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B J Cummings

Publications and source records attributed to B J Cummings.

At least 55 records · Page 3Linked to original sources
PubMed1994

Immunohistochemical evidence for apoptosis in Alzheimer's disease.

Recently, in vitro studies conducted in our laboratory and others have suggested that apoptosis may have a role in the neuronal cell death associated with Alzheimer's disease (AD). To evaluate this hypothesis, the hippocampi and entorhinal cortices of AD, aged control, and surgical biopsy tissue were examined using the ApopTag system for the detection of DNA fragmentation and DNA strains to reveal nuclear morphology. Numerous neuronal nuclei displaying distinct morphological characteristics of apoptosis were present within tangle-bearing neurons as well as non-tangle-bearing neurons in AD brain, whereas few or no such nuclei were detected in control brain. Our in vivo results support the hypothesis that apoptosis may be one mechanism leading neuronal cell death in AD.

Aged↗
PubMed1994

Early phosphorylation of tau in Alzheimer's disease occurs at Ser-202 and is preferentially located within neurites.

Within the neurofibrillary tangles (NFTs) and dystrophic neurites (DNs) of Alzheimer's disease (AD), the cytoskeletal protein tau is abnormally hyperphosphorylated. In this study we evaluate the phosphorylation of specific residues on tau within different phases of the formation of NFTs. Two monoclonal antibodies, AT8 and PHF-1, were used to selectively recognize phosphorylated Ser-202 and Ser-396 of PHF-tau protein, respectively. We found that abnormal phosphorylation of tau appears to occur first at Ser-202 in DNs, then at Ser-202 in the soma and finally at Ser-396 in DNs and NFTs. These results suggest that abnormal phosphorylation at Ser-202 of PHF-tau in DNs represents one of the earliest neuropathological changes within the neurites of vulnerable neurons and may have a pivotal role in the initial pathogenesis of AD.

Aged↗
PubMed1994

Subpopulations of dystrophic neurites [correction of neuritis] in Alzheimer's brain with distinct immunocytochemical and argentophilic characteristics.

Using two monoclonal antibodies, tau-1 and PHF-1, and a sequential staining method combining double-labeling immunofluorescence and Bielschowsky silver staining, we have demonstrated the presence of two populations of dystrophic neurites (DNs) with distinct immunocytochemical and argentophilic characteristics. Tau-1 and PHF-1 immunoreactivity were co-localized in many DNs. However, approximately 20% of the DNs were immunoreactive for PHF-1 only. PHF-1 single-labeled DNs were not visible or very weak with Bielschowsky silver stain. Of DNs continuous with neurofibrillary tangles (NFTs), tau-1/PHF-1 double-labeled DNs were continuous with intracellular NFTs only, while PHF-1 single-labeled DNs were continuous with extracellular NFTs only. Furthermore, the population of DNs that cluster around extracellular NFTs is different from those that cluster around or within senile plaques. The combined use of tau-1 and PHF-1 immunocytochemistry may provide a more accurate indication of the number of extracellular DNs and extracellular NFTs, which may aid in the diagnosis of severe and advanced AD cases.

Aged↗
PubMed1994

Increased immunoreactivity for Jun- and Fos-related proteins in Alzheimer's disease: association with pathology.

The protein products of the Jun and Fos immediate early gene (IEG) families are cooperative transcriptional regulatory factors implicated in regulating the expression of many genes. The levels of a variety of proteins such as the amyloid precursor protein and basic fibroblast growth factor are altered in Alzheimer's disease (AD), thus the events regulating these changes are of interest. Both of these genes contain an activator protein-1 consensus sequence which may be responsive to regulation by immediate early genes. In order to evaluate the potential involvement of IEGs in AD pathology, we have examined Jun- and Fos-related protein immunoreactivity in control and AD brain. Specifically, we investigated the correspondence of immunoreactivity for Jun and Fos proteins with immunoreactivity for paired helical filament-1 (PHF-1), a marker for neurofibrillary tangles which recognizes abnormally phosphorylated tau, glial fibrillary acidic protein (GFAP), and thioflavine staining in double-labeling experiments. An intensification of both Jun and Fos immunoreactivity was observed in AD cases; in addition, both Jun and Fos immunoreactivity were colocalized with PHF-1 in some neurons in AD brain. Jun and Fos immunoreactivity were also colocalized with GFAP-positive astrocytes distributed in the cortex of AD and control cases, and surrounding thioflavine-stained plaques in AD brain. These observations suggest that members of the Jun and Fos IEG families may play a role in AD pathology.

