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B J Cummings

Publications and source records attributed to B J Cummings.

At least 37 records · Page 2Linked to original sources
PubMed1998

Plaque biogenesis in brain aging and Alzheimer's disease. II. Progressive transformation and developmental sequence of dystrophic neurites.

Plaque-associated dystrophic neurites are a common pathological feature in the brains of patients with Alzheimer's disease (AD). In the present study, we investigated the relative abundance and progressive transformation of the amyloid precursor protein (APP), neurofilament (NF) and paired helical filament (PHF) tau-positive dystrophic neurites, within plaques in non-demented controls versus plaque-associated dystrophic neurites in mild or severe AD using double and triple immunolabeling. We also determined the argentophilia of the various sub-populations of dystrophic neurites. In aged non-demented brain, approximately half of the APP-positive plaques contained NF-immunopositive dystrophic neurites; rarely were PHF/tau-positive dystrophic neurites detectable. In contrast, in the AD brain, three-fourths of the APP-positive plaques contained NF-positive dystrophic neurites and half contained PHF/tau neurites. We also observed focal patches of hyper-phosphorylated NF and/or PHF/tau within APP-immunopositive dystrophic neurites, which appeared similar to retrograde degeneration, whereas we never observed focal accumulations of APP within NF- or PHF/tau-positive fibers. We hypothesize that plaque-associated dystrophic neurites within plaques develop in a particular sequence: APP-positive dystrophic neurites appear first and are non-argentophilic. This is followed by the appearance of NF-positive dystrophic neurites, where a subset of NF-positive dystrophic neurites are lightly argentophilic. Over time, PHF/tau-positive dystrophic neurites develop and are strongly argentophilic. These data suggest that dystrophic neurites can develop retrogradely from focal plaque damage to induce somatic and dendritic degeneration and potentially contribute to neurofibrillary tangle formation.

Aged↗
PubMed1997

The progression of beta-amyloid deposition in the frontal cortex of the aged canine.

Brains from 41 aged canines (> or = 10 years of age) were examined immunohistochemically to characterize the laminar distribution and age-related progression of beta-amyloid (A beta) in frontal cortex. We classified the A beta patterns into four distinct types. Type I was characterized by small, faint deposits of A beta in deep cortical layers. Type II consisted of diffuse deposits of A beta mainly in layers V and VI. Type III had both dense plaques in superficial layers, and diffuse deposits in deep layers. Finally, Type IV had solely dense plaques throughout all layers of cortex. We compared the A beta distribution pattern between the Old canines (10-15 years, n = 22) and the Very Old canines (> 15 years, n = 19). The Old group primarily had negative staining, or Type I and Type II patterns of amyloid deposition (73%). Conversely, the Very Old group had predominantly Types II, III and IV deposits (89.5%), a difference that was significant (P < 0.05). We suggest that A beta deposition in canine frontal cortex is a progressive age-related process beginning with diffuse deposits in the deep cortical layers followed by the development of deposits in outer layers. In support of this hypothesis, the deeper layer diffuse plaques in the Very Old group of dogs also contain the largest proportion of beta-amyloid with an isomerized aspartic acid residue at position 7, indicating that these deposits had been present for some time. We also observed fiber-like A beta immunoreactivity within regions of diffuse A beta deposits. These fibers appeared to be degenerating neurites, which were negative for hyperphosphorylated tau. Therefore, these fibers may represent a very early form of neuritic change that precede tau hyperphosphorylation or develop by an alternative pathway.

Aging↗
PubMed1997

Open field activity and human interaction as a function of age and breed in dogs.

Open field (OF) activity was studied in kennel reared purebred beagles from two separate colonies (2-13 years in age) and pound source mixed breed dogs (9 months to 10 years in age). Dogs were observed for 10 min sessions and records were taken of: locomotion, urination, sniffing, grooming, rearing, vocalizing, jumping frequencies and inactivity (16). Since dogs are uniquely social towards people, we also measured human interaction (HI), which recorded the same behaviors as during OF when a person was present in the room. Measures of exploratory behavior decreased as a function of age in pound source dogs in the OF test, but not in beagles from either colony. No breed differences were found between the young dogs. In the HI test, age effects were found in beagles but not pound source dogs. OF activity correlated with tests of cognitive function, but differences were found between the three groups. These findings indicate that OF activity is age-sensitive in dogs, but that breed and test conditions are also essential factors.

Aging↗
PubMed1997

Does a centralized radiotherapy system provide adequate access to care?

