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Biomedical subjects

J P O'Callaghan

Publications and source records attributed to J P O'Callaghan.

At least 19 recordsLinked to original sources
PubMed2006

A threshold neurotoxic amphetamine exposure inhibits parietal cortex expression of synaptic plasticity-related genes.

Compulsive drug abuse has been conceptualized as a behavioral state where behavioral stimuli override normal decision making. Clinical studies of methamphetamine users have detailed decision making changes and imaging studies have found altered metabolism and activation in the parietal cortex. To examine the molecular effects of amphetamine (AMPH) on the parietal cortex, gene expression responses to amphetamine challenge (7.5 mg/kg) were examined in the parietal cortex of rats pretreated for nine days with either saline, non-neurotoxic amphetamine, or neurotoxic AMPH dosing regimens. The neurotoxic AMPH exposure [three doses of 7.5 mg/kg/day AMPH (6 h between doses), for nine days] produced histological signs of neurotoxicity in the parietal cortex while a non-neurotoxic dosing regimen (2.0 mg/kg/day x 3) did not. Neurotoxic AMPH pretreatment resulted in significantly diminished AMPH challenge-induced mRNA increases of activity-regulated cytoskeletal protein (ARC), nerve growth-factor inducible protein A (NGFI-A), and nerve growth-factor inducible protein B (NGFI-B) in the parietal cortex while neither saline pretreatment nor non-neurotoxic AMPH pretreatment did. This effect was specific to these genes as tissue plasminogen activator (t-PA), neuropeptide Y (NPY) and c-jun expression in response to AMPH challenge was unaltered or enhanced by amphetamine pretreatments. In the striatum, there were no differences between saline, neurotoxic AMPH, and non-neurotoxic AMPH pretreatments on ARC, NGFI-A or NGFI-B expression elicited by the AMPH challenge. These data indicate that the responsiveness of synaptic plasticity-related genes is sensitive to disruption specifically in the parietal cortex by threshold neurotoxic AMPH exposures.

Amphetamine↗
PubMed2006

Health effects of subchronic exposure to diesel-water-methanol emulsion emission.

The U.S. Environmental Protection Agency's National Ambient Air Quality Standards for ozone and particulate matter (PM) require urban non-attainment areas to implement pollution-reduction strategies for anthropogenic source emissions. The type of fuel shown to decrease combustion emissions components versus traditional diesel fuel, is the diesel emulsion. The Lubrizol Corporation, in conjunction with Lovelace Respiratory Research Institute and several subcontracting laboratories, recently conducted a health assessment of the combustion emissions of PuriNOx diesel fuel emulsion (diesel-water-methanol) in rodents. Combustion emissions from either of two, 2002 model Cummins 5.9L ISB engines, were diluted with charcoal-filtered air to exposure concentrations of 125, 250 and 500 microg total PM/m3. The engines were operated on a continuous, repeating, heavy-duty certification cycle (U.S. Code of Federal Regulations, Title 40, Chapter I) using Rotella-T 15W-40 engine oil. Nitrogen oxide (NO) and PM were reduced when engines were operated on PuriNOx versus California Air Resources Board diesel fuel under these conditions. Male and female F344 rats were housed in Hazleton H2000 exposure chambers and exposed to exhaust atmospheres 6 h/day, five days/week for the first 11 weeks and seven days/week thereafter. Exposures ranged from 61 to 73 days depending on the treatment group. Indicators of general toxicity (body weight, organ weight, clinical pathology and histopathology), neurotoxicity (glial fibrillary acidic protein assay), genotoxicity (Ames assay, micronucleus, sister chromatid exchange), and reproduction and development were measured. Overall, effects observed were mild. Emulsion combustion emissions were not associated with neurotoxicity, reproductive/developmental toxicity, or in vivo genotoxicity. Small decreases in serum cholesterol in the 500-microg/m3 exposure group were observed. PM accumulation within alveolar macrophages was evident in all exposure groups. The latter findings are consistent with normal physiological responses to particle inhalation. Other statistically significant effects were present in some measured parameters of other exposed groups, but were not clearly attributed to emissions exposure. Positive mutagenic responses in several strains of Salmonella typhimurium were observed subsequent to treatment with emulsion emissions subfractions. Based on the cholesterol results, it can be concluded that the 250-microg/m3 exposure level was the no observed effect level. In general, biological findings in exposed rats and bacteria were consistent with exposure to petroleum diesel exhaust in the F344 rat and Ames assays.

