Search

Signaling pathways within the mitotic mechanism temporally orchestrate spindle assembly with chromosome capture and alignment, and then coordinate initiation of chromosome segregation with spindle breakdown and cytokinesis for reproductive success. Kinetochore localized Mad2p acts in the spindle assembly checkpoint pathway during prophase and prometaphase to monitor bipolar attachment of chromosomes to spindle microtubules as well as proper tension at kinetochores. Once established, Mad2p is not degraded, but instead transits to spindle poles preceding the metaphase/anaphase transition in human and yeast cells. Whether conserved relocalization of Mad2p to poles is a final step in the spindle assembly checkpoint pathway or whether the post-metaphase transition allows Mad2p to cooperate in anaphase events leading to mitotic exit has been unknown. We examined post-metaphase localization of Mad2p in fission yeast. Our observations indicate an extended signaling pathway for Mad2p that includes kinetochore to bipolar localization at spindle poles, then additional transitions from bipolar to unipolar to equatorial. We determined that Mad2p associates with the microtubule organizing center complex through direct binding to Alp4p and that microtubule motor proteins Kinesin-14 Pkl1 and Dynein contribute to Mad2p anaphase transitions. At anaphase B onset, bipolar to unipolar transitions of both Mad2p and the septation inititiation network (SIN) kinase Cdc7 are observed. We determined that Mad2p and Cdc7p transitions monitor different events in anaphase, but that neither are required for anaphase B initiation. Our findings indicate that altered Mad2p anaphase spindle localizations can reflect changes in spindle function during mitotic exit that could contribute to fidelity in anaphase events.

An innovative data mining algorithm was developed by TSC for application to long-term, wide area ground moving target indication (GMTI) radar databases obtained from both airborne and space-based Intelligence, Reconnaissance and Surveillance (ISR) systems. The algorithm can discover high-value targets of opportunity including convoys in dense civilian background traffic, and was recently demonstrated for a GMTI database collected by an operational Air Force ISR platform. Further investigations are using a realistic computer simulation of vehicle traffic. In the algorithm, vehicle detection sequences are linked over multiple scans and then analyzed by Hough transform (HT) processing. The HT can resolve closely spaced vehicles and characterize target kinematics to provide real-time operator cueing or support GMTI radar forensic analysis. These data mining algorithms have been successfully applied to actual and simulated GMTI radar databases with a per scan probability of target detection as low as 50%, false alarm rates as high as one per km of road, and civilian vehicle densities up to 10 per km. Thus they can complement conventional tracking algorithms in areas of dense background traffic where false tracks and data-to-track misassociation is a serious problem.

The APOE epsilon4 allele has emerged as a major genetic factor for Alzheimer disease (AD), and its presence has been associated with an increase in beta-amyloid senile plaques (SPs) and neuritic plaques (NPs). Whether it affects neurofibrillary tangle (NFT) accumulation or cholinergic losses in AD remains controversial. In contrast, the epsilon2 allele has been reported to decrease the risk for AD. However, its effect on neuropathologic and neurochemical markers of disease is unclear.To investigate the relationship between APOE genotype and both pathologic severity and cholinergic dysfunction in AD.In an autopsy series of 296 patients with AD, APOE genotype was determined in blood or postmortem brain tissue. NPs and NFTs were counted in the midfrontal (MF), inferior parietal (IP), and superior temporal (ST) cortices and the hippocampus. Choline acetyltransferase (ChAT) activity was assessed in the MF, IP, and ST cortices.Compared with patients with no epsilon4 alleles, epsilon4 carriers (patients with either one or two epsilon4 alleles) did not differ significantly with regard to any pathologic or neurochemical measures, except for increased ST NPs. However, when cases were stratified into three groups according to the number of epsilon4 alleles, patients with two epsilon4 alleles had significantly more NPs and NFTs in all neocortical regions than those with either one or no epsilon4 alleles. The association of the epsilon4/4 genotype with neocortical pathologic severity remained significant even after adjusting for age at onset or age at death. In contrast, there were no significant group differences with regard to neocortical ChAT activity. When pathologic and neurochemical measures were compared between patients with the epsilon2 allele and those without, a strong relationship emerged between the epsilon2 allele and decreased NPs in all neocortical regions.The epsilon4 allele does not predict cholinergic decline in AD. Although the presence of a single epsilon4 allele appears to have no effect, the presence of two epsilon4 alleles is an important determinant of both NP and NFT accumulation. A putative protective role for the epsilon2 allele in AD may be mediated by reduced plaque burden.

We present an approach to automatically register and fuse IR and MMW images for concealed weapon detection. The distortion between the two images is assumed to be a rigid body transformation without rotation and we assume that the scale factor can be found from both the sensor parameters and the distance ratio of the object to the two sensors. Our registration procedure involves image segmentation, binary correlation and other image processing algorithms. Our fusion method involves a pyramidal image decomposition scheme based on the wavelet transform. Performance of the image registration and image fusion algorithm is illustrated through an example.

