bluuebunny/crossref_metadata_2025_split huggingface dataset:
Current drug targets for Alzheimer's disease treatment
Authors: Lahiri Debomoy K. , Farlow Martin R. , Greig Nigel H. , Sambamurti Kumar 
Published: October 2002

AbstractAlzheimer's disease (AD), the most common form of dementia among the elderly, is a progressive, degenerative disorder of the brain with a loss of memory and cognition. A defining characteristic of AD is the deposition of amyloid fibrils and neurofibrillary tangles in the brain of afflicted individuals. Biochemically, they are mainly composed of β‐amyloid protein (Aβ) and phosphorylated tau proteins, respectively. There is also a loss of the presynaptic markers of the cholinergic system, such as acetylcholine, in the brain areas related to memory and learning. The biochemical pathways leading to AD are presently unknown and are a subject of intensive study with current theories favoring a hypothesis where Aβ aggregates to toxic forms that induce tau phosphorylation and aggregation. It is believed that this ultimately leads to dysfunction and death of cholinergic neurons, and compensation for this loss had been the primary focus of first generation therapeutic agents. The amyloid and tau hypotheses have lead to a focus on amyloid and tau as therapeutic targets. The current therapeutic goals are to reduce amyloid levels, prevention of amyloid aggregation/toxicity and tau phosphorylation/aggregation. AD has a heterogeneous etiology with a large percentage termed sporadic AD arising from unknown causes and a smaller fraction of early onset familial AD (FAD) caused by mutations in several genes, such as the β‐amyloid precursor protein (APP) and presenilins (PS1, PS2). Other genes, such as apolipoprotein E (APOE), are considered to be risk factors for AD. Several proteins, such as APP, APOE, BACE (β‐amyloid cleaving enzyme), PS1/2, secretases, and tau play important roles in the pathology of AD. Therefore, attempts are being made to develop new inhibitors for BACE, PS‐1 and γ‐secretase for treatment of AD. There is also a significant advancement in understanding the function of cholinesterase (ChE) in the brain and the use of ChE inhibitors in AD. The mechanism of a new generation of acetyl‐ and butyrylChE inhibitors is being studied and tested in human clinical trials for AD. Other strategies, such as vaccination, anti‐inflammatory agents, cholesterol‐lowering agents, anti‐oxidants and hormone therapy, are also being studied for treating or slowing the progression of AD. Developments of early diagnostic tools based on quantitative biochemical markers will be useful to better follow the course of the disease and to evaluate different therapeutic strategies. In the present review, we attempt to critically examine recent trends in AD research from neurochemical to clinical areas. We analyze various neurobiological mechanisms that provide the basis of new targets for AD drug development. These current research efforts should lead to a deeper understanding of the pathobiochemical processes that occur in the AD brain to effectively diagnose and prevent their occurrence. Drug Dev. Res. 56:267–281, 2002. © 2002 Wiley‐Liss, Inc.
Preclinical progress with CHF2819, a novel orally active acetylcholinesterase inhibitor
Authors: Cassano Tommaso , Carratù M. Rosaria , Coluccia Addolorata , Di Giovanni Vincenzo , Steardo