The promotional effect of testosterone on induction of prostate-cancer in MNU-sensitized L-W rats.

Large metastasizing prostate adenocarcinomas (PAs) were induced in L-W rats by a single intravenous (i.v.) inoculation of methylnitrosourea (MNU) and then single subcutaneous implants of testosterone propionate (TP) at intervals of 2 months. This procedure induced PAs in approximately 90% of rats in an average of 11 months. PAs did not develop spontaneously in L-W rats under age 20 months. With this model system, it was demonstrated that within a 14-month observation period, significant numbers of PAs were elicited by TP implants in L-W rats after intervals of 1 week, 1 month and 2 months following the inoculation of MNU. A direct relationship was also demonstrated between amount of TP administered to L-W rats and the resulting incidence of PAs. TP is characterized as a prostate-directed promoter of PA, following a single inoculation of MNU which served as the tumor initiator.

Age-related changes in cardiac norepinephrine release: role of calcium movement.

The purpose of this study was to determine if the age-related decrease in norepinephrine (NE) release from cardiac adrenergic nerve terminals is due to a defect in Ca2+ movement into the nerve terminal or to an alteration in Ca2+ activation of intracellular events leading to NE release. NE release was assessed in cardiac synaptosomes prepared from 6- and 24-month-old male F344 rats. K(+)-induced NE release was significantly greater in young vs old rats. Raising extracellular [Ca2+] increased NE release, but NE release always remained higher in the younger animals. Ionomycin, a Ca2+ ionophore, induced NE release from cardiac synaptosomes, and there was no age difference in the response. The age-related reduction in NE release induced by K+ and the capacity of ionomycin to induce similar NE release in young and old cardiac synaptosomes points to a reduction in Ca2+ movement during depolarization.

Effect of age, gender, rat strain, and dietary restriction, on norepinephrine release from cardiac synaptosomes.

The purpose of the present study was to determine if dietary restriction affected NE release from cardiac synaptosomes obtained from old male F344 rats. Female F344 rats and male and female B/N rats were also examined to determine if age-related changes in norepinephrine (NE) release capacity in the heart are strain- and/or gender-specific. F344 and Brown-Norway (B/N) rats were examined at 6, 12, and 24 months; B/N rats were also examined at 28-30 months. K(+)-induced NE release significantly declined with age in male F344 and B/N rats; this decline was attenuated in female rats and in dietary restricted rats, especially at 24 months. The present study demonstrates that aging reduces the capacity of cardiac adrenergic nerve terminals to release NE, this age-related change is not strain specific, and that dietary restriction and gender alter the extent of this change with age.

Prenatal cocaine exposure alters norepinephrine release from cardiac adrenergic nerve terminals.

The effect of prenatal cocaine exposure on the development of the cardiac adrenergic nervous system was assessed in neonatal rabbits. Pregnant does received cocaine (4 mg/kg, i.v., bid) or saline during gestational days 8 to 29. Hearts were obtained on postnatal days 10, 20, 30, and 50. Adrenergic nerve function was assessed by measuring 3H-norepinephrine (NE) uptake and 3H-NE release from cardiac synaptosomes. NE uptake increased with postnatal age and was not affected by cocaine exposure. K(+)-induced NE release increased with age, was significantly less in cocaine exposed rabbits compared to saline exposed rabbits at days 10, and 20, but was similar at days 30 and 50. NE release induced by ionomycin, a Ca2+ ionophore, did not change with age, was significantly greater in cocaine exposed rabbits compared to saline exposed rabbits at days 10, 20, and 30, but was similar at day 50. Wet heart weight, heart weight per body weight, and NE content of the hearts were not affected by cocaine exposure. These results suggest that prenatal cocaine exposure delays the development of the mechanisms responsible for Ca2+ influx during K(+)-induced depolarization and increases the neurosecretory response to intracellular Ca2+.

Cardiovascular hypertrophy and increased vascular contractile responsiveness following repeated cocaine administration in rabbits.