It is argued that problems in the development of large computer-based systems indicate that a new discipline is needed at the systems engineering level. Designing systems with distributed processing and databases requires analysis of critical end-to-end processing flows to determine feasibility and proper allocation. An expanded skills base would be required to perform either systems, software, or hardware engineers to perform the necessary tradeoff studies. This paper informs managers, engineers, educators, and researchers about the need for computer-based systems engineering and the strategic opportunities this discipline provides for systems engineering improvement. >

I describe some insight obtained from a lattice calculation on the possibility that the light scalar mesons are \qbar^2 q^2 states rather than \qbar q. First I review some general features of \qbar^2 q^2 states in QCD inspired quark models. Then I describe a lattice QCD calculation of pseudoscalar meson scattering amplitudes, ignoring quark loops and quark annihilation, which finds indications that for sufficiently heavy quarks there is a stable four-quark bound state with JPC=0{++} and non-exotic flavor quantum numbers., 13 pages, 4 images, uses aipproc.cls

A method is described which utilizes the difference in vapor pressure between C60 and heavier fullerenes to produce ultrahigh purity C60. Fullerene extract is introduced into one end of a distillation column with a series of evenly spaced perforated baffles inside. The extract is heated to 970 K under high vacuum, and a linear temperature gradient is established along the column. As the mixed fullerene vapor effuses down the column, it becomes enriched in the more volatile species. C60 with a purity of 99.97% has been obtained. This method shows promise in the purification of more exotic fullerene compounds.

Track-to-track fusion is an important part in multisensor fusion. In practice, the process noise is not negligible due to target manoeuvring and sensors typically communicate infrequently to save communication bandwidth. In such situations, the measurements from two sensors are not conditionally independent due to the common process noise from the underlying system. This dependence phenomena was also observed by Bar-Shalom (1981) where a formula was derived to compute the cross-covariance of two track estimates obtained by different sensors. Based on the results, a fusion formula was subsequently derived (Bar-Shalom et al. (1986)) to combine the local estimates which took into account the dependency between the two estimates. This paper points out the implicit approximation made by Bar-Shalom et al. and shows that the result turns out to be optimal only in the maximum likelihood sense. A performance evaluation technique is then proposed to study the performance of various track-to-track fusion techniques. The results provide performance bounds of different techniques under various operating conditions which can be used in designing a fusion system.

Provides an understanding of the issues related to the transfer of requirements engineering technology from research (early state of the art) to practice (real people performing real projects). Applications include: industrial education; the university laboratory; and Rome laboratory. >

Advances in microprocessor and network technology have led to the proliferation of complex systems with distributed processing and databases, internal communication systems, and heterogeneous components. The processing components can by themselves comprise a system, or they can be embedded in a physical system such as an automobile aircraft, or medical diagnostic system. Both the encompassing system and the processing system are known as computer-based systems (CBSs). Developing large computer-based systems with complex dynamics and component interdependencies requires analysis of critical end-to-end processing flows to determine feasibility and proper allocation. Currently, no engineering discipline provides the knowledge base for the necessary trade-off studies concerning software, hardware and communication components; a new discipline is needed at the systems engineering level. The paper defines the need for a discipline devoted to engineering of computer based systems, identifies current practice and needed research, and suggests improvements that are achievable today. >

The requirements driven design (RDD) languages, methods, and tools were developed to address the problems of defining and designing operational systems. The authors present the application of the RDD concepts to manufacturing system design, emphasizing the concerns of rapid prototyping/simulation. >

We investigated the potential mechanisms through which Cerebrolysin, a neuroprotective noothropic agent, might affect Alzheimer's disease pathology. Transgenic (tg) mice expressing mutant human (h) amyloid precursor protein 751 (APP751) cDNA under the Thy-1 promoter (mThy1-hAPP751) were treated for four weeks with this compound and analyzed by confocal microscopy to asses its effects on amyloid plaque formation and neurodegeneration. In this model, amyloid plaques in the brain are found much earlier (beginning at 3 months) than in other tg models. Quantitative computer-aided analysis with anti-amyloid-beta protein (A beta) antibodies, revealed that Cerebrolysin significantly reduced the amyloid burden in the frontal cortex of 5-month-old mice. Furthermore, Cerebrolysin treatment reduced the levels of A beta(1-42). This was accompanied by amelioration of the synaptic alterations in the frontal cortex of mThy1-hAPP751 tg mice. In conclusion, the present study supports the possibility that Cerebrolysin might have neuroprotective effects by decreasing the production of A beta(1-42) and reducing amyloid deposition.

The low-density lipoprotein receptor-related protein (LRP) is an abundant neuronal cell surface receptor that regulates amyloid beta-protein (Abeta) trafficking into the cell. Specifically, LRP binds secreted Abeta complexes and mediates its degradation. Previously, we have shown in vitro that the uptake of Abeta mediated by LRP is protective and that blocking this receptor significantly enhances neurotoxicity. To further characterize the effects of LRP and other lipoprotein receptors on Abeta deposition, an in vivo model of decreased LRP expression, receptor-associated protein (RAP)-deficient (RAP-/-) mice was crossed with human amyloid protein precursor transgenic (hAPP tg) mice, and plaque formation and neurodegeneration were analyzed. We found that, although the age of onset for plaque formation was the same in hAPP tg and hAPP tg/RAP-/- mice, the amount of amyloid deposited doubled in the hAPP tg/RAP-/- background. Moreover, these mice displayed increased neuronal damage and astrogliosis. Together, these results further support the contention that LRP and other lipoprotein receptors might be neuroprotective against Abeta toxicity and that this receptor might play an integral role in Abeta clearance.

