No description available.

Master of Science / Department of Kinesiology / Thomas J. Barstow / Background and Aim: Long-term microgravity exposure, via spaceflight or -6° head-down tilt bedrest, has been shown to produce significant cardiovascular deconditioning and decreases in exercise performance. However, there is little known about how acute microgravity exposure influences the cardiovascular system’s ability to adjust to increases in physical work. Therefore, the aim of this study was to compare cardiovascular and exercise performance during acute upright, supine and -6° head-down tilt positions. Methods: Seven healthy inactive men performed maximal cycle exercise (VO2peak) tests in the upright, supine, and -6° head-down tilt on separate days. Oxygen consumption and heart rate were measured continuously throughout the testing procedures. Cardiac output (acetylene exhalation technique) was measured periodically and interpolated to the 100-watt work rate. Stroke volume was calculated from cardiac output and heart rate data. Results: Peak oxygen uptake and heart rate were significantly decreased in the supine and -6° head-down tilt positions compared to the upright (VO2peak 2.01±0.46, 2.01±0.51 versus 2.32±0.61 L/min respectively; peak heart rate 161±13, 160±14 versus 172±11 bmp). However, cardiac output at 100-watts was similar in all three-exercise positions. Calculated stroke volume at 100-watts was significantly higher in the -6° head-down tilt position compared to the upright position (76.6±4.7 versus 71.2±4.5, ml). Conclusion: These results suggest that exercise capacity is immediately decreased upon exposure to a microgravity environment, prior to any cardiovascular deconditioning. Therefore, an astronaut’s exercise performance should be evaluated with exercise tests in the -6° head-down tilt position prior to space flight in order to establish a baseline response.

Neoplastic events can be marked by uncontrolled cell proliferation, and thus, one major focus of cancer research has been to identify treatments which reduce or inhibit cell growth. Over the years, various compounds, both naturally occurring and chemically synthesized, have been utilized to inhibit neoplastic cell proliferation. Two such oncostatic agents, melatonin and retinoic acid, have been shown to suppress the growth of hormone-responsive breast cancer in a similar time-course. Currently, separate clinical protocols exist for the administration of retinoids and melatonin as adjuvant therapies for cancer. In vitro studies were conducted to examine effects of a sequential treatment regimen of melatonin followed 24 hours later by retinoic acid (RA) on the proliferation of the estrogen receptor (ER)-positive MCF-7 human breast tumor cells line Incubation of hormonally-responsive MCF-7 and T47D cells with melatonin (10--9 M) followed 24 hours later by RA (10--9 M) resulted in the complete cessation of cell proliferation and induction of apoptosis as was evidenced by the formation of a ladder of nucleosomal oligomers when viewed by agarose gel electrophoresis. The apoptotic effect of this sequential treatment with melatonin and RA appears to be both cell and regimen specific since (a) ER-negative MDA-MB-231 and BT-20 breast tumor cells were unaffected, and (b) the simultaneous administration of melatonin and RA was not associated with apoptosis in any of the breast cancer cell lines studied. Furthermore, no induction of a cytocidal effect is observed in cells pre-treated with RA followed by melatonin, suggesting that melatonin is priming the cells to the effects of RA. There also appears to be a minimum pre-treatment time with melatonin of 12 h necessary in order to induce the apoptotic effect. It has been shown also that pre-treatment of MCF-7 cells for 24 hours with melatonin sensitizes the cells to the effects of RA, and that a much lower concentration of RA can be used to induce an apoptotic effect. This sensitization of the cells to RA is not due to up-regulation of RAR or RXR expression since Western blot analysis demonstrated no change in expression of RAR or RXR in response to treatment with melatonin and RA. The sequential treatment regimen of melatonin followed by RA induced cytocidal effects in MCF-7 cells by activating pathways leading to apoptosis. This was evidenced by decreased ER and Bcl-2 as well as increased Bak and Bax expression. Taken together, the results suggest that use of an appropriate regimen of melatonin and RA inhibits the proliferation and induces apoptosis in ER-positive human breast cancer, and should be considered for pre-clinical and clinical evaluation against ER-positive human breast cancer / acase@tulane.edu

