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Biomedical subjects

D Dewar

Publications and source records attributed to D Dewar.

At least 19 recordsLinked to original sources
PubMed2006

Eleven-year survival from an intra-dermal melanoma.

Stage IV metastatic malignant melanoma of unknown primary (TxNxM1a) is known to have a poor prognosis. However, some patients suffering from cutaneous disease originally thought to represent metastasis have fared much better than expected. We report a patient who has survived 11 years following such a diagnosis. Due to the prolonged survival and absence of an identified primary, it is unlikely that the lesion was metastatic but may represent one of a number of other possibilities. A small number of similar cases in the literature suggest a need for awareness of this unusual group of patients.

Adult↗
PubMed2006

Alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid-mediated excitotoxic axonal damage is attenuated in the absence of myelin proteolipid protein.

In vivo and in vitro studies have shown that alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-receptor-mediated excitotoxicity causes cytoskeletal damage to axons. AMPA/kainate receptors are present on oligodendrocytes and myelin, but currently there is no evidence to suggest that axon cylinders contain AMPA receptors. Proteolipid protein (PLP) and DM20 are integral membrane proteins expressed by CNS oligodendrocytes and located in compact myelin. Humans and mice lacking normal PLP/DM20 develop axonal swellings and degeneration, suggesting that local interactions between axons and the oligodendrocyte/myelin unit are important for the normal functioning of axons and that PLP/DM20 is involved in this process. To determine whether perturbed glial-axonal interaction affects AMPA-receptor-mediated axonal damage, AMPA (1.5 nmol) was injected into the caudate nucleus of anesthetized Plp knockout and wild-type male mice (n = 13). Twenty-four hours later, axonal damage was detected by using neurofilament 200 (NF 200) immunohistochemistry and neuronal damage detected via histology. AMPA-induced axonal damage, assessed with NF 200 immunohistochemistry, was significantly reduced in Plp knockout mice compared with wild-type mice (P = 0.015). There was no significant difference in the levels of neuronal perikaryal damage between the Plp knockout and wild-type mice. In addition, there was no significant difference in the levels of glutamate receptor subunits GluR1-4 or KA2 in Plp knockout compared with wild-type littermates. The present study suggests that PLP-mediated interactions among oligodendrocytes, myelin, and axons may be involved in AMPA-mediated axonal damage.

Animals↗
PubMed2001

White matter damage following systemic injection of the mitochondrial inhibitor 3-nitropropionic acid in rat.

Oxidative stress has been implicated as a pathogenic mediator of neuronal perikarya cell death. Axons and oligodendrocytes, components of white matter, could also be vulnerable to oxidative damage. An experimental model of oxidative stress was induced by systemic injection of 3-nitropropionic acid (3-NPA). Animals received an i.p. injection of 10, 15, 20 or 30 mg/kg 3-NPA or vehicle and were killed 24 h later. 3-NPA produced a concentration-dependent increase in axonal pathology within the striatum reflected by the amount of beta-APP and SNAP-25 accumulation. Axonal damage was anatomically coincident with the neuronal lesion. There was no neuronal or axonal damage in the subcortical white matter or cerebral cortex in any of the animals treated with 3-NPA. Manganese superoxide dismutase (Mn-SOD) immunoreactivity was present in the vehicle and all 3-NPA treated groups. The amount of Mn-SOD cellular staining was concentration-dependently increased within the striatum supporting a role for oxidative stress in the mechanism of 3-NPA neurotoxicity. Oligodendrocyte-like cells within the subcortical white matter were immunopositive for calpain-mediated spectrin breakdown products and increased in a concentration-dependent manner. Therefore in this experimental model, mitochondrial inhibition may lead to the initiation of oxidative stress and calpain activation, which could mediate cytoskeletal breakdown in axons and oligodendrocytes suggesting an interaction between at least two pathogenic mechanisms.

Amyloid beta-Protein Precursor↗
PubMed2001

APC I1307K increases risk of transition from polyp to colorectal carcinoma in Ashkenazi Jews.

