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Biomedical subjects

D J Connor

Publications and source records attributed to D J Connor.

At least 19 recordsLinked to original sources
PubMed2006

Circulating cholesterol levels, apolipoprotein E genotype and dementia severity influence the benefit of atorvastatin treatment in Alzheimer's disease: results of the Alzheimer's Disease Cholesterol-Lowering Treatment (ADCLT) trial.

CONTEXT: Recent evidence suggests that treatment of mild-to-moderate Alzheimer's disease (AD) with atorvastatin provides significant benefit on the Alzheimer Disease Assessment Scale-Cognitive (ADAS-cog) after 6 months. OBJECTIVE: To determine if benefit on ADAS-cog performance produced by atorvastatin is influenced by severity of cognitive impairment, circulating cholesterol levels, or apolipoprotein E genotype. DESIGN: A double-blind, placebo-controlled, randomized (1:1) trial with a 1-year exposure to atorvastatin calcium or placebo. SETTING: A single-site study at the clinical research center of the Sun Health Research Institute. PARTICIPANTS: Ninety-eight individuals with mild-to-moderate AD (MMSE score of 12-28) provided informed consent, and 67 were randomized. Stable dose use of cholinesterase inhibitors, estrogen and vitamin E was allowed, as was the use of many other medications in the treatment of co-morbidities. Participants using cholesterol-lowering medications or being treated for major depression or a psychiatric condition were excluded. INTERVENTION: Once daily atorvastatin calcium (80 mg; two 40 mg tablets) or placebo. MAIN OUTCOME MEASURES: A primary outcome measure was change ADAS-cog sub-scale score. Secondary outcome measures included scores on the MMSE, and circulating cholesterol levels. The Apolipoprotein E genotype was established for each participant. RESULTS: A significant positive effect on ADAS-cog performance occurred after 6 months of atorvastatin therapy compared with placebo. This positive effect was more prominent among individuals entering the trial with, (i) higher MMSE scores, (ii) cholesterol levels above 200 mg/dl or (iii) if they harbored an apolipoprotein-E-4 allele compared with participants not responding to atorvastatin treatment. Individuals in the placebo group tended to experience more pronounced deterioration if their cholesterol levels exceeded 200 mg/dl or they harbored an apolipoprotein-E-4 allele. CONCLUSION: Atorvastatin therapy may be of benefit in the treatment of mild-to-moderately affected AD patients, but the level of benefit produced may be predicated on earlier treatment, an individual's apolipoprotein E genotype or whether the patient exhibits elevated cholesterol levels.

Aged↗
PubMed2006

Bochdalek hernia in a soldier.

Congenital diaphragmatic hernias are most often seen in infants. They may rarely be discovered in adulthood. This case report describes the management of a soldier presenting with acute bowel obstruction and respiratory embarrassment in a military hospital. The surgical repair was achieved with a laparotomy. Effective epidural analgesia and early physiotherapy were axiomatic of his uncomplicated post-operative course.

Diaphragmatic Eventration↗
PubMed2002

HMG-CoA reductase inhibitors (statins) in the treatment of Alzheimer's disease and why it would be ill-advise to use one that crosses the blood-brain barrier.

Increased circulating cholesterol has been long linked to an increased risk of coronary artery disease (CAD), and is now linked to an increased risk of developing Alzheimer s disease (AD). We first showed the neuropathologic link between CAD and AD as increased incidence of cerebral senile plaques in both disorders. We then showed that AD-like neuropathology occurred in the brains of cholesterol-fed rabbits; including increased -amyloid (Ab). Currently there are a number of transgenic mouse models of AD that exhibit enhanced Ab pathology if cholesterol diet is administered. Culture studies clearly show that excess cholesterol enhances beta-metabolism of amyloid precursor protein (APP) and production of -amyloidogenic peptides, and that sufficiently reducing cholesterol levels by inhibition of synthesis completely inhibits all beta-metabolism of APP. Our finding that the elevated levels of Ab in rabbits fed cholesterol diet could be cleared from the brain by resuming a control diet prompted the hypothesis that lowering cholesterol levels in the blood of AD patients may be of some clinical benefit. Pilot data suggests that therapeutically lowering circulating cholesterol may attenuate Ab production in the cholesterol-fed rabbit brain, may stabilize cognitive performance in mildly impaired AD patients, and may reduce the risk of developing AD. Accordingly, we have initiated a double-blind treatment trial evaluating Atorvastatin Na+ among 120 mild-to-moderately impaired AD subjects randomized to one of two groups receiving placebo or active drug once a day. Atorvastatin is one of a general class of HMG-CoA reductase inhibitor drugs called statins that lower cholesterol by inhibition of synthesis. We chose to use Atorvastatin in this AD Treatment Trial because it does not cross the blood-brain-barrier, and believe it would be ill-advised to use a statin that does. This position stems from the observations that excess cholesterol inhibits cholesterol synthesis and increases Ab production, that Ab kills cells in part by inhibiting cholesterol synthesis, and that statins acting at the neuronal level could further exacerbate degeneration in AD by further inhibition of necessary cholesterol synthesis.

