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Biomedical subjects

B J Cummings

Publications and source records attributed to B J Cummings.

At least 19 recordsLinked to original sources
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↗
PubMed1992

Adjuvant radiation therapy for colorectal cancer.

BACKGROUND: Despite apparently complete resection of cancers of the rectum or colon, many patients have recurrences in the area from which their primary cancer was excised and in more distant organs. Radiation therapy has been used either alone or in combination with chemotherapy as an adjuvant to surgery to reduce the risk of recurrence. METHODS: The literature describing the results of adjuvant radiation treatment for colorectal cancer was reviewed. RESULTS: In randomized studies in patients with moderately advanced rectal cancers (T2-4 N0, M0 or N1-3, M0) adjuvant radiation therapy has often reduced the risk of pelvic recurrence, but has had little effect on survival rates or the risk of extrapelvic metastases. Recent reports show that combined radiation and chemotherapy can improve both disease-free survival and survival rates. Such treatment has caused only moderate toxicity in most studies. Nonrandomized studies in patients in whom small superficial rectal cancers are treated by local excision suggest that adjuvant radiation therapy reduces the risk of pelvic recurrence after this limited surgery and allows anorectal function to be preserved. Strategies similar to those developed for the treatment of rectal cancer are being studied in patients with colon cancer. CONCLUSIONS: In moderately advanced rectal cancers, the combination of chemotherapy and radiation is more effective than radiation alone in reducing local recurrence and increasing survival rates. Additional trials are needed to improve results and to refine drug and radiation schedules. Radiation alone may be sufficient as an adjuvant treatment when combined with local excision of small rectal cancers. The role of radiation in the adjuvant treatment of colon cancer is investigational. There is a need to more accurately delineate the patients with colorectal cancer most likely to benefit from adjuvant therapy.

Aged↗
PubMed1992

Gliotoxic actions of excitatory amino acids.

Cultures of neonatal Type I astrocytes of the rat were exposed to a series of excitatory amino acid analogs to identify those compounds that were gliotoxic. In addition to L-alpha-aminoadipate, a previously identified gliotoxin, L-homocysteate, L-serine-O-sulfate, L-alpha-amino-4-phosphonobutyrate and L-alpha-amino-3-phosphono-propionate were also found to induce a sequence of degenerative events that led to the lysis of the astrocytes. Cellular injury was assessed by quantifying the activity of lactate dehydrogenase present in the surviving astrocytes. Prior to lysis, the cells went through a succession of distinctive morphological changes, the most prominent of which involved nuclear alterations. The nuclei appeared swollen, contained "pale" or "watery" nucleoplasm and exhibited a very prominent nuclear membrane and obvious nucleoli. These astrocytes appeared quite similar in appearance to the Alzheimer's Type II astrocytes, principally associated with the pathology of hepatic encephalopathy. The nuclear anomalies, which are thought to be indicative of cellular damage and compromised function, were also produced by the endogenous transmitters L-glutamate and L-aspartate, although with time, the affected astrocytes appeared to recover and return to normal morphology, without lyzing. These findings suggest that excessive levels of excitatory amino acids may induce cellular damage to astrocytes, as well as neurons. Once damaged, the resulting reductions in astrocyte function may further contribute to CNS losses and the overall pathology attributed to the excitatory amino acids.

Alzheimer Disease↗
PubMed1992

Aggregation of the amyloid precursor protein within degenerating neurons and dystrophic neurites in Alzheimer's disease.