The present series of experiments examined selected brain regions to determine the effects of the gonadal steroids, estrogen and testosterone, on the reactivity of the nitric oxide synthase, NADPH-diaphorase. The results of the first experiment indicated that estrogen administration significantly increased NADPH-diaphorase reactivity 29% in the horizontal limb of the diagonal band of Broca, while testosterone administration significantly reduced NADPH-diaphorase reactivity 27% in the vertical limb of the diagonal band of Broca. The results of the second experiment indicated that 11.8% of NADPH-diaphorase neurons in the vertical limb of the diagonal band of Broca also were immunoreactive for the androgen receptor, while 7.8% of NADPH-diaphorase neurons in the horizontal limb of the diagonal band of Broca additionally were immunoreactive for the androgen receptor. In the ventromedial nucleus of the hypothalamus, however, 90.7% of NADPH-diaphorase also were immunoreactive for the androgen receptor. The results of a third experiment indicated that NADPH-diaphorase reactivity in the ventromedial nucleus of the hypothalamus was significantly increased by 40% in intact female rats sacrificed during proestrus when compared to gonadectomized female rats. NADPH-diaphorase reactivity in either the vertical limb or horizontal limb of the diagonal band of Broca did not significantly fluctuate over the estrous cycle in intact female rats sacrificed during diestrus, proestrus, or estrus. The results of a fourth experiment indicated that NADPH-diaphorase reactivity was not significantly decreased in the diagonal band of Broca of intact male rats when compared to castrated male rats. Collectively, these results indicate that experimental titers of the steroid hormone, testosterone, reduce the reactivity of the nitric oxide synthase, NADPH-diaphorase, in the diagonal band of Broca of male rats. Physiological titers of testosterone, however, do not significantly reduce the reactivity of NADPH-diaphorase in the diagonal band of Broca of male rats. Testosterone may affect NADPH-diaphorase reactivity by a genomic mechanism, as a population of NADPH-diaphorase neurons also were immunoreactive for the androgen receptor. In addition, the present results indicate that experimental titers of the steroid hormone, estrogen, increase the reactivity of NADPH-diaphorase in the diagonal band of Broca of female rats. Alternatively, physiological titers of estrogen do not significantly increase the reactivity of NADPH-diaphorase in the diagonal band of Broca of female rats. However, physiological titers of estrogen do significantly increase the reactivity of NADPH-diaphorase in the ventromedial nucleus of the hypothalamus. These results are in general agreement with previous reports that indicate experimental titers of estrogen increase the reactivity of NADPH-diaphorase, and additionally indicate that NADPH-diaphorase reactivity in the ventromedial nucleus of the hypothalamus is significantly increased during the estrous cycle of intact cycling female rats / acase@tulane.edu

The hippocampal organotypic slice culture was used to study injury in the CNS. Studies characterized factors that influenced regenerative events in the hippocampal dentate gyrus, concomitant changes in glial cell populations, and examined the role of neuroglia in repair of damaged neural tissues Deafferentation of the hippocampus causes dentate granule cell axons, known as the mossy fibers, to initiate collateral neurite sprouting. Following axonal degeneration, mossy fibers form collaterals that invade the dental molecular layer, which contains denervated granule cell dendrites (Zimmer and Gahwiler, 1987) Factors influencing mossy fiber collateral sprouting were identified and found to include time in culture, positional origin of the slice culture along the septo-temporal axis of the hippocampus, and the presence of attached subicular-entorhinal cortical tissues. Additionally, differential damage to mossy fibers was not the basis for the differences in collateral sprouting along the septo-temporal axis Slice cultures were used to investigate glial cell responses to lesion-induced injury in the hippocampus. These experiments demonstrated a temporal correlation between reactive microglia, IL-1$\beta$, and astrocytic hypertrophy over a period of 10 days in vitro (DIV). Microglia were identified using lectin histochemistry, astrocytes and IL-1$\beta$ expressing cells were identified using immunocytochemical markers Reactive microglia steadily decreased as resting microglia increased over 10 DIV. IL-1$\beta$ (+) cells showed a similar pattern of temporal and regional distribution as reactive and resting microglial elements. The onset of astroglial hypertrophy in the dentate gyrus correlated closely with the timecourse of mossy fiber collateral sprouting described. Thus, in hippocampal slice cultures a transient and regional distribution of reactive and resting microglia, IL-1$\beta$ (+) cells and astrocytes occurs within the dentate gyrus during the first 10DIV Excessive numbers of reactive microglia have been correlated with the development and progression of neurodegenerative disease (Dickson, 1990). Experiments were conducted to identify activated and resting microglia, and their reactions to damage incurred during culture preparation. Spontaneous neurodegenerative sites were observed within the first 6DIV as well as within specific regions of the slice cultures. The addition of L-leucine methyl ester to slice cultures significantly reduced the frequency and distribution of neurodegeneration within the first 6DIV / acase@tulane.edu

No description available.

