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Biomedical subjects

P G Sullivan

Publications and source records attributed to P G Sullivan.

At least 19 recordsLinked to original sources
PubMed2006

Multiple-trait multiple-country genetic evaluations for udder health traits.

International genetic bull evaluations of somatic cell counts (SCC) from 8 different Holstein populations and clinical mastitis from 3 of these populations were inferred simultaneously using a multiple-trait-multiple-country evaluation (MT-MACE) model. This model considered effective independent weighting factors and multivariately deregressed national genetic evaluations for countries with multiple-trait national models. Predictions of genetic merit from MT-MACE and their reliabilities were compared with the corresponding results from 2 separate single-trait-multiple-country evaluations (ST-MACE) for different groups of bulls. The assumed heritabilities for clinical mastitis (h(2) = 0.02 to 0.05) were substantially lower than the heritabilities for SCC (h(2) = 0.08 to 0.27). The predictive ability of MT-MACE was essentially equal to or better than the predictive ability of ST-MACE for all country-trait combinations, but both methods yielded effectively unbiased and consistent consecutive predictions (correlation > 0.93). Both sets of predictions also agreed well with future national genetic evaluations for bulls receiving additional daughter information (correlation > 0.96), except for evaluations for which within-country correlations were utilized internationally, but not nationally (correlation = 0.86 to 0.97). The reliabilities for MT-MACE were essentially equal to or higher than reliabilities for ST-MACE, depending on the trait and group of bulls in question. Reliabilities increased most for young bulls, and for clinical mastitis in countries that did not use the within-country correlations with SCC in the national evaluation (up to a 23% increase in average reliability).

Animals↗
PubMed2004

Mitochondrial uncoupling as a therapeutic target following neuronal injury.

Mitochondrial dysfunction is a prominent feature of excitotoxic insult and mitochondria are known to play a pivotal role in neuronal cell survival and death following injury. Following neuronal injury there is a well-documented increase in cytosolic Ca(2+), reactive oxygen species (ROS) production and oxidative damage. In vitro studies have demonstrated these events are dependent on mitochondrial Ca(2+) cycling and that a reduction in membrane potential is sufficient to reduce excitotoxic cell death. This concept has gained additional support from experiments demonstrating that the overexpression of endogenous mitochondrial uncoupling proteins (UCP), which decrease the mitochondrial membrane potential, decreases cell death following oxidative stress. Our group has demonstrated that upregulation of UCP activity can reduce excitotoxic-mediated ROS production and cell death whereas a reduction in UCP levels increases susceptibility to neuronal injury. These findings raise the possibility that mitochondrial uncoupling could be a potential novel treatment for acute CNS injuries.

Animals↗
PubMed2002

Mifepristone protects CA1 hippocampal neurons following traumatic brain injury in rat.

The present study addresses mineralocorticoid receptor and glucocorticoid receptor effects on hippocampal neuron viability after experimental traumatic brain injury. Rats were pretreated for 48 h with vehicle, the mineralocorticoid receptor antagonist spironolactone, or the glucocorticoid receptor antagonist mifepristone (RU486) and subsequently subjected to sham operation or unilateral controlled cortical impact injury. To determine the effects of receptor antagonist pretreatments on cell survival, neurons in regions CA1, CA3, and dentate gyrus of the hippocampal formation were counted 24 h post-injury using the optical fractionator method. Injury decreased the number of viable neurons in CA1 and CA3 of vehicle-pretreated animals. Notably, this cell loss was prevented in CA1 by RU486 pretreatment. Neuronal loss was also observed in dentate gyrus. The effects of receptor blockade and injury on the expression of viability-related genes were also assessed by comparing relative bcl-2, bax, and p53 messenger RNA levels using in situ hybridization analysis. Spironolactone and RU486 decreased basal bcl-2 messenger RNA levels in CA1 and dentate gyrus but did not affect basal bax or p53 levels. Injury decreased bcl-2 messenger RNA levels in dentate gyrus but did not affect bax or p53 levels in vehicle-pretreated animals. These data demonstrate that RU486 pretreatment prevents the loss of CA1 pyramidal neurons 24 h after traumatic brain injury. RU486 modulation of bcl-2, bax, or p53 messenger RNA expression does not predict neuronal viability at this time point, suggesting that RU486-mediated preservation of CA1 neurons does not involve transcriptional regulation of these cell death-related genes.

Animals↗
PubMed2001

Zn(2+) induces permeability transition pore opening and release of pro-apoptotic peptides from neuronal mitochondria.