Water hammer is defined as a sudden increase in pipe pressure, which results in pressure waves that travel along the pipe at sonic velocities. In the wake of the pressure wave, dynamic stresses are created in the pipe wall, which contribute to pipe failures. A finite element analysis, computer program was used to determine the three dimensional dynamic stresses which result from pipe wall vibration at a distance from the end of a pipe, during a water hammer event. The analysis was used to model a moving shock wave in a pipe, using a step pressure wave. Both aluminum and steel were modeled for an 8 NPS pipe, using Abaqus® . For either material, the maximum stress was seen to be equal when damping was neglected. At the time the maximum stress occurred, the hoop stress was equivalent to twice the stress that would be expected if an equivalent static stress was applied to the inner wall of the pipe. At the same time, the radial stress was limited to the magnitude of the applied pressure, and the axial stress was equal to zero.Copyright © 2002 by ASME

We investigated the potential mechanisms through which Cerebrolysin™, a neuroprotective noothropic agent, might affect Alzheimer’s disease pathology. Transgenic (tg) mice expressing mutant human (h) amyloid precursor protein 751 (APP751) cDNA under the Thy-1 promoter (mThyl-hAPP751) were treated for four weeks with this compound and analyzed by confocal microscopy to asses its effects on amyloid plaque formation and neurodegeneration. In this model, amyloid plaques in the brain are found much earlier (beginning at 3 months) than in other tg models. Quantitative computer-aided analysis with anti-amyloid-β protein (Aβ) antibodies, revealed that Cerebrolysin significantly reduced the amyloid burden in the frontal cortex of 5-month-old mice. Furthermore, Cerebrolysin treatment reduced the levels of Aβ1–42. This was accompanied by amelioration of the synaptic alterations in the frontal cortex of mThyl-hAPP751 tg mice. In conclusion, the present study supports the possibility that Cerebrolysin might have neuroprotective effects by decreasing the production of Af and reducing amyloid deposition.

Summary A new system for sampling from arterial cannulae has been designed which avoids the need to aspirate flushing solution before taking a sample and limits blood loss. The new system was compared with a standard sampling system and direct arterial sampling using in vitro models. A series of haemoglobin concentrations wen- prepared and sampled using the three sampling methods. There were no clinically significant differences in the values obtained with the different sampling techniques.

The electronic structure of an isolated Ca@C60 molecule was probed by photoelectron spectroscopy (PES) of Ca@C 60 − , generated by laser desorption of a preformed Ca@C60/fullerene thin film. The PES spectrum of Ca@C60 was found to be similar to that of C 60 − , except that Ca@C60 has an electron affinity of 3.0 eV, about 0.3 eV higher than that of C60. The spectrum suggests that Ca atom donates its two 4s electrons to the C60 t lu lowest unoccupied molecular orbital. Thus, the interaction between the central Ca atom and C60 is quite ionic, and Ca@C60 can essentially be expressed as Ca2+@C 60 2− .

We investigated the relationship between the loss of nicotinic acetylcholine receptors (nAChR) and the cognitive decline or neuropathological changes seen in Alzheimer's Disease (AD) and dementia with Lewy bodies (DLB). Midfrontal (MF) cortex of 31 AD, 24 DLB and 11 non-demented controls was examined. Total plaque (TP), neuritic plaque (NP) and neurofibrillary tangle (NFT) counts were obtained. NAChR binding was assayed using 3H-epibatidine [3H-EPI]. Last Blessed Information-Memory-Concentration scores (BIMC), Mini-Mental State Examination (MMSE), Mattis Dementia Rating Scale (DRS) scores were collected. There were no correlations between 3H-EPI binding and TP, NP, NFTs counts in either AD or DLB. Last BIMC, MMSE, DRS scores did not correlate with 3H-EPI binding in AD or DLB. Thus, decline in cognitive function does not correlate with loss of nAChR in DLB or AD at the end of life suggesting that later in these diseases, loss of nAChR binding is not a reliable marker of cognitive function in AD or DLB. Loss of nAChR activity does not appear to be related to plaques or NFTs in AD or DLB.

Objective: To determine the timing of cholinergic loss and reduction of synapses in AD. Background: Decrements in neocortical synapses and cholinergic function occur in AD and correlate with cognitive decline. However, how early in the disease process these changes appear remains unclear. Methods: An autopsy series of 89 demented patients with pathologically confirmed AD (National Institute on Aging and Consortium to Establish a Registry for Alzheimer’s Disease criteria) and 18 normal control subjects (NC). The AD cases were stratified according to their last Mini-Mental State Examination (MMSE) score prior to death as mild (MMSE = 20; n = 14), moderate (MMSE = 10 to 19; n = 20), severe (MMSE = 1 to 9; n = 29), and very severe (MMSE = 0; n = 26). Midfrontal (MF) synapse density was assessed by dot-immunobinding assay for synaptophysin (Syn), and MF choline acetyltransferase (ChAT) activity was determined using standard protocols. Results: Compared with those in NC, neither Syn nor ChAT was appreciably reduced in patients with mild AD at death. Decline of ChAT was significant only in AD patients who died in the late stages of the disease and was maximal in those who had more severely deteriorated. In contrast, decline of Syn was significant and almost maximal in patients in intermediate or moderate stages. Consequently, the last MMSE score prior to death correlated more strongly with ChAT than Syn when the AD cohort included more impaired patients ( r = 0.46 versus 0.40). The reverse occurred when only less impaired patients (MMSE = 10) were included in the analyses ( r = 0.28 versus 0.64). There was only a modest correlation between Syn and ChAT activity. Conclusions: The results imply an asynchronous pattern of decline of synapses and cholinergic activity, with Syn loss preceding ChAT decrements. However, neither MF synapse reduction nor cholinergic dysfunction appears to be an early event in AD.