Clinical Trial↗
PubMed2001

Tec 6 vaporiser.

Explore the source record for details and available documents.

Anesthesia, General↗
PubMed1998

Cognitive profiles of autopsy-confirmed Lewy body variant vs pure Alzheimer disease.

OBJECTIVE: To compare the cognitive profiles of patients with autopsy-confirmed Alzheimer disease (AD), with or without concomitant Lewy bodies, on 2 dementia screening measures. METHODS: Profiles on subtests of the Mattis Dementia Rating Scale (range, 105-125) and of component items of the Mini-Mental State Examination were compared between 23 patients with uncomplicated AD and 23 patients with concomitant AD and Lewy body pathology (Lewy body variant [LBV]). RESULTS: Although the groups did not differ significantly regarding age, years of education, total Mini-Mental State Examination score, or total Mattis Dementia Rating Scale score, the AD group performed significantly worse than the LBV group on the Mattis Dementia Rating Scale Memory subscale (P < .005). In contrast, the LBV group demonstrated poorer performance than the pure AD group on the Initiation/Perseveration subscale (P < .02). The groups did not differ significantly on the Attention, Construction, or Conceptualization subscales. The same overall pattern of results was obtained when subgroups with mild to moderate and moderate to severe dementia were examined separately, with the additional finding that in the mild-to-moderate range patients with dementia and LBV performed worse than patients with pure AD on the Construction subscale. CONCLUSIONS: The difference in pattern of cognitive deficits among patients with pure AD vs those with AD and LBV is similar to that seen between AD and more subcortical/frontal dementias (eg, Huntington disease) This suggests that the concomitant Lewy body pathology significantly contributes to the presentation of the cognitive dysfunction in individuals with LBV.

Aged↗
PubMed1993

Comparison of the effects of single and combined neurotoxic lesions of the nucleus basalis magnocellularis and dorsal noradrenergic bundle on learning and memory in the rat.

Groups of rats received bilateral destruction of either the nucleus basalis magnocellularis (NBM) by infusion of ibotenic acid, the dorsal noradrenergic bundle (DNB) by infusion of 6-hydroxydopamine, or both NBM + DNB (COMB). These lesion groups along with sham operated controls were trained on a food reinforced spatial delayed conditional discrimination task in a T-maze. All four groups were able to attain a criterion of 85% correct responses despite significant group differences in the number of trials to criterion and number of correct responses during training. Performance of the DNB and NBM groups on acquisition trials was significantly lower than controls, significantly higher than the COMB group, but not significantly different from each other. When tested at delays of 30-300 s, all groups demonstrated parallel rates of decline in performance. On reversal learning trials, the NBM and COMB groups were significantly impaired, whereas the performance of the DNB group was better than controls. No significant interaction between the DNB and NBM lesions was observed on any of the behavioral measures. Biochemical analyses demonstrated significant reductions of choline acetyltransferase (ChAT) activity in cortex but not hippocampus of the NBM and COMB groups, and a significant reduction of norepinephrine (NE) in cortex and hippocampus of the DNB and COMB but not the NBM group. The concentration of other monoamine and amino acid neurotransmitters in the lesion groups were unchanged from controls. These results suggest that DNB and NBM lesions produce separate and independent cognitive impairments that do not severely disrupt retention of trial independent (reference memory) and trial dependent (working memory) information on this T-maze task.

Amino Acids↗
PubMed1993

An analysis of sap flow in mountain ash (Eucalyptus regnans) forests of different age.