PURPOSE: In the Canadian province of Ontario, all radiotherapy is provided by a centrally managed provincial network of nine cancer centers. The primary goal of this study was to determine whether this highly centralized radiotherapy system provides adequate and equitable access to care for the province's dispersed population. METHODS: The Ontario Cancer Registry (OCR) was used to identify 295,386 cases of invasive cancer, excluding nonmelanoma skin cancer, which were diagnosed in Ontario between 1984 and 1991. Electronic radiotherapy records from each of the province's radiotherapy centers were linked to the registry at the level of the individual case. RESULTS: The proportion of incident cases treated with radiotherapy was 18.8% at 4 months after diagnosis, 23.7% at 1 year, 25.8% at 2 years, 28.2% at 5 years, and 29.1% at 8 years. These rates of radiotherapy use are much lower than the accepted national and international targets, and lower than rates reported from other jurisdictions. The rate of radiotherapy use at 1 year varied significantly from county to county across Ontario (range, 18.6% to 32.4%; P < 10(-6)), and the highest rates were recorded in communities close to radiotherapy centers. There was a common geographic pattern of rate variations among several disease groups, including breast cancer, lung cancer, the genitourinary malignancies, and the gastrointestinal malignancies. CONCLUSION: The low and uneven rates of radiotherapy use across the province indicate that Ontario's centralized radiotherapy system does not, at present, provide adequate or equitable access to care.

Cancer Care Facilities↗
PubMed1997

Symposium on rectal cancer: 3. The case for adjuvant radiotherapy for rectal cancer.

Adjuvant radiotherapy for rectal cancer is intended to eradicate subclinical deposits of cancer cells not removed at surgery. These residual cells are found most commonly at the resection margin of the primary tumour and in transected cancer-bearing lymphatics or vessels. Refinements in surgical technique have been associated with a reduction in the risk of pelvic recurrence in some nonrandomized series. However, clinical trials have shown that the combinations of radiotherapy and chemotherapy, and in some instances radiotherapy alone, reduce the risk of recurrence and may improve survival rates compared with those of surgery alone. It is premature to consider that adjuvant pelvic radiotherapy is unnecessary.

Humans↗
PubMed1996

Constructional apraxia in Alzheimer's disease correlates with neuritic neuropathology in occipital cortex.

A variety of measures of neuropathology in Alzheimer's disease (AD) correlate with dementia severity. However, the role of beta-amyloid protein and abnormally phosphorylated tau protein in the decline of specific cognitive abilities is unknown. "Constructional praxis' (e.g., copying, constructing) is believed to require integrity of the parietal-occipital lobes. Unlike most other cognitive tasks, some AD patients are able to perform some constructional tasks even late in the disease course. Thus, it may be an ideal task to evaluate the relationship between various measures of AD neuropathology and cognitive performance. Fixed brain tissue was obtained from 16 AD patients who were cognitively assessed shortly before death. Parietal, frontal, entorhinal, and occipital cortices were examined by immunocytochemistry for beta-amyloid protein and abnormally phosphorylated tau protein at both early and later stages of neuropil thread and tangle formation. Constructional praxis in AD was strongly related to early-stage tau hyperphosphorylation in occipital cortex. Praxis ability was specific in that it was not significantly related to pathology in other areas and non-constructive tasks were not associated with occipital cortex pathology. In contrast, global dementia severity was related to beta-amyloid deposition in entorhinal, parietal, and frontal regions. These findings suggest that occipital cortex is critical for some constructional praxis tasks and that some regionally localizable tasks may be good indices of underlying pathology in corresponding brain regions.

Aged↗
PubMed1996

Plaque biogenesis in brain aging and Alzheimer's disease. I. Progressive changes in phosphorylation states of paired helical filaments and neurofilaments.