Recent studies have shown that amyloid precursor protein (APP), which plays a central role in Alzheimer's disease (AD), protects against excitotoxic neuronal injuries by regulating the function of the glial glutamate transporters. The mechanisms underlying these effects and their relationship to the neurodegenerative process in AD are under intense scrutiny. In this context, the main objective of the present study was to determine if overexpression of mutant human APP in transgenic mouse brains results in altered functioning of the excitatory amino acid transporters (EAATs). Transgenic mice expressing the 695 amino acid form of the human APP from the Thy-1 promoter showed a significant decrease in B(max) and K(D) for aspartate uptake when compared to nontransgenic controls. This decrease in glutamate transporter activity was associated with decreased protein expression of glial specific glutamate transporters, EAAT1 and 2, but did not affect mRNA levels. These results suggest that expression of mutant forms of APP disturbs astroglial transport of excitatory amino acids at the posttranscriptional level leading, in turn, to increased susceptibility to glutamate toxicity.

Objective: To investigate the relationship between apolipoprotein E ( APOE ) genotype and both cholinergic dysfunction and synapse loss in AD. Background: A reduction in neocortical synapses and marked losses in the cholinergic system occur in AD. It has been suggested that the number of APOE e4 alleles is inversely related to choline acetyltransferase (ChAT) activity, thereby influencing cholinergic function. Whether APOE genotype may influence neocortical synapse loss remains unclear. Methods: An autopsy series of 182 patients with AD (National Institute on Aging and Consortium to Establish a Registry for Alzheimer’s Disease criteria) and 16 normal controls (NC). APOE genotype was determined in blood samples or in postmortem brain tissue. Midfrontal synapse counts (AU/μg) were quantified by a dot-immunobinding assay for synaptophysin (Syn). Midfrontal ChAT activity (nmol/h/100 mg) was assessed using standard assays. Results: Mean midfrontal ChAT activity and Syn were both significantly reduced in patients with AD compared with NC. The relationship between ChAT activity and number of e4 allele copies in AD was complex, with ChAT activity lower in patients with either two or no e4 alleles compared with those with one e4 allele. There was no relationship between APOE genotype and synapse loss in AD. Syn density was almost identical across the three genotypes. Conclusions: Unlike other studies, we failed to detect a linear relationship between ChAT activity and number of e4 allele copies in the midfrontal cortex of this large sample of patients with AD. Our data also show that the presence of e4 allele does not influence midfrontal synapse loss in AD. This suggests that factors other than APOE genotype may be operative in the decline in midfrontal cholinergic function and synapses seen in AD.

To evaluate cholinergic activity in diseases with Lewy bodies (LB; LB variant of AD [LBV], diffuse LB disease [DLBD], and Parkinson's disease [PD]) to determine if 1) AD changes are requisite to cholinergic dysfunction, 2) cholinergic activity declines to the same extent in neocortical and archicortical areas, and 3) cholinergic loss is influenced by APOE genotype.Like AD, diseases with LB are associated with decreased choline acetyltransferase (ChAT) activity. Increased APOE epsilon4 allele frequency has been reported in LBV. Whether APOE genotype affects cholinergic function in LBV remains unclear.An autopsy series of 182 AD (National Institute on Aging and Consortium to Establish a Registry for Alzheimer's Disease criteria), 49 LBV, 11 PD, 6 DLBD, and 16 normal control (NC) subjects. APOE genotype and ChAT activity (nmol/h/100 mg) in the midfrontal and hippocampal cortices were determined.Mean midfrontal ChAT activity was markedly reduced in diseases with LB (LBV: 53.3 +/- 39.0; PD: 54.8 +/- 35.7; DLBD: 41.3 +/- 24.8) compared to NC (255.4 +/- 134.6; p0.001) and AD (122.6 +/- 78.9; p0.05). Among diseases with LB, midfrontal ChAT activity was decreased to a similar extent in patients with (LBV) and without (DLBD and PD) AD pathology. Although mean ChAT activity for LBV was less than half that for AD in the midfrontal cortex, it was similar to that for AD in the hippocampus (LBV: 243.5 +/- 189.7; AD: 322.8 +/- 265.6; p0.05). However, hippocampal ChAT activity for both AD and LBV was lower than that for NC (666.5 +/- 360.3; p0.001). The epsilon4 allele dosage did not influence midfrontal ChAT activity in LBV.Marked losses in midfrontal ChAT activity occur in diseases with LB, independent of coexistent AD changes. A greater midfrontal, as opposed to hippocampal, cholinergic deficit may differentiate LBV from AD. The lack of a relationship between epsilon4 allele dosage and midfrontal ChAT activity suggests that other factors may play a role in its decline in LBV.