Aged↗
PubMed1994

The variation of small bowel volume within the pelvis before and during adjuvant radiation for rectal cancer.

Prior to adjuvant postoperative radiation therapy for carcinoma of the rectum, 21 consecutive patients had small bowel barium studies to determine whether there was an optimal interval between ingestion of barium sulphate and imaging, and whether the volume of small bowel within the posterior pelvis was constant throughout the course of treatment. It was found that the optimum interval prior to imaging after ingestion of barium was 1.5-2 h. For seven patients there was no, or minimal, small bowel visualised within the posterior pelvis at any time. For six patients there was an apparently fixed loop of bowel within the posterior pelvis at simulation, both before and during treatment. For a further eight, the small bowel was mobile and the volume of bowel within the posterior pelvis was reduced by bladder distension. Seven of these eight patients had repeat studies during the course of treatment and in five the difference between the appearance of the small bowel with the bladder full and empty was lost. It is concluded that the displacement of small bowel from the posterior pelvis by bladder distension may not be reliably maintained throughout a course of pelvic radiation.

Barium Sulfate↗
PubMed1994

Beta-amyloid-induced changes in cultured astrocytes parallel reactive astrocytosis associated with senile plaques in Alzheimer's disease.

One neuropathological characteristic of Alzheimer's disease is an abundance of reactive astrocytes, particularly in association with senile plaques. Neither the factor(s) responsible for initiating the reactive astrocytosis nor the effects of this event on disease progression are known. We investigated the possibility that beta-amyloid protein, the primary constituent of plaques, contributes to reactive astrocytosis by comparing results derived from both culture studies and immunohistochemical analyses of Alzheimer brain tissue. We report that beta-amyloid peptides, in an aggregation-dependent manner, rapidly induce a reactive phenotype in cultured rat astrocytes. Reactive morphological changes are accompanied by increased immunoreactivities for glial fibrillary acidic protein and basic fibroblast growth factor. Although toxic to other types of central nervous system cells, aggregated beta-amyloid peptides do not significantly decrease astrocyte viability. Rather, the processes of cultured astrocytes envelop aggregated deposits of beta-amyloid peptide. In Alzheimer brain, the processes of reactive astrocytes were also observed to engulf beta-amyloid deposits. Similar to the in vitro findings, the astrocytic response was associated only with beta-amyloid plaques exhibiting an aggregated structure. Further, the plaque-associated reactive astrocytes showed enhanced immunoreactivities for glial fibrillary acidic protein and basic fibroblast growth factor. These data suggest that beta-amyloid which has assembled into beta-sheet fibrils significantly contributes to the reactive astrocytosis characteristic of Alzheimer's disease. Thus, in addition to its hypothesized direct effects on neuronal viability, beta-amyloid may also influence disease progression indirectly via reactive astrocytosis.

Aged↗
PubMed1994

Adjuvant radiation for rectal cancer: when and with what?

This review outlines the progress made in recently reported trials to establish an effective adjuvant treatment for the surgical management of rectal cancer. Many of the trials of preoperative and postoperative radiation conducted over the past two decades are now mature. Moderate-to-high doses of radiation given prior to or following surgery reduce pelvic tumor recurrence rates but have little effect on survival. The coupling of radiation with cytotoxic chemotherapy, particularly 5-fluorouracil-based protocols, has been reported to improve survival as well as reduce the risk of recurrence in the pelvis and elsewhere. The status of ongoing trials is outlined.

Chemotherapy, Adjuvant↗
PubMed1993

Identification and distribution of axonal dystrophic neurites in Alzheimer's disease.