Diurnal measurements of sap velocity were made in 50-, 90-, 150- and 230-year-old mountain ash (Eucalyptus regnans F. Muell.) forests in the North Maroondah catchment (southeast Australia) over the periods January 8, 1990 to April 4, 1990 and October 29, 1990 to April 16, 1991. Over the two periods, daily mean sap velocities for the four forests, in order of increasing age, were 11.5, 11.4, 9.9 and 11.8 cm h(-1) respectively. Daily mean sap velocity did not differ significantly among the 50-, 90- and 230-year-old plots. However, in the 150-year-old trees it was significantly smaller by an average of 14%. Sap velocity varied diurnally and also between positions within individual trees and among trees both within and between stands. Despite this variability, the sampling intensity and duration were sufficient to establish that behavior was highly correlated among individuals within plots. There was a significant decline with age in the overstory sapwood conducting area of these forests. In order of increasing age, the values were 6.7, 6.1, 4.2 and 4.0 m(-2) ha(-1), respectively. When combined with daily mean sap velocity, these data allowed the calculation of overstory water use. Over the experimental period, water use of the overstory decreased with age ranging, on average, from 1.86 mm day(-1) for the 50-year-old plot to 0.81 mm day(-1) for the 230-year-old plot. Mean daily water use for the two intermediate-aged forests was 1.67 and 1.00 mm day(-1), respectively. Annual water use decreased with forest age from 679 mm for the 50-year-old stand to 296 mm for the 230-year-old stand. This difference corresponds to 3.8 x 10(3) m(3) ha(-1). The annual water use of the intermediate-aged stands was 610 and 365 mm for the 90- and 150-year-old stands, respectively.

Journal Article↗
PubMed1992

Behavioral effects of concurrent lesions of the nucleus basalis magnocellularis and the dorsal noradrenergic bundle.

The effects of separate and concurrent lesions to the cholinergic and noradrenergic (NE) systems were assessed in two water mazes. Lesion of the nucleus basalis magnocellularis (NBM) decreased performance in a spatial memory task (Morris water maze) while lesions of the dorsal NE bundle (DNB) enhanced the acquisition of this task independent of the NBM effects. Both lesions impaired performance on a water-escape motivated T-maze; however, the deficits induced by the combined lesion did not differ from the effects of either lesion alone. Neither lesion, nor their combination, had significant effects on open field activity. Biochemical analyses revealed almost total loss of NE in the cortex and hippocampus after DNB lesion, with relatively minor changes in other catecholamines or metabolites. Choline acetyltransferase activity was not significantly altered by the DNB lesion but was decreased in the cortex by the NBM lesion. These results suggest a task-specific effect of DNB lesion that is detectable under conditions of mild stress when floor effects are minimized.

Analysis of Variance↗
PubMed1992

Hippocampal phosphoinositide turnover is altered by hippocampal sympathetic ingrowth and cholinergic denervation.

Cholinergic denervation of the hippocampus, by medial septal (MS) lesions, results in an unusual neuronal rearrangement in which peripheral sympathetic nerves, which originate from the superior cervical ganglia, grow into the hippocampal formation. To assess the functional significance of hippocampal sympathetic ingrowth (HSI), hydrolysis of phosphoinositides was examined in three groups: control, MS lesions + sham ganglionectomy (HSI group); and MS lesions + ganglionectomy (MSGx; no ingrowth). Four months after surgery, both norepinephrine (NE) and carbachol were found to produce a dose-dependent increase in the hydrolysis of hippocampal phosphoinositides in all groups. However, the presence of HSI, when compared to control and MSGx groups, significantly enhanced the turnover of phosphoinositides when stimulated by carbachol, but not NE. In further studies, the time course of this effect was studied. One week after surgery, carbachol-stimulated phosphoinositide turnover was equivalent among all groups; by 2 weeks, phosphoinositide turnover was enhanced in the HSI and MSGx group; by 4 weeks, PI turnover was markedly diminished in the MSGx group when compared to both the HSI and control groups, which were equivalent to each other. To ensure that the ganglionectomy alone did not alter phosphoinositide turnover, a ganglionectomy-alone group was studied at the 4-week time point. In this group, phosphoinositide turnover was equivalent to controls, suggesting no influence of the superior cervical ganglia on this response. In all groups, atropine inhibited carbachol-stimulated phosphoinositide turnover. These results suggest that both cholinergic denervation (i.e., MSGx group) and HSI produce marked functional alterations in hippocampal metabolic activity.

