Low-Molecular-Weight Thiols and Thioredoxins Are Important Players in Hg(II) Resistance in Thermus thermophilus HB27.

Mercury (Hg), one of the most toxic and widely distributed heavy metals, has a high affinity for thiol groups. Thiol groups reduce and sequester Hg. Therefore, low-molecular-weight (LMW) and protein thiols may be important cell components used in Hg resistance. To date, the role of low-molecular-weight thiols in Hg detoxification remains understudied. The mercury resistance (mer) operon of Thermus thermophilus suggests an evolutionary link between Hg(II) resistance and low-molecular-weight thiol metabolism. The mer operon encodes an enzyme involved in methionine biosynthesis, Oah. Challenge with Hg(II) resulted in increased expression of genes involved in the biosynthesis of multiple low-molecular-weight thiols (cysteine, homocysteine, and bacillithiol), as well as the thioredoxin system. Phenotypic analysis of gene replacement mutants indicated that Oah contributes to Hg resistance under sulfur-limiting conditions, and strains lacking bacillithiol and/or thioredoxins are more sensitive to Hg(II) than the wild type. Growth in the presence of either a thiol-oxidizing agent or a thiol-alkylating agent increased sensitivity to Hg(II). Furthermore, exposure to 3 µM Hg(II) consumed all intracellular reduced bacillithiol and cysteine. Database searches indicate that oah2 is present in all Thermus sp. mer operons. The presence of a thiol-related gene was also detected in some alphaproteobacterial mer operons, in which a glutathione reductase gene was present, supporting the role of thiols in Hg(II) detoxification. These results have led to a working model in which LMW thiols act as Hg(II)-buffering agents while Hg is reduced by MerA.IMPORTANCE The survival of microorganisms in the presence of toxic metals is central to life's sustainability. The affinity of thiol groups for toxic heavy metals drives microbe-metal interactions and modulates metal toxicity. Mercury detoxification (mer) genes likely originated early in microbial evolution in geothermal environments. Little is known about how mer systems interact with cellular thiol systems. Thermus spp. possess a simple mer operon in which a low-molecular-weight thiol biosynthesis gene is present, along with merR and merA In this study, we present experimental evidence for the role of thiol systems in mercury resistance. Our data suggest that, in T. thermophilus, thiolated compounds may function side by side with mer genes to detoxify mercury. Thus, thiol systems function in consort with mer-mediated resistance to mercury, suggesting exciting new questions for future research.

Mechanisms of extracellular S0 globule production and degradation in Chlorobaculumtepidum via dynamic cell-globule interactions.

The Chlorobiales are anoxygenic phototrophs that produce solid, extracellular elemental sulfur globules as an intermediate step in the oxidation of sulfide to sulfate. These organisms must export sulfur while preventing cell encrustation during S0 globule formation; during globule degradation they must find and mobilize the sulfur for intracellular oxidation to sulfate. To understand how the Chlorobiales address these challenges, we characterized the spatial relationships and physical dynamics of Chlorobaculum tepidum cells and S0 globules by light and electron microscopy. Cba. tepidum commonly formed globules at a distance from cells. Soluble polysulfides detected during globule production may allow for remote nucleation of globules. Polysulfides were also detected during globule degradation, probably produced as an intermediate of sulfur oxidation by attached cells. Polysulfides could feed unattached cells, which made up over 80% of the population and had comparable growth rates to attached cells. Given that S0 is formed remotely from cells, there is a question as to how cells are able to move toward S0 in order to attach. Time-lapse microscopy shows that Cba. tepidum is in fact capable of twitching motility, a finding supported by the presence of genes encoding type IV pili. Our results show how Cba. tepidum is able to avoid mineral encrustation and benefit from globule degradation even when not attached. In the environment, Cba. tepidum may also benefit from soluble sulfur species produced by other sulfur-oxidizing or sulfur-reducing bacteria as these organisms interact with its biogenic S0 globules.

Strategies for optical control and simultaneous electrical readout of extended cortical circuits.

