Biomedical subjects
Publications and source records attributed to D Parkinson.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
The beta-amyloid protein deposited in senile plaques and cerebral blood vessels in the Alzheimer's disease brain is derived from the larger transmembrane spanning amyloid precursor protein. The present study investigates the effects of heat shock on the expression and processing of amyloid precursor protein in a normal human fetal astrocytic cell line CC2565 using reverse transcription-polymerase chain reaction, in situ hybridization histochemistry and western blot analysis. Heat shock led to an increase in the messenger RNA encoding Kunitz protease inhibitor isoforms of amyloid precursor protein, which peaked at 4h post-heat shock. This increase was confined to the messenger RNA encoding amyloid precursor protein-751, with a decrease in amyloid precursor protein-770 and no change in amyloid precursor protein-695. This shift in splicing was accompanied by a significant decrease in secreted amyloid precursor protein and an increase in beta-secretase processing within the cell. These findings demonstrate that astrocytes in vitro demonstrate a striking response to heat shock. This is unlikely to be due to a direct action on the promoter region of the gene, since the response is specific for one splice variant; amyloid precursor protein-751 messenger RNA. This increase in expression is further accompanied by a decrease in secretion of amyloid precursor protein, implying a shift in processing towards an intracellular route, possibly via the actions of the beta-secretase enzyme, which is known to be potentially amyloidogenic. Such a mechanism may contribute to amyloidosis in the intact brain in response to cellular stress, such as head injury.
The lengthy, continuous, slender extradural neural axis compartment (EDNAC), which extends from the coccyx to the orbit, has been not so much discovered as recognized. Through this compartment run arteries, myelinated and unmyelinated nerves, and valveless veins. Adipose tissue is abundant in the orbital and spinal segments, possibly due to movement requirements, although it is very sparse in the skull base segment, the last segment to be recognized as a continuation of the EDNAC, which connects Breschet's veins to the orbit. The lateral sellar compartment (in older terminology, the cavernous sinus) is an enlarged segment of this EDNAC along the skull base connecting the orbit with the extradural space through the superior orbital fissure and down the dorsum to Breschet's veins of the basilar process of the occipital bone. Understanding the continuity of the EDNAC should help the student understand any segment, particularly the skull base. As Batson noted, "Living anatomy is slowly editing and replacing the anatomy of the dead room."
A novel polyclonal antibody (Ab993), specific for a KPI domain epitope of APP, was characterised for use in immunoprecipitation, Western blotting and immunohistochemistry. Conditioned medium from NTera2/D1 cells was used for immunoprecipitation and Western blots. Paraffin-embedded human brain sections were used for immunohistochemistry. The antibody recognised KPI-containing APP on Western blots after standard solubilisation but immunoprecipitation of soluble APP required reduction with 2-mercaptoethanol followed by alkylation of reduced sulphydryl bonds with sodium iodoacetate. Immunohistochemical staining of human brain sections was significantly enhanced by this pre-treatment. Microwaving of sections also increased immunolabelling, by a mechanism that was additive to reduction and alkylation. Incubation in 80% formic acid did not confer any enhancement of immunoreactivity. Ab993, applied with the methods reported here, is expected to be valuable in investigations of the pathogenesis of Alzheimer's disease to determine the source of the beta-amyloid peptide.
Previously we proposed that Schwann cell development from the neural crest is a two-step process that involves the generation of one main intermediate cell type, the Schwann cell precursor. Until now Schwann cell precursors have only been identified in the rat, and much remains to be learned about these cells and how they generate Schwann cells. Here we identify this cell in the mouse and analyze its transition to form Schwann cells in terms of timing, molecular expression, and extracellular signals and intracellular pathways involved in survival, proliferation, and differentiation. In the mouse, the transition from precursors to Schwann cells takes place 2 days earlier than in the rat, i.e., between embryo days 12/13 and 15/16, and is accompanied by the appearance of the 04 antigen and the establishment of an autocrine survival circuit. Beta neuregulins block precursor apoptosis and support Schwann cell generation in vitro, a process that is accelerated by basic fibroblast growth factor 2. The development of Schwann cells from precursors also involves a change in the intracellular survival signals utilized by neuregulins: To block precursor death neuregulins need to signal through both the mitogen-activated protein kinase and the phosphoinositide-3-kinase pathways although neuregulins support Schwann cell survival by signaling through the phosphoinositide-3-kinase pathway alone. Last, we describe the generation of precursor cultures from single 12-day-old embryos, a prerequisite for culture studies of genetically altered precursors when embryos are non-identical with respect to the transgene in question.
