PubMed Health⌕ Search

Biomedical subjects

W C Wallace

Publications and source records attributed to W C Wallace.

At least 19 recordsLinked to original sources
PubMed2001

Characterization of the neurotrophic interaction between nerve growth factor and secreted alpha-amyloid precursor protein.

The expression and secretion of amyloid precursor protein (beta APP) is increased in rat cerebral cortices that have been denervated by subcortical lesions of the nucleus basalis of Meynert. The physiological role of the secreted beta APP in response to this injury has not been established. We have previously shown that secreted beta APP produced by alpha-secretase activity (sAPP(alpha)) potentiates the neuritogenic activity of nerve growth factor (NGF) in vitro on naive PC12 cells. In this investigation, we have further characterized the neurotrophic interaction of NGF and sAPP(alpha) using differentiated PC12 cells and rat primary cortical neurons. NGF required the expression of beta APP to maintain a neuronal phenotype. Reduction of endogenous beta APP expression by introduction of antisense oligonucleotides in the presence of NGF resulted in loss of neurites from differentiated PC12 cells but no apparent cell death. Addition of exogenous sAPP(alpha) (60--200 pM) potentiated the protective activity of NGF in serum-deprived differentiated PC12 cells as determined by retention of neurites and cell viability. In addition, exogenous sAPP(alpha) increased neuron viability in both short-term (3 days) cortical neuron cultures grown in the absence of serum and in long-term (9 days) cultures grown with serum. Disruption of the insulin signaling pathway by reduction of IRS-1 expression inhibited the ability of sAPP(alpha) to potentiate neurotrophic activity. These observations suggest that sAPP(alpha) acts as an injury-induced neurotrophic factor that interacts with NGF to enhance neuronal viability using the insulin signaling pathway.

Amyloid Precursor Protein Secretases↗
PubMed2000

New epidemiology for postoperative nosocomial infections.

Changes in health care delivery systems over the last decade have resulted in a major increase in outpatient surgery and a higher severity of illness for inpatients. We sought to determine the effects of this change on the epidemiology of postoperative surgical infections. Historical data on incidence and epidemiology of infection were obtained from peer-reviewed articles published between 1960 and 1999 (MEDLINE). All nosocomial infections in 5035 patients admitted to a tertiary-care university hospital surgical intensive care unit between January 1994 and December 1997 were prospectively identified and classified as wound, urinary tract, bloodstream, or pneumonia. Incidence of bacterial isolates at each site was also recorded. From these data we determined infection rates per 100 admissions. We also identified all device-related nosocomial infections and calculated infection rates. Comparisons between time periods were made. In the 1960s wound infections constituted the predominant postoperative infection at 46 per cent. This was replaced by urinary tract infection in the 1970s (44%) and 1980s (32%) and closely followed by bloodstream infections (25%). In the 1990s nosocomial pneumonia became the most common postoperative infection, comprising 43 per cent of surgical intensive care unit infections. Analysis of the bacteriology also revealed changing trends with primarily gram-positive organisms in the 1960s followed by an increase in methicillin-resistant Staphylococcus in the 1970 to 1980s, and currently resistant gram-negative bacteria predominate. The incidence of fungal infections has steadily increased. This survey identified a new epidemiology for postoperative surgical infections. Over the last several decades the reported wound infections have been markedly decreased and there is little change in urinary tract infection. Nosocomial pneumonia with resistant gram-negative bacteria now predominates along with increased incidence of fungal infections. Currently, postoperative infections are now more severe, involve critical organs, and require close monitoring of the changing patterns of pathogens.

Ambulatory Surgical Procedures↗
PubMed1999

Improved survival following massive transfusion in patients who have undergone trauma.