BACKGROUND & AIMS: The I1307K allele of the APC gene has been shown to confer a modestly elevated risk of colorectal cancer in the Ashkenazi Jewish population (relative risk, 1.5-1.7). However, it is unclear whether the alteration predisposes to adenomas and whether the genetic information can be used in clinical practice. To further address the pathogenic significance of I1307K, we offered both a genetic test and a screening program to individuals considered to be at increased risk for colorectal cancer. We compared the prevalence of polyps and their characteristics between carriers and noncarriers. METHODS: Invitations to participate in a DNA and colonoscopy screening program were mailed, together with a family questionnaire, to 3540 households forming the Jewish Community in Ottawa. The I1307K variant was analyzed in 242 eligible respondents who were selected because they had a personal or family history of colon cancer. Nearly 80% of these respondents (n = 189; age range, 32-83 years) consented to undergo a single colonoscopic examination. RESULTS: The overall carrier frequency of I1307K in the study group was 10.3%. A higher proportion of heterozygous gene carriers was found in the subgroup of colon cancer survivors (27%) than among asymptomatic individuals (8%, P < 0.02). A total of 59 polyps were identified in 44 subjects. Histologically confirmed adenomatous polyps were diagnosed in 11.8% of carriers and 12.8% of noncarriers (P > 0.5). No significant differences in polyp size, multiplicity, location, degree of villosity, or age-dependent prevalence were found between the 2 groups of participants. CONCLUSIONS: The high frequency of I1307K colorectal cancer patients found in the Ashkenazi Jewish community of Ottawa and the equivalent proportion of carriers and noncarriers who developed adenomatous polyps suggest that in this community, I1307K is associated with a significant predisposition to carcinoma but not adenoma.

Adenomatous Polyps↗
PubMed2001

Ebselen protects both gray and white matter in a rodent model of focal cerebral ischemia.

BACKGROUND AND PURPOSE: The neuroprotective efficacy of an intravenous formulation of the antioxidant ebselen has been comprehensively assessed with specific regard to conventional quantitative histopathology, subcortical axonal damage, neurological deficit, and principal mechanism of action. METHODS: Transient focal ischemia (2 hours of intraluminal thread-induced ischemia with 22 hours of reperfusion) was induced in the rat. Ebselen (1 mg/kg bolus plus 1 mg/kg per hour IV) or vehicle was administered at the start of reperfusion and continued to 24 hours. Neurological deficit was assessed 24 hours after ischemia. Gray matter damage was evaluated by quantitative histopathology. Axonal damage was determined with amyloid precursor protein immunohistochemistry used as a marker of disrupted axonal flow and Tau-1 immunohistochemistry to identify oligodendrocyte pathology. Oxidative damage was determined by 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 4-hydroxynonenal (4-HNE) immunohistochemistry. RESULTS: Ebselen significantly reduced the volume of gray matter damage in the cerebral hemisphere (by 53.6% compared with vehicle, P<0.02). Axonal damage was reduced by 46.8% (P<0.002) and the volume of oligodendrocyte pathology was reduced by 60.9% (P<0.005). The neurological deficit score was reduced by 40.7% (P<0.05) and the volume of tissue immunopositive for 8-OHdG and 4-HNE was reduced by 65% (P<0.002) and 66% (P<0.001), respectively, in ebselen-treated animals. CONCLUSIONS: Delayed (2-hour) treatment with intravenous ebselen significantly reduced gray and white matter damage and neurological deficit associated with transient ischemia. The reduction in tissue displaying evidence of oxidative stress suggests that the major mechanism of action is attenuation of free radical damage.

Animals↗
PubMed2000

Density and pharmacology of alpha5 subunit-containing GABA(A) receptors are preserved in hippocampus of Alzheimer's disease patients.

The anatomical localization and pharmacology of alpha5 subunit-containing GABA type-A receptors in the human hippocampal formation of Alzheimer's disease patients were studied with an alpha5 receptor selective ligand, [3H]L-655,708 and compared to age-matched human controls. Autoradiographic analyses revealed a heterogeneous distribution of [3H]L-655,708 binding sites in CA1-CA3 areas with high levels in stratum oriens, stratum pyramidale and stratum radiatum contrasting with low levels in stratum lacunosum. The highest quantity of alpha5 receptors was found in the molecular layer of the dentate gyrus. This pattern of expression was identical in both hippocampus from control and Alzheimer's disease subjects. Quantitative studies demonstrated that the number of [3H]L-655,708 binding sites is well preserved in Alzheimer's disease with only a moderate reduction (25-30%) in the CA1 subfield and entorhinal cortex. Furthermore, saturation and competition experiments with [3H]L-655,708 and representative benzodiazepine site ligands revealed that alpha5 receptors in Alzheimer's hippocampus have an alpha5beta2/3gamma2 pharmacology and structure as in control human brain.Overall, the data reported here provide evidence for a specific expression and relative sparing of alpha5 subunit-containing gamma-aminobutyric acid type-A receptors in the hippocampus of Alzheimer's patients.