Dystrophic neurites (DNs) are one of the neuropathological characteristics of Alzheimer's disease (AD). Previously, it has been suggested that tau-immunoreactive DNs are of dendritic origin and that axonal and dendritic dystrophic neurites are morphologically indistinguishable. In the present study, two monoclonal antibodies, tau-1 and PHF-1, were used to examine sections of the hippocampal formation from AD and normal aged brains. Both antibodies stained dendritic DNs as well as axonal DNs. Axonal DNs were clearly seen in axonal fiber tracts, white matter and hippocampal terminal regions. Axonal DNs arising from neurofibrillary tangles were easily detected in CA3 and CA1. The morphological appearance of axonal DNs varied with the neuron type from which it originated. The most distinctive feature of tau-1 or PHF-1 immunostained axonal DNs was their uneven contour, alternating swollen and shrunken segments and short rod or cone shaped fragments. In contrast, dendritic dystrophic neurites are thicker and more tortuous. It appears that while DNs are both dendritic and axonal in origin, axonal DNs are more prevalent and widespread in the AD brain than previously realized and may represent one of the main pathological lesions in AD.

Aged↗
PubMed1993

A randomized trial of radiation therapy compared to split course radiation therapy combined with mitomycin C and 5 fluorouracil as initial treatment for advanced laryngeal and hypopharyngeal squamous carcinoma.

Two hundred and twelve patients with previously untreated advanced squamous carcinoma of the larynx or hypopharynx were randomized to receive initial treatment with radiotherapy, 50 Gy in 20 fractions in 28 days or split course radiotherapy and concurrent chemotherapy, 25 Gy in 10 fractions in 14 days followed by a 4 week rest and a further 25 Gy in 10 fractions in 14 days starting on day 43; Mitomycin C was given on day 1 and day 43 and 5FU continuous infusions on days 1--4 and days 43--46. Surgery was reserved for persistent or recurrent disease. Two hundred and nine of the 212 patients randomized were included in the analyses. Outcome analyses were performed at a median follow-up interval of 4.4 years. No patients were lost to follow-up. No significant difference was found between the two arms for the end points of local relapse-free rate (p = 0.91), regional relapse-free rate (p = 0.17, adjusted) or overall survival (p = 0.86). Eight-eight patients had attempted surgical resection following radiotherapy failure. The contribution of salvage surgery to overall survival was similar for both arms of the study as was the surgical complication rate. Serious late radiation toxicity was minimal (3% in the RT group, 0% in the radiation therapy plus chemotherapy group). The result of the trial shows no advantage in terms of local control or survival for the experimental treatment arm of split course radiotherapy and concurrent chemotherapy with Mitomycin C and 5 Fluorouracil compared to radiotherapy alone.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Local excision and post-operative radiation therapy for rectal carcinoma.

PURPOSE: To assess the patterns of failure and outcome following conservative surgery and post-operative radiation therapy for rectal cancer. METHODS AND MATERIALS: Twenty-five patients underwent post-operative radiation therapy (50 Gy in 20 fractions over 4 weeks) following local excision or electrocoagulation for carcinoma of the rectum. None of the patients had palpable residual disease following surgery. Selection factors for post-operative radiation therapy were refusal of a permanent colostomy, excessive operative risk of an abdominal perineal resection and concern regarding local control with conservative surgery alone. RESULTS: Six of 25 patients developed failure at the primary site. There was no lymph node failure. All five patients with primary failure alone underwent abdominal perineal resection and 2 remained free of recurrence. With a median follow-up of 6 years, 20 of 25 patients remained alive and free of disease. There was no apparent influence of age, sex, type of surgery, tumor size, distance of tumor from anal verge, tumor configuration, resection margins, integrity of the resected tissue, depth of invasion, differentiation, presence of lymphatic or vascular channel invasion, radiation dose or field size on local control and survival. One of 15 patients failed locally when the overall treatment time was 30 days or less, whereas 5 of 10 patients developed local failure when the overall treatment time exceeded 30 days. Sixteen of 20 patients in whom cancer did not recur retained normal anorectal function. All four patients with grade 3 early morbidity and the only patient with Grade 3 late morbidity were amongst the group of 13 patients treated with large AP-PA fields (mean: 15 x 19 cm2). CONCLUSION: In selected patients who are at high risk of local recurrence following local excision alone, and who refuse a colostomy or are at high operative risk from radical surgery, post-operative radiation therapy is an alternative to radical surgery.