The effects of repeated cocaine administration on contractile responses were studied in adult rabbits. Repeated cocaine exposure caused a significant increase in the maximal response of the aorta to the agonists norepinephrine and serotonin as well as the receptor- independent stimulus KCl when compared to the saline controls. Cocaine exposure caused a significant increase in the wet weights of both heart and aorta. When the contraction was normalized to the wet weight of the aorta there was no difference between rabbits administered cocaine and saline. Acute cocaine administration caused a time-dependent increase in immunoreactivity of the proto-oncogene c-Fos in the aorta. These results show that repeated cocaine administration leads to the development of cardiovascular hypertrophy.

Prenatal cocaine exposure affects the development of aortic adrenergic innervation and contractile responses.

This study examines the effects of prenatal cocaine administration on the development of vascular sympathetic innervation and contractile responsiveness. Rabbits received cocaine (4 mg/kg, iv, bid) or saline during gestational days 8 to 29. Aortas were obtained on postnatal days 10, 20, 30 and 50. Vascular smooth muscle responsiveness was assessed by measuring aortic contractile responses to norepinephrine (NE) and to other vasoconstrictors. Vascular adrenergic innervation was evaluated by measuring desipramine sensitive [3H]-NE uptake into aortic ring segments and aortic NE content. [3H]-NE uptake and NE content were reduced at postnatal days 10 and 20 in the rabbits exposed prenatally to cocaine. Differences were not observed at postnatal days 30 or 50. The contractile response to NE was reduced in rabbits exposed to cocaine prenatally. Maximal response and potency were decreased at postnatal day 10 and potency was still decreased at day 20, but not at the older ages. Contractile responses to serotonin (5-HT) and angiotensin II (AII) were not affected by prenatal cocaine exposure. These results suggest that prenatal cocaine exposure delays the development of aortic adrenergic innervation and alpha adrenoceptor responsiveness.

Corrections for accidental coincidences and attenuation in maximum-likelihood image reconstruction for positron-emission tomography.

Reconstruction procedures that account for attenuation in forming maximum-likelihood estimates of activity distributions in positron-emission tomography are extended to include regularization constraints and accidental coincidences. A mathematical model is used for these effects. The corrections are incorporated into the iterations of an expectation-maximization algorithm for numerically producing the maximum-likelihood estimate of the distribution of radioactivity within a patient. The images reconstructed with this procedure are unbiased and exhibit lower variance than those reconstructed from precorrected data.

A hardware architecture using finite-field arithmetic for computing maximum-likelihood estimates in emission tomography.

A special-purpose hardware architecture is proposed to implement the expectation-maximization algorithm to compute, in clinically useful times, the maximum-likelihood estimate of a radionuclide distribution for a positron-emission tomogram from time-of-flight measurements. Two-dimensional convolutions required for forming the estimate are converted into a series of one-dimensional convolutions that can be evaluated in parallel. Each one-dimensional convolution is evaluated using a number-theoretic transform. All numerical calculations are performed using finite-field arithmetic. To avoid the use of large finite fields and to increase parallelism, each convolution is performed by a series of convolutions with small digits in a Galois field. The hardware architecture allows a two-dimensional convolution of dimension NxN to be formed with O(N) operations, permitting one iteration of the expectation-maximization algorithm to be formed in approximately 100 ms when N=128 and the number of view angles is 32.

The Effect of Accidental Coincidences in Time-of-Flight Positron Emission Tomography.

An accidental coincidence is defined as the erroneous registration of two photons, originating from separate positron annihilations, as having originated from the same positron annihilation. Previous analyses which did not consider accidental coincidences indicated that for a certain radioactivity distribution a gain in image signal-to-noise ratio of about 5 dB is achieved by the time-of-flight method over the conventional method. Subsequent experiments have validated this prediction in low counting rate situations. For higher, typical counting rates these experiments showed a significantly larger gain of about 9 dB, which was attributed to the way in which the time-of-flight method suppresses the degrading effects of accidental coincidences. We present an analytical model, extended from a previous model, which considers accidental coincidences. Calculations of signal-to-noise ratio, using this model, compare well with the experiments and show that the additional gain is indeed due to the treatment of accidental coincidences. An understanding of the model leads to an intuitive explanation of the gain mechanism and a determination of an effective coincidence-timing window that is achieved by the time-of-flight method.