Administration, Inhalation↗
PubMed2005

Aging, stress and the hippocampus.

Functional loss often occurs in many body systems (e.g., endocrine, cognitive, motor) with the passage of years, but there is great individual variation in the degree of compromise shown. The current focus on brain aging will continue because demographic trends indicate that the average lifespan will show a continued increase. There is increasing emphasis on understanding how aging contributes to a decline in brain functions, cognition being a prime example. This is due in part to the fact that dementias and other losses in brain function that sometimes accompany aging cause an obvious decline in the quality of life and these deficits are of more concern as the number of elderly increase. Stress also is a ubiquitous aspect of life and there is now a greater interest in understanding the role of stress and the stress response in brain aging. The key role of the hippocampus and its related brain structures in cognition, as well as in the feedback control of the response to stress, have made this brain area a logical focus of investigation for those interested in the impact of stress on brain aging. Here, we describe how the hippocampus changes with age and we examine the idea that age-related changes in the secretion patterns of the hypothalamic-pituitary adrenal (HPA) axis can contribute to aging of this structure. We also examine the proposal that stress, perhaps due to compromised HPA axis function, can contribute to hippocampal aging through exposure to excessive levels of glucocorticoids. The aging hippocampus does not appear to suffer a generalized loss of cells or synapses, although atrophy of the structure may occur in humans. Thus, age-related cognitive impairments are likely related to other neurobiological alterations that could include changes in the signaling, information encoding, plasticity, electrophysiological or neurochemical properties of neurons or glia. Although excessive levels of glucocorticoids are able to interfere with cognition, as well as hippocampal neuronal integrity, and aging is sometimes accompanied by an increase in these steroids because of inadequate feedback control of the HPA axis, none of these are a foregone consequence of aging. The general preservation of cells and the plastic potential of the hippocampus provide a focus for the development of pharmacological, nutritive or lifestyle strategies to combat age-related declines in the hippocampus as well as other brain areas.

Aging↗
PubMed2003

Effects of aging and stress on hippocampal structure and function.

Aging is often simply defined as the decline in various body systems and functions (eg, endocrine, cognitive, motor, etc) that occur with the passage of time, although the degree of deterioration can vary greatly across individuals. Increases in average life span have brought a greater focus on brain aging. There is an emphasis on understanding how aging contributes to a decline in brain functions (eg, cognition) because such a decline adversely affects the quality of life. The hippocampus is a key brain structure for cognition and the feedback control of the stress response. Herein we describe how the hippocampus changes with age and we examine the idea that age-related changes in the secretory patterns of the hypothalamic-pituitary adrenal (HPA) axis can contribute to hippocampal aging. We also examine the proposal that cumulative stress, perhaps due to compromised HPA axis function, can contribute to hippocampal aging by subjecting it to exposure to excessive levels of glucocorticoids. The aging hippocampus does not appear to suffer a generalized loss of cells or synapses, although atrophy of the structure may occur in humans. Thus, age-related cognitive impairments are likely related to other neurobiological alterations that could include changes in the signaling, information encoding, and plastic, electrophysiological, or neurochemical properties of neurons or glia. Dysfunction of the HPA axis sometimes occurs with aging, and while excessive glucocorticoids can disrupt cognition as well as hippocampal neuronal integrity, these are not an inevitable consequence of aging. The general preservation of cells and the plastic potential of the hippocampus provide a focus for the development of pharmacological, nutritional, or life-style strategies to combat age-related declines.

Aging↗
PubMed2003

Quantification of regional glial fibrillary acidic protein levels in Alzheimer's disease.