HYPOTHESIS: Survival following massive transfusion in patients who have undergone trauma has improved during the past 10 years. DESIGN: Retrospective cohort study. SETTING: Academic level I trauma center in an urban community. PATIENTS: All patients who underwent trauma and who received greater than 50 U of packed red blood cells or whole blood in the 48 hours following admission to the emergency department. INTERVENTIONS: Data were obtained from blood bank records, the trauma registry, patient medical records, and hospital purchasing records. Patients were divided into 2 groups for comparison (early [1988-1992] and late [1993-1997] periods). MAIN OUTCOME MEASURES: Survival and changes in trauma care provision. RESULTS: Survival following massive transfusion in patients who have undergone trauma has significantly increased during the past 10 years (16% vs 45%, early vs late period, P = .03). Factors associated with poor outcome included male sex, major vascular injury, high Injury Severity Score, severe acidosis, prolonged hypotension, refractory hypothermia, and decreased use of platelet transfusion (all P<.05). In the later period, there was more aggressive correction of coagulopathy, more efficient use of warming measures, decreased operative times for the initial operation, and increased use of component therapy (all P<.05). CONCLUSIONS: Survival following massive transfusion has significantly (P = .03) increased during the past 10 years. Factors that may have contributed to this include more effective and efficient rewarming procedures, improved application of damage control techniques, more aggressive correction of coagulopathy, and improved blood banking procedures.

Adult↗
PubMed1999

Nosocomial infections in the surgical intensive care unit: a difference between trauma and surgical patients.

In 1970, the Centers for Disease Control and Prevention (CDC) established the National Nosocomial Infection Surveillance System to assist institutions with infection surveillance, data collection, and processing. This facilitates interinstitutional comparison for nosocomial infection rates. Nosocomial infection rates in the surgical intensive care unit have been shown to be different from the medical intensive care unit. Whether there exists a difference in infection rates between trauma and surgical patients in the intensive care unit has not been established. Our objective was to determine whether there is a difference in rates of nosocomial infections between trauma and surgical patients in the surgical intensive care unit. From January 1995 through December 1997, we reviewed 3715 admissions to the surgical intensive care unit and separated them into trauma (1272) or surgical (2443) cases. We documented all nosocomial pneumonias, urinary tract infections, bloodstream infections, and surgical site infections. From these data we determined infection rates per 100 admissions. We also identified all device-related nosocomial infections and calculated infection rate by current CDC standards using number of device infections divided by number of device-days times 1000. We found that the overall trauma patient infection rate was 11.64 per cent compared with 6.43 per cent for surgical patients (P<.001). Using conventional infection rate criteria, trauma patients had higher frequency in the rate of ventilator-associated pneumonia (6.13% vs. 2.50%; P<0.001), urinary tract infection (2.36 versus 1.76; P<0.2), and bloodstream infection (2.52% versus 1.27%; P<0.01). However, when using the CDC guidelines, which correct for the number of device-days for infections, only the difference in rate of pneumonia between the two groups reached statistical significance (23.9 rate for trauma patients vs. 16.7 for the surgery group; P<0.005). We conclude that trauma patients are at higher risk for nosocomial infections than routine surgical patients. Because of this difference, centers should collect and report data separately for trauma and surgical patients in the intensive care unit. Specific attention should be focused on the causes and prevention of increased rates of nosocomial pneumonia in trauma patients.

Bacteremia↗
PubMed1998

Peroxisomal disease cell lines with cellular plasmalogen deficiency have impaired muscarinic cholinergic signal transduction activity and amyloid precursor protein secretion.

We tested whether alterations in membrane lipid composition associated with peroxisomal diseases affect muscarinic cholinergic signal transduction activity and amyloid precursor protein (APP) secretion in cultured human skin fibroblasts and Chinese hamster ovary (CHO) mutants. We found that in cell lines from patients with peroxisomal disorders where plasmalogen levels were low, the low-Km GTPase activity was not induced by carbachol, and APP secretion was reduced. This effect on signal transduction activity was not associated with decreased levels of the M1-muscarinic cholinergic receptor or its associated heterotrimeric G-protein. Specifically, this decrease was associated with a plasmalogen deficiency since a CHO cell line with only a deficit in plasmalogens was as severely affected as were generalized peroxisomal disorder cell lines. Thus, plasmalogens appear to be implicated in muscarinic cholinergic signal transduction and secretion of APP. These results provide new insights about the pathophysiology of peroxisomal diseases and may be relevant to Alzheimer's disease where reduced plasmalogen levels have been reported.