Rapid entry of Ca(2+) or Zn(2+) kills neurons. Mitochondria are major sites of Ca(2+)-dependent toxicity. This study examines Zn(2+)-initiated mitochondrial cell death signaling. 10 nm Zn(2+) induced acute swelling of isolated mitochondria, which was much greater than that induced by higher Ca(2+) levels. Zn(2+) entry into mitochondria was dependent upon the Ca(2+) uniporter, and the consequent swelling resulted from opening of the mitochondrial permeability transition pore. Confocal imaging of intact neurons revealed entry of Zn(2+) (with Ca(2+)) to cause pronounced mitochondrial swelling, which was far greater than that induced by Ca(2+) entry alone. Further experiments compared the abilities of Zn(2+) and Ca(2+) to induce mitochondrial release of cytochrome c (Cyt-c) or apoptosis-inducing factor. In isolated mitochondria, 10 nm Zn(2+) exposures induced Cyt-c release. Induction of Zn(2+) entry into cortical neurons resulted in distinct increases in cytosolic Cyt-c immunolabeling and in cytosolic and nuclear apoptosis-inducing factor labeling within 60 min. In comparison, higher absolute [Ca(2+)](i) rises were less effective in inducing release of these factors. Addition of the mitochondrial permeability transition pore inhibitors cyclosporin A and bongkrekic acid decreased Zn(2+)-dependent release of the factors and attenuated neuronal cell death as assessed by trypan blue staining 5-6 h after the exposures.

Animals↗
PubMed2001

Cyclosporin A treatment following spinal cord injury to the rat: behavioral effects and stereological assessment of tissue sparing.

The immunosuppressant drug cyclosporin A (CsA) has significant neuroprotective properties following CNS injury. In the present study, we assessed the efficacy of CsA therapy following a moderate spinal cord injury (SCI). Adult female rats were injured with the NYU impactor from a height of 12.5 mm, and CsA or vehicle therapy was initiated 15 min after the injury. All animals were behaviorally tested with the BBB locomotor rating scale prior to morphological assessment of changes in the spinal cord. CsA therapy failed to significantly improve the behavioral recovery following the injury. Using a unique stereological approach to assess tissue damage, it was determined that CsA did not alter the amount of spared tissue. The possible neuroprotective effects of CsA, observed in other models of CNS injury, do not appear to influence SCI pathology, perhaps reflecting both anatomical and physiological differences between these distinct regions of the CNS.

Animals↗
PubMed2000

Continuous infusion of cyclosporin A postinjury significantly ameliorates cortical damage following traumatic brain injury.

Traumatic brain injury (TBI) results in the rapid necrosis of cortical tissue at the site of injury. In the ensuing hours and days, secondary injury exacerbates the original damage resulting in significant neurological dysfunction. Recent reports from our lab demonstrate that a bolus injection of the immunosuppressant cyclosporin A (CsA) is neuroprotective following TBI. CsA transiently inhibits the opening of the mitochondrial permeability transition pore and maintains calcium homeostasis in isolated mitochondria. The present study utilized a unilateral controlled cortical impact model of TBI to assess whether the neuroprotective effects of CsA could be extended by chronic infusion. Adult rats were subjected to a moderate (2 mm) cortical deformation and the extent of cortical damage was assessed using modern stereological techniques. Animals were administrated a 20 mg/kg intraperitoneal bolus of CsA or vehicle 15 min postinjury and osmotic minipumps were implanted subcutaneously to deliver CsA (4.5 or 10 mg/kg/day) or vehicle. All animals receiving CsA demonstrated a significant reduction in lesion volume, with the highest dose offering the most neuroprotection (74% reduction in lesion volume). These results extend our previous findings and demonstrate that chronic infusion of CsA is neuroprotective following TBI. These findings also suggest that the mechanisms responsible for tissue necrosis following TBI are amenable to manipulation.

Animals↗
PubMed2000

Cyclosporin ameliorates traumatic brain-injury-induced alterations of hippocampal synaptic plasticity.

Although traumatic brain injury (TBI) often results in impaired learning and memory functions, the underlying mechanisms are unknown and there are currently no treatments that can preserve such functions. We studied plasticity at CA3-CA1 synapses in hippocampal slices from rats subjected to controlled cortical impact TBI. Long-term potentiation (LTP) of synaptic transmission was markedly impaired, whereas long-term depression (LTD) was enhanced, 48 h following TBI when compared to unoperated and sham control rats. Post-TBI administration of cyclosporin A, a compound that stabilizes mitochondrial function, resulted in a highly significant amelioration of the impairment of LTP and completely prevented the enhancement of LTD. Our data suggest that alterations in hippocampal synaptic plasticity may be responsible for learning and memory deficits resulting from TBI and that agents such as cyclosporin A that stabilize mitochondrial function may be effective treatments for TBI.