OBJECTIVES: Our objectives were to quantify glial fibrillary acidic protein (GFAP) in brains of Alzheimer's disease (AD) cases, and non-AD controls to determine the regions with the most severe gliosis in AD. MATERIAL AND METHODS: In a case control design, we used an enzyme-linked immunosorbent assay (ELISA) to quantify GFAP in frozen brain from four areas of neocortex in 10 AD cases, 10 age-matched controls, and 10 younger controls from the Honolulu-Asia Aging Study autopsy archive. RESULTS: Median age at death was 83.5 years for cases and age-matched controls, and 77 years for younger controls. For the AD cases compared with the age-matched controls, levels of GFAP in occipital (P=0.01), parietal (P=0.028), and temporal lobes (P=0.004) (but not frontal) were significantly higher in the cases. The median GFAP excess in AD cases compared with age matched controls was highest in the temporal lobe. CONCLUSIONS: Regional quantification of GFAP reveals that the glial response is most prominent in the temporal lobe in AD.

Aged↗
PubMed2002

Obesity exacerbates chemically induced neurodegeneration.

Obesity is a major risk factor associated with a variety of human disorders. While its involvement in disorders such as diabetes, coronary heart disease and cancer have been well characterized, it remains to be determined if obesity has a detrimental effect on the nervous system. To address this issue we determined whether obesity serves as a risk factor for neurotoxicity. Model neurotoxicants, methamphetamine (METH) and kainic acid (KA), which are known to cause selective neurodegeneration of anatomically distinct areas of the brain, were evaluated using an animal model of obesity, the ob/ob mouse. Administration of METH and KA resulted in mortality among ob/ob mice but not among their lean littermates. While METH caused dopaminergic nerve terminal degeneration as indicated by decreased striatal dopamine (49%) and tyrosine hydroxylase protein (68%), as well as an increase in glial fibrillary acidic protein by 313% in the lean mice, these effects were exacerbated under the obese condition (96%, 86% and 602%, respectively). Similarly, a dosage of KA that did not increase glial fibrillary acidic protein in lean mice increased the hippocampal content of this protein (93%) in ob/ob mice. KA treatment resulted in extensive neuronal degeneration as determined by Fluoro-Jade B staining, decreased hippocampal microtubule-associated protein-2 immunoreactivity and increased reactive gliosis in ob/ob mice. The neurotoxic outcome in ob/ob mice remained exacerbated even when lean and ob/ob mice were dosed with METH or KA based only on a lean body mass. Administration of METH or KA resulted in up-regulation of the mitochondrial uncoupling protein-2 to a greater extent in the ob/ob mice, an effect known to reduce ATP yield and facilitate oxidative stress and mitochondrial dysfunction. These events may underlie the enhanced neurotoxicity seen in the obese mice. In summary, our results implicate obesity as a risk factor associated with chemical- and possibly disease-induced neurodegeneration.

Animals↗
PubMed2002

Chemically induced neuronal damage and gliosis: enhanced expression of the proinflammatory chemokine, monocyte chemoattractant protein (MCP)-1, without a corresponding increase in proinflammatory cytokines(1).

Enhanced expression of proinflammatory cytokines and chemokines has long been linked to neuronal and glial responses to brain injury. Indeed, inflammation in the brain has been associated with damage that stems from conditions as diverse as infection, multiple sclerosis, trauma, and excitotoxicity. In many of these brain injuries, disruption of the blood-brain barrier (BBB) may allow entry of blood-borne factors that contribute to, or serve as the basis of, brain inflammatory responses. Administration of trimethyltin (TMT) to the rat results in loss of hippocampal neurons and an ensuing gliosis without BBB compromise. We used the TMT damage model to discover the proinflammatory cytokines and chemokines that are expressed in response to neuronal injury. TMT caused pyramidal cell damage within 3 days and a substantial loss of these neurons by 21 days post dosing. Marked microglial activation and astrogliosis were evident over the same time period. The BBB remained intact despite the presence of multiple indicators of TMT-induced neuropathology. TMT caused large increases in whole hippocampal-derived monocyte chemoattractant protein (MCP)-1 mRNA (1,000%) by day 3 and in MCP-1 (300%) by day 7. The mRNA levels for tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6, cytokines normally expressed during the earliest stage of inflammation, were not increased up to 21 days post dosing. Lipopolysaccharide, used as a positive control, caused large inductions of cytokine mRNA in liver, as well as an increase in IL-1beta in hippocampus, but it did not result in the induction of astrogliosis. The data suggest that enhanced expression of the proinflammatory cytokines, TNF-alpha, IL-1beta and IL-6, is not required for neuronal and glial responses to injury and that MCP-1 may serve a signaling function in the damaged CNS that is distinct from its role in proinflammatory events.