Using a monoclonal antibody raised against purified, native, human protease nexin-2/amyloid precursor protein, which recognizes an amino terminal epitope on the amyloid precursor protein and detects all major isoforms of amyloid precursor protein, we examined the localization of the amyloid precursor protein within Alzheimer's and aged control brains. Very light cytoplasmic neuronal amyloid precursor protein staining but no neuritic staining was visible in control brains. In the Alzheimer's brain, we detected numerous amyloid precursor protein-immunopositive neurons with moderate to strong staining in select regions. Many neurons also contained varying levels of discrete granular, intracellular accumulations of amyloid precursor protein, and a few pyramidal neurons in particular appeared completely filled with amyloid precursor protein granules. "Ghost"-like deposits of amyloid precursor protein granules arranged in pyramidal, plaque-like shapes were identified. We detected long, amyloid precursor protein-immunopositive neurites surrounding and entering plaques. Many contained swollen varicosities along their length or ended in bulbous tips. Amyloid precursor protein immunoreactivity in the Alzheimer's brain was primarily present as granular deposits (plaques). The amyloid precursor protein granules do not appear to co-localize within either astrocytes or microglia, as evidenced by double-labeling immunohistochemistry with anti-glial fibrillary acidic protein and anti-leukocyte common antigen antibodies or Rinucus cummunicus agglutin lectin. Amyloid precursor protein could occasionally be detected in blood vessels in Alzheimer's brains. The predominantly neuronal and neuritic localization of amyloid precursor protein immunoreactivity indicates a neuronal source for much of the amyloid precursor protein observed in Alzheimer's disease pathology, and suggests a time-course of plaque development beginning with neuronal amyloid precursor protein accumulation, then deposition into the extracellular space, subsequent processing by astrocytes or microglia, and resulting in beta-amyloid peptide accumulation in plaques.

Aged↗
PubMed1992

Localization of heparan sulfate glycosaminoglycan and proteoglycan core protein in aged brain and Alzheimer's disease.

Two monoclonal antibodies, one which recognizes a glycosaminoglycan epitope present in heparan sulfate glycosaminoglycan and another which recognizes the core protein of a basement membrane heparan sulfate proteoglycan, were used to study the distribution and localization of these components in Alzheimer's disease and control brain. The cytoplasm of neurons, and occasional neurofibrillary tangles, senile plaques and astrocytes were immunopositive for the heparan sulfate glycosaminoglycan antibody in control brains. In Alzheimer's tissue, however, the number and intensity of these elements was more extensive than in control brains. In addition, within the Alzheimer's brains studied, the nuclei of select neurons and a small number of microglia were also immunopositive for heparan sulfate glycosaminoglycan in contrast to controls, where nuclei and neuroglia were immuno-negative. Some senile plaques in Alzheimer's tissue also contained strong heparan sulfate glycosaminoglycan-positive neurites which were not seen in controls. In Alzheimer's tissue, double labeling for heparan sulfate glycosaminoglycans and the beta-amyloid protein in adjacent sections revealed that, in general, heparan sulfate glycosaminoglycan- and beta-amyloid protein-immunopositive plaques were co-localized. Occasionally, however, beta-amyloid-positive plaques were seen without heparan sulfate glycosaminoglycan immunoreactivity and vice versa. Heparan sulfate glycosaminoglycan immunoreactivity and Tau immunoreactivity co-localized in many neurofibrillary tangles; however a small number of heparan sulfate glycosaminoglycan-positive neurofibrillary tangles did not co-localize with Tau-positive neurofibrillary tangles. In contrast, the heparan sulfate proteoglycan antibody immunostained only the walls of blood vessels and a few senile plaques in Alzheimer's brains and primarily blood vessels in control brains. Heparan sulfate glycosaminoglycan immunostaining was present within neurons, glia, neurofibrillary tangles and senile plaques in Alzheimer's tissue. These results suggest that heparan sulfate-like molecules play an important role in the pathogenesis of the characteristic lesions of Alzheimer's disease and could serve as a marker reflecting early pathological changes.

Aged↗
PubMed1992

beta-Amyloid induces neuritic dystrophy in vitro: similarities with Alzheimer pathology.

beta-Amyloid protein, the major component of neuritic plaques found in Alzheimer's disease, has been implicated as a potential contributor to the disease's progressive neuropathology. We report that within a two day exposure to aggregates of synthetic beta-amyloid peptide, the neurites of cultured rat hippocampal neurons adopt a dystrophic appearance. Observed morphological changes in the neurites include beading, fragmentation, terminal swelling and tortuous growth patterns. The degenerative changes are similar to those observed in neurites associated with neuritic plaques, suggesting that beta-amyloid may induce the neuritic abnormalities of Alzheimer neuropathology.