Amyloid beta-Protein Precursor↗
PubMed1998

Amyloid precursor protein modulates the interaction of nerve growth factor with p75 receptor and potentiates its activation of trkA phosphorylation.

We have recently shown that the secreted form of amyloid precursor protein (APPs) potentiates the neurotrophic actions of nerve growth factor (NGF). The combined presence of NGF and APPs in low concentrations resulted in a synergistic potentiation of NGF neuritogenic activity on PC12 cells. Therefore, the effect of APPs on NGF receptor-binding has been examined. In the presence of APPs, the apparent affinity of NGF's low affinity binding site increased by a factor of 2.5. In addition, a 2- to 2.5-fold decrease in the number of sites was observed, although APPs did not compete with NGF for the same binding sites. These effects of APPs were not caused by direct interaction with NGF itself. In addition, APPs synergistically potentiated the tyrosine phosphorylation of trkA due to NGF. These results suggest that an increased affinity of p75 for NGF may underlie the potentiation of neurotrophic actions of NGF by APPs, and that increase may be caused by an indirect interaction between APPs and p75.

Amyloid beta-Protein Precursor↗
PubMed1997

Amyloid precursor protein potentiates the neurotrophic activity of NGF.

Cortical amyloid precursor protein (APP) is induced and secreted in response to subcortical lesions of cholinergic innervation. To understand the physiological role of the induced APP, we have characterized its neurotrophic activity on PC12 cells. Highly purified human APP751 (50-1000 pM) induced outgrowth of neurites. The neurotrophic activity was inhibited by an antibody that was directed to the C-terminal portion of the secreted APP but not by an antibody directed to the KPI domain. The neurotrophic activity of APP was independent of the TrkA NGF receptor because neither phospholipase C-gamma1 nor TrkA exhibited tyrosine phosphorylations with APP treatment. Furthermore, APP stimulated neurite outgrowth from PC12 cells lacking TrkA receptors. At lower concentrations (10-50 pM), APP synergistically potentiated the neurotrophic effects of NGF when added with NGF or before NGF as a priming pretreatment. These results implicate APP, a rapidly induced protein in the injured cortex, as a potentiating agent that may render compromised neurons more responsive to low levels of NGF or other neurotrophins.

Amyloid beta-Protein Precursor↗
PubMed1997

Amyloid precursor protein requires the insulin signaling pathway for neurotrophic activity.

Picomolar concentrations of purified amyloid precursor protein (APP) potentiate the neurotrophic activity of suboptimal concentrations of NGF on PC12 cells. To understand the molecular basis for this potentiation, we have characterized the signal transduction pathway used by APP for its neurotrophic activity. APP stimulated the tyrosine phosphorylation of a number of proteins including insulin receptor substrate-1 (IRS-1). Incubation of naive cells with antisense oligonucleotides to IRS-1 mRNA resulted in a dramatic reduction of IRS-1 levels and inhibition of APP stimulated neurite outgrowth. Phosphotidylinositol 3-kinase became associated with IRS-1 and activated upon APP stimulation. Extracellular signal-regulated kinase (ERK 1 and ERK 2) phosphorylation was detected by both immunoblot analysis and immunocytochemistry using antibodies directed to their phosphorylated (and hence, activated) form. There was also an elevation of ERK kinase activity. The potentiation of NGF activity was reflected in a correspondingly synergistic elevation of tyrosine phosphorylated ERK. The pattern of signal transduction targets indicates that APP potentiated the neurotrophic effects of NGF via the activation of the IRS-1 signaling pathway.

