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Biomedical subjects

D M Hodgson

Publications and source records attributed to D M Hodgson.

At least 19 recordsLinked to original sources
PubMed2003

Bacterial enterotoxins are associated with resistance to colon cancer.

One half million patients suffer from colorectal cancer in industrialized nations, yet this disease exhibits a low incidence in under-developed countries. This geographic imbalance suggests an environmental contribution to the resistance of endemic populations to intestinal neoplasia. A common epidemiological characteristic of these colon cancer-spared regions is the prevalence of enterotoxigenic bacteria associated with diarrheal disease. Here, a bacterial heat-stable enterotoxin was demonstrated to suppress colon cancer cell proliferation by a guanylyl cyclase C-mediated signaling cascade. The heat-stable enterotoxin suppressed proliferation by increasing intracellular cGMP, an effect mimicked by the cell-permeant analog 8-br-cGMP. The antiproliferative effects of the enterotoxin and 8-br-cGMP were reversed by L-cis-diltiazem, a cyclic nucleotide-gated channel inhibitor, as well as by removal of extracellular Ca(2+), or chelation of intracellular Ca(2+). In fact, both the enterotoxin and 8-br-cGMP induced an L-cis-diltiazem-sensitive conductance, promoting Ca(2+) influx and inhibition of DNA synthesis in colon cancer cells. Induction of this previously unrecognized antiproliferative signaling pathway by bacterial enterotoxin could contribute to the resistance of endemic populations to intestinal neoplasia, and offers a paradigm for targeted prevention and therapy of primary and metastatic colorectal cancer.

Bacterial Toxins↗
PubMed2001

Intracerebroventricular interleukin-1beta impairs clearance of tumor cells from the lungs: role of brain prostaglandins.

We have previously demonstrated that central administration of interleukin (IL)-1beta suppresses natural killer (NK) cell activity, impairs NK-mediated lung clearance of tumor cells, and enhances tumor colonization. The central pathways activated by IL-1beta are as yet unknown. Using an in vivo model of tumor colonization, this study examined the role of central noradrenergic, opioid and prostaglandin mechanisms in mediating the effect of IL-1beta on lung clearance of tumor cells. We demonstrate that central noradrenergic and opioid systems are not critically involved in this effect. Neither depletion of central noradrenergic pathways, or administration of the opioid antagonist, naltrexone (50 ug), blocked the impaired lung clearance of MADB106 tumor cells induced by central administration of IL-1beta (20 ng). Central prostaglandins (PGs) do, however, appear to play a critical role. Central administration of the prostaglandin antagonist, diclofenac (250 ug), but not ibuprofen, completely blocked the effect of IL-1beta on lung clearance of tumor cells. Antagonism of the effects of IL-1beta was shown to be due to the effects of centrally and not of peripherally acting prostaglandins.

Adenocarcinoma↗
PubMed2001

Neonatal endotoxin exposure influences HPA responsivity and impairs tumor immunity in Fischer 344 rats in adulthood.

Recent research in rodents has demonstrated that exposure to bacterial endotoxin during the neonatal period alters the development of the hypothalamic-pituitary-adrenal axis resulting in hypersecretion of corticosterone after stress-exposure in adulthood. Given the known interactions between glucocorticoids and the immune system it was hypothesized that such alterations may impact on immune outcomes. Fischer 344 rats were treated with endotoxin (50 microg/kg Salmonella enteritidis, i.p.) or the vehicle on postpartum d 1, 3, 5, and 7. In adulthood, animals were subjected to chronic stress (6 x 10 h/d restraint stress), and the effect on resistance to tumor colonization (experiment 1) and natural killer cell activity (experiment 2) was assessed. Experiment 3 assessed corticosterone responses to acute stress in adulthood after neonatal endotoxin or saline treatment. Neonatal endotoxin exposure resulted in a 2-fold increase in tumor colonization (p < 0.001) and a significant impairment in the activity of natural killer cells (p < 0.01), cells critically involved in the surveillance and eradication of tumor cells. Neonatal endotoxin exposure also resulted in a significant decrease in gain weight that persisted into adulthood (p < 0.05), and potentiation of corticosterone responses to acute stress in adulthood (p < 0.05). We conclude that neonatal endotoxin exposure produces long-term changes in the hypothalamic-pituitary-adrenal axis, and has significant long-term effects on immune function, specifically in terms of resistance to tumor colonization in adulthood.