Alzheimer Disease↗
PubMed1992

Concomitant radiotherapy and chemotherapy for anal cancer.

Concomitant radiotherapy/chemotherapy is widely used to treat epidermoid cancers of the anal canal. The drugs most frequently combined with radiotherapy are 5-fluorouracil and mitomycin, but other schedules include 5-fluorouracil and cisplatin, 5-fluorouracil alone, or bleomycin alone. Since mechanisms of possible interaction between radiotherapy and the cytotoxic drugs are not well understood, schedules have been developed empirically. Randomized trials comparing radiotherapy/chemotherapy with radical radiotherapy alone have not yet been completed. In nonrandomized studies, however, some drug and radiotherapy combinations appear to be superior to radiotherapy alone. Combined modality therapy has resulted in 5-year survival rates of 65% to 80%; approximately 85% of patients retain anorectal function when the primary tumor is controlled by concomitant radiotherapy/chemotherapy.

Anus Neoplasms↗
PubMed1991

Results of external beam irradiation for rectal carcinomas locally recurrent after local excision or electrocoagulation.

The outcome of 42 patients who developed locally recurrent rectal carcinoma after initial local excision or electrocoagulation was presented. Five patients received combined surgery and radiotherapy (XRT). The remaining 37 patients were managed by XRT alone. The overall 5 year actuarial survival and local control rates were 21 and 22%, respectively. For patients who received XRT alone, the 5 year actuarial survival and local control rates were 20 and 15%, respectively. The corresponding figures were 35 and 40% for patients who received a total XRT dose of 50 Gy or more. One patient who underwent combined treatment developed rectal and bladder incontinence requiring surgery. For patients with rectal recurrence after initial conservative surgery, XRT is an alternative to abdominoperineal resection if major surgical resection is contraindicated.

Adult↗
PubMed1991

Epidermoid anal cancer: treatment by radiation alone or by radiation and 5-fluorouracil with and without mitomycin C.

One hundred ninety-two patients with primary epidermoid cancer of the anal canal were treated by a series of prospectively designed, sequential non-randomized protocols of radiation alone (RT), radiation with concurrent 5-Fluorouracil and Mitomycin C (FUMIR), or radiation with concurrent 5-Fluorouracil only (FUR). The 5-year cause-specific survival rates were 69% overall, 68% RT, 76% FUMIR, 64% FUR. The primary tumor was controlled by radiation with or without chemotherapy in 68% (130/191) overall, 56% (32/57) by RT, 86% (59/69) by FUMIR, 60% (39/65) by FUR. The results with FUMIR were significantly better than with either RT alone or FUR, and except in tumors up to 2 cm in size, this superiority was found in all T stages. Regional lymph node metastases were controlled in 33 of 38 (87%) overall. The finding of clinically detectable regional lymph node metastases at presentation did not affect survival significantly in any treatment group. Anorectal function was preserved in 88% of the patients in whom the primary tumor was controlled, and in 64% overall. The delivery of 5FU and MMC concurrently with uninterrupted radical irradiation, 50 Gy in 20 fractions in 4 weeks, produced severe acute and late normal tissue morbidity. Split course treatment, and reduction of the daily fractional dose to 2 Gy, diminished the severity of normal tissue damage. Omission of Mitomycin C reduced acute hematological toxicity, but was associated with a decreased primary tumor control rate. The most effective treatment protocols as measured by survival rates, primary anal tumor control rates, and the likelihood of conservation of anorectal function included the administration of both Mitomycin C and 5-Fluorouracil concurrently with radiation therapy.

Adult↗
PubMed1991

Combined radiation therapy, mitomycin C, and 5-fluorouracil for locally recurrent rectal carcinoma: results of a pilot study.