Amyloid beta-Protein Precursor↗
PubMed1997

Pharmacological modulation of Alzheimer's beta-amyloid precursor protein levels in the CSF of rats with forebrain cholinergic system lesions.

Abnormal deposition and accumulation of Alzheimer's amyloid beta-protein (A beta) and degeneration of forebrain cholinergic neurons are among the principal features of Alzheimer's disease. Studies in rat model systems have shown that forebrain cholinergic deficits are accompanied by induction of cortical beta-amyloid precursor protein (beta-APP) mRNAs and increased levels of secreted beta-APP in the CSF. The studies reported here determined whether the CSF levels of secreted beta-APP could be altered pharmacologically. In different experiments, rats with lesions of the forebrain cholinergic system received injections of vehicle, a muscarinic receptor antagonist scopolamine, or one of two cholinesterase inhibitors - diisopropyl phosphorofluoridate (DFP) or phenserine. Scopolamine was administered to determine whether the levels of beta-APP in the CSF could be increased by anticholinergic agents. The cholinesterase inhibitors were administered to determine whether the forebrain cholinergic system lesion-induced increases in CSF beta-APP could be reduced by cholinergic augmentation. Scopolamine administration led to a significant increase in the CSF levels of secreted beta-APP in sham-lesioned rats. Phenserine, a novel, reversible acetyl-selective cholinesterase inhibitor, significantly decreased the levels of secreted beta-APP in the CSF of forebrain cholinergic system-lesioned rats whereas DFP, a relatively non-specific cholinesterase inhibitor, failed to affect CSF levels of secreted beta-APP. These results suggest that the levels of secreted beta-APP in the CSF can be pharmacologically modulated but that this modulation is dependent upon the status of the forebrain cholinergic system and the pharmacological properties of the drugs used to influence it.

Alzheimer Disease↗
PubMed1995

Chronic elevation of secreted amyloid precursor protein in subcortically lesioned rats, and its exacerbation in aged rats.

Subcortically lesioned rats were used as an animal model of some of the neurochemical and behavioral deficits of Alzheimer's disease (AD) to investigate the in vivo expression and metabolism of amyloid precursor protein (APP). Previously, the rapid and persistent induction of APP was described in cerebral cortices after disruption of its cholinergic, serotonergic, or noradrenergic afferents. In the present study, this induction was found to lead to the elevated secretion of APP into the cerebrospinal fluid of lesioned animals. Lesions of the forebrain cholinergic system in aged rats caused an even greater increase in the CSF levels of secreted APP. Antibodies to the extracellular domain of APP detected the protein whereas antibodies to the cytoplasmic region did not, indicating that the APP present in CSF was of the soluble form. Immunoprecipitation with an A beta sequence-specific antibody followed by immunoblot analysis indicated that a significant portion of secreted APP was of the species that contains at least the first 28 amino acids of the A beta sequence (APP gamma or APPA beta). By contrast, very low levels of A beta peptide were detected in CSF. The secretion was accompanied by an elevation of cellular C-terminal fragments of the APP in the lesioned cortex. Consistent with our previous results, this increased APP secretion was caused by lesions of subcortical cholinergic and serotonergic systems. The postlesion time course of APP secretion showed an initial reduction of APP (1 hr postlesion) in CSF followed by an eventual twofold elevation 1-6 weeks later. These results indicate that the induction of APP in response to loss of subcortical innervation leads to elevated secretion of a soluble form of cortically derived APP that contains significant portions of the A beta sequence.

Aging↗
PubMed1994

Erythroid failure in Diamond-Blackfan anemia is characterized by apoptosis.