Explore the source record for details and available documents.
Despite reports that i.v. melphalan is active in the settings of conditioning regimens utilizing high-dose chemotherapy for autologous bone marrow transplantation and in isolated limb perfusion for the treatment of malignant melanoma, its activity at conventional doses has never been defined in this disease. We conducted a phase II study of conventional-dose i.v. melphalan (30 mg/m2) in 17 patients with metastatic melanoma. All patients were previously untreated with chemotherapy with performance status 0, 1 or 2. Forty-seven cycles were given with a median of two cycles. One patient was not evaluable due to early death. There were no responses in the 16 patients, resulting in a 0% response rate (95% confidence interval = 0-17%). We conclude that conventional-dose melphalan by i.v. administration has no appreciable activity in patients with metastatic malignant melanoma.
PURPOSE: To determine the short- and long-term efficacy and toxicity of the high-dose intravenous bolus interleukin 2 (IL-2) regimen in patients with metastatic melanoma. PATIENTS AND METHODS: Two hundred seventy assessable patients were entered onto eight clinical trials conducted between 1985 and 1993. IL-2 (Proleukin [aldesleukin]; Chiron Corp, Emeryville, CA) 600,000 or 720,000 IU/kg was administered by 15-minute intravenous infusion every 8 hours for up to 14 consecutive doses over 5 days as clinically tolerated with maximum support, including pressors. A second identical treatment cycle was scheduled after 6 to 9 days of rest, and courses could be repeated every 6 to 12 weeks in stable or responding patients. Data were analyzed through fall 1996. RESULTS: The overall objective response rate was 16% (95% confidence interval, 12% to 21%); there were 17 complete responses (CRs) (6%) and 26 partial responses (PRs) (10%). Responses occurred with all sites of disease and in patients with large tumor burdens. The median response duration for patients who achieved a CR has not been reached and was 5.9 months for those who achieved a PR. Twelve (28%) of the responding patients, including 10 (59%) of the patients who achieved a CR, remain progression-free. Disease did not progress in any patient responding for more than 30 months. Baseline performance status and whether patients had received prior systemic therapy were the only predictive prognostic factors for response to IL-2 therapy. Toxicities, although severe, generally reversed rapidly after therapy was completed. Six patients (2%) died from adverse events, all related to sepsis. CONCLUSION: High-dose IL-2 treatment seems to benefit some patients with metastatic melanoma by producing durable CRs or PRs and should be considered for appropriately selected melanoma patients.
Explore the source record for details and available documents.
It is well established that hypothermia will protect cerebral and cord tissue against necrosis from prolonged ischemia. The optimum depth of hypothermia and safe total time has not yet been established. There is considerable evidence that hypothermia may be useful as a treatment adjunct after trauma or ischemias, but the same caveats apply. There are agreed risks, the exact nature of which are unknown, and there are suspicions that hypothermia after the insult may be only delaying the natural recovery processes.
Claudios Galen (119-199 a.d.) dissected lower animals with parasellar carotid retia bathed in venous blood and transposed his findings to human anatomy. Andreas Vesalius (1514-1564) corrected most of Galen's errors but apparently never looked into this small, extradural compartment, nor, apparently, did Winslow (Exposition Anatomique de la Structure du Corps Humain. London: N. Prevast, 1734), who christened it the "cavernous sinus," (CS) presumably thinking that it would resemble the corpora cavernosa of the penis. Multiple surgical explorations, gross dissections, microscopic views, and vascular casts from early fetuses to an 81 year old have been examined and reviewed. The CS is not a dural sinus nor is it cavernous. The compartment is extradural, and the venous structures contained within consist of a greatly variable plexus of extremely thin-walled veins. The name, CS, is a barrier to the understanding of the structure and function of this extradural anatomical jewel box, which contains fat, myelinated and nonmyelinated nerves, arteries, and a plexus of veins. It is proposed that this name be changed, because it is inaccurate and misleading. The replacement should leave no doubt about its meaning. The lateral sellar compartment is descriptive and accurate. The veins within are a parasellar plexus.
Explore the source record for details and available documents.