less reliable technique for use in these patients than in others. Also, the authors found that after electrode implantation, the brain surface can shift more than 10 mm relative to the skull compared with its preoperative location, substantially degrading the accuracy of the comparison of electrophysiological measurements made in the deformed brain and fMR studies obtained preoperatively. CONCLUSIONS: These two findings indicate that studies of this sort are currently of limited use for validating fMR imaging and should be interpreted with care. Additional image analysis research is necessary to solve the problems caused by patients' motion and brain deformation.

Cerebral Cortex↗
PubMed2000

Neuron/target matching between chorda tympani neurons and taste buds during postnatal rat development.

During postnatal development, a relationship is established between the size of individual taste buds and number of innervating neurons. To determine whether rearrangement of neurons that innervate taste buds establishes this relationship, we labeled single taste buds at postnatal day 10 (P10) and again at either P15, P20, or P40 with retrograde fluorescent neuronal tracers. The number of single- and double-labeled geniculate ganglion cells was counted, and the respective taste bud volumes were measured for the three groups of rats. The current study replicates findings from an earlier report demonstrating that the larger the taste bud, the more geniculate ganglion cells that innervate it. This relationship between taste bud size and number of innervating neurons is not apparent until P40, when taste bud size reaches maturity. These findings are extended here by demonstrating that the number of neurons that innervate taste buds at P10, when taste bud size is small and relatively homogeneous, predicts the size that the respective taste bud will become at maturity. Moreover, while there is some neural rearrangement of taste bud innervation from P10 to P40, rearrangement does not impact the relationship between taste bud size and innervating neurons. That is, the neurons that maintain contact with taste buds from P10 through P40 accurately predict the mature taste bud size. Therefore, the size of the mature taste bud is determined by P10 and relates to the number of sensory neurons that innervate it at that age and the number of neurons that maintain contact with it throughout the first 40 days of postnatal development.

Age Factors↗
PubMed2000

Behavioral taste responses of developmentally NaCl-restricted rats to various concentrations of NaCl.

The behavioral taste responses of developmentally NaCl-restricted rats were examined with a brief-exposure taste test. Neurophysiological and morphological alterations have been reported in rats whose dietary sodium is restricted during pre- and postnatal development, yet there exists little data discerning their behavioral response to tastants. Control and developmentally NaCl-restricted rats were maintained on a low-NaCl diet and trained to lick from individually presented sipper tubes. Each subject received 4 days of testing on various NaCl concentrations. Results indicate that developmentally NaCl-restricted rats have dramatically increased lick rates to NaCl solutions. These responses are likely due to some combination of factors including (a) numbers and type of active chorda tympani fibers, (b) compensatory responses to NaCl-solutions from other nerves of the oral cavity, and (c) increased sensitivity of central taste systems to NaCl.

Animals↗
PubMed1999

Early dietary sodium restriction disrupts the peripheral anatomical development of the gustatory system.

Dietary sodium restriction has profound effects on the development of peripheral taste function and central taste system anatomy. This study examined whether early dietary sodium restriction also affects innervation of taste buds. The number of geniculate ganglion cells that innervate single fungiform taste buds were quantified for the midregion of the tongue in two groups of rats: those fed either a low-sodium diet and those fed a sodium replete diet (control rats) from early prenatal development through adulthood. The same mean number of ganglion cells in developmentally sodium-restricted and control adult rats innervated taste buds on the midregion of the tongue. However, the characteristic relationship of the larger the taste bud, the more neurons that innervate it did not develop in sodium-restricted rats. The failure to form such a relationship in experimental rats was likely due to a substantially smaller mean taste bud volume than controls and probably not to changes in innervation. Further experiments demonstrated that the altered association between number of innervating neurons and taste bud size in restricted rats was reversible. Feeding developmentally sodium-restricted rats a sodium replete diet at adulthood resulted in an increase in taste bud size. Accordingly, the high correlation between taste bud volume and innervation was established in sodium-replete rats. Findings from the current study reveal that early dietary manipulations influence neuron-target interactions; however, the effects of dietary sodium restriction on peripheral gustatory anatomy can be completely restored, even in adult animals.

Animals↗
PubMed1999

Automatic compensation of motion artifacts in MRI.