Action Potentials↗
PubMed2000

Dose-response curve and optimal dosing regimen of cyclosporin A after traumatic brain injury in rats.

Acute neuropathology following experimental traumatic brain injury results in the rapid necrosis of cortical tissue at the site of injury. This primary injury is exacerbated in the ensuing hours and days via the progression of secondary injury mechanism(s) leading to significant neurological dysfunction. Recent evidence from our laboratory demonstrates that the immunosuppressant cyclosporin A significantly ameliorates cortical damage following traumatic brain injury. The present study extends the previous findings utilizing a unilateral controlled cortical impact model of traumatic brain injury in order to establish a dose-response curve and optimal dosing regimen of cyclosporin A. Following injury to adult rats, cyclosporin A was administrated at various dosages and the therapy was initiated at different times post-injury. In addition to examining the effect of cyclosporin A on the acute disruption of the blood-brain barrier following controlled cortical impact, we also assessed the efficacy of cyclosporin A to reduce tissue damage utilizing the fluid percussion model of traumatic brain injury. The findings demonstrate that the neuroprotection afforded by cyclosporin A is dose-dependent and that a therapeutic window exists up to 24h post-injury. Furthermore, the optimal cyclosporin dosage and regimen markedly reduces disruption of the blood-brain barrier acutely following a cortical contusion injury, and similarly affords significant neuroprotection following fluid percussion injury. These findings clearly suggest that the mechanisms responsible for tissue necrosis following traumatic brain injury are amenable to pharmacological intervention.

Animals↗
PubMed2000

Traumatic brain injury reduces hippocampal alpha7 nicotinic cholinergic receptor binding.

Changes in the expression of central nervous system (CNS) neurotransmitter receptors may contribute to behavioral and physiological deficits that occur following traumatic brain injury (TBI). Studies investigating the neurochemical basis for the protracted cognitive dysfunction that follows TBI have focused in part on cholinergic mechanisms. The present study compared the effects of mild and moderate cortical contusion injury (CCI) on the density of cholinergic receptor subtypes, NMDA-type glutamate receptors, and calcium channel expression. Quantitative autoradiography was used to determine the effects of CCI on receptor expression, 48 h following injury. The most robust and consistent change in receptor binding was in the density of alpha7 nicotinic receptors as determined by alpha-[125I]-bungarotoxin (BTX) binding. Bilateral deficits in BTX binding were present following both mild and moderate levels of injury. In contrast, changes in the density of alpha3/alpha4 nAChr's, muscarinic AChr's, NMDA-type glutamate receptors, and L-type calcium channel expression were more regionally restricted and lower in magnitude, as compared to changes in BTX binding. The high calcium permeability of the alpha7 nAChr may be related to the extensive decrease in BTX binding that occurs following TBI.

Animals↗
PubMed2000

Dietary supplement creatine protects against traumatic brain injury.

Creatine, one of the most common food supplements used by individuals at almost every level of athleticism, promote gains in performance, strength, and fat-free mass. Recent experimental findings have demonstrated that creatine affords significant neuroprotection against ischemic and oxidative insults. The present experiments investigated the possible effect of creatine dietary supplementation on brain tissue damage after experimental traumatic brain injury. Results demonstrate that chronic administration of creatine ameliorated the extent of cortical damage by as much as 36% in mice and 50% in rats. Protection seems to be related to creatine-induced maintenance of mitochondrial bioenergetics. Mitochondrial membrane potential was significantly increased, intramitochondrial levels of reactive oxygen species and calcium were significantly decreased, and adenosine triphosphate levels were maintained. Induction of mitochondrial permeability transition was significantly inhibited in animals fed creatine. This food supplement may provide clues to the mechanisms responsible for neuronal loss after traumatic brain injury and may find use as a neuroprotective agent against acute and delayed neurodegenerative processes.

Animals↗
PubMed1999

Exacerbation of damage and altered NF-kappaB activation in mice lacking tumor necrosis factor receptors after traumatic brain injury.