Aged↗
PubMed1993

Neuritic involvement within bFGF immunopositive plaques of Alzheimer's disease.

As early as 1928, Cajal suggested that plaques contain a trophic substance which attracts neurites. Recently, basic fibroblast growth factor (bFGF) levels were shown to be elevated in Alzheimer's disease (AD) and localized to plaques and neurofibrillary tangles. We sought to clarify the subtype of plaques which contain bFGF and provide more detail on bFGFs neuronal and vascular localization in normal aged brain, AD brain, and Down's syndrome (DS) brain. We combined double-labeling immunocytochemistry for bFGF with heparan sulfate glycosaminoglycans, beta-amyloid, and thioflavine fluorescence. In addition, the neuritic markers tau-1 and PHF-1 were combined with bFGF staining. Eleven AD, five nondemented controls, and four DS cases were examined. Most bFGF immunopositive plaques contained numerous dystrophic fibers, indicating they were of the neuritic subtype. We also detected a variety of bFGF-positive cells, including hilar, dentate granule, pyramidal, and stellate neurons, as well as astrocytes. The basement membrane of large and small arterioles also contained bFGF. bFGF immunoreactivity within neurons, astrocytes and the vasculature was increased in AD cases relative to controls. Immunoreactivity within the DS cases was intermediate. These results suggest that bFGF is up-regulated in AD and support the hypothesis that bFGF may attract neurites into plaques. Alternatively, an injured neurite may induce bFGF production by responding glia, resulting in further neuritic attraction.

Aged↗
PubMed1993

Radiation therapy for colorectal cancer.

The role of radiation therapy in the management of colorectal cancer has become more clearly defined as the number of clinical studies has grown. It is now evident that radiation is capable of sterilizing subclinical deposits of cancer at doses tolerable by adjacent normal tissues, and to a lesser extent, these doses can control more bulky cancers. The integration of radiation and chemotherapy has already led to some improvement in survival rates in the adjuvant treatment of rectal cancer. The further development of such combinations seems likely to improve tumor control and survival rates in many stages of cancer. In the next decade, it is also likely that there will be refinement of the use of radiation through better understanding of the biology of colorectal cancer, perhaps supplemented by the development of predictive assays that can guide both the selection of patients for treatment and the choice of the most effective radiation schedule.

Colorectal Neoplasms↗
PubMed1993

Life span changes in the verbal categorization of odors.

An odor description task was used to explore age-related change in odor perception based on 1.19 million U.S. and Canadian respondents (ages 10-90 years) to the National Geographic Smell Survey. Respondents sampled six microencapsulated odorants and selected 1 of 11 descriptors to characterize each smell. Four odors were characterized by strong consensus endorsement of a single descriptor. This consensus weakened with advancing age, and nonmodal descriptors were endorsed more frequently. Nonmodal responses were neither randomly selected, nor systematically biased across odors. Rather, they showed odor-specific patterns of change. Together, these results suggest a marked change in odor categorization across the life span. Odor descriptor profiles were used to generate age-specific multidimensional scaling maps. Stimulus configurations were stable from the third through fifth decades. Those from the sixth through ninth decades showed major displacements for two odors, and suggest that the sweet dimension of odor quality may be particularly variable with maturation.

Adolescent↗
PubMed1993

Mitomycin in anal canal carcinoma.