Patient motion during the acquisition of a magnetic resonance image can cause blurring and ghosting artifacts in the image. This paper presents a new post-processing strategy that can reduce artifacts due to in-plane, rigid-body motion in times comparable to that required to re-scan a patient. The algorithm iteratively determines unknown patient motion such that corrections for this motion provide the best image quality, as measured by an entropy-related focus criterion. The new optimization strategy features a multi-resolution approach in the phase-encode direction, separate successive one-dimensional searches for rotations and translations, and a novel method requiring only one re-gridding calculation for each rotation angle considered. Applicability to general rigid-body in-plane rotational and translational motion and to a range of differently weighted images and k-space trajectories is demonstrated. Motion artifact reduction is observed for data from a phantom, volunteers, and patients.

Algorithms↗
PubMed1999

Nonrigid registration using free-form deformations: application to breast MR images.

In this paper we present a new approach for the nonrigid registration of contrast-enhanced breast MRI. A hierarchical transformation model of the motion of the breast has been developed. The global motion of the breast is modeled by an affine transformation while the local breast motion is described by a free-form deformation (FFD) based on B-splines. Normalized mutual information is used as a voxel-based similarity measure which is insensitive to intensity changes as a result of the contrast enhancement. Registration is achieved by minimizing a cost function, which represents a combination of the cost associated with the smoothness of the transformation and the cost associated with the image similarity. The algorithm has been applied to the fully automated registration of three-dimensional (3-D) breast MRI in volunteers and patients. In particular, we have compared the results of the proposed nonrigid registration algorithm to those obtained using rigid and affine registration techniques. The results clearly indicate that the nonrigid registration algorithm is much better able to recover the motion and deformation of the breast than rigid or affine registration algorithms.

Breast↗
PubMed1999

A system for microscope-assisted guided interventions.

We present a system for surgical navigation using stereo overlays in the operating microscope aligned to the operative scene. This augmented reality system provides 3D information about nearby structures and offers a significant advancement over pointer-based guidance, which provides only the location of one point and requires the surgeon to look away from the operative scene. With a previous version of this system, we demonstrated feasibility, but it became clear that to achieve convincing guidance through the magnified microscope view, a very high alignment accuracy was required. We have made progress with several aspects of the system, including automated calibration, error simulation, bone-implanted fiducials and a dental attachment for tracking. We have performed experiments to establish the visual display parameters required to perceive overlaid structures beneath the operative surface. Easy perception of real and virtual structures with the correct transparency has been demonstrated in a laboratory and through the microscope. The result is a system with a predicted accuracy of 0.9 mm and phantom errors of 0.5 mm. In clinical practice errors are 0.5-1.5 mm, rising to 2-4 mm when brain deformation occurs.

Bone Cysts↗
PubMed1999

Stereo augmented reality in the surgical microscope.

We present an augmented reality system that allows surgeons to view features from preoperative radiological images accurately overlaid in stereo in the optical path of a surgical microscope. The purpose of the system is to show the surgeon structures beneath the viewed surface in the correct 3-D position. The technical challenges are registration, tracking, calibration and visualisation. For patient registration, or alignment to preoperative images, we use bone-implanted markers and a dental splint is used for patient tracking. Both microscope and patient are tracked by an optical localiser. Calibration uses an accurately manufactured object with high contrast circular markers which are identified automatically. All ten camera parameters are modelled as a bivariate polynomial function of zoom and focus. The overall system has a theoretical overlay accuracy of better than 1 mm. Implementations of the system have been tested on seven patients. Recent measurements in the operating room conformed to our accuracy predictions. For visualisation the system has been implemented on a graphics workstation to enable high frame rates with a variety of rendering schemes. Several issues of 3-D depth perception remain unsolved, but early results suggest that perception of structures in the correct 3-D position beneath the viewed surface is possible.

Depth Perception↗
PubMed1998

Quantitative relationships between taste bud development and gustatory ganglion cells.