Adenocarcinoma↗
PubMed1999

Intracerebral interleukin-1beta impairs response to tumor invasion: involvement of adrenal catecholamines.

Interleukin-1beta (IL-1beta) is released within the brain following stress, trauma, infection, and in specific brain disorders. This centrally acting IL-1beta has recently been shown to impair peripheral immunity. Central administration of IL-1beta suppresses natural killer (NK) cell activity impairs lung clearance of tumor cells and enhances tumor colonization. Using an in vivo model of tumor colonization (lung clearance of NK-sensitive MADB106 adenocarcinoma cells), this study examined the role of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) in mediating these effects. We demonstrate that adrenalectomy significantly attenuated the impaired lung clearance of MADB106 tumor cells induced by intracerebroventricular (i.c.v.) administration of IL-1beta (20 ng). Supplementing adrenalectomized animals with corticosterone did not reinstate the effect. The effect of IL-1beta on lung clearance was blocked by pretreatment with the beta-adrenergic antagonist, nadolol (0.5 mg/kg), but not by the alpha-antagonist phentolamine (5 mg/kg). Peripheral noradrenergic pathways are not implicated given that systemic administration of the noradrenergic neurotoxin, 6-hydroxydopamine, did not block the effect of IL-1beta. Taken together, these findings indicate that IL-1beta impairs lung clearance of MADB106 tumor cells via the actions of adrenal catecholamines, most likely epinephrine, acting at beta-adrenergic receptors in the periphery.

Adrenal Glands↗
PubMed1999

Lysosphingomyelin prevents behavioral aberrations and hippocampal neuron loss induced by the metabotropic glutamate receptor agonist quisqualate.

1. Excessive excitation of brain neurons by the excitatory neurotransmitter, glutamate, induces a cascade of events leading to increased intracellular Ca++, neuronal degeneration and death. 2. Recent in vitro research has demonstrated that a natural cationic amphiphile in the brain, lysosphingomyelin, may be able to prevent neuronal degeneration by repressing phosphosinositidase-C overactivation induced by excessive excitation of the metabotropic glutamate receptor. 3. This research tested the latter finding in vivo in a rat model of glutamate excitotoxicity. Intracerebroventricular (i.c.v.) administration of the Group 1 metabotropic glutamate receptor (mGluR) agonist, quisqualate, produced seizures, akinesia, destruction of hippocampal pyramidal cell dendritic microtubule-associated protein-2, and major loss of hippocampal CA sector neurons. 4. Prophylactic i.c.v. infusion of lysosphingomyelin powerfully attenuates these quisqualate-induced behaviors and prevents neuronal degeneration. 5. Lysosphingomyelin may be of clinical use in allaying progressive Group 1 mGluR-induced hippocampal cognitive and motor disorders including Alzheimer's disease, brain seizure, and stroke.

Animals↗
PubMed1999

Clozapine in community practice: a 3-year follow-up study in the Australian Capital Territory.

OBJECTIVE: This paper aims to present the first data on the long-term use of clozapine in an entire cohort of patients encountered in a community, the Australian Capital Territory. It examines the clinical and financial outcomes 3 years after the prescription of clozapine to a cohort of 37 patients. METHOD: Experience during the 2 years before clozapine was prescribed was compared with experience in the following 3 years on the basis of a retrospective review of official records. Data included hospital and hostel bed use and an estimate of treatment costs. In addition, changes in living circumstances and employment status were assessed and treating psychiatrists reported the presence of side effects and their impressions of clinical change since clozapine was prescribed. RESULTS: Compared with the preclozapine period, there were significant reductions postclozapine in hospital admissions (year 3) and hospital bed-days (year 2) by the total cohort and in hospital bed-days and hospital expenditure for those patients (n = 25) who remained on clozapine (years 2 and 3). There was no significant increase or decrease postclozapine in the estimated combined cost of treatment attributable to bed use (hospital or hostel), clozapine tablets, blood monitoring, and the employment of a Clozapine Coordinator. Clinically, all patients who stayed on clozapine were reported to be moderately or markedly improved. Five of nine patients who were not taking clozapine at study's end were unimproved or deteriorated. CONCLUSIONS: The findings of significant clinical improvement without evidence of increased cost lend support for the selective use of clozapine in community practice.