BACKGROUND: To dissect the intricate workings of neural circuits, it is essential to gain precise control over subsets of neurons while retaining the ability to monitor larger-scale circuit dynamics. This requires the ability to both evoke and record neural activity simultaneously with high spatial and temporal resolution. NEW METHOD: In this paper we present approaches that address this need by combining micro-electrocorticography (µECoG) with optogenetics in ways that avoid photovoltaic artifacts. RESULTS: We demonstrate that variations of this approach are broadly applicable across three commonly studied mammalian species - mouse, rat, and macaque monkey - and that the recorded µECoG signal shows complex spectral and spatio-temporal patterns in response to optical stimulation. COMPARISON WITH EXISTING METHODS: While optogenetics provides the ability to excite or inhibit neural subpopulations in a targeted fashion, large-scale recording of resulting neural activity remains challenging. Recent advances in optical physiology, such as genetically encoded Ca(2+) indicators, are promising but currently do not allow simultaneous recordings from extended cortical areas due to limitations in optical imaging hardware. CONCLUSIONS: We demonstrate techniques for the large-scale simultaneous interrogation of cortical circuits in three commonly used mammalian species.

Comparison of spin-echo and gradient-echo T1-weighted and spin-echo T2-weighted images at 3T in evaluating term-neonatal myelination.

SUMMARY: A prior clinical report of 3T MR imaging in subsequently healthy very premature neonates imaged at term-equivalent age found that both gradient recalled-echo-T1WI and spin-echo-T2WI showed higher rates of myelinated structures, compared with spin-echo-T1WI. The current study set out to assess those rates on the same sequences at 3T in term neonates and thus consisted of 16 term neonates with normal-appearing MR imaging findings who subsequently had normal findings at clinical follow-up. Two neuroradiologists independently assessed 19 structures in those infants on all 3 sequences. Gradient recalled-echo-T1WI showed a slightly higher rate of myelination (57.2%-72.4% of all structures) and interobserver agreement (κ = 0.546, P < .0001) than spin-echo-T2WI (58.2%-64.8%; κ = 0.468, P < .0001), while spin-echo-T1WI had the lowest myelination rate and agreement (25.0%-48.4%; κ = 0.384, P < .0001). Both observers noted that the following structures were myelinated in 88%-100% of patients on gradient recalled-echo-T1WI: the brachium of the inferior colliculus, decussation of the superior cerebellar peduncle, habenular commissure, medial lemniscus, pyramidal decussation, posterior limb of the internal capsule, and superior cerebellar peduncle; on spin-echo-T2WI, there was myelination in 88%-100% of the following structures: the brachium of the inferior colliculus, decussation of the superior cerebellar peduncle, inferior cerebellar peduncle, medial lemniscus, and posterior limb of the internal capsule. In conclusion, this study confirmed that similar to the findings in term-equivalent-age premature infants, myelination changes in term neonates may be best assessed on both gradient recalled-echo-T1WI and spin-echo-T2WI at 3T, and not on spin-echo-T1WI.

A class of mixtures of dependent tail-free processes.

We propose a class of dependent processes in which density shape is regressed on one or more predictors through conditional tail-free probabilities by using transformed Gaussian processes. A particular linear version of the process is developed in detail. The resulting process is flexible and easy to fit using standard algorithms for generalized linear models. The method is applied to growth curve analysis, evolving univariate random effects distributions in generalized linear mixed models, and median survival modelling with censored data and covariate-dependent errors.

T1rho and T2rho MRI in the evaluation of Parkinson's disease.

Prior work has shown that adiabatic T(1rho) and T(2rho) relaxation time constants may have sensitivity to cellular changes and the presence of iron, respectively, in Parkinson's disease (PD). Further understanding of these magnetic resonance imaging (MRI) methods and how they relate to measures of disease severity and progression in PD is needed. Using T(1rho) and T(2rho) on a 4T MRI scanner, we assessed the substantia nigra (SN) of nine non-demented moderately affected PD and ten gender- and age-matched control participants. When compared to controls, the SN of PD subjects had increased T(1rho) and reduced T(2rho). We also found a significant correlation between asymmetric motor features and asymmetry based on T(1rho). This study provides additional validation of T(1rho) and T(2rho) as a means to separate PD from control subjects, and T(1rho) may be a useful marker of asymmetry in PD.

Tick (Acari: Ixodidae) infestation at two rural, seasonal camps in Maine and Vermont.

In July 2008, owners of seasonal camps in Vermont and Maine were exposed to large numbers of questing ticks after opening their camps for the season. Examination of collected specimens revealed that the camp in Vermont was infested with Ixodes cookei Packard, and the camp in Maine was infested with Ixodes marxi Banks. In both instances, numerous tick bites were reported by residents. Both camps were also occupied by wildlife during the off-season, primarily squirrels (Maine) and skunks (Vermont). Subsequent samples from the Vermont site were tested for the presence of Powassan encephalitis virus, though no viral activity was detected.