Twenty-two patients underwent combined radiation therapy (XRT), mitomycin C (MMC), and 5-fluorouracil (5FU) for rectal carcinoma, locally recurrent following either abdominoperineal or anterior resections. All patients presented with symptomatic unresectable pelvic cancer. The protocol XRT doses were 45-50 Gy/20/4-6 weeks. Chemotherapy consisted of MMC 10 mg/m2 on day 1, and 5FU 15 mg/kg/day on days 1, 2, and 3 of XRT, both given by intravenous bolus injection. Only 2 of 22 patients remained NED at 5 years following treatment. All but four patients eventually experienced progression of pelvic disease. Ten of 22 patients were unable to complete the treatment protocol because of excessive acute hematological and gastrointestinal toxicity. Five patients developed neutropenic sepsis, one of whom died. Combined XRT, MMC, and 5FU as used in this study had no apparent advantage over XRT alone in terms of pelvic disease or survival, and produced significant toxicity.

Adenocarcinoma↗
PubMed1991

Adult paratesticular sarcomas: a review of 21 cases.

We reviewed 21 patients more than 16 years old who were seen with a diagnosis of paratesticular sarcoma from 1958 to 1987. Of the patients 14 presented with primary disease and 7 with recurrent disease. The survival of the primarily treated patients was 58% at 5 years, calculated by the product limit method. Of the 14 patients with primary disease 13 had grade 3/4 or 4/4 sarcoma and 13 of 14 underwent initial radical orchiectomy. In addition, 6 of the 14 patients underwent an adjuvant operation or radiotherapy to the groin, or groin and scrotum, and none had local relapse. Some patients also had chemotherapy. Three patients underwent adjuvant retroperitoneal node dissection and 2 had microscopically positive nodes. All 3 patients remain without relapse. Six patients had relapse: 2 locally, 2 in the retroperitoneal nodes and 2 with distant metastases. Only 1 patient (with scrotal recurrence) was salvaged. Of the 7 patients referred with recurrent disease none was salvaged. In this series there is a 2 of 14 (14%) risk of local failure and a 4 of 14 (28%) risk of retroperitoneal relapse after radical orchiectomy. Since salvage has not proved successful, patients with rhabdomyosarcoma, intermediate or high grade malignant fibrous histiocytoma, or fibrosarcoma should be considered for adjuvant retroperitoneal node dissection. All patients should undergo adjuvant dissection or irradiation of the ipsilateral pelvic and groin nodes, and scrotum.

Adolescent↗
PubMed1991

Bladder cancer: long-term follow-up results of patients treated with radical radiation.

Carcinoma of the bladder is commonly treated for cure with external beam radiation. Whilst short-term results are associated with a good chance of disease control there is little information about the long-term results of such therapy. We present a retrospective review of the Princess Margaret Hospital experience in treating transitional cell carcinoma of the bladder and emphasis on the long-term follow-up of patients treated with radiotherapy (XRT). Between 1972 and 1980, 355 patients were treated with a radical course of external beam radiation. The overall survival was 20% at 10 years and the cause-specific survival was 32%. Radiation treatment resulted in a long-term bladder preservation in at least 25% of patients. The majority of long-term survivors without evidence of relapse were patients with T1 (solitary tumours), T2 and T3a tumours. This subgroup represents patients with disease favourable for treatment with radiation. Factors affecting response to the XRT and survival included T stage and tumour bulk. Radiation complications were frequent and were usually associated with local disease recurrence.

Adult↗
PubMed1990

Anal cancer.

Combined modality treatment with radiation, chemotherapy, and conservative surgery controls most epidermoid cancers of the anal canal and advanced squamous cell cancers of the perianal skin. Anorectal function is preserved in about 70% of patients or more. Five-year survival rates are similar to those previously obtained with radical surgery or radical radiation therapy. The cytotoxic drugs 5-Fluorouracil and Mitomycin C are frequently given concurrently with radiation, but other effective regimens have also been described. The mechanisms of interaction of radiation and cytotoxic drugs in the treatment of anal cancer are not known.

Anus Neoplasms↗