Paired helical filament (PHF)/tau immunoreactive dystrophic neurites are a common pathological feature in the brain of patients with Alzheimer's disease. Recent studies suggest that swollen neurofilament-immunoreactive neurites are also present in senile plaques. In the present study, we investigated whether PHF/tau-positive dystrophic neurites are located in all subtypes of plaques and whether swollen neurofilament-immunoreactive neurites are hyper-phosphorylated, using a battery of antibodies to PHF/tau, neurofilament, and beta-amyloid protein. PHF/tau-positive dystrophic neurites were present in and around nearly all subtypes of plaques, including small amyloid deposits, diffuse plaques, and perivascular plaques in the hippocampal formation of Alzheimer brain. The earlier changes were detectable with AT8 antibody and later changes with PHF-1 antibody. Plaque-associated PHF/tau-positive dystrophic neurites were rare or absent in the hippocampal formation of normal aged brain. Swollen neurofilament-positive neurites appeared to be hyper-phosphorylated in Alzheimer's disease and to a lesser degree in aged control brains. Neurites that contained hyper-phosphorylated tau as well as neurofilament were strongly argentophilic because both populations of dystrophic neurites stained with silver stains. Swollen neurofilament-positive plaque-associated neurites were often present in the absence of PHF/tau-positive plaque-associated dystrophic neurites. These data suggest that PHF/tau-positive dystrophic neurites are a common component of all subtypes of plaques in Alzheimer brain and neurofilament protein in swollen neurites, like tau protein, is hyper-phosphorylated. Hyper-phosphorylated neurofilaments in plaque-associated neurites may represent one of the earliest cytoskeletal changes in vulnerable neurons in Alzheimer's disease and aged control brains.

Aged↗
PubMed1996

A phase I study of combined radiation therapy with 5-fluorouracil and low dose folinic acid in patients with locally advanced pancreatic or biliary carcinoma.

PURPOSE: To evaluate the toxicities of a Phase I study of radiation therapy with concurrent 5-fluorouracil (5FU) and low dose folinic acid in patients with locally advanced pancreatic or biliary carcinoma. METHODS AND MATERIALS: Twenty-seven patients with locally advanced carcinoma of the pancreas (n = 19), bile duct (n = 7), and gall bladder (n = 1) were entered into a Phase I study of combined radiation therapy, 5FU, and folinic acid. Radiation was given as a split course of 40 Gy in 20 daily fractions with a gap of 2 weeks after 20 Gy. 5-Fluorouracil, 300 to 375 mg/m2/day and folinic acid, 20 mg/m2/day were given as an i.v. bolus daily for 5 days beginning on day 1 and again on day 29. RESULTS: Eight patients developed Grade 3 or 4 toxicities (National Cancer Institute common toxicity criteria) including nausea and vomiting (n = 4), oral mucositis (n = 4), myelosuppression (n = 2), infection (n = 2), and diarrhea (n = 1). Four patients did not complete the planned protocol due to treatment toxicities. There were two treatment deaths secondary to septic neutropenia. Treatment toxicity appeared to be related to age (> 70), performance status (ECOG = 2), and 5FU dose (> 350 mg/m2/day). CONCLUSION: This protocol is poorly tolerated by elderly patients or those with poor performance status, and 350 mg/m2/day is our recommended dose for 5FU as given in this protocol.

Adult↗
PubMed1996

Localization and cell association of C1q in Alzheimer's disease brain.

The complement protein, C1q, has been shown to bind to fibrillar beta-amyloid, resulting in the activation of the classical complement pathway. C1q has also been found associated with most but not all amyloid deposits in brain. To determine whether C1q is exclusively associated with plaques containing the fibrillar form of beta-amyloid, normal and Alzheimer brain were immunohistochemically double labeled using thioflavine, which specifically stains beta-amyloid in a beta-sheet conformation, and an affinity- purified antibody to human C1q. C1q immunostaining was colocalized with nearly all thioflavine-positive plaques, while C1q was not detected in beta-amyloid immunopositive plaques which were thioflavine-negative. Beta-amyloid plaques in nondemented controls (which are typically thioflavine-negative) were also negative for C1q. Microglia and astrocytes of reactive morphology were also associated with C1q-positive plaques and neurons. Interestingly, many neuronal cells in the AD brain, but not microglia or astrocytes, stained prominently with anti-C1q. Neurons in control brain were not C1q positive. Our data suggest that some of these C1q-positive structures were neurofibrillary tangles immunoreactive for hyperphosphorylated tau, which may be binding extracellular C1q. However, a large number of the C1q-positive neurons had intact cell morphology; suggesting that these cells may be synthesizing this critical complement component. Since the presence of C1q suggests the activation of complement and/or the activation of proinflammatory events, and the specific class of plaques that contain C1q are the type that corresponds to observed clinical dementia, these findings further support the hypothesis that complement plays a role in the pathogenesis of AD.

Alzheimer Disease↗
PubMed1996

Beta-amyloid accumulation correlates with cognitive dysfunction in the aged canine.