Biodistribution studies of a water-soluble radioactive metallofullerene compound have been conducted using BALB/c mice. To this end, a sample containing Ho x @C 82 (x = 1, 2) was purified and derivatized to prepare the water-soluble metallofullerol, Ho x @C 82 (OH) y . This metallofullerol was then neutron-activated ( 165 Ho[n,γ] 166 Ho) to prepare the 166 Ho x @C 82 (OH) y analog as a radiotracer, which was monitored, after intravenous administration, for up to 48 hours by using dissection radioanalysis, and its biodistribution was compared with a control compound, Na 2 [ 166 Ho(DTPA)(H 2 O)]. Results showed selective localization of the 166 Ho x @C 82 (OH) y tracer in the liver but with slow clearance, as well as uptake by bone without clearance. In contrast, excretion of the control compound was nearly quantitative after 1 hour. The fate of 166 Ho was also explored by a metabolism study of 166 Ho x @C 82 (OH) y in Fischer rats. Results indicated 20% excretion of intact 166 Ho x @C 82 (OH) y within 5 days. The present findings demonstrate the feasibility of using water-solubilized metallofullerene radiotracers to monitor the fate of fullerene-based materials in animals, and suggest that water-solubilized fullerene materials, in general, may be useful components in drug design.

Excitatory neurotransmitters such as glutamate are required for the normal functioning of the central nervous system but can trigger excitotoxic neuronal injury if allowed to accumulate to abnormally high levels. Their extracellular levels are controlled primarily by transmitter uptake into astrocytes. Here, we demonstrate that the amyloid protein precursor may participate in the regulation of this important process. The amyloid protein precursor has been well conserved through evolution, and a number of studies indicate that it may function as an endogenous excitoprotectant. However, the mechanisms underlying this neuroprotective capacity remain largely unknown. At moderate levels of expression, human amyloid protein precursors increased glutamate/aspartate uptake in brains of transgenic mice, with the 751-amino acid isoform showing greater potency than the 695-amino acid isoform. Cerebral glutamate/aspartate transporter protein levels were higher in transgenic mice than in non-transgenic controls, whereas transporter mRNA levels were unchanged. Amyloid protein precursor-dependent stimulation of aspartate uptake by cultured primary astrocytes was associated with increases in protein kinase A and C activity and could be blocked by inhibitors of these kinases. The stimulation of astroglial excitatory amino acid transport by amyloid protein precursors could protect the brain against excitotoxicity and may play an important role in neurotransmission.

Despite their race, ethnicity, gender, or sexual preference, students remain similar in one respect: their need to belong. Student affairs administrators are responsible for helping students make appropriate social transitions so that college degrees become realities, a task that is complicated when the student is and inner-city commuter.

Dementia with Lewy bodies (DLB) is the second leading cause of cognitive impairment among the elderly. While it is usually accompanied by the neocortical neuritic plaques (NP) and entorhinal neurofibrillary tangles (NFT) characteristic of Alzheimer disease (AD), and so can be construed as a Lewy body variant of AD (LBV), it also occurs in pure form as diffuse Lewy body disease (DLBD). We assessed cognitive status in 17 DLB patients (12 with LBV and 5 with DLBD) and compared the results with 12 AD subjects and 5 controls. We then sought to determine which neuropathologic abnormalities correlated with cognitive impairment. Among DLB cases, neocortical Lewy body (LB) counts, modified Braak stages of NFT burden in the entorhinal cortex, neocortical NP counts, and loss of choline acetyltransferase (ChAT) activity all correlated with dementia severity. Unlike AD, neocortical NFT and anti-synaptophysin reactivity were uncorrelated with DLB dementia. Despite comparable LB counts and ChAT losses, the DLBD were significantly less demented than the LBV patients. We conclude that neocortical LB and ChAT depletion contribute to cognitive impairment in DLB and that concomitant AD pathology in LBV, represented by higher Braak stages and NP, promotes increased dementia severity compared with that encountered in DLBD.

Recent studies have suggested that neuronal populations that contain glutamate receptors are vulnerable to damage mediated by the human immunodeficiency virus 1 (HIV-1). Somatostatin-immunoreactive neurons contain, among other elements, glutamate receptors, and might therefore be susceptible to HIV-mediated damage. In order to test this hypothesis, we compared patterns of somatostatin immunoreactivity in the cortex and subcortex of autopsied AIDS cases with and without HIV encephalitis (HIVE). Somatostatin immunoreactivity in the frontal cortex interneurons, hippocampal pyramidal and nonpyramidal cells, and globus pallidus was significantly reduced in HIVE. Radioimmunoassay demonstrated a comparable decrease in somatostatin levels in the neocortex of HIVE cases. The decrease in somatostatin immunoreactivity in the neocortex was inversely correlated with the severity of HIVE and global cognitive performance, but not with the extent of the astroglial reaction. These findings indicate that somatostatin-immunoreactive neurons in the cortex are susceptible to damage mediated by HIV and that deficient functioning of this neuronal population might contribute to the cognitive dysfunction observed in AIDS patients.