Aged↗
PubMed2000

Quantitative assessment of ischemic pathology in axons, oligodendrocytes, and neurons: attenuation of damage after transient ischemia.

Axons and oligodendrocytes are vulnerable to cerebral ischemia. The absence of quantitative methods for assessment of white matter pathology in ischemia has precluded in vivo evaluation of therapeutic interventions directed at axons and oligodendrocytes. The authors demonstrate here that the quantitative extent of white matter pathology was reduced by restoration of cerebral blood flow after 2 hours of middle cerebral artery occlusion. Focal ischemia was induced in anesthetized rats by intraluminal thread placement, either transiently (for 2 hours) or permanently. At 24 hours after induction of ischemia, axonal damage was determined by amyloid precursor protein (APP) immunohistochemistry, and the ischemic insult to oligodendrocytes was assessed by Tau-1 immunostaining in the same sections. In adjacent sections, ischemic damage to neuronal perikarya was defined histologically. The hemispheric extent of axonal damage was reduced by 70% in the transiently occluded animals from that in permanently occluded animals. The volumes of oligodendrocyte pathology and of neuronal perikaryal damage were reduced by 62% and 58%, respectively, in the transiently occluded animals. These results demonstrate that this methodologic approach for assessing ischemic damage in axons and oligodendrocytes can detect relative alterations in gray and white matter pathology with intervention strategies.

Amyloid beta-Protein Precursor↗
PubMed2000

NMDA receptor blockade fails to alter axonal injury in focal cerebral ischemia.

The ability of the NMDA receptor antagonist, MK-801, to protect myelinated axons after focal cerebral ischemia has been examined. Amyloid precursor protein (APP) immunocytochemistry was used to assess the anatomic extent of axonal injury, and conventional histopathology was used to assess the volume of ischemic damage to neuronal perikarya. The middle cerebral artery was permanently occluded in 16 cats. The cats were treated with either vehicle or MK-801 as a 0.5-mg/kg bolus at 15 minutes before middle cerebral artery occlusion, followed by an infusion of 0.14 mg/kg per hour. After 6 hours, the animals were killed and the brains processed for histology and immunocytochemistry. The volume of neuronal necrosis was determined from 16 preselected coronal levels of the brain. The circumscribed zones of APP accumulation in axons were mapped onto images at the same 16 coronal levels, and quantitative analysis was performed using a transparent counting grid, randomly placed over each image. The histologic appearance and anatomic location of axons with increased APP immunoreactivity was similar in animals treated with vehicle and MK-801. MK-801 failed to reduce the hemispheric APP score significantly. In vehicle-treated animals, there was a significant association between the volume of neuronal necrosis and the amount of APP immunoreactivity. MK-801 significantly reduced the slope of the association between the volume of neuronal necrosis and the amount of APP immunoreactivity compared with that observed in vehicle-treated animals. As a result, the ratio of hemispheric APP score and volume of neuronal necrosis was significantly increased with MK-801 treatment. The inability of NMDA receptor antagonists to protect axons may limit their functional efficacy in improving functional outcome after stroke.

Amyloid beta-Protein Precursor↗
PubMed2000

The lipid peroxidation by-product 4-hydroxynonenal is toxic to axons and oligodendrocytes.

Lipid peroxidation and the cytotoxic by-product 4-hydroxynonenal (4-HNE) have been implicated in neuronal perikaryal damage. This study sought to determine whether 4-HNE was involved in white matter damage in vivo and in vitro. Immunohistochemical studies detected an increase in cellular and axonal 4-HNE within the ischemic region in the rat after a 24-hour period of permanent middle cerebral artery occlusion. Exogenous 4-HNE (3.2 nmol) was stereotaxically injected into the subcortical white matter of rats that were killed 24 hours later. Damaged axons detected by accumulation of beta-amyloid precursor protein (beta-APP) were observed transversing medially and laterally away from the injection site after intracerebral injection of 4-HNE. In contrast, in the vehicle-treated animals, axonal damage was restricted to an area immediately surrounding the injection site. Exogenous 4-HNE produced oligodendrocyte cell death in culture in a time-dependent and a concentration-dependent manner. After 4 hours, the highest concentration of 4-HNE (50 micromol/L) produced 100% oligodendrocyte cell death. Data indicate that lipid peroxidation and production of 4-HNE occurs in white matter after cerebral ischemia and the lipid peroxidation by-product 4-HNE is toxic to axons and oligodendrocytes.