Tumor necrosis factor alpha (TNFalpha) is widely expressed in both neurons and glia and has been shown to be upregulated after traumatic brain injury (TBI). TNFalpha receptor activation results in activation of the transcription factor nuclear factor kappaB (NF-kappaB), which may serve an antiapoptotic role via the induction of target genes manganese superoxide dismutase (MnSOD) and/or calbindin. In the present study, we used a controlled cortical impact model of TBI with pertinent lines of transgenic mice to combine both morphological characterization and molecular analysis to elucidate the role of TNFalpha after TBI. Measurements of both the lesion volume and the blood-brain barrier breach indicated exacerbations in mice rendered genetically deficient in both the p55 and p75 TNFalpha receptors (TNFR-KO) compared with wild-type animals. Additionally, animals genetically altered to overexpress MnSOD showed a significant decrease in lesion volume compared with that of control littermates, whereas no alterations were observed in mice lacking the calcium-binding protein calbindin D28k. Analysis of NF-kappaB activation and relative levels of MnSOD revealed delayed responses in the injured cortex of TNFR-KO animals compared with wild-type animals, implying that endogenous TNFalpha may be neuroprotective after TBI.

Animals↗
PubMed1999

Cyclosporin A attenuates acute mitochondrial dysfunction following traumatic brain injury.

Experimental traumatic brain injury (TBI) results in a rapid and significant necrosis of cortical tissue at the site of injury. In the ensuring hours and days, secondary injury exacerbates the primary damage, resulting in significant neurological dysfunction. Recent reports from our lab and others have demonstrated that the immunosuppressant cyclosporin A (CsA) is neuroprotective following TBI. The opening of the mitochondrial permeability transition pore (MPTP) is inhibited by CsA, thereby maintaining the mitochondrial membrane potential and calcium homeostasis in isolated mitochondrial. In the present study we utilized a unilateral controlled cortical impact model of TBI to assess mitochondrial dysfunction in both isolated mitochondria and synaptosomes to elucidate the neuroprotective role of CsA. The results demonstrate that administration of CsA 15 min postinjury significantly attenuates mitochondrial dysfunction as measured using several biochemical assays of mitochondria integrity and energetics. Following TBI, mitochondria isolated from the injured cortex of animals treated with CsA demonstrate a significant increase in mitochondria membrane potential and are resistant to the induction of mitochondrial permeability transition compared to vehicle-treated animals. Similarly, synaptosomes isolated from CsA-treated animals demonstrate a significant increase in mitochondria membrane potential, accompanied by lower levels of intramitochondrial Ca2+ and reactive oxygen species production than seen in vehicle-treated animals. These results suggest that the neuroprotective properties of CsA are mediated through modulation of the MPTP and maintenance of mitochondria homeostasis. Amelioration of cortical damage with CsA indicates that pharmacological therapies can be devised which will significantly alter neurological outcome after injury.

Animals↗
PubMed1999

Cyclosporin A significantly ameliorates cortical damage following experimental traumatic brain injury in rodents.

Experimental traumatic brain injury (TBI) results in a rapid and significant necrosis of cortical tissue at the site of injury. In the ensuing hours and days, secondary injury exacerbates the original damage, resulting in significant neurological dysfunction. Young adult animals were treated either 5 min before or immediately after a cortical injury with the immunosuppressant cyclosporin A (CsA). All animals treated with CsA demonstrated a significant reduction in the amount of cortical damage 7 days following TBI. The effect was observed in adult rats and in two different strains of adult mice following systemic administration of the drug. Cyclosporin A has known effects on mitochondria by inhibiting the opening of the permeability transition pore and maintaining calcium homeostasis. These results with a clinically approved drug demonstrate an almost 50% reduction in lesion volume and suggest that the mechanisms responsible for tissue necrosis following TBI are amenable to manipulation. Since CsA also has known interactions with calcineurin and may be providing neuroprotection through that mechanism, additional animals were treated with the immunosuppressant FK 506. FK 506 failed to protect against the cortical damage. Amelioration of cortical damage with CsA indicates that pharmacological therapies can be devised that will significantly alter neurological outcome after injury.

Animals↗
PubMed1999

Genetic trends and breed overlap derived from multiple-breed genetic evaluations of beef cattle for growth traits.

Genetic evaluations for a multiple-breed population of beef cattle were used to estimate genetic trends for five breeds, and genetic differences and overlap among 14 breeds. Genetic evaluations studied were for direct contributions to birth weight, gain from birth to 200 and 365 d, and maternal contribution to gain from birth to 200 d. Almost all genetic trends were positive, but the magnitude of the trends varied among breeds. Trends were nonlinear between 1985 and 1995 for most breed and trait combinations. The rates of increase in genetic trends were generally higher for the lighter weight breeds, and lighter weight breeds had faster growth rate genetic trends at 1995 than the heavier breeds. Genetic trend estimates for yearling gain at 1995 were 2.46, 2.23, 1.73, 1.70, and 1.46 kg/yr for Angus, Hereford, Limousin, Charolais, and Simmental, respectively. Corresponding birth weight genetic trends were .130, .226, .049, .130, and .048 kg/yr. Mean genetic differences between breeds have been decreasing in magnitude due to these differences in genetic trends between heavier and lighter breeds. Genetic variation for the traits studied seemed to be greater within than between breeds for calves born and cows calving between 1993 and 1995. Genetic trends at 1995 suggest that ratios of within:between breed variation will increase and that across-breed genetic improvement initiatives for growth traits will become more important in the future.