Synaptic loss and neurofibrillary pathology are major contributors to the cognitive deficits in Alzheimer’s disease (AD), indicating an altered connectivity of association neurocircuitries. Synaptic damage occurs early in the development of AD, suggesting that synapse pathology is a primary rather than a secondary event. The mechanisms of synaptic damage and neurodegeneration in AD are not completely understood. Recent studies have suggested that abnormal expression and/or processing of growth-associated proteins in the central nervous system might play a role in the mechanisms leading to synaptic damage and neurodegeneration in AD. Prominent among these proteins are amyloid precursor protein (APP), apolipoprotein E (apoE), and non Aβ amyloid component (NAC) precursor (NACP). All of these molecules have several common features: 1) modulation of synaptic function, 2) involvement in amyloidogenesis, and 3) mutations (APP) and polymorphisms (APOE, NACP) that are associated with a higher risk for AD. Abnormal functioning of synaptic-related proteins with amyloidogenic potential might play a central role in the pathogenesis of AD. In this context, the main objectives of this manuscript are to review the contribution of synaptic alterations to the mechanisms of dementia in AD and to discuss some of the possible mechanisms through which malfunctioning of APP, apoE and NACP might lead to synaptic damage and plaque formation in AD.

The mechanisms of synapse damage in Alzheimer's disease (AD) are not fully understood. Deficient functioning of glutamate transporters might be involved in synaptic pathology and neurodegeneration by failing to clear excess glutamate at the synaptic cleft. In AD, glutamate transporter activity as assessed by D-[3H]aspartate binding is decreased; however, it is not clear to what extent it is associated with the neurodegenerative process and cognitive alterations. For this purpose, levels of D- and L-[3H]aspartate binding in midfrontal cortex were correlated with synaptophysin levels, brain spectrin degradation product levels, and clinical and neuropathological indicators of AD. Compared to control brains, AD brains displayed a 34% decrease in levels of D-[3H]aspartate binding, a 30% decrease in L-[3H]aspartate binding, and a 48% loss of synaptophysin immunoreactivity. Increased levels of brain spectrin degradation products correlated with a decrease in levels of D-[3H] and L-[3H]aspartate binding, and decreased levels of synaptophysin immunoreactivity. Levels of L-[3H]aspartate binding correlated with levels of synaptophysin immunoreactivity. These results suggest that decreased glutamate transporter activity in AD is associated with increased excitotoxicity and neurodegeneration, supporting the possibility that abnormal functioning of this system might be involved in the pathogenesis of synaptic damage in AD.

Apolipoprotein E (apoE) is involved in the development and regeneration of the central nervous system (CNS). Recent studies have shown that the expres sion of allele e4 of APOE is a major risk factor for Alzheimer’s disease (AD), a neurodegenerative disorder associated with synaptic loss, amyloid deposition and disruption of the neuronal cytoskeleton. In order to better understand the mechanisms by which apoE is involved in AD, it is necessary to understand the physiological role of this molecule in the intact CNS. For this purpose, we studied the fate of synaptic and dendritic populations during aging and after injury to the CNS in apoE-deficient (knockout) mice. In apoE deficient homozygous mice, there was an age-dependent 15%–40% loss of synaptophysin-immunoreactive nerve terminals and microtubule-associated protein 2-immunoreactive dendrites in the neocortex and hippocampus, when compared to controls. Dendritic alterations were observed as early as 4 months of age. Ultrastructural analysis revealed extensive dendritic vacuolization and disruption of the endomembrane system and cytoskeleton in apoE-deficient homozygous mice. The dendritic damage was accompanied by a decreased immunoreactivity for cytoskeletal markers α and β tubulin (but not kinesin) in the cell bodies and processes of neurons of apoE-deficient mice. In addition, apoE-deficient homozygous mice showed a delay in the patterns of reinnervation of the outer molecular layer of the hippocampal dentate gyrus after perforant pathway transection, and in the neocortex after intraperitoneal kainic acid injection. These results support the contention that apoE might play an important role in maintaining the stability of the synapto-dendritic apparatus, and that altered or deficient functioning of this molecule could underlie the synaptic and cytoskeletal alterations observed in AD.

Apolipoprotein E (apoE) is involved in the development and regeneration of the central nervous system (CNS). ApoE may also be necessary to maintain the integrity of the synapto-dendritic complexity. We analyzed the synaptic alterations in the CNS of apoE-deficient (knockout) mice during the aging process. In apoE-deficient homozygous mice, there was an age-dependent 15 to 40% loss of synaptophysin-immunoreactive nerve terminals and microtubule-associated protein 2-immunoreactive dendrites in the neocortex and hippocampus, when compared to controls. Dendritic alterations were observed as early as 4 months of age. Ultrastructural analysis revealed extensive dendritic vacuolization and disruption of the endomembrane system and cytoskeleton in apoE-deficient homozygous mice. Further immunocytochemical studies of the neuronal cytoskeleton showed that in apoE-deficient mice there was a decrease in the immunoreactivity of alpha and beta tubulin (but not kinesin) in the cell bodies and processes. These results support the contention that apoE might play an important role in maintaining the stability of the synapto-dendritic apparatus and that altered or deficient functioning of this molecule could underlie the synaptic and cytoskeletal alterations in Alzheimer's disease.