It is well known that beta-amyloid accumulates abnormally in Alzheimer's disease; however, beta-amyloid's relationship to cognitive dysfunction has not been clearly established and is often confounded by the presence of neurofibrillary tangles. We used canines to investigate the relationship between beta-amyloid accumulation and cognitive function in an animal model of aging lacking neurofibrillary tangles. The performance of 20 canines (11 purebred beagles and 9 mongrels) on a battery of six cognitive tasks was measured. These tasks included Reward Approach and Object Approach learning, as well as Discrimination, Reversal, Object Recognition, and Spatial learning and memory. Aged canines were impaired on some tasks but not others. beta-Amyloid-immunopositive plaques were found in many of the older animals. Plaques were all of the diffuse subtype and many contained intact neurons detected with double-labeling for neurofilaments. No neurofibrillary tangles were detected. beta-Amyloid was also associated with the processes of many neurons and with blood vessels. Using computerized image analysis, we quantified the area occupied by beta-amyloid in entorhinal cortex, frontal cortex, and cerebellum. Controlling for age-related increases in beta-amyloid, we observed that increased beta-amyloid deposition is strongly associated with deficits on Discrimination learning (r = .80), Reversal learning (r = .65), and Spatial learning (r = .54) but not the other tasks. There were a few differences between breeds which are discussed in the text. Overall, these data suggest that beta-amyloid deposition may be a contributing factor to age-related cognitive dysfunction prior to the onset of neurofibrillary tangle formation.

Alzheimer Disease↗
PubMed1996

Anal canal cancer: current treatment and results.

Combined radiation and chemotherapy is established as the preferred treatment for primary epidermoid cancer of the anal canal. This approach allows preservation of anorectal function without any apparent decrease in the survival rates obtained in the past with radical surgery. Most experience has been gained with radiation, 5-Fluorouracil (5-FU) and mitomycin C, but radiation, 5-FU and cisplatin are also effective. Regional lymph node metastases can be eradicated by radiation and chemotherapy, but cancers which have metastasized to regional nodes or to extrapelvic organs carry a poor prognosis. Extrapelvic metastases and recurrent pelvic cancer respond poorly to systemic chemotherapy, and to combinations of radiation and chemotherapy. Cisplatin combined with 5-FU is the most effective treatment presently available in such situations. No effective systemic adjuvant therapy has yet been devised.

Anal Canal↗
PubMed1995

Image analysis of beta-amyloid load in Alzheimer's disease and relation to dementia severity.

The protein beta-amyloid is said to be central to the disease process of Alzheimer's disease (AD). Several groups have developed transgenic models that overexpress the amyloid precursor protein or beta-amyloid and then develop AD-like neuropathology. Another report suggests that beta-amyloid accumulation in old dogs correlates with cognitive impairment. However, many other researchers argue that beta-amyloid deposition in senile plaques is a secondary event because plaque numbers in man do not correlate well with cognition. We set out to analyse this conumdrum in man. We selected 16 mild to severely demented AD cases on the basis of mini-mental state exam scores (MMSE; n = 16). We also included 4 controls who represented the upper range of cognitive ability. We used a computer-based image analysis of cross-sectional area of the brain occupied by beta-amyloid immunopositive deposition. We used this technique in preference to conventional methods of manual plaque counts and found a strong relation between beta-amyloid load in entorhinal cortex and cognition measured on various scales (r = -0.93 versus the Blessed IMC). Our study suggests that the size of cortical area affected by beta-amyloid deposition is an important factor in the clinical manifestation of dementia, and lends support to the possibility that beta-amyloid is central to the aetiology of AD.

Aged↗
PubMed1995

Immunoreactivity for Bcl-2 protein within neurons in the Alzheimer's disease brain increases with disease severity.

Bcl-2 protein has been suggested to be one of the proteins preventing apoptosis in a variety of cell types. Recently, apoptosis has been suggested to have an important role in the pathogenesis of Alzheimer's disease (AD). We have utilized Bcl-2 immunohistochemical methods to examine Bcl-2 in the hippocampus and entorhinal cortex of AD patients ranging in clinical and neuropathological severity from mild to severe and compared these results to those obtained from age-matched controls. Immunoreactivity for Bcl-2 was predominantly found within neurons. Bcl-2 immunostaining within AD tissue was increased relative to controls in most neurons of the entorhinal cortex, subiculum, CA1, CA2, CA3, hilus and dentate gyrus. Relative Bcl-2 staining increased in parallel with increasing disease severity. However, neurons exhibiting immunoreactivity for markers of neurofibrillary tangle formation (AT8 and PHF-1) showed reduced Bcl-2 staining, suggesting that Bcl-2 may be down regulated in these degenerating neurons. Bcl-2 immunoreactivity within astrocytes and the vasculature was also increased in AD. These results suggest that Bcl-2 protein may have a role in compensation responses to AD pathology, perhaps affording to the remaining neurons a margin of protection from apoptosis.