Iterative deblurring for CT metal artifact reduction.

Iterative deblurring methods using the expectation maximization (EM) formulation and the algebraic reconstruction technique (ART), respectively, are adapted for metal artifact reduction in medical computed tomography (CT). In experiments with synthetic noise-free and additive noisy projection data of dental phantoms, it is found that both simultaneous iterative algorithms produce superior image quality as compared to filtered backprojection after linearly fitting projection gaps. Furthermore, the EM-type algorithm converges faster than the ART-type algorithm in terms of either the I-divergence or Euclidean distance between ideal and reprojected data in the authors' simulation. Also, for a given iteration number, the EM-type deblurring method produces better image clarity but stronger noise than the ART-type reconstruction. The computational complexity of EM- and ART-based iterative deblurring is essentially the same, dominated by reprojection and backprojection. Relevant practical and theoretical issues are discussed.

An evaluation of maximum likelihood reconstruction for SPECT.

A reconstruction method for SPECT (single photon emission computerized tomography) that uses the maximum likelihood (ML) criterion and an iterative expectation-maximization (EM) algorithm solution is examined. The method is based on a model that incorporates the physical effects of photon statistics, nonuniform photon attenuation, and a camera-dependent point-spread response function. Reconstructions from simulation experiments are presented which illustrate the ability of the ML algorithm to correct for attenuation and point-spread. Standard filtered backprojection method reconstructions, using experimental and simulated data, are included for reference. Three studies were designed to focus on the effects of noise and point-spread, on the effect of nonuniform attenuation, and on the combined effects of all three. The last study uses a chest phantom and simulates Tl-201 imaging of the myocardium. A quantitative analysis of the reconstructed images is used to support the conclusion that the ML algorithm produces reconstructions that exhibit improved signal-to-noise ratios, improved image resolution, and image quantifiability.

Noise and edge artifacts in maximum-likelihood reconstructions for emission tomography.

Images produced in emission tomography with the expectation-maximization algorithm have been observed to become more noisy and to have large distortions near edges as iterations proceed and the images converge towards the maximum-likelihood estimate. It is our conclusion that these artifacts are fundamental to reconstructions based on maximum-likelihood estimation as it has been applied usually; they are not due to the use of the expectation-maximization algorithm, which is but one numerical approach for finding the maximum-likelihood estimate. In this paper, we develop a mathematical approach for suppressing both the noise and edge artifacts by modifying the maximum-likelihood approach to include constraints which the estimate must satisfy.

Deblurring subject to nonnegativity constraints when known functions are present with application to object-constrained computerized tomography.

The reconstruction of tomographic images is often treated as a linear deblurring problem. When a high-density, man-made metal object is present somewhere in the image field, it is a deblurring problem in which the unknown function has a component that is known except for some location and orientation parameters. We first address general linear deblurring problems in which a known function having unknown parameters is present. We then show how the resulting iterative solution can be applied to tomographic imaging in the presence of man-made foreign objects, and we apply the result, in particular, to X-ray computed tomography imaging used in support of brachytherapy treatment of advanced cervical cancer.

Developmental toxicity interactions of salicylic acid and radiofrequency radiation or 2-methoxyethanol in rats.