Adult↗
PubMed1998

Psychosine blocks quisqualate-induced glutamate excitotoxicity in hippocampal CA sector neurons.

Quisqualate is a potent specific agonist for Group 1 metabotropic glutamate receptors (mGluR's), that activate G protein-coupled phospholipase C (PLC) in a molecular signal-transduction mechanism that raises cytoplasmic Ca2+ and, when excessive, damages hippocampal neurons. Psychosine (beta-galactosylsphingosine), a cationic lysosphingolipid occurring naturally in nervous tissues, dose-dependently inhibited PLC activation induced by metabotropic alpha 1-adrenergic receptor signaling in cultured rat brain astrocytes in vitro. In the present study, we have tested neuroprotective efficacy of psychosine in vivo, in a rat model of glutamate excitotoxicity induced by intracerebroventricular (i.c.v.) administration of quisqualate. A sublethal i.c.v. dose of quisqualate caused episodes of prolonged akinesia and convulsions, and major damage to pyramidal neurons of the hippocampal CA1 and CA3 sector, but not to granule cell neurons of the dentate gyrus. Prior infusion of psychosine greatly attenuated quisqualate-induced behaviors, and fully prevented destruction by quisqualate of vulnerable hippocampal neurons. Psychosine may prove useful in prophylaxis of neurodegenerative disorders that arise from intensive hippocampal Group 1 mGluR stimulation.

Animals↗
PubMed1998

Intracerebral HIV glycoprotein (gp120) enhances tumor metastasis via centrally released interleukin-1.

Infection with the human immunodeficiency virus (HIV) is associated with a high incidence of cancers. This relationship does not appear to be due to a direct effect of the virus, and may be mediated by neuroimmune interactions since the HIV glycoprotein, gp120, enters the brain soon after infection with HIV, and intracerebroventricular (i.c.v.) infusion of gp120 suppresses aspects of cellular and tumor immunity. It has been speculated that this suppression may be attributed to the release of interleukin-1 (IL-1) in the brain induced by gp120. Using an in vivo tumor model, we examined the effect of centrally administered gp120 on tumor metastasis and lung clearance of mammary adenocarcinoma (MADB106) tumor cells in rats, and the role played by brain IL-1 in mediating these effects. We demonstrate that central administration of gp120 (4 microg) significantly (p<0.05) increased the retention of tumor cells in the lungs and significantly (p<0.02) enhanced the development of tumor metastases. Central administration of IL-1beta (10 ng) also significantly (p<0.05) increased retention of tumor cells in the lungs. The effect of gp120 on lung retention of tumor cells was blocked by co-administration of alpha-melanocyte stimulating hormone (alpha-MSH, 20 ng), a hormone that blocks many of the biological effects of IL-1, or the IL-1 receptor antagonist (50 microg). Given that systemic administration of gp120 or IL-1beta had no effect on the retention of tumor cells in the lungs, these findings indicate that gp120-induced secretion of IL-1 within the brain most likely mediates the effects of gp120 on tumor metastasis. These findings suggest a possible neuroimmune mechanism to account for the increased incidence and aggressiveness of tumors in HIV-infected patients.

Adenocarcinoma↗
PubMed1997

Effect of biphasic waveforms on transvenous defibrillation thresholds in patients with coronary artery disease.

This study is a prospective, randomized comparison of monophasic and biphasic defibrillation thresholds in 19 patients with a single transvenous lead. Despite using reverse polarity and optimal tilts for the monophasic waveform, the defibrillation threshold was reduced with biphasic shocks from 15.8 +/- 11.3 to 11.5 +/- 6.1 (p <0.05) with comparable reductions of leading edge voltage and current.

Aged↗
PubMed1997

Chronic dietary restriction influences tumor metastasis in the rat: parametric considerations.

