The association between white blood cell count and acute myocardial infarction mortality in patients > or =65 years of age: findings from the cooperative cardiovascular project.

OBJECTIVES: The purpose of the study was to examine the association between white blood cell (WBC) count on admission and 30-day mortality in patients with acute myocardial infarction (AMI). BACKGROUND: Elevations in WBC count have been associated with the development of AMI and with long-term mortality in patients with coronary artery disease. However, the relationship between WBC count and prognosis following AMI is less clear. METHODS: Using the Cooperative Cardiovascular Project database, we evaluated 153,213 patients > or = 65 years of age admitted with AMI. RESULTS: An increasing WBC count is associated with a significantly higher risk of in-hospital events, in-hospital mortality and 30-day mortality. Relative to those patients in the lowest quintile, patients in the highest quintile were three times more likely to die at 30 days (10.3% vs. 32.3%; p < 0.001). After adjustment for confounding factors, WBC count was found to be a strong independent predictor of 30-day mortality (odds ratio = 2.37; 95% confidence interval 2.25 to 2.49, p = 0.0001 for the highest quintile of WBC count). CONCLUSIONS: White blood cell count within 24 h of admission for an AMI is a strong and independent predictor of in-hospital and 30-day mortality as well as in-hospital clinical events. Although the mechanism of the association remains speculative, the results of this study have important clinical implications for risk-stratifying patients with AMI.

Structure and functions of human cerebrospinal fluid lipoproteins from individuals of different APOE genotypes.

Recent data have implicated apolipoprotein E (apoE) in neuritic outgrowth, synaptic stability, and Alzheimer's disease; these data led us to examine the normal role of apoE-containing lipoproteins in the central nervous system (CNS). We isolated lipoproteins from human cerebrospinal fluid (CSF) in order to examine their composition and potential functions. CSF particles were composed of approximately one-third protein, one-third phospholipid, and one-third cholesterol. ApoE3 formed homodimers and heterodimers with apoA-II, while apoE4, as expected, was monomeric. We addressed the function of CSF lipoproteins with assays of cholesterol efflux and cholesterol influx. CSF lipoproteins decreased intracellular levels of cholesterol in cholesterol-loaded fibroblasts, suggesting these particles can act to remove excess lipids from cells. CSF lipoproteins competed for 125I-labeled LDL degradation by fibroblasts, suggesting they can also interact with the LDL receptor. Furthermore, CSF lipoproteins labeled with the fluorescent dye Dil were internalized by neuroglioma cells and primary neurons and astrocytes in culture. Together, these data support a model of CSF lipoproteins acting to remove lipids from degenerating cells and delivering lipids to cells for new membrane synthesis or storage.

Brain expression of apolipoproteins E, J, and A-I in Alzheimer's disease.

Inheritance of the epsilon 4 allele of apolipoprotein (apo) E is associated with increased risk of Alzheimer's disease (AD) and with increased beta-amyloid peptide (A beta) deposition in the cortex. Apo E is a member of a family of exchangeable apos, characterized by the presence of amphipathic alpha-helical segments that allow these molecules to act as surfactants on the surface of lipoprotein particles. Two members of this family, apo E and apo J, have been shown to bind soluble A beta, and both are associated with senile plaques in the AD cortex. We now have studied the pattern of brain apo expression and found that five members of this class are present: apo A-I, A-IV,D,E, and J. By contrast, apos A-II, B, and C-II were not detectable. Immunohistochemistry revealed that, in addition to apo E and apo J, apo A-I immunostained occasional senile plaques in AD cortex. Immunoblot analysis showed no difference in the relative amounts of any of these apos in tissue homogenates of frontal lobe from AD or control patients. Comparison by APO E genotype showed no differences in the amount of apo E in brain among APO E epsilon 3/3, epsilon 3/4, or epsilon 4/4 individuals; however, a significant decrease in the amount of apo J was associated with the APO E epsilon 4 allele. No differences in apo J levels were detected in CSF samples of AD subjects. We propose that several members of the exchangeable apo family may interact with A beta deposits in senile plaques through common amphipathic alpha-helical domains. Competition among these molecules for binding of A beta or A beta aggregates may influence the deposition of A beta in senile plaques.

Glycogen synthase kinase 3 alpha and 3 beta do not colocalize with neurofibrillary tangles.