Both genetic and environmental factors affect the progression of Alzheimer's disease (AD). The presence of cortical Lewy bodies in AD patients is associated with an altered presentation of AD pathology suggestive of an interaction between the pathogenesis of Lewy bodies and AD lesions. Since the CYP2D6B mutant allele is often present in patients with Lewy body diseases (Parkinson's disease and Lewy body variant of AD), we extended these prior observations by studying the neuropathology associated with the presence of the CYP2D6B mutant allele in a pure AD population without Lewy bodies. AD patients who possessed the CYP2D6B mutant allele, in comparison with those without the CYP2D6B allele, were found to have a smaller decline in two synaptic markers, choline acetyltransferase and synaptophysin, in the frontal cortex relative to normal control values. On the other hand, senile plaques and neurofibrillary tangles were not significantly affected by the presence of the CYP2D6B mutant allele in the frontal cortex of AD patients. Association of the CYP2D6B mutant allele with Lewy body formation in both Parkinson's disease and the Lewy body variant of AD and with the milder synaptic pathology in pure AD without Lewy bodies suggest that depending on the contribution of other genetic and environmental factors, this mutant allele may be involved with different aspects of neurodegeneration.

In the present study we observed that while platelet-derived growth factor (PDGF)-BB is exclusively expressed by neurons in the human brain, PDGF-AA is expressed in neurons and blood vessels. In Alzheimer's disease (AD), antibodies against PDGF-BB (but not PDGF-AA) recognized the neurofibrillary alterations of this disease. The levels of PDGF-BB correlated with the patterns of synaptic loss and sprouting while PDGF-AA immunostaining of the vessels was correlated with glial proliferation. Immunostaining was completely abolished when the antibodies were preincubated with their respective purified recombinant PDGF. Western blot analysis showed that antibodies against PDGF recognized a 31 kDa protein that was mildly increased in AD. These data suggest that PDGF, as well as other neurotrophic factors, play an important role in the mechanisms of neurofibrillary pathology in AD.

Expression of the HIV-1 envelope protein gp120 in brains of transgenic (tg) mice induces extensive neurodegeneration (Toggas, S. M., E. Masliah, E. M. Rockenstein, G. F. Rall, C. R. Abraham, and L. Mucke. 1994. Nature [Lond.]. 367:188-193.). To further analyze the pathogenesis of gp120-induced neurotoxicity and to assess the neuroprotective potential of human amyloid precursor proteins (hAPPs) in vivo, different hAPP isoforms were expressed in neurons of gp120/hAPP-bigenic mice: hAPP751, which contains a Kunitz-type protease inhibitor domain, or hAPP695, which lacks this domain. Bigenic mice overexpressing hAPP751 at moderate levels showed significantly less neuronal loss, synapto-dendritic degeneration, and gliosis than singly tg mice expressing gp120 alone. In contrast, higher levels of hAPP695 expression in bigenic mice failed to prevent gp120-induced brain damage. These data indicate that hAPP can exert important neuroprotective functions in vivo and that the efficiency of this protection may depend on the hAPP isoform expressed and/or on the level of neuronal hAPP expression. Hence, molecules that mimic beneficial APP activities may be useful in the prevention/treatment of HIV-1-associated nervous system damage and, perhaps, also of other types of neural injury.

Double stranded (ds) RNA activated protein kinase PKR was discovered over 30 years ago as a downstream mediator of the interferon signal pathway. Initial studies focused on PKR's anti-virus and pro-inflammatory effects. More recently, PKR has been found to be involved in signal transduction pathways critical for the negative regulation of cell growth and initiation of apoptosis. Significantly, loss of PKR expression/activity has been associated with increased growth of human breast carcinoma, B-cell CLL, and T-cell ALL using patient samples. Furthermore, PKR activity is increased in bone marrow progenitor cells isolated from patients with myelodysplastic syndrome (MDS) which undergo significant apoptosis compared to normal marrow progenitors not observed when evolved to AML. Thus, in the process of MDS evolution to leukemia, PKR expression/activity may be downregulated by a process that is currently unclear. To explore the role of PKR in MDS/AML we have constructed a transgenic mouse model expressing human PKR (TgPKR) under control of vav regulatory elements to drive expression specifically in hematopoietic-tissue. We hypothesized transgenic expression of human PKR would exert an inhibitory effect on mouse hematopoiesis, cause ineffective blood cell production, and thus simulate a disease process similar to human MDS. In our preliminary data, quantitative PCR and immunoblotting results confirm that human PKR is specifically expressed in spleen, thymus and bone marrow (BM) but not in liver, kidney, intestine, muscle and other tissues outside hematopoiesis in TgPKR mice. Aberrant activation of transcription factor STAT1 and MAPKinases ERK1/2 occurs in hematopoietic cells from the TgPKR mice. In addition, inhibitory cytokines including interferon gamma, CXCL9 and 10 are overexpressed. Initial characterization of BM cells from TgPKR mice indicates a higher level of uninduced/basal apoptosis in growth medium and increased apoptosis upon withdrawal of growth factors compared to cells from wild type (WT) littermates. Furthermore, BM cells from TgPKR mice display >20% reduced colonies (CFU-GM and CFU-GEMM) which contain 40% less cells than those from WT littermates. Significantly, histopathological analysis of BM and spleen from TgPKR mice reveals a ∼20% increase in bone marrow cellularity with a striking increase in dysplastic megakaryocytes that are either small without nuclear lobation or of normal size but with hypolobation or separated nuclear lobes. Taken together our results demonstrate that transgenic expression of hPKR induces an MDS-like condition in mice characterized by reduced BM cell survival, increased apoptosis and reduced proliferation and differentiation of BM progenitor/stem cells. Thus, increased PKR expression in patients may, at least in part, lead to a BM failure state similar to MDS. Thus, future anti-MDS therapies that inhibit PKR may be clinically useful. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1350. doi:1538-7445.AM2012-1350