Animals↗
PubMed1992

Independent effects of age and nucleus basalis magnocellularis lesion: maze learning, cortical neurochemistry, and morphometry.

The effects of age and lesion of the cholinergic nucleus basalis magnocellularis (NBm) were assessed behaviorally, morphologically, and biochemically. Groups consisted of rats lesioned 1 month before testing, rats lesioned 13 months before testing, and their respective age-matched controls. Both age and lesion independently induced behavioral deficits in performance on two water maze tasks. The combined effect of these two factors produced behavioral deficits equal to the sum of the individual impairments. NBm lesion produced a 28% decrease in anterior cortical choline acetyltransferase activity and a 20% decrease in synaptophysin immunoreactivity in the neocortex that was stable over a 12-month period. Neither neuritic plaque nor neurofibrillary-tanglelike structures were found in the brains of 18-month-old control rats, nor were they found in NBm-lesioned rats examined 15 months postlesion. There was an age-related decrease in homovanillic acid levels in both control and NBm groups, which suggests a decrease in dopamine turnover. These results show a lack of biochemical and behavioral recovery after NBm lesion and suggest that the effects of age on behavior are independent of NBm-cortical dysfunction.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Behavioral impairments after lesions of the nucleus basalis by ibotenic acid and quisqualic acid.

Ibotenic acid (IBO) or quisqualic acid (QUIS) was infused into the region of the nucleus basalis magnocellularis (NBm) in F344 rats in order to behaviorally and biochemically characterize the effects of these two neurotoxins. QUIS infusion resulted in a slightly higher depletion of choline acetyltransferase (ChAT) activity in both anterior and posterior regions of cortex than did lesions caused by infusion of IBO. Both QUIS- and IBO-treated rats demonstrated significantly longer latencies than controls to find a hidden platform in a Morris water maze task. In addition, QUIS-treated rats performed significantly better than IBO-treated rats in the water maze. Analysis of swim speed and open field behavior did not show significant differences in general motor activity. Passive avoidance retention was unaffected by either neurotoxin. Cortical amino acid levels, [3H]neurotensin binding, dopamine, norepinephrine, and serotonin levels were unaffected by either neurotoxin. The levels of HVA and 5-HIAA in the IBO and QUIS groups were significantly reduced compared to controls, but were not significantly different from each other. Histological examination showed greater damage to non-NBm structures with IBO than with QUIS, including the basolateral nucleus of the amygdala and the reticular formation of the thalamus. The greater behavioral deficit seen after IBO lesions may be due to damage to other areas rather than differences in the extent of depletion of corticai ChAT, amino acids, catecholamines or indolamines.

Amino Acids↗
PubMed1991

The role of cholinergic projections from the nucleus basalis in memory.

The behavioral effects of lesions of the nucleus basalis magnocellularis (NBM) are reviewed, focusing on the anatomical extent of the lesion, the involvement of neurotransmitter systems and the alterations in memory processes. Most behavioral deficits after NBM lesions can be attributed to damage to the NBM itself, although during spontaneous or pharmacologically induced recovery, other brain structures might play a role. The neurochemical deficit underlying the behavioral impairments is most likely the decrease in cholinergic functioning, since, for example, enhancement of cholinergic functioning is sufficient for behavioral improvement. However, since the lesions are not specific for cholinergic neurons, the extent to which noncholinergic damage causes behavioral deficits is still unclear. Finally, lesions of the NBM impair memory, but affect also other behavioral processes, such as discrimination and habituation. A common process underlying these various impairments could be that of insufficiently focused processing of stimuli.

Animals↗
PubMed1989

Reversal of an aluminum-induced behavioral deficit by administration of deferoxamine.

Administration of aluminum sulfate in the drinking water of male Sprague-Dawley rats for 30 days resulted in a reduction in the number of days to reach extinction criterion on a passive avoidance task (38% control level). The behavioral deficit was not due to nonspecific effects caused by lower fluid consumption. Partial reversal of the deficit was produced by discontinuing aluminum treatment 2 weeks prior to testing (p less than .05). Injection of the aluminum chelator deferoxamine returned the performance of the aluminum-treated animals to control levels in a dose-dependent manner but had no effect on control animals. No differences in open-field activity were evident across groups. These results indicate that the behavioral impairment is a specific, reversible, toxic effect of the aluminum administration.