One hundred and ten patients with primary epidermoid cancers of the anal canal were treated in a series of prospectively designed, nonrandomized protocols of split-course radiation therapy with concurrent administration of 5-fluorouracil (5-FU) with or without mitomycin. The addition of mitomycin was associated with improved primary tumor control rates (87 vs. 58% at 4 years, p = 0.005) and improved 4-year actuarial cause-specific survival (80 vs. 64%, p = 0.02). Hematologic toxicity was the most frequent acute side effect of mitomycin use. No long-term toxicity was attributed to mitomycin only. Mitomycin appeared to benefit patients principally through improved control of cancer in the irradiated volume; there was no evidence of reduced risk of extrapelvic metastases. Several investigators have reported high rates of control of epidermoid anal cancers with preservation of anorectal function following concurrent treatment with mitomycin, 5-FU, and radiation. Mitomycin's role in anal cancer is being evaluated in a randomized clinical trial by the Radiation Therapy Oncology Group. The mechanisms of any interactions between mitomycin and radiation or other cytotoxic drugs in clinical practice remain to be determined.

Actuarial Analysis↗
PubMed1992

Deposition of beta/A4 immunoreactivity and neuronal pathology in transgenic mice expressing the carboxyl-terminal fragment of the Alzheimer amyloid precursor in the brain.

The deposition of amyloid in senile plaques and along the walls of the cerebral vasculature is a characteristic feature of Alzheimer disease. The peptide comprising the carboxyl-terminal 100 amino acids of the beta-amyloid precursor protein (beta APP) has been shown to aggregate into amyloid-like fibrils in vitro and to be neurotoxic, suggesting that this fragment may play a role in the etiology of Alzheimer disease. To address this question, we expressed this carboxyl-terminal 100-amino acid peptide of beta APP in transgenic mice under the control of the brain dystrophin promoter. We used an antibody to the principal component of amyloid, beta/A4, to demonstrate cell-body and neuropil accumulation of beta/A4 immunoreactivity in the brains of 4- and 6-month-old transgenic mice. Only light cytoplasmic staining with this antibody was visible in control mice. In addition, immunocytochemical analysis of the brains with an antibody to the carboxyl terminus of beta APP revealed abnormal aggregation of this epitope of beta APP within vesicular structures in the cytoplasm and in abnormal-appearing neurites in the CA2/3 region of the hippocampus in transgenic mice, similar to its aggregation in the cells of Alzheimer disease brains. Thioflavin S histochemistry suggested accumulations of amyloid in the cerebrovasculature of transgenic mice with the highest expression of the beta APP-C100 transgene. These observations suggest that expression of abnormal carboxyl-terminal subfragments of beta APP in vivo may cause amyloidogenesis and specific neuropathology.

Amyloid beta-Protein Precursor↗
PubMed1992

bFGF promotes the survival of entorhinal layer II neurons after perforant path axotomy.

Infusion of basic fibroblast growth factor (bFGF) prevents the loss of cholinergic neurons in the septum/diagonal band of broca following fimbria-fornix transection. However, an in vivo test of whether bFGF will also rescue injured non-cholinergic or cortical neurons has not been carried out. Previous studies have shown that the majority of layer II stellate neurons utilize an excitatory amino acid as their neurotransmitter. In order to determine if bFGF acts on non-cholinergic cortical neurons, a paradigm was developed to examine whether or not bFGF could spare layer II entorhinal stellate cells from axotomy induced death or atrophy. Axotomy of the medial entorhinal cortex fibers projecting to the dentate gyrus of the hippocampal formation via the perforant path lead to retrograde cell loss in entorhinal cortex. Fourteen or thirty days after a unilateral knife cut axotomy of the perforant path, layer II of medical entorhinal cortex showed a 28% decrease in large stellate neurons as well as many weakly stained, hollow cells compared to the non-lesioned side or naive controls. Layer IV neurons, however, which do not project via the perforant path, showed little detectable change in the number of cells ipsilateral to the knife-cut as compared to the contralateral side. Intraventricular infusion of bFGF over a period of 14 days reduced the 28% cell loss to less than 6%. Thus, bFGF is capable of preventing cortical neuronal loss and/or atrophy associated with retrograde degeneration of non-cholinergic neurons following axotomy.

Animals↗