Animals↗
PubMed2001

Phenobarbital and dizocilpine can block methamphetamine-induced neurotoxicity in mice by mechanisms that are independent of thermoregulation.

Body temperature profiles observed during methamphetamine (METH) exposure are known to affect dopamine and tyrosine hydroxylase (TH) levels in the striatum of mice; hyperthermia potentiates depletion while hypothermia is protective against depletions. In the current study, the doses of METH were sufficiently great that significant dopamine and TH depletions occurred even though hypothermia occurred. Four doses, administered at 2 h intervals, of 15 mg/kg (4x15 mg/kg) D-METH significantly decreased TH and dopamine levels to 50% of control in mice becoming hypothermic during dosing in a 13 degrees C environment. Phenobarbital or dizocilpine during METH exposure blocked the depletions while diazepam did not. Phenobarbital and dizocilpine did not block depletions by altering the hypothermic profiles from that observed during METH only exposure. Here we show that phenobarbital and dizocilpine can block measures of METH neurotoxicity by non-thermoregulatory mechanisms.

Animals↗
PubMed2001

Phosphorylation of protein phosphatase inhibitor-1 by Cdk5.

Protein phosphatase inhibitor-1 is a prototypical mediator of cross-talk between protein kinases and protein phosphatases. Activation of cAMP-dependent protein kinase results in phosphorylation of inhibitor-1 at Thr-35, converting it into a potent inhibitor of protein phosphatase-1. Here we report that inhibitor-1 is phosphorylated in vitro at Ser-67 by the proline-directed kinases, Cdk1, Cdk5, and mitogen-activated protein kinase. By using phosphorylation state-specific antibodies and selective protein kinase inhibitors, Cdk5 was found to be the only kinase that phosphorylates inhibitor-1 at Ser-67 in intact striatal brain tissue. In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. The state of phosphorylation of inhibitor-1 at Ser-67 was dynamically regulated in striatal tissue by glutamate-dependent regulation of N-methyl-d-aspartic acid-type channels. Phosphorylation of Ser-67 did not convert inhibitor-1 into an inhibitor of protein phosphatase-1. However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation.

Animals↗
PubMed2001

Surgical and radiological significance of variants of Bühler's anastomotic artery: a report of three cases.

Arterial anastomoses between the celiac trunk (CT) and superior mesenteric artery (SMA) include three variants. 1) The main anastomosis is the gastroduodenal artery (GDA), which is an important branch of the common hepatic artery and anastomoses with branches of the inferior pancreatic duodenal artery, a branch of the SMA. 2) The dorsal pancreatic artery (DPA) is usually a branch of the splenic artery, which anastomoses with the anterior and posterior pancreaticoduodenal arcades via a right transverse branch of the DPA (Kirk's arcade). 3) A less well known and rarely reported arterial anastomosis between the CT and SMA described by Buhler (1904). Three patients in whom variants of this anastomosis were present on retrospective analysis of three hundred consecutive combined CT and SMA arteriograms are reported. The embryological basis of its development, the surgical and radiological significance of the anastomotic artery are discussed.

Abdominal Pain↗
PubMed2001

Evolution of a rational use of opioids in chronic pain.

Since the isolation of morphine from opium by Serturner in 1806, morphine, which Osler referred to as "God's own medicine", has remained the analgesic of choice for the treatment of severe pain despite its known addictive potential and the attempts to replace it with synthetic or semi-synthetic medications. Its early use was based on clinical experience alone until the identification of the opioid receptors and endogenous opioids 25 years ago. Advances in pharmacology and pharmacokinetics and the development of precision equipment to quantify the parent drugs and their metabolites in plasma have provided a better understanding of the mechanisms of action as well as adverse effects. Clinicians can now select the drug and route of administration to suit the patient's needs. The objective of care now is for clinical observation to be reinforced by randomized controlled trials and evidence-based medicine, but controlled clinical trials are lacking for the use of opioids in chronic pain.