Extensive synaptic and neuritic alterations in the neocortex and limbic system are characteristically found in Alzheimer's disease (AD). However, it is not known how early in the development of the disease these alterations occur. For the present study, we compared the synaptic and neuritic alterations among cases classified clinically and neuropathologically as early, mild and advanced AD. In early AD there was a 20% loss of synaptophysin-immunoreactive presynaptic terminals in the outer molecular layer of the hippocampal dentate gyrus (but not in the neocortex and entorhinal cortex), accompanied by increased amyloid precursor protein (APP) and Alz50 immunoreactivity in hippocampal and entorhinal cortex pyramidal neurons. These results suggest that abnormal neuronal expression of APP and cytoskeletal proteins in early stages might be involved in the mechanisms of synaptic pathology in AD.

Neocortical decreases in synaptic density correlate significantly with the cognitive impairment seen in Alzheimer disease. Recently available monoclonal antibodies (MAb) have made possible the highly specific and sensitive detection of synapse-associated proteins in immunocytochemical and immunochemical techniques. We describe a simple yet highly sensitive dot-immunobinding assay for relative quantification of the synapse marker protein synaptophysin in human brain homogenate fractions with the mouse MAb SY38. Fractions prepared from control and Alzheimer specimens were blotted to nitrocellulose membranes and reacted with SY38, rabbit secondary antibody, and iodinated protein A. A relative standard curve was constructed to normalize results from multiple assay runs. We correlated the results with the more complex immunocytochemical synaptic density measurement technique of immunolabeling coupled with laser confocal imaging, showing good correlation at r = 0.821. Results from Alzheimer cases showed a 40% decrease in synaptophysin immunoreactivity in midfrontal cortex compared with normal controls.

The protein p105 is a nuclear antigen associated with cell proliferation. Recent investigations have indicated that many molecules previously considered to be growth-associated are actually involved in plasticity of the central nervous system.For the present study, using immunohistochemical and immunochemical techniques in control and Alzheimer's disease (AD) brain, we explored the possibility that p105 could be involved in the aberrant sprouting response. AD tissue was used because in this disorder, the neuronal sprouting processes display a disruption in their cytoskeleton and the microtubule-associated protein, tau is abnormally phosphorylated. Control experiments were performed with the p105 antibody from an independent source, and with an antibody against Ki-67.The antibody against p105 (but not against Ki-67) immunolabeled the tangles, neuropil threads, and a subpopulation of fusiform neurites in the plaque. The p105 immunoreactivity was colocalized with tau and the numbers of tangles immunostained with p105 antibody correlated with the number of tangles immunolabeled with an antibody against tau. Western blot analysis of human brain homogenates showed that the antibody against p105 immunostained a major band at an estimated molecular weight of 105 kilodaltons and a secondary band at 84 kilodaltons. In AD frontal cortex, there was a significant increase in the 84 kilodalton band in the particulate, but not in the cytosolic fraction.The characterization of the patterns of expression of this class of nuclear antigen in the brain might provide important clues as to the mechanisms of plasticity and abnormal growth under normal conditions, as well as in AD.

One of the missions of the American Academy of Nursing is to formulate strategies for health policy. To arrive at these strategies, Academy members share their thoughts, knowledge, and imagination in working groups at Academy meetings. The Expert Panel on Older Adults, one of these working groups, asked for interested members to formulate a policy paper on wellness and health promotion of the elderly for presentation at the AAN meeting in Los Angeles last October. This was done, and AAN members at that meeting shared their views on the paper. Now, this draft is being published here to invite all Nursing Outlook readers to review and comment on the policy recommendations that have been formulated. We encourage feedback so your ideas can be considered in the development of the paper. The paper will be submitted for approval to the AAN Committee on Health Policy Reform.

Previous in vitro studies have suggested that amyloid precursor protein (APP) could be involved in cell surface adhesion, neuritic growth and survival of hippocampal neurons. In the present study, involvement of APP in aberrant sprouting in Alzheimer's disease (AD) was studied by comparing immunolabeling patterns of anti-APP and anti-growth-associated protein 43 (anti-GAP43). Confocal laser imaging of frontal cortex sections double-immunolabeled for APP and GAP43 showed an increase, in AD, of presynaptic boutons immunostained with anti-GAP43 that contained anti-APP immunoreactivity. The neuritic plaques in AD cases presented intense anti-GAP43 immunoreactive abnormal neurites colocalized with anti-APP. Three-dimensional reconstruction of the plaques showed that anti-APP was colocalized with anti-GAP43 in 57.5% of the aberrant sprouting neurites. We conclude that co-expression of APP with GAP43 in the plaque might be involved in the aberrant sprouting response observed in AD.

not Available.