Alum Compounds↗
PubMed1989

Continuous physostigmine infusion in rats with excitotoxic lesions of the nucleus basalis magnocellularis: effects on performance in the water maze task and cortical cholinergic markers.

Acute peripheral administration of physostigmine inhibits cortical acetylcholinesterase (AChE) for about 1 hr in the rat and improves performance on learning and memory paradigms after excitotoxic lesions of the nucleus basalis magnocellularis (NBM) in rats. This study examined the effects of continuous systemic infusion of physostigmine using osmotic minipumps. One week of continuous physostigmine infusion in normal animals inhibited cortical AChE activity in a dose-dependent manner. Doses causing near maximal (0.06 mg/kg/hr) and ED50 (0.0075 mg/kg/hr) inhibition of cortical AChE activity were used to determine the effects of continuous physostigmine administration on spatial learning in the water maze in rats with bilateral ibotenic acid lesions of the NBM. Physostigmine had no effect on the acquisition of the maze task but prevented the retention deficit measured in untreated NBM-lesioned rats. Physostigmine treatment also improved the search strategy during the spatial probe trial compared to the untreated NBM-lesioned rats. The two doses of physostigmine examined did not produce differential responses on behavioral measures. Although NBM lesions significantly depleted cortical AChE activity, physostigmine treatment reduced the activity further in a dose-dependent manner. Whereas neither the lesion nor the low dose of physostigmine altered cortical receptor binding, the higher dose of physostigmine significantly down-regulated cortical muscarinic receptor binding by 28%. These data demonstrate that enhancement of acetylcholine neurotransmission can improve memory loss and spatial strategy associated with excitotoxic NBM lesions.

Acetylcholinesterase↗
PubMed1988

Chronic, oral aluminum administration to rats: cognition and cholinergic parameters.

Administration of aluminum sulfate in the drinking water of male Sprague-Dawley rats for thirty days resulted in an impairment of both consolidation and extinction of a passive avoidance task. No impairment of performance was observed on an active avoidance task, radial arm maze or open field activity measure. Biochemical analysis indicated a slight (less than 10%) but significant increase in hippocampal muscarinic receptor number after aluminum treatment as determined by tritiated quinuclidinyl benzilate (3H-QNB) binding. No changes were found in choline acetyltransferase (ChAT) activity, phosphoinositide hydrolysis, 3H-QNB binding in the cortex or tritiated pirenzepine (3H-PZ) binding in the hippocampus or cortex. These results indicate that cholinergic degeneration was not the cause of the observed cognitive impairments.

Administration, Oral↗
PubMed1986

Increased acetylcholine synthesis and release in brains of cats with GM1 gangliosidosis.

Cholinergic processes were measured in motor cortex, hippocampus, and striatum of cats in the terminal stages of GM1 gangliosidosis and compared to those of control cats. The greatest difference observed was elevation in the rate of K+-stimulated release of acetylcholine (ACh) from brain slices prepared from affected cats. The K+-stimulated release of endogenous ACh was increased by 31-43% and of newly synthesized ACh by 19-80% in brain slices from different brain regions. All regions that were examined were affected but the greatest effects occurred in cortex. The rate of synthesis of ACh was elevated in cortical and hippocampal slices. Choline acetyltransferase activity in brain regions of cats with GM1 gangliosidosis was not significantly different from that in controls, whereas high-affinity choline transport in cortical synaptosomes was elevated. Muscarinic receptor binding sites were reduced in the cortex, hippocampus, and striatum of GM1 mutant cats, whereas the apparent affinity was not altered. These results indicate that there are major alterations of cholinergic function in the brains of cats with GM1 gangliosidosis.

Acetylcholine↗
PubMed1983

Cefonicid concentrations in serum and atrial tissue during open-heart surgery.

Cefonicid was administered intramuscularly 1 h before open-heart surgery to seven patients in doses of 1 g each and to six patients in doses of 2 g each. Cefonicid concentrations were measured in the right atrial biopsy and in serum at onset of surgery, at time of atrial biopsy, 15 min after starting cardiopulmonary bypass, and at completion of cardiopulmonary bypass. Concentrations in the atrial biopsy and in serum at all periods exceeded the minimal inhibitory concentrations for organisms most frequently responsible for postoperative infections.

Aged↗