Radiofrequency (RF) radiation is used in a variety of workplaces where workers are concurrently exposed to chemicals. Combined exposure to RF radiation (10 MHz) and the industrial solvent, 2-methoxyethanol (2ME), produces enhanced teratogenicity in rats. The purpose of the present research was to determine if the synergistic effects noted for RF radiation and 2ME are generalizable to other chemicals. Since salicylic acid (SA) is widely used as an analgesic and is teratogenic in animals, SA was selected to address generalizability. Based on the literature and our pilot studies, 0, 250, or 350 mg/kg SA were administered by gavage on gestation Day 9 or 13 to rats. Concurrently rats given SA on Day 9 were exposed to RF radiation sufficient to maintain colonic temperature at 41 degrees C for 60 min (or sham). Those given SA on Day 13 were also given 0 or 100 mg/kg 2ME (gavage). Dams were sacrificed on gestation Day 20, and the fetuses were examined for external malformations. The data provide no evidence of synergistic interactions between RF radiation and salicylic acid (resorptions and malformations). Limited evidence of antagonism was observed between 2ME and salicylic acid (fetal weights). This investigation highlights the importance of additional research on interactions in developmental toxicology, and emphasizes the need to consider combined exposure effects when developing both physical agent and chemical agent exposure guidelines and intervention strategies.

Serum lipids in spontaneously hypertensive rats and Sprague-Dawley rats fed menhaden oil.

Dietary n-3 fatty acids, abundant in fish oil, exert a variety of effects that attenuate cardiovascular disease. In this study, we assessed the effect of fish oil (menhaden oil) on the serum lipid profile in hypertensive and normotensive rats. Spontaneously hypertensive rats (SHR) or Sprague-Dawley rats (SD) were fed either standard powdered diet (L-485), or L-485 + 5% menhaden oil (MO) or L-485 + 5% corn oil (CO) from weaning through eight months of age. Systolic blood pressure (BP) was periodically determined on SHR. Serum lipid profiles were performed at eight months on samples taken from the exposed hearts of anesthetized, fasted rats. SHR, compared with SD (diets combined) had significantly lower triacylglycerols (TG), higher cholesterol (CHOL), higher high density lipoprotein cholesterol (HDL CHOL), higher low density lipoprotein cholesterol (LDL CHOL), and a higher LDL:HDL ratio. Comparisons among diets (strains combined) revealed that rats fed MO had the lowest values for TG, CHOL, LDL and LDL:HDL; HDL did not vary with diet. SHR were less responsive to diet-induced changes than were SD; no decrease in TG, LDL or LDL:HDL was observed in SHR, nor was degree of hypertension altered in SHR by the MO or CO diet. In summary, MO is more effective than CO in shifting the lipid profile of rats toward one that is less atherogenic. However, the SD rat is more susceptible to diet-induced lipid modification than is the SHR.

Automatic target recognition organized via jump-diffusion algorithms.

Proposes a framework for simultaneous detection, tracking, and recognition of objects via data fused from multiple sensors. Complex dynamic scenes are represented via the concatenation of simple rigid templates. The variability of the infinity of pose is accommodated via the actions of matrix Lie groups extending the templates to individual instances. The variability of target number and target identity is accommodated via the representation of scenes as unions of templates of varying types, with the associated group transformations of varying dimension. We focus on recognition in the air-to-ground and ground-to-air scenarios. The remote sensing data is organized around both the coarse scale associated with detection as provided by tracking and range radars, along with the fine scale associated with pose and identity supported by high-resolution optical, forward looking infrared and delay-Doppler radar imagers. A Bayesian approach is adopted in which prior distributions on target scenarios are constructed via dynamical models of the targets of interest. These are combined with physics-based sensor models which define conditional likelihoods for the coarse/fine scale sensor data given the underlying scene. Inference via the Bayes posterior is organized around a random sampling algorithm based on jump-diffusion processes. New objects are detected and object identities are recognized through discrete jump moves through parameter space, the algorithm exploring scenes of varying complexity as it proceeds. Between jumps, the scale and rotation group transformations are generated via continuous diffusions in order to smoothly deform templates into individual instances of objects.

B6 vitamer content of rat tissues measured by isotope tracer and chromatographic methods.