Primate reaching cued by multichannel spatiotemporal cortical microstimulation.

Both humans and animals can discriminate signals delivered to sensory areas of their brains using electrical microstimulation. This opens the possibility of creating an artificial sensory channel that could be implemented in neuroprosthetic devices. Although microstimulation delivered through multiple implanted electrodes could be beneficial for this purpose, appropriate microstimulation protocols have not been developed. Here, we report a series of experiments in which owl monkeys performed reaching movements guided by spatiotemporal patterns of cortical microstimulation delivered to primary somatosensory cortex through chronically implanted multielectrode arrays. The monkeys learned to discriminate microstimulation patterns, and their ability to learn new patterns and new behavioral rules improved during several months of testing. Significantly, information was conveyed to the brain through the interplay of microstimulation patterns delivered to multiple electrodes and the temporal order in which these electrodes were stimulated. This suggests multichannel microstimulation as a viable means of sensorizing neural prostheses.

Identifying barriers to prehospital thrombolysis in the treatment of acute myocardial infarction.

BACKGROUND AND OBJECTIVES: After an acute myocardial infarction (AMI) prehospital thrombolysis (PHT) reduces mortality compared with inhospital thrombolysis. In practice, a relatively small proportion of the total population with AMI receives PHT. This study was designed to identify the current barriers to PHT. METHODS: A retrospective practice review of 57 consecutive patients treated in or before arrival at a district general hospital emergency department. All patients received thrombolysis for an AMI. RESULTS: The main barriers to delivery of PHT appear to be the inclusion and exclusion criteria laid out in the ambulance service central guidelines. Despite recent widening of the inclusion criteria, 54% of patients eligible for immediate treatment on arrival in hospital either received or were eligible for PHT. CONCLUSION: To increase the number of patients who are eligible for PHT these guidelines need to be revised further in line with inhospital criteria for thrombolysis.

Predicting the probability of abortion in dairy cows: a hierarchical Bayesian logistic-survival model using sequential pregnancy data.

Although abortion contributes substantially to poor reproductive health of dairy herds, little is known about the predictability of abortion based on age, previous abortion or gravidity (number of previous pregnancies). A poor understanding of effects of maternal factors on abortion risk exists, in part, because of methodological difficulties related to non-independence of multiple pregnancies of the same cow in analysis of fetal survival data. We prospectively examined sequential pregnancies to investigate relationships between fetal survival and putative dam risk factors for 2991 abortions from 24,706 pregnancies of 13,145 cows in nine California dairy herds. Relative risks and predicted probabilities of abortion (PPA) were estimated using a previously described hierarchical Bayesian logistic-survival model generalized to incorporate longitudinal data of multiple pregnancies from a single cow. The PPA increased with increasing dam age at conception, with increasing number of previous abortions, and if the previous pregnancy was aborted >60 days in gestation. The PPA decreased with increasing gravidity and with increasing number of days open. For cows that aborted, the median time to fetal death decreased slightly as gravidity increased. The study considers several methodological issues faced in epidemiologic investigations of fetal health, including multi-modal hazard functions, extensive censoring and non-independence of multiple pregnancies. The model improves our ability to predict bovine abortion and to characterize fetal survival, which have important applications to herd health management.

Dose response of milk fat to intravenous administration of the trans-10, cis-12 isomer of conjugated linoleic acid.

Intravenous infusion of conjugated linoleic acid (CLA) was evaluated as a simpler method than abomasal infusion and the feeding of calcium salts to examine milk fat depression. The objectives were to determine the dose-dependent response of milk fat and plasma metabolites to intravenous administration of the trans-10, cis-12 isomer of CLA, an isomer identified to possess an inhibitory effect on milk fat synthesis. Four multiparous Holstein cows averaging 123 +/- 30 d in milk were randomly assigned to treatments in a 4 x 4 Latin square design. Catheters were inserted into the jugular vein for infusions and blood sampling. Treatments consisted of intravenous infusions of 0, 2, 4, and 6 g/d CLA (> 95% trans-10, cis-12 CLA). Infusates contained 72 g/d of a parenteral solution, saline, and CLA to 90 ml. Periods were of 5 d duration with a 7 d wash out. Milk was sampled at each milking and analyzed for fat, protein, and fatty acids. Blood samples were obtained on the last day of each period. Dry matter intake (22.4 +/- 2.4 kg/d), milk yield (28.5 +/- 3.3 kg/d), and protein percent (3.26 +/- 0.08%) of cows were not affected by treatment. However, milk fat percentage was reduced linearly with increasing doses of CLA. Milk fat percentage was 4.17, 3.53, 3.29, and 2.92% on d 5 for treatments 0, 2, 4, and 6 g/d CLA, respectively. Concentrations (4.2 mg/g of fat) of cis-9, trans-11 CLA in milk fat were not affected by treatment. However, an increase in the trans-10, cis-12 CLA content of milk fat was observed. Milk fat contained 0.00, 0.02, 0.06, and 0.10 mg of trans-10, cis-12 CLA per g of fat (SEM = 0.065) for treatments 0, 2, 4, and 6 g/d CLA, respectively. Plasma NEFA concentration increased linearly with the dose of the trans-10, cis-12 CLA. Intravenous infusion of the trans-10, cis-12 isomer of CLA depressed milk fat in a linear manner over the range of infusion studied and, therefore, is an alternative to abomasal infusion.

Effect of dose of calcium salts of conjugated linoleic acid (CLA) on percentage and fatty acid content of milk fat in midlactation holstein cows.

Increasing conjugated linoleic acid (CLA) content of milk fat from lactating dairy cattle has become a research interest due to the possible health benefits afforded humans consuming CLA. Dietary supplementation of CLA to lactating dairy cows is one potential method by which CLA content of milk and dairy products may be enhanced. Feeding CLA in calcium salt form could potentially deliver CLA to the lower digestive tract through prevention of biohydrogenation by rumen microbes. Milk fat depression (MFD) occurs when cows receive CLA-60, a commercially available CLA source containing numerous CLA isomers, abomasally. Our objectives were to determine the quantity of CLA as calcium salts required to elicit maximal MFD and to evaluate the effects of CLA supplementation on fatty acid composition of milk fat. Five Holstein cows at approximately 93 DIM were utilized in a 5 x 5 balanced Latin square crossover design. Periods were 14-d in length with a 5-d treatment phase and 9-d rest phase. Treatments were 5-d supplementation of 0, 12.5, 25, 50, and 100 g of CLA-60 in calcium salt form. Milk samples were collected on d 5 of CLA supplementation and analyzed for composition and fatty acid profile. Regression analysis of milk fat data suggested that MFD was not maximized over the dose levels investigated, despite delivery of 34.5 g of trans-10, cis-12 CLA in the 100-g dose of CLA. Supplementation with 50 and 100 g of CLA per day resulted in a reduction of milk fat percent of 29 and 34%, respectively. Trend analysis indicated a linear decrease in the milk fat content of caprylic, capric, and lauric acids as the dose of CLA increased. Milk fat content of cis-9, trans-11, and trans-10, cis-12 CLA increased at an increasing rate as dose increased.

Application of Bayesian inference to characterize risks associated with low doses of low-LET radiation.

Improved risk characterization for stochastic biological effects of low doses of low-LET radiation is important for protecting nuclear workers and the public from harm from radiation exposure. Here we present a Bayesian approach to characterize risks of stochastic effects from low doses of low-LET radiation. The stochastic effect considered is neoplastic transformation of cells because it relates closely to cancer induction. We have used a published model of neoplastic transformation called NEOTRANS1. It is based on two different classes of cellular sensitivity for asynchronous, exponentially growing populations (in vitro). One sensitivity class is the hypersensitive cell; the other is the resistant cell. NEOTRANS1 includes the effects of genomic damage accumulation, DNA repair during cell cycle arrest, and DNA misrepair (non-lethal repair errors). The model-associated differential equations are solved for conditions of in vitro irradiation at a fixed rate. Previously published solutions apply only to high dose rates and were incorrectly assumed to apply to only high-LET radiation. Solutions provided here apply to any fixed dose rate and to both high- and low-LET radiations. Markov chain Monte Carlo methods are used to carry out the Bayesian inference of the low-dose risk for neoplastic transformation of aneuploid C3H 10T1/2 cells for X-ray doses from 0 to 1000 mGy. We have assumed that for this low-dose range only the hypersensitive fraction of the cells are affected. Our results indicate that the initial slope of the risk vs dose relationship for neoplastic transformation is as follows: (1) directly proportional to the fraction, f1, of hypersensitive cells; (2) directly proportional to the radiosensitivity of the genomic target; and (3) inversely proportional to the rate at which hypersensitive cells with radiation-induced damage are committed to undergo correct repair of genomic damage. Further, our results indicate that very fast molecular events are associated with the commitment of cells to the correct repair pathway. Results also indicate a relatively large probability for misrepair that leads to genomic instability. Our results are consistent with the view that for very low doses, dose rate is not an important variable for characterizing low-LET radiation risks so long as age-related changes in sensitivity do not occur during irradiation.

Interference in spectrophotometric analysis of cerebrospinal fluid by haemolysis induced by transport through a pneumatic tube system.

The hypothesis that sending blood-stained cerebrospinal fluid (CSF) through a pneumatic tube causes in vitro haemolysis has been tested. Spectrophotometric scanning of CSF supernatants demonstrated a significantly greater absorbance at 415 nm in those CSF samples that had been sent through the tube system compared to those that had not (P=0.0034). It is concluded that passage of blood-stained CSF down a pneumatic tube system causes in vitro haemolysis, accompanied by the release of oxyhaemoglobin from the lysed cells into the surrounding CSF. In view of this observation, it is recommended that CSF samples requiring spectrophotometric analysis, as part of the investigation of subarachnoid haemorrhage, should not be transported via a pneumatic tube system.

A ribulose-1,5-bisphosphate carboxylase/oxygenase (RubisCO)-like protein from Chlorobium tepidum that is involved with sulfur metabolism and the response to oxidative stress.

A gene encoding a product with substantial similarity to ribulose-1,5-bisphosphate carboxylase/oxygenase (RubisCO) was identified in the preliminary genome sequence of the green sulfur bacterium Chlorobium tepidum. A highly similar gene was subsequently isolated and sequenced from Chlorobium limicola f.sp. thiosulfatophilum strain Tassajara. Analysis of these amino acid sequences indicated that they lacked several conserved RubisCO active site residues. The Chlorobium RubisCO-like proteins are most closely related to deduced sequences in Bacillus subtilis and Archaeoglobus fulgidus, which also lack some typical RubisCO active site residues. When the C. tepidum gene encoding the RubisCO-like protein was disrupted, the resulting mutant strain displayed a pleiotropic phenotype with defects in photopigment content, photoautotrophic growth and carbon fixation rates, and sulfur metabolism. Most important, the mutant strain showed substantially enhanced accumulation of two oxidative stress proteins. These results indicated that the C. tepidum RubisCO-like protein might be involved in oxidative stress responses and/or sulfur metabolism. This protein might be an evolutional link to bona fide RubisCO and could serve as an important tool to analyze how the RubisCO active site developed.

Aging and the neuroendocrine regulation of reproduction and body weight.

Aging in men is associated with a decline in trophic factors such as testosterone (T), alterations in body composition and impaired energy and body weight regulation. We performed studies to investigate the mechanisms underlying age-related changes in the neuroendocrine control of testis function, body composition, food intake and body weight in the Brown Norway (BN) rat. We found that similar to aging men, male BN rats demonstrate both primary and secondary testicular failure with aging without confounding age-related tumors, hormonal changes and systemic illnesses. With aging, these animals have blunted circadian variations in luteinizing hormone (LH) and T, and decreased hypothalamic gonadotropin-releasing hormone (GnRH) synthetic capacity with preserved pituitary gonadotropin responses to GnRH. We found that aging male BN rats have increased peripheral and visceral adiposity associated with increased insulin and leptin levels, and decreased relative lean body mass and muscle mass. We found that these rats exhibit reduced food intake and body weight gain associated with decreased hypothalamic neuropeptide Y (NPY) gene expression in the arcuate nucleus (ARC), both during ad-libitum feeding and after a 72-h fast. Recently, we found that old male BN rats treated chronically with troglitazone, an insulin sensitizer, lowered high insulin and leptin levels, decreased body fat, and corrected the blunted food intake and body weight gain response to fasting without affecting basal ARC NPY gene expression. These findings suggested that hyperinsulinemia and/or hyperleptinemia associated with aging may contribute to the age-related impairment in energy and weight regulation. Our studies suggest that the aging male BN rat is an excellent model to investigate the mechanisms underlying the age-associated changes in the neuroendocrine control of body composition, energy intake and body weight.