Programmed cell death, also known as apoptosis, is frequently initiated when cells are deprived of specific trophic factors. To investigate if accelerated apoptosis contributes to the pathogenesis of Diamond-Blackfan anemia (DBA), a rare pure red blood cell aplasia of childhood, we studied the effect of erythropoietin (epo) deprivation on erythroid progenitors and precursors from the bone marrow of DBA patients as compared with hematologically normal controls. Apoptosis in response to epo deprivation was evaluated by enumeration of colony-forming unit-erythroid (CFU-E)- and burst-forming unit-erythroid (BFU-E)-derived colonies in plasma clot semisolid culture and by the identification of typical DNA oligosomes by gel electrophoresis from marrow mononuclear cells in liquid culture. In all DBA patients there was a marked decrease in CFU-E- and BFU-E-derived colony formation compared with normal controls at comparable time points of epo deprivation, with a complete loss of CFU-E-derived colonies in semisolid culture by 9 hours of epo deprivation versus 48 hours in controls. The BFU-E-derived colony response to epo deprivation displayed a similar pattern of decrement. Apoptotic changes assessed by the presence of characteristic DNA fragmentation began in the absence of epo deprivation and were readily detected within 3 hours of epo deprivation in DBA cultures versus 9 hours in controls. We conclude that DBA is characterized by accelerated apoptosis as measured by the loss of erythroid progenitor clonogenicity and increased progenitor and precursor DNA fragmentation leading to the formation of characteristic oligosomes, consistent with an intrinsic erythroid-progenitor defect in which increased sensitivity to epo deprivation results in erythroid failure.

Adolescent↗
PubMed1994

Heat shock proteins protect against stress-related phosphorylation of tau in neuronal PC12 cells that have acquired thermotolerance.

A68, or PHF-tau, is an abnormally phosphorylated form of the microtubule-associated protein tau, which is a primary protein constituent of paired helical filaments (PHFs) and, ultimately, of Alzheimer's disease-associated neurofibrillary tangles (NFTs). Previously, we have shown that in heat-shocked neuronal PC12 cells, tau is hyperphosphorylated and transformed to an A68-like state as determined by immunologic and biochemical criteria. In the present study, we investigated the role of heat shock protein of 72 kDa (hsp72) in the protection of tau against hyperphosphorylation during heat shock. Neuronal PC12 cells were exposed either directly to a heat shock (45 degrees C for 30 min) or to a conditioning heat stress (43 degrees C for 90 min followed by a 4 hr recovery at 37 degrees C) followed by the heat shock. Hsp72 was maximally induced immediately after heat shock in conditioned (acquired thermotolerant, ATT) cells, while unconditioned (nonacquired thermotolerant, non-ATT) cells required 9 hr of recovery to exhibit maximal hsp72 induction. The differential time course of hsp72 induction during recovery of ATT and non-ATT cells correlated with the presence of normal tau. Immediately after the heat shock, when hsps were maximally induced, ATT cells exhibited the normal form of tau. With longer recovery times, the levels of hsp72 were reduced and tau was hyperphosphorylated. A similar correlation was observed in non-ATT cells. In the presence of L-azetidyl 2-carboxylic acid, ATT cells synthesized nonfunctional hsp72, as exhibited by the inability of the cells to recover from the effects of heat shock.(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation, Physiological↗
PubMed1991

Increased biosynthesis of Alzheimer amyloid precursor protein in the cerebral cortex of rats with lesions of the nucleus basalis of Meynert.

The nucleus basalis of Meynert was lesioned by infusion of N-methyl-D-aspartate (NMDA) unilaterally in adult rat brain. Seven days post lesion we observed that polysomes isolated from the cerebral cortex affected by the lesion synthesized 2.6-fold greater amounts of the Alzheimer amyloid precursor protein (AAPP) compared to the nonlesioned side of the same rat brain. This increase exhibited specificity to AAPP in that overall protein synthesis was not altered by the lesion. The increase of AAPP did not alter the ratio of AAPP isotypes in rat brain (in which AAPP 695, which is lacking the protease inhibitor insert remains the predominant form). The increased synthesis did not result in the apparent accumulation of mature AAPP. These results indicate that a cholinergic lesion which models many of the neurochemical changes observed in Alzheimer's disease induces the expression of AAPP in a major projection region, the cerebral cortex.