Aged↗
PubMed1995

Adenocarcinoma of the rectum treated by radical external radiation therapy.

PURPOSE: To assess the long-term survival and response rates of patients with primary rectal cancer to radical radiation therapy. METHODS AND MATERIALS: Between 1978 and 1987, 229 patients were treated at the Princess Margaret Hospital with radical external radiation therapy for adenocarcinoma of the rectum. Patients were treated with radiation either because they were considered to have unresectable tumors, were medically unfit, or refused surgery, or for a combination of these factors. Doses ranged from 40 Gy in 10 fractions by a split course over 6 weeks to 60 Gy in 30 fractions in 6 weeks. The most commonly prescribed treatment was 52 Gy target absorbed dose in 20 daily fractions over 4 weeks. RESULTS: The overall 5-year actuarial survival rate was 27%; for patients with mobile tumors, it was 48%, partially fixed 27%, and fixed tumor 4%. Forty-eight of the 97 patients (50%) with mobile tumors, 11 of the 37 patients (30%) with partially fixed tumors, and 7 of the 77 patients (9%) with fixed tumors had clinically complete tumor regression following radiation. Of these, 18 of the mobile, 6 of the partially fixed, and 5 of the fixed tumors later relapsed locally. Fifty patients had salvage surgery after failing to achieve complete remission or for local relapse, with a 5-year actuarial survival rate of 42% from the time of surgery. CONCLUSION: Although radiation therapy can cure some patients with mobile or partially fixed rectal adenocarcinomas who refuse or are unsuitable for surgery, local control remains a problem; salvage surgery should be considered in patients who relapse or fail to go into complete remission and who are fit to undergo surgery. For patients with fixed rectal cancers, high-dose external-beam radiation should be part of a planned preoperative regimen or be palliative in intent.

Actuarial Analysis↗
PubMed1995

Early association of reactive astrocytes with senile plaques in Alzheimer's disease.

The fibrillar beta-amyloid protein (A beta) plaques of Alzheimer's disease (AD) are associated with reactive astrocytes and dystrophic neurites and have been suggested to contribute to neurodegenerative events in the disease. We recently reported parallel in vitro and in situ findings, suggesting that the adoption of a reactive phenotype and the colocalization of astrocytes with plaques in AD may be mediated in large part by aggregated A beta. Thus, A beta-mediated effects on astrocytes may directly affect disease progression by modifying the degenerative plaque environment. Alternatively, plaque-associated reactive astrocytosis may primarily represent a glial response to the neural injury associated with plaques and not significantly contribute to AD pathology. To investigate the validity of these two positions, we examined the differential colocalization of reactive astrocytes and dystrophic neurites with plaques. Hippocampal sections from AD brains--ranging in neuropathology from mild to severe--were triple-labeled with antibodies recognizing A beta protein, reactive astrocytes, and dystrophic neurites. We observed not only plaques containing both or neither cell type, but also plaques containing (1) reactive astrocytes but not dystrophic neurites and (2) dystrophic neurites but not reactive astrocytes. The relative proportion of plaques colocalized with reactive astrocytes in the absence of dystrophic neurites is relatively high in mild AD but significantly decreases over the course of the disease, suggesting that plaque-associated astrocytosis may be an early and perhaps contributory event in AD pathology rather than merely a response to neuronal injury. These data underscore the potentially significant contributions of reactive astrocytosis in modifying the plaque environment in particular and disease progression in general.

Adult↗
PubMed1995

Spatial learning and memory as a function of age in the dog.

Spatial learning and memory were studied in dogs of varying ages and sources. Compared to young dogs, a significantly higher proportion of aged dogs could not acquire a spatial delayed nonmatching-to-sample task. A regression analysis revealed a significant age effect during acquisition. Spatial memory was studied by comparing performance at delay interval of 20, 70, and 110 s. At short delays aged and young dogs were similar; at longer delays, errors increased to a greater extent in old than in young dogs; however this was not statistically significant. It was possible to identify 2 groups of aged animals, age-impaired and age-unimpaired. Several of the dogs were also tested on an object recognition memory task, which was more difficult to learn than the spatial task. The possibility that these findings are confounded by breed differences is considered. Overall, the present results provide further evidence of the value of a canine model of aging.

Aging↗