Aldehydes↗
PubMed2000

Association of interleukin-1 gene polymorphisms with Alzheimer's disease.

Interleukin-1 (IL-1) is markedly overexpressed in Alzheimer's disease. We found the IL-1A 2,2 genotype in 12.9% of 232 neuropathologically confirmed Alzheimer's disease patients and 6.6% of 167 controls from four centers in the United Kingdom and United States (odds ratio, 3.0; controlled for age and for ApoE [apolipoprotein E] genotype). Homozygosity for both allele 2 of IL-1A and allele 2 of IL-1B conferred even greater risk (odds ratio, 10.8). IL-1 genotypes may confer risk for Alzheimer's disease through IL-1 overexpression and IL-1-driven neurodegenerative cascades.

Aged↗
PubMed1999

Drug development for stroke: importance of protecting cerebral white matter.

Multiple pharmacological mechanisms have been identified over the last decade which can protect grey matter from ischaemic damage in experimental models. A large number of drugs targeted at neurotransmitter receptors and related mechanisms involved in ischaemic damage have advanced to clinical trials in stroke and head injury based on their proven ability to reduce grey matter damage in animal models. The outcome to date of the clinical trials of neuroprotective drugs has been disappointing. Although the failure to translate preclinical pharmacological insight into therapy is multifactorial, we propose that the failure to ameliorate ischaemic damage to white matter has been a major factor. The recent development of quantitative techniques to assess ischaemic damage to cellular elements in white matter, both axons and oligodendrocytes, allows rigorous evaluation of pharmacologic mechanisms which may protect white matter in ischaemia. Such pharmacological approaches provide therapeutic opportunities which are both additional or alternatives to those currently being evaluated in man.

Animals↗
PubMed1999

Interindividual differences in the levels of the glutamate transporters GLAST and GLT, but no clear correlation with Alzheimer's disease.

Alzheimer's disease is a common progressive neurodegenerative disease of unknown etiology. Several different pathological processes have been identified in the brains of Alzheimer patients. To determine if reduced glutamate uptake is a contributing factor, we have measured the levels of the glutamate transporter proteins GLAST (EAAT1) and GLT (EAAT2) in human autopsy samples. The postmortem proteolysis of these proteins turned out to be fairly rapid. Brains from 10 Alzheimer and 10 control patients were therefore obtained with a relatively short postmortem delay (5 hr on average). GLT (N-terminal and central parts), GLAST (C-terminal), glial fibrillary acidic protein (GFAP) and inositol (1,4,5)-triphosphate (IP3)-receptor immunoreactivities were determined in the cingulate and inferior temporal gyri by immunoblotting. The Na+-dependent "binding" of D-[3H]aspartate and the glutamate uptake after solubilization and reconstitution in liposomes were determined for comparison. An individual variation in GLAST and GLT levels was found, but no significant correlation with Alzheimer's disease, except for a 14% lower ratio of N-terminal to central GLT immunoreactivity (P < 0.04). The levels of GLAST and GLT showed negative correlation in agreement with the idea that these proteins are differentially regulated. In conclusion, Alzheimer's disease brains can have both normal and reduced levels of GLAST and GLT.

ATP-Binding Cassette Transporters↗
PubMed1999

Long-term effects of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate and 6-nitro-7-sulphamoylbenzo(f)quinoxaline-2,3-dione in the rat basal ganglia: calcification, changes in glutamate receptors and glial reactions.