Acetylcholinesterase↗
PubMed1991

Reduced in vitro phosphorylation of synapsin I (site 1) in Alzheimer's disease postmortem tissues.

Homogenates prepared from the temporal cortex and hippocampus of individuals who had histopathologically confirmed Alzheimer's disease exhibited reduced in vitro cyclic AMP-dependent phosphorylation of synapsin I, neuronal phosphoprotein. One specific phosphorylation site (site 1) was affected while two other sites, which are phosphorylated by calcium/calmodulin kinase II, exhibited no such differences. Other phosphoproteins such as pyruvate dehydrogenase, did not show these differences. The reductions were not observed in either cerebellum or thalamus of Alzheimer's disease brain. Analysis by immunoblots indicated that the reductions were not caused by a decrease in absolute amounts of the protein. The reduced AD synapsin I phosphorylation was not overcome by the addition of purified cyclic AMP-dependent protein kinase. No differences were detected in total cyclic AMP-dependent protein kinase activity between the control and Alzheimer samples. However, dephosphorylation of the synapsin I prior to the in vitro phosphorylation reversed the differences observed between the control and AD homogenates. Thus, the reduced in vitro phosphorylation of the synapsin I in the Alzheimer homogenate reflects a reduced phosphorylatability of the protein due to either an increased phosphate content or some other alteration of the phosphorylation site.

Alzheimer Disease↗
PubMed1989

Alzheimer's disease-associated reduction of polysomal mRNA translation.

Polysomes from the frontal cortices of individuals who had histopathologically confirmed Alzheimer's disease were compared with polysomes from individuals who exhibited no neuropathological conditions. The cytosolic polysome yield from Alzheimer's disease frontal cortex was reduced 40% compared with that obtained from control frontal cortex. The translational activity per unit polysome of the Alzheimer's disease polysomes was only 50% of control in a reticulocyte lysate in vitro translation assay in which human polysomes do not undergo reinitiation. These differences exhibited brain region specificity in that polysomes isolated from Alzheimer's disease cerebellum were not different from control cerebellar polysomes. Thus, the disruptions are not due to a secondary and general response of the entire brain to the disease. These reductions were reflected by similar decreases in the translation of the mRNA for high molecular weight neurofilament polypeptide. Thus, the inhibition of polysomal mRNA translation is a mechanism by which gene expression is impaired in pathologically involved brain regions of individuals afflicted by Alzheimer's disease.

Aged↗
PubMed1982

The effects of platelet secretion inhibitors on protein phosphorylation.

Protein phosphorylation was investigated in human platelets after stimulation to secretion by thrombin. After stimulation by thrombin at 4 degrees C (in which secretion is inhibited), phosphorylations of the 80, 56, and 38 kDa polypeptides and dephosphorylation of the 67 kDa phosphopeptide eventually occurred. The phosphorylations of the 27 and 20 kDa polypeptides remained inhibited until the temperature was increased to 37 degree C, which also resulted in secretion. Various stimulants and inhibitors of platelet function were used to characterize individual protein phosphorylations. The divalent-cation ionophore, A23187, induced the phosphorylations (or dephosphorylation) of the same proteins as thrombin with the exception of the 80 kDa protein, which remained incompletely phosphorylated. The intracellular calcium antagonist, TMB-8, inhibited thrombin-stimulated secretion and phosphorylation of all the polypeptides except the 80 kDa protein. The dephosphorylation of the 67 kDa phosphoprotein was not affected by TMB-8. Incubation of platelets with prostaglandin E1 and isobutylmethylxanthine inhibited thrombin-stimulated secretion and the phosphorylation of the 38 and 20 kDa protein and increased the phosphorylation of the 67 and 27 kDa phosphoproteins. These observations may be used to correlate protein phosphorylation with secretion, suggesting a possible sequence of intracellular events that mediate thrombin-stimulated secretion.

1-Methyl-3-isobutylxanthine↗