Analgesics, Opioid↗
PubMed2001

The detection of central nervous system tissue on beef carcasses and in comminuted beef.

We report the development and validation of a fluorescent enzyme-linked immunosorbent assay (ELISA) for glial fibrillary acidic protein (GFAP), which can be used as a rapid and sensitive method to detect CNS tissue in meat products. The fluorometric assay is sensitive to 0.2 ng GFAP and has an intra-assay coefficient of variation (CV) of 2.0% and an interassay CV of 14.1%. Bovine spinal cord and brain demonstrate dose-response curves that are parallel to GFAP standards, whereas peripheral sciatic nerve and cervical ganglia also cross-react at high tissue levels. The use of another central nervous system marker, syntaxin 1-B, was not effective for neural tissue detection. Less than 1.0 ng GFAP per mg tissue was found on most beef subprimals and advanced meat recovery (AMR) product. Occasional samples contained higher levels of GFAP, probably because of contamination by the carcass-splitting saw, incomplete removal of the spinal cord, or a chance sampling of a major nerve. Further reduction of CNS content was facilitated by removal of the cervical vertebrae and the spinal canal prior to processing beef chuck bones through AMR equipment. The presence of GFAP was very low (0.037 ng/mg) in beef patties collected from major processors throughout the USA. The presence of normal sausage ingredients or heating the product to 80 degrees C for 60 min did not affect the detection of GFAP. Heating the product to 115 degrees C for 100 min eliminated the detectability of GFAP.

Animals↗
PubMed2000

Expression of fos-related antigen-2 in rat hippocampus after middle cerebral arterial occlusion.

AP-1 transcription factors have been shown to be induced in the brain after ischemic injury. However, their roles in neuronal survival or death have yet to be defined. Here, we report the discovery of elevated nuclear levels of fos-related antigen-2 (FRA-2) in the nuclei of hippocampal neurons seven days after middle cerebral artery occlusion (MCAO). Expression of FRA-2 and AP-1 DNA binding activity is elevated in hippocampi ipsilateral as well as contralateral to MCAO. Using Fluoro-Jade staining as a marker of neurodegeneration, FRA-2 was not found to be expressed in degenerating neurons. Thus, FRA-2 is expressed in neurons that survive ischemic insult suggesting a role for this transcription factor in neuronal adaptation to the post-injury state.

Animals↗
PubMed2000

Comparative study of fluoxetine, sibutramine, sertraline and dexfenfluramine on the morphology of serotonergic nerve terminals using serotonin immunohistochemistry.

We compared the effects of treatment with high doses of fluoxetine, sibutramine, sertraline, and dexfenfluramine for 4 days on brain serotonergic nerve terminals in rats. Methylenedioxymethamphetamine (MDMA) and 5,7-dihydroxytryptamine (5,7-DHT) were used as positive controls because both compounds deplete brain serotonin. Food intake and body weight changes were also monitored and yoked, pair-fed animals were used to control for possible changes in morphology due to nutritional deficits. Fluoxetine, sibutramine, sertraline and dexfenfluramine all produced a significant reduction in body weight. Fluoxetine, sibutramine and sertraline treatment resulted in no depletion of brain serotonin but produced morphological abnormalities in the serotonergic immunoreactive nerve network. In contrast, dexfenfluramine and MDMA depleted brain serotonin and produced morphological changes in the serotonin nerve network. These results indicate that even though fluoxetine, sibutramine and sertraline do not deplete brain serotonin, they do produce morphological changes in several brain regions (as identified by serotonin immunohistochemistry). Dexfenfluramine and MDMA, on the other hand, markedly deplete brain serotonin and also produce morphological changes. Collectively, these results lend support to the concept that all compounds acting on brain serotonin systems, whether capable of producing serotonin depletion or not, could produce similar effects on the morphology of cerebral serotonin systems.