Glycogen synthase kinase (GSK) 3 alpha and 3 beta are two proline-directed serine/ threonine kinases that have been shown in vitro to hyperphosphorylate tau, and therefore, may contribute to neurofibillary tangle (NFT) formation in Alzheimer's disease (AD). We report here that, in the human hippocampal formation of both control and AD individuals, GSK 3 alpha and 3 beta are immunohistochemically localized to neurons within the presubiculum > CA1, CA3, and CA4 subfields of the hippocampus, layers III > II > IV, V, VI of entorhinal cortex, and occasional neurons in layers III, V, and VI of temporal neocortex. By contrast, NFTs occur primarily in CA1. subiculum, layers II and IV of entorhinal cortex, and layers II, III, and V of temporal neocortex. The presubiculum and other subfields are frequently spared. Thus, localization of GSK 3 alpha and GSK 3 beta does not correspond to the expected pattern of neuronal vulnerability to NFT formation in AD. Interpreted within the limitations of immunohistochemical detection, these results argue against a major role of GSK 3 alpha or GSK 3 beta in NFT formation in AD.

Clinical and pathological correlates of apolipoprotein E epsilon 4 in Alzheimer's disease.

Inheritance of the apolipoprotein E (apoE) epsilon 4 allele is associated with a high likelihood of developing Alzheimer's disease (AD). The pathophysiologic basis of this genetic influence is unknown. We reasoned that understanding the influence of apoE epsilon 4 on the clinical course and neuropathological features of AD may provide tests of potential mechanisms. We carried out a prospective longitudinal study to compare the age of onset, duration, and rate of progression of 359 AD patients to apoE genotype. Thirty-one of the individuals who died during the study were available for quantitative neuropathological evaluation. Statistically unbiased stereological counts of neurofibrillary tangles (NFTs) and A beta deposits were assessed in a high-order association cortex, the superior temporal sulcus. Analysis of clinical parameters compared with apoE genotype showed that the epsilon 4 allele is associated with an earlier age of onset but no change in rate of progression of dementia. Quantitative neuropathological assessment revealed that NFTs were strongly associated with clinical measures of dementia duration and severity but not with apoE genotype. A beta deposition, by contrast, was not related to clinical features but was elevated in association with apoE epsilon 4. These results indicate that apoE epsilon 4 is associated with selective clinical and neuropathological features of AD and support hypotheses that focus on an influence of apoE epsilon 4 on amyloid deposition.

Multiple, diverse senile plaque-associated proteins are ligands of an apolipoprotein E receptor, the alpha 2-macroglobulin receptor/low-density-lipoprotein receptor-related protein.

Both apolipoprotein E and its receptor, the low-density-lipoprotein receptor-related protein (LRP), are associated with senile plaques in Alzheimer's disease. We examined the relationship of other LRP-related molecules to senile plaques. LRP is a multifunctional receptor that binds and rapidly internalizes at least seven ligands: apolipoprotein E, activated alpha 2-macroglobulin, tissue and urokinase-type plasminogen activators, plasminogen activator inhibitor-1, lipoprotein lipase, and lactoferrin. Using immunohistochemistry, we showed that all of these ligands, representing a diverse group of otherwise apparently unrelated proteins, accumulate on senile plaques. We also studied expression of the receptor-associated protein, a physiological inhibitor of LRP, in the hippocampal formation from normal subjects and Alzheimer's disease patients. Receptor-associated protein colocalizes with LRP on neuronal soma, but not on neuronal processes or reactive astrocytes. It is not present on senile plaques. These results suggest that senile plaque-associated LRP can bind its ligands, but clearance of these compounds may be impaired in the vicinity of senile plaques.

Functional alterations in Alzheimer's disease: decreased glucose transporter 3 immunoreactivity in the perforant pathway terminal zone.

Positron emission tomography (PET) studies measuring glucose utilization have demonstrated cerebral hypometabolism in Alzheimer's disease (AD). The anatomic and biochemical basis for this observation remains unknown. We have examined the distribution in the hippocampal formation of the neuron-specific glucose transporter 3 (Glut3) protein. Using quantitative immunohistochemistry, we find a large reduction (49.5%) in Glut3 immunoreactivity in the outer portion of the molecular layer of the dentate gyrus in AD brains. This region corresponds to the terminal zone of the perforant pathway, whose cells of origin in layer II of the entorhinal cortex are selectively destroyed in AD. Because glucose uptake reflects metabolic demand, these results suggest a decrement of functional activity in the deafferented dentate gyrus granule cells. Generalizing from this observation, decreased glucose uptake seen on PET studies may reflect, in part, decreased glucose transport and utilization in functionally deafferented cortical fields.

All-terrain vehicle accidents: the experience of one hospital located near a major recreational area.

In two separate studies, charts of 169 all-terrain vehicle (ATV) accident victims admitted to the emergency department of Desert Hospital in Palm Springs, California, were reviewed. Twenty-four percent of the cases were women, 30% were hospitalized, and 1% (two patients) died. The youngest patient was 3 and the oldest was 76. About 31% had been drinking, and the major type of bony injury (16%) was to the clavicle, ribs, or sternum. The accident rate was calculated as ten accidents per 1,000 ATV rider days, which is comparable to the ski accident rate of six per 1,000 skier days. The three-wheeled variety of ATV is responsible for nearly all the accidents.