Previous data from our laboratory indicate that 25 mM ibotenic acid induces intracellular calcifications in the rat basal forebrain. Because of the lack of specificity of ibotenic acid for a glutamate receptor subtype, a dose-response study with alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate was undertaken and calcified areas (identified with Alizarin Red staining) as well as astro- and microglial reactions (by autoradiography with [3H]lazabemide and [3H]Ro 5-4864) were quantified at one month post-lesion. alpha-Amino-3-hydroxy-5-methyl-4-isoxazole propionate administered into the globus pallidus induced, in a dose-dependent manner, the formation of calcium deposits and the activation of both glial cells, the microglial reaction being particularly robust. From this study, a dose of 5.4 mM alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate was selected for further experiments. [3H]alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate, [3H]dizocilpine maleate and [3H]PN 200-110 binding in vitro were performed to assess autoradiographically whether the tissue damage was associated with changes in glutamate receptors and calcium channel binding sites. In the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate-treated animals, the specific binding of [3H]alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate was significantly reduced by 28% in the lesioned ventral pallidum, whereas it was unchanged in the globus pallidus and substantia innominata. In these three nuclei, calcifications developed and an increase in both glial markers was measured. In contrast, the binding of [3H]PN 200-110 and [3H]dizocilpine maleate were unaffected. Co-injection of 15 mM 6-nitro-7-sulphamoylbenzo(f)quinoxaline-2,3-dione, a selective alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate/kainate receptor antagonist, prevented the formation of calcium concretions, the microglial reaction and the decrease in [3H]alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate binding but it failed to inhibit totally the astroglial reaction induced by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate. This may suggest that the microglial reaction and calcification take place through different mechanisms from the astrogliosis associated with the neuronal loss. In conclusion, acute administration of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate in the rat globus pallidus elicits a dose-dependent calcification process associated with a chronic reaction of astrocytes and microglia. alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate-induced injury is accompanied by a slight reduction of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors in the ventral pallidum, whereas the binding of N-methyl-D-aspartate and L-type calcium channels receptors remains unchanged in any lesioned nucleus.

Animals↗
PubMed1999

Calpain activation and cytoskeletal protein breakdown in the corpus callosum of head-injured patients.

Calpain-mediated breakdown of the cytoskeleton has been proposed to contribute to brain damage resulting from head injury. We examined the corpus callosum from patients who died after a blunt head injury in order to determine if there was evidence of these pathophysiological events in a midline myelinated commissure that is susceptible to damage after human head injury. Western blotting revealed marked reductions in the levels of neurofilament triplet proteins 200 and 68kDa in the corpus callosum of head-injured patients compared with control subjects. Neurofilament 200kDa levels were significantly reduced as detected by either phosphorylation-dependent or -independent antibodies. In contrast, there were minimal changes in the levels of beta-tubulin or the microtubule-associated protein, tau, in the head-injured patients, although amyloid precursor protein immunostaining demonstrated axonal damage in 9 of the 10 patients. The inactive 800kDa and active 76kDa subunits of mu-calpain were present in control subjects and head-injured patients. However, there was a significant increase in the levels of calpain-mediated spectrin breakdown products in head-injured patients compared with the control subjects. The results demonstrate that following human blunt head injury, there is a significant degradation of neurofilament proteins and increased levels of calpain-mediated spectrin breakdown products within the corpus callosum. Therefore, our data support the hypothesis that calpain-mediated breakdown of the cytoskeleton may contribute to axonal damage after head injury.

Adult↗
PubMed1999

The apolipoprotein E epsilon2 allele and the pathological features in cerebral amyloid angiopathy-related hemorrhage.

Cerebral amyloid angiopathy (CAA) is associated with apolipoprotein E (APOE gene, apoE protein) polymorphism: current evidence suggests that the epsilon4 allele is a risk factor for the development of CAA and the epsilon2 allele predisposes to hemorrhage. We sought to determine the relationship between the APOE epsilon2 allele and both the immunoreactivity profiles and vascular complications of CAA. We performed immunohistochemistry for amyloid beta-protein (A beta), apoE, cystatin C, and activated microglia, and examined the morphology of cortical and leptomeningeal vessels in 37 CAA-related hemorrhage (CAAH), 26 Alzheimer disease (AD) patients, and 20 controls. The extent of immunostaining of vessels for A beta, apoE, cystatin C, and perivascular activated microglia increased from controls through AD to a maximum in CAAH patients. Among cases with CAA (37 CAAH, 19 AD, and 6 controls, n = 62) vascular apoE (p < 5 x 10(-4)), cystatin C (p < 10(-4)), activated microglia (p < 10(-4)), vessels with a high ratio of wall thickness to lumen diameter (p < 0.003) as well as dilated/microaneurysmal vessels (p < 0.01) were present more frequently in patients with hemorrhage than without; however, these features were not associated with the APOE epsilon2 allele. Fibrinoid necrosis alone was associated with the APOE epsilon2 allele (p < 0.04) and we suggest that over-representation of APOE epsilon2 in CAAH may result from its association with fibrinoid necrosis.

Aged↗