Animals↗
PubMed1998

Traumatic brain injury alters synaptic homeostasis: implications for impaired mitochondrial and transport function.

This study utilized a unilateral controlled cortical impact model of traumatic brain injury to assess disruptions of synaptic homeostasis following trauma. Adult rats were subjected to a moderate (2 mm) cortical deformation and synaptosomes were prepared from the entire ipsilateral (injured) hemisphere or dissected into different regions (hippocampus, injured cortical area including penumbra, residual hemisphere) at various times postinjury (10 and 30 min, and 1, 6, and 24 h). Synaptosomes from the corresponding regions of the contralateral hemisphere were used as controls to assess alterations in synaptic ATP levels, lipid peroxidation, and glutamate and glucose transport. The results demonstrate significant time-dependent alterations in synaptic homeostasis, which included an immediate reduction in ATP levels, coupled with a significant increase in lipid peroxidation within 30 min postinjury. Lipid peroxidation demonstrated a biphasic response with elevations observed 24 h postinjury, a time at which decreases in glutamate and glucose transport occurred. These results suggest that disruption of synaptic homeostasis is an extremely early event following trauma that should be considered when designing pharmacological interventions.

Adenosine Triphosphate↗
PubMed1997

Neuronal cell loss in the CA3 subfield of the hippocampus following cortical contusion utilizing the optical disector method for cell counting.

Unilateral cortical contusion in the rat results in cell loss in both the cortex and hippocampus. Pharmacological intervention with growth factors or excitatory neurotransmitter antagonists may reduce cell loss and improve neurological outcome. The window of opportunity for such intervention remains unclear because a detailed temporal analysis of neuronal loss has not been performed in the rodent cortical contusion model. To elucidate the time course of hippocampal CA3 neuronal death ensuing cortical contusion, we employed the optical disector method for assessing the total number of CA3 neurons at 1 and 6 hours, 1, 2, 10, and 30 days following injury. This stereological technique allows reporting of total cell numbers within a given region and is unaffected by change in the volume of the structure or cell size. A rapid and significant reduction in neurons/mm3 in the ipsilateral CA3 field was observed by 1 h following trauma. However, a significant increase in neurons/mm3 was seen at 30 days postinjury. This surprising finding is a result of CA3 volume shrinkage and redistribution of CA3 neurons. Utilization of the optical disector reveals that regardless of an increase in neurons/mm3 at 30 days following injury, CA3 cell loss reaches 41% of control animals by 1 day posttrauma and remains near that level at all subsequent time points examined. It is estimated that there are about 156,000 neurons in the CA3 region in control animals. By 1 h following cortical contusion the cell population decreases to 93,000 neurons indicating a very rapid cell loss. This suggests a window of less than 24 h for pharmacological intervention in order to save CA3 neurons following cortical contusion.

Animals↗
PubMed1993

Characteristics of periodontal mechanoreceptors supplying cat canine teeth which have sustained orthodontic forces.

The characteristics of these mechanoreceptors were investigated after orthodontic forces had been applied for either 3 days or 12 weeks, and also 8 weeks after the tooth had been moved into a new position and the tissues allowed to recover. Electrophysiological recordings were made from single mechanosensitive units dissected from the inferior alveolar nerve and each was characterized by applying forces to the tooth crown. The characteristics were compared with those of receptors innervating normal teeth. Three days after the onset of tooth movement, the periodontal mechanoreceptors had higher thresholds to forces applied at slow rates and lower discharge frequencies. Twelve weeks after the onset of tooth movement, the mechanoreceptors again had higher force thresholds and lower discharge frequencies but also responded to applied forces over a narrower range of directions and adapted more rapidly than the controls. After the tooth had been moved into a new position and the tissues allowed to recover, the mechanoreceptor characteristics were nearer to normal but they still had raised thresholds to forces applied at slow rates, lower discharge frequencies, and responded to applied forces over a narrower range of directions. It seems likely that the altered receptor characteristics would have resulted from a combination of disorganization of the collagen matrix and direct injury to the nerve terminals.

Action Potentials↗