Animals↗
PubMed2000

Requirement for DARPP-32 in progesterone-facilitated sexual receptivity in female rats and mice.

DARPP-32, a dopamine- and adenosine 3',5'-monophosphate (cAMP)-regulated phosphoprotein (32 kilodaltons in size), is an obligate intermediate in progesterone (P)-facilitated sexual receptivity in female rats and mice. The facilitative effect of P on sexual receptivity in female rats was blocked by antisense oligonucleotides to DARPP-32. Homozygous mice carrying a null mutation for the DARPP-32 gene exhibited minimal levels of P-facilitated sexual receptivity when compared to their wild-type littermates. P significantly increased hypothalamic cAMP levels and cAMP-dependent protein kinase activity. These increases were not inhibited by a D1 subclass dopamine receptor antagonist. P also enhanced phosphorylation of DARPP-32 on threonine 34 in the hypothalamus of mice. DARPP-32 activation is thus an obligatory step in progestin receptor regulation of sexual receptivity in rats and mice.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2000

Long-term induction of Fos-related antigen-2 after methamphetamine-, methylenedioxymethamphetamine-, 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine- and trimethyltin-induced brain injury.

A long-term induction of Fos-related antigens has been shown in neurons after brain injury, suggesting that Fos-related antigens are involved in enhancing the transcription of genes related to the process of regeneration and repair. In the present study, we report that levels of Fos-related antigen-2 are elevated in several models of chemically induced brain injury. Trimethyltin, which causes degeneration of neurons primarily in the hippocampus and other limbic regions, results in a five-fold induction of Fos-related antigen-2 immunoreactivity in neurons in the pyramidal and dentate layers of the hippocampus starting at seven days post-treatment and persisting for 60days. Methamphetamine and methylenedioxymethamphetamine, agents which cause degeneration of dopaminergic nerve terminals in the striatum of the mouse, cause an increase in Fos-related antigen-2 immunoreactivity which begins at three days post-treatment and returns to basal levels by days 5 and 15, respectively. Treatment with 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine elevated levels of Fos-related antigen-2 in the mouse striatum at three days post-treatment. This abbreviated time-course of Fos-related antigen-2 induction is consistent with less severe insult (terminal damage) relative to trimethyltin (cell death), but induction occurs during the period of regeneration and repair in both models. Dexfenfluramine, a non-neurotoxic amphetamine, does not induce Fos-related antigen-2 expression. Decreasing core temperature of the mouse, which blocks amphetamine-induced neurotoxicity, also blocks Fos-related antigen-2 induction. In summary, Fos-related antigen-2 is induced in models of both cell death and terminal degeneration, suggesting that this transcription factor may serve as a universal signal transduction molecule involved in the regulation of genes related to regeneration and repair in the CNS.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2000

The diagnostic yield of intravenous urography.

BACKGROUND: Intravenous urography (IVU) is considered an integral imaging component of the nephro-urological work-up in a wide array of clinical settings. At our institution there is an open-access policy with regard to requesting IVU studies. METHODS: In a prospective, blinded observational study we undertook to assess the diagnostic yield of IVU with respect to the source of referral (i.e. Urology, Nephrology, GP, A & E, other speciality) and the presenting features, such as renal colic, haematuria, bladder outflow obstruction, recurrent urinary tract infection (UTI) etc. Two hundred consecutive patients were evaluated. RESULTS: Overall, 23% of tests were positive. There was a highly significant difference in diagnostic yield between the groups (P<0.001 for both referral source and test indication). A positive result was most likely after referral by a kidney specialist (37.1%) and when the test indication was renal colic (42%) or haematuria (32%). The yield was <15% in all other circumstances, with 94.9% and 92.1% of GP- and other hospital speciality-initiated IVUs being negative. When investigating recurrent UTI, 91.7% of tests were negative and 86.2% were negative when the indication was bladder outflow obstruction. CONCLUSIONS: It is suggested that an open access policy for IVU is not justified, especially when cost and the risk associated with contrast media and radiation exposure are taken into account. Our study supports the abandonment of routine IVU in the investigation of UTI and bladder outflow obstruction.

Adolescent↗