To determine whether patterns of taste bud innervation change during postnatal rat development, the number of geniculate ganglion cells that innervate single taste buds were quantified in adult and developing rats. While there was a large variation in numbers of ganglion cells that innervate individual taste buds, there was a high degree of organization in the system. Namely, the number of labeled geniculate ganglion cells innervating a taste bud was highly correlated with the size of the taste bud. This relationship between taste bud size and number of innervating ganglion cells develops over a prolonged postnatal period and is not established until postnatal day 40 (P40), when taste buds reach their adult size. In a second series of experiments, we sought to determine whether neural rearrangement of chorda tympani neurons is responsible for the development of this relationship by double-labeling single taste buds at different ages. We found that the number of ganglion cells innervating individual taste buds on P10 predicts the size that taste buds become by P40. This finding suggests that neural rearrangement is not responsible for establishing the relationship between taste bud size and the number of innervating ganglion cells during development. More importantly, it strongly suggests that the 'neural template' for the mature innervation pattern is determined during early postnatal development.

Animals↗
PubMed1998

Innervation of single fungiform taste buds during development in rat.

To determine whether the innervation of taste buds changes during postnatal development, the number of geniculate ganglion cells that innervated single fungiform taste buds were quantified in the tip- and midregions of the tongue of adult and developing rats. There was substantial variation in both the size of individual taste buds and number of geniculate ganglion cells that innervated them. Importantly, taste bud morphology and innervation were highly related. Namely, the number of labeled geniculate ganglion cells that innervated a taste bud was highly correlated with the size of the taste bud (r = 0.91, P < .0003): The larger the taste bud, the more geniculate ganglion cells that innervated it. The relationship between ganglion cell number and taste bud volume emerged during the first 40 days postnatal. Whereas there was no difference in the average number of ganglion cells that innervated individual taste buds in rats aged 10 days postnatal through adulthood, taste bud volumes increased progressively between 10 and 40 days postnatal, at which age taste bud volumes were similar to adults. The maturation of taste bud size was accompanied by the emergence of the relationship between taste bud volume and number of innervating neurons. Specifically, there was no correlation between taste bud size and number of innervating geniculate ganglion cells in 10-, 20-, or 30-day-old rats, whereas taste bud size and the number of innervating ganglion cells in 40-day-old rats were positively correlated (r = .80, P < .002). Therefore, the relationship between taste bud size and number of innervating ganglion cells develops over a prolonged postnatal period and is established when taste buds grow to their adult size.

Afferent Pathways↗
PubMed1998

Conformationally defined retinoic acid analogues. 4. Potential new agents for acute promyelocytic and juvenile myelomonocytic leukemias.

We recently synthesized several conformationally constrained retinoic acid (RA) analogues [8-(2'-cyclohexen-1'-ylidene)-3, 7-dimethyl-2,4,6-octatrienoic acids with different alkyl substituents at 2' (R1) and 3' (R2) positions on the cyclohexene ring] (Muccio et al. J. Med. Chem. 1996, 39, 3625) as cancer chemopreventive agents. UAB8 (R1 = Et; R2 = iPr), which contains sufficient steric bulk at the terminal end of the polyene chain to mimic the trimethylcyclohexenyl ring of RA, displayed biological properties similar to those of RA. To explore the efficacy of this retinoid in acute promyelocytic leukemia (APL) and juvenile myelomonocytic leukemia (JMML), we evaluated UAB8 isomers in in vitro assays which measure the capacity of retinoids to inhibit aberrant myeloid colony growth from blood or bone marrow cells obtained from human JMML patients and in assays measuring the potential of retinoids to differentiate NB4 cells (an APL cell line). Both (all-E)- and (13Z)-UAB8 were 2-fold more active than RA in the NB4 cell differentiation assay; however, only (all-E)-UAB8 had comparable activity to the natural retinoids in the JMML cell assays. These results were compared to the biological effectiveness of a new retinoid, UAB30 [8-(3', 4'-dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4, 6-octatrienoic acid], which had different nuclear receptor binding and transactivational properties than UAB8. Relative to (all-E)-RA and (all-E)-UAB8, (all-E)-UAB30 bound well to RARalpha but did not activate transcription-mediated RARalpha homodimers, even though it was effective in RARbeta- and RARgamma-mediated transactivational assays. In APL assays, this retinoid had much reduced activity and was only moderately effective in JMML assays and in cancer chemoprevention assays.

Animals↗