Feeding [14C]pyridoxine to growing rats for 146 days produced uniform labelling of the total vitamin B6 pool, thus permitting the radioactivity to be used as an absolute standard for evaluating the accuracy of vitamin B6 analyses. The results demonstrated that trichloroacetic acid extraction followed by cation exchange chromatography accurately measures the B6 vitamers. It is essential to homogenize tissues in a protein-denaturing agent in order to avoid shifts in the vitamer content, particularly in liver. In rats approximately 80% of the radioactivity was found in carcass and 8-9% each in liver and skin. Pyridoxamine phosphate equalled or exceeded the concentration of pyridoxal phosphate in heart, brain and kidney. The total vitamin B6 pool in weanling and adult rats averaged about 16 nmol/g body wt. Meta-phosphoric acid extraction followed by reverse phase chromatography gave good agreement with the cation exchange method in rat liver but with cat plasma yielded pyridoxal phosphate values below those of the cation exchange or enzymatic methods. The discrepancies encountered between different homogenization techniques and chromatographic methods emphasize the need for constant vigilance and continual verification of results by independent methods.

Effects of age, dietary restriction and germ-free environment on glutathione-related enzymes in Lobund-Wistar rats.

The effects of age, dietary restriction and germ-free environment on glutathione peroxidase (GP), glutathione reductase (GR) and glutathione-S-transerases (GT) were studied in 48 Lobund-Wistar male rats obtained through the Lobund Aging Study. The treatment design was a 2 x 2 x 3 factorial design (environment x food level x age). Four rats were killed at 6, 18 and 30 months for each of the following groups of rats: conventional ad libitum (CV-A), conventional restricted (CV-R), germ-free ad libitum (GF-A) and germ-free restricted (GF-R). The dietary restriction (DR) was 30%. The activities of the three enzymes in the liver cytosolic fraction were determined. The activities of DR and GT were not affected by age, and were significantly lower in the rats raised in the GF environment than in those raised in the CV environment. DR significantly increased GR in the GF environment. The total GP activity was not affected by age but significantly increased by DR and a GF environment, suggesting that these life prolonging conditions provide greater protection against organic hydroperoxides and low concentrations of hydrogen peroxide.

Effects of age and dietary restriction on liver glutathione transferase activities in Lobund-Wistar rats.

Glutathione-S-transferases (GST) are a group of enzymes which detoxify electrophilic xenobiotics (including drugs, carcinogens and their metabolites), and thus may be involved in the age-related pathologic process. Effects of a 30% dietary restriction on liver GST activities toward seven substrates were studied in male Lobund-Wistar (L-W) rats at 6, 12, 18, 24 and 30 months of age. The enzyme activities in the ad libitum (AL) group toward 1-chloro-2,4-dinitrobenzene (CDNB), bromosulfophthalein (BSP), 4-nitropyridine-N-oxide (NPNO), p-nitrobenzyl chloride (NBC), trans-4-phenyl-3-buten-2-one (PBO) and styrene oxide (STOX) did not change with age, while those toward 1,2-dicholoro-4-nitrobenzene (DCNB) decreased after middle age. The enzyme activities in the dietary restricted (DR) group toward CDNB and STOX did not change with age, while those toward DCNB, BSP, NPNO, NBC and PBO decreased after middle age. The DR group had significantly higher GST activities than the AL group, especially at 18 months, when BSP, NPNO, NBC and PBO were used as the substrates. Dietary restriction did not affect GST activities toward all seven substrates at old age. These results are substrate-specific, indicating that isozyme-specific changes in GST activities occur with dietary restriction and aging. The results suggest that dietary restriction enhances liver detoxification capability associated with GSH conjugation in middle age, which may contribute to the delaying of the age-related pathologic process until a later point in life in this animal model.

Local computed tomography via iterative deblurring.

X-ray computed tomography is a major imaging modality. An iterative deblurring method is adapted for local reconstruction in parallel-beam and cone-beam geometries, utilizing only x-rays passing through a region of interest. The feasibility is demonstrated in numerical simulation with noise-free and noisy projection data. The iterative deblurring method has the theoretical advantages of maintaining nonnegativity, converging monotonically and minimizing Csiszàr's I-divergence.