Chronic dietary restriction is a well-documented means of inhibiting tumor growth. This study examines the effects of chronic dietary restriction on tumor metastasis in the rat. We investigate the effect of 1) the degree of food restriction, 2) the effect of preexposure to food restriction, and 3) the duration of food restriction after tumor inoculation on tumor metastasis. We also compare two methods of dietary restriction: 1) the time that food is available and 2) the amount of food available. Our findings demonstrate that rats restricted to 50% of ad libitum diet for one week before inoculation with MADB106 tumor cells and for three weeks after inoculation exhibit a significant (p < 0.001) reduction in lung colonization compared with animals fed ad libitum. Animals restricted to access to food for 4 hrs/day (60% of ad libitum) for the same period of time exhibit significantly (p < 0.005) greater lung tumor colonization than animals fed ad libitum. Preadaptation to the feeding regimen for one week before tumor inoculation proved to be critical in inhibiting tumor metastasis. The tumor-inhibitory effect was not significantly influenced by the duration of restriction after inoculation or by the manner in which food restriction was implemented. Finally, we demonstrate that inhibition of tumor colonization may be mediated by enhanced natural killer cell activity in the early postinoculation period.

Adenocarcinoma↗
PubMed1996

Microinjection of thyrotropin-releasing hormone analogue into the central nucleus of the amygdala stimulates gastric contractility in rats.

The effect on gastric contractility following bilateral microinjection of thyrotropin-releasing hormone (TRH) analog, RX 77368, into the central nucleus of the amygdala was examined in fasted, urethane-anesthetized rats. Extraluminal force transducers were used to measure gastric corpus contractility. Bilateral microinjection of RX 77368 (0.5 microgram, 1.0 microgram, n = 6 each) stimulated gastric contractility for up to 120 min post-injection, P < 0.05. Gastric contractility was not significantly stimulated by microinjection of 0.1 microgram RX 77368, 0.1% bovine serum albumin (BSA) into the central nucleus or RX 77368 (0.5 microgram, 1.0 microgram) into sites adjacent to the central nucleus. Peak responses (1.0 microgram) occurred 40 min post-injection and represented a 16-26-fold increase over basal values. The frequency of gastric contraction waves was attenuated for 0-90 min in rats receiving central amygdaloid microinjection of RX 77368 (0.1, 0.5 or 1.0 microgram) versus rats microinjected with the vehicle or RX 77368 into sites adjacent to the central nuclei. The stimulatory effect of RX 77368 (1.0 microgram) on gastric contractility was abolished by subdiaphragmatic vagotomy. These results indicate that the TRH analog, RX 77368, acts within the central amygdala to vagally stimulate gastric contractility.

Amygdala↗
PubMed1996

Development of fetal movement--fetal heart rate coupling from 20 weeks through term.

This study documents the development of fetal heart rate (FHR) change in response to fetal movement (FM) in healthy fetuses from 20 weeks' gestational age through term. Thirty-one fetuses received 50 min of Doppler-based monitoring at 20, 24, 28, 32, 36 and 38-39 weeks. FHR and FM were continuously digitized. A coupling index was computed as the percentage of FMs associated with increases in FHR of 5 beats/min or more within -5 or +15 s of movement onset. The latency between FM onset and FHR change was also computed, as were the amplitude and duration of all movements. FM and FHR became more integrated with advancing gestation. Coupling increased and the latency between FM and FHR changes decreased. Maternal age, blood pressure and fetal sex did not affect FM-FHR coupling, but fetuses of women who reported greater stress in their daily lives and had faster heart rates displayed reduced coupling. These data suggest that the development of FM-FHR coupling reflects the development of the central nervous system during gestation, and that development may be affected by maternal factors.

Adult↗
PubMed1996

The role of hypophyseal and adrenal mechanisms in the hypoalgesic response to non-contingent food delivery in the rat.

Exposure to non-contingent food delivery has been shown to elicit an increase in nociceptive thresholds in rats. This hypoalgesia has previously been shown to be reversible by the opiate antagonist naloxone. Given that most opioid forms of SIA are found to rely on an intact pituitary-adrenal axis, this research examined the possibility that the hypoalgesic response to non-contingent food delivery is also hormonally mediated. Hypophysectomy (Expt. 1) but not bilateral adrenalectomy (Expt. 2) was found to completely attenuate the hypoalgesic response to non-contingent food delivery. Preliminary data from ongoing research is presented that points to the possible involvement of the hypophyseal peptides beta-endorphin and adrenocorticotropin hormone (ACTH).

Adrenalectomy↗