Log-linear and logistic modeling of dependence among diagnostic tests.

We developed log-linear and logistic-modeling approaches to investigate dependence among diagnostic tests. To illustrate the approaches, we used published data for swine toxoplasmosis, bovine paratuberculosis, and swine brucellosis. These diseases were selected because each animal's true disease status was known, at least five tests were used, and the serologic tests had been previously shown to have moderate-to-high pairwise dependence in test sensitivities (and sometimes in test specificities). Log-linear and logistic modeling yielded similar results for swine toxoplasmosis and swine brucellosis. However, logistic modeling could not be used to investigate test dependence for bovine paratuberculosis because of quasi-separation in the data attributable to two fecal-based tests having specificities of 100%. Findings from our modeling indicated that 3 (modified agglutination, enzyme-linked immunosorbent assay (ELISA), latex agglutination) of 5 serologic tests for toxoplasmosis and 2 (rivanol and particle concentration fluorescence immunoassay) of 6 serologic tests for brucellosis were adequate for diagnosis. For bovine paratuberculosis, both fecal-based tests (Herrold's egg-yolk culture and radiometric culture) and 1 (ELISA) of 3 serologic tests were necessary in serial and parallel testing schemes.

Daily melatonin administration to middle-aged male rats suppresses body weight, intraabdominal adiposity, and plasma leptin and insulin independent of food intake and total body fat.

Pineal melatonin secretion declines with aging, whereas visceral fat, plasma insulin, and plasma leptin tend to increase. We have previously demonstrated that daily melatonin administration at middle age suppressed male rat intraabdominal visceral fat, plasma leptin, and plasma insulin to youthful levels; the current study was designed to begin investigating mechanisms that mediate these responses. Melatonin (0.4 microg/ml) or vehicle was administered in the drinking water of 10-month-old male Sprague Dawley rats (18/treatment) for 12 weeks. Half (9/treatment) were then killed, and the other half were submitted to cross-over treatment for an additional 12 weeks. Twelve weeks of melatonin treatment decreased (P<0.05) body weight (BW; by 7% relative to controls), relative intraabdominal adiposity (by 16%), plasma leptin (by 33%), and plasma insulin (by 25%) while increasing (P<0.05) locomotor activity (by 19%), core body temperature (by 0.5 C), and morning plasma corticosterone (by 154%), restoring each of these parameters toward more youthful levels. Food intake and total body fat were not changed by melatonin treatment. Melatonin-treated rats that were then crossed over to control treatment for a further 12 weeks gained BW, whereas control rats that were crossed to melatonin treatment lost BW, but food intake did not change in either group. Feed efficiency (grams of BW change per g cumulative food intake), a measure of metabolic function, was negative in melatonin-treated rats and positive in control rats before cross-over (P<0.001); this relationship was reversed after cross-over (P<0.001). Thus, melatonin treatment in middle age decreased BW, intraabdominal adiposity, plasma insulin, and plasma leptin, without altering food intake or total adiposity. These results suggest that the decrease in endogenous melatonin with aging may alter metabolism and physical activity, resulting in increased BW, visceral adiposity, and associated detrimental metabolic consequences.

Cross-sectional and longitudinal analysis of age-associated changes in body composition of male Brown Norway rats: association of serum leptin levels with peripheral adiposity.

Aging-associated alterations in body composition are accompanied by changes in the endocrine system. We evaluated, in male Brown Norway rats, the effects of aging on body composition and the association with serum levels of leptin, insulin, and testosterone. Body composition was assessed cross-sectionally in male rats (3, 8, 17, and 29 months) by a combination of dual energy x-ray absorptiometry (DEXA) and dissection of specific muscles and adipose depots. Longitudinal changes in body composition were quantified by DEXA before and after 3 months of ad-libitum feeding. Body weight, lean mass, absolute and percentage fat increased with age, whereas percentage of lean mass decreased. Leptin and insulin levels increased with age in proportion to adiposity; the increase in leptin with age was related to increased total and peripheral, but not visceral, fat. Testosterone decreased with age, and was associated with decreased lean and skeletal muscle mass. These findings suggest that alterations in body composition with age may be due to decreased trophic and increased lipogenic hormones. Relative to other rodent models, Brown Norway rats undergo shifts in body composition and in the hormonal milieu that are consistent with changes seen in aging humans.