The jaw adductor muscles in strepsirrhines were dissected and their fiber architecture was quantified. Bite force and leverage were estimated using values for physiological cross-sectional area (PCSA) of the jaw adductors and lateral photographs of skulls. Jaw adductor mass, PCSA, fiber length, and bite force scale isometrically to body size. An experiment carried out at the Duke Lemur Center demonstrated that ingested food size also scales isometrically to body size. Folivorous strepsirrhines are characterized by short jaw adductor fibers, uniformly small ingested food size, large masseter and medial pterygoid muscles (in PCSA and mass), and large estimated bite force for their jaw length. Large-bodied folivores have especially large jaw adductors. Small-bodied folivores have especially short jaws, but do not have especially large jaw adductors. Folivores probably can generate large bite forces; they possess short jaws (short bite load arms) and/or large jaw adductor cross-sectional areas. Frugivorous strepsirrhines are characterized by long jaws, large (but variable) ingested food size, large temporalis muscles, and small estimated bite force for their jaw length. Frugivores have long jaw adductor fibers that likely maintain tension during the ingestion of large objects (e.g., fruits). The temporalis is large in frugivores, not because it has superior leverage during incision, but because its fibers likely do not stretch as much at wide gapes as those of the other adductors. Correlations between osteological landmarks and jaw adductor dimensions in strepsirrhines were used to infer jaw adductor dimensions in <em>Adapis parisiensis</em> and <em>Leptadapis magnus</em> (Adapinae) from the Eocene of Europe. Inferred PCSA and lateral photographs were used to estimate bite force and leverage in these adapines. An analysis of shearing quotients was also performed. Inferred jaw adductor mass, PCSA, bite force, and shearing quotients are great in adapines relative to extant strepsirrhines. All anatomical signals suggest a diet rich in tough leaves and other structural plant parts, perhaps with some small fruits. <em>Adapis</em> was likely more folivorous than <em>Leptadapis</em>. / Dissertation

<p>Humans are more carnivorous than other hominoids. It has been hypothesized that, during the evolution of this increased carnivory, hominins transitioned through a scavenging niche made viable by certain carnivoran taxa (especially sabertooths) that may have lacked the morphology necessary to fully utilize all parts of carcasses (e.g., marrow), therefore leaving an open niche in the form of high-quality scavengable remains available for hominins. In this dissertation, I examine the postcanine dentition of modern carnivorans, using quantifications of occlusal radii of curvature and intercuspid notches, and study the correlation of this morphology with carcass-processing behavior. I use these correlations to deduce the carcass-processing capabilities of the Plio-Pleistocene carnivores of South Africa (a guild for which we have a good appreciation of taxonomic diversity, and that existed at an important time during the evolution of our lineage - possibly the time that we transitioned into that guild), and compare these results with those of previous studies that relied on more conventional morphological measures.</p><p>Both radius of curvature and intercuspid notch data do a good job of separating taxa by dietary category, revealing subtle patterns including possible differences in the carcass-processing abilities of fossil and modern members of some extant species. Other strong trends confirm that the "hunting-hyena," Chasmaporthetes, was probably a hypercarnivore, and not a durophage like its modern confamilial taxa. Somewhat surprisingly, results do not support the hypothesis that sabertooth felids were more hypercarnivorous than modern felids. Furthermore, though the sympatric hypercarnivorous taxa were more numerous, so to were the durophageous taxa, with one taxon, Pachycrocuta, probably exceeding the durophageous capabilities of modern durophages.</p><p>As such, this dissertation shows no evidence that members of the paleo-carnivore guild were capable of producing higher quality scavengable carcasses than are modern carnivorans, and thus, based on these analyses of fossil carnivorans, it does not appear that high-quality scavengable remains were more available in the Plio-Pleistocene than there are today. Therefore, though there is clear evidence from other sources that hominins did scavenge at least occasionally, this dissertation does not support the hypothesis that there was an open niche consisting of high-quality scavengable remains.</p> / Dissertation

<p>The specification of a single axon and multiple dendrites is the first observable event during neuronal morphogenesis and such structural specialization underlies neural connectivity and nervous system function. Numerous intracellular signaling components that are required for axon specification have been described but how such signaling paradigms are initiated by extracellular factor(s) within the embryonic milieu is poorly understood. Here, I describe how transforming growth factor-&beta; (TGF-&beta;), an embryonic morphogen that directs structural plasticity and growth in various cell types, initiates signaling pathways both in vivo and in vitro to fate naïve neurites into axons. Using conditional knockout strategies, I found that cortical neurons lacking the type II TGF-&beta; receptor (T&beta;R2) fail to initiate axons during development, and interestingly, fail to engage radial migration. In cultured neurons, exogenous TGF-&beta; is sufficient to direct the rapid growth and differentiation of an axon and genetic enhancement of receptor activity promotes the formation of multiple axons. The cellular polarization of receptor activity occurs through the interaction of the type-I TGF-&beta; receptor with Par6, a component of the axon-specifying Par3/Par6 polarity complex. Receptor distribution is restricted to axons, and downstream signaling events required for axon specification are triggered when Par6 is phosphorylated by T&beta;R2. Together, these results indicate that TGF-&beta; is the extrinsic cue for neuronal polarity in vivo and directs neuronal polarity by controlling Par6 activity and cellular migration during axon generation.</p> / Dissertation

Interleukin-2 (IL-2), an immunomodulatory cytokine first isolated from the immune system, plays an essential role in the maturation of T lymphocytes. This thesis focusses on the neuroanatomical features of IL-2 and IL-2 receptors in the central nervous system, the neuromodulatory role of IL-2 on hippocampal acetylcholine release, and possible intracellular signalling mechanisms following IL-2 receptor activation in the brain. / Using immunoautoradiography, IL-2-like immunoreactivities were observed in a selected pattern in the central nervous system, with particularly high densities seen in the hippocampal formation and the hypothalamus of the rodent brain. The cellular localisation of the immunostaining using immunohistochemical approaches reveals that this staining was seen most evidently on cell perikarya especially in areas of high labelling density. The distribution of IL-2 receptor binding sites using both in vitro receptor autoradiography and immunoautoradiography (anti-TAC antibody against the IL-2 receptor a chain) shows that IL-2 receptors are selectively distributed in the rodent brain, with the highest densities observed in the hippocampal formation and the hypothalamus, in accordance with the localisation of IL-2 peptide immunostaining. The postulated neuromodulatory role of IL-2 and IL-2 receptors in the hippocampus was investigated next focusing on cholinergic parameters (acetylcholine release) on the basis of previous results from our laboratory (Araujo et al., 1989). / The neuromodulatory effects of IL-2 on acetylcholine (ACh) release was investigated using in vitro rat brain slices superfusion. IL-2 exerted potent effects on hippocampal ACh release, acting as a potentiating agent at low (pM) concentrations, while inhibiting release at higher (low nM) concentrations. An inhibitory effect (10 nM IL-2) on ACh release was also observed in the frontal cortex, but not in the parietal cortex or the striatum. This action was not shared by other interleukins such as IL-6. Both the stimulatory and inhibitory effects of IL-2 in hippocampal ACh release were blocked by an anti-IL-2 receptor antibody (TAC), suggesting the requirement of a genuine IL-2 receptor for both effects. The potentiating, in contrast to the inhibitory effect, was insensitive to tetrodotoxin, suggesting a direct action (or in close proximity) of IL-2 on cholinergic terminals to stimulate hippocampal ACh release. The inhibitory effect of IL-2 on ACh release was abolished by both bicuculline and phaclofen, suggesting the involvement of GABA acting on both GABA$ sb{ rm A}$ and GABA$ sb{ rm B}$ receptors present in the rat hippocampal formation. / The signalling mechanisms of the IL-2 receptor in the rat brain was studied next in vitro by measuring the effects of IL-2 on cytidine-diphosphate diacylglycerol (CDP-DAG) turnover in rat brain slices. IL-2 potently inhibited basal CDP-DAG turnover in the frontal cortex and hypothalamus, but not in the hippocampus or striatum. However, IL-2 inhibited carbachol-stimulated CDP-DAG turnover in the hippocampus. This decrease was in parallel to an increase in choline production, suggesting a role for phospholipase D in brain IL-2 receptor signalling. (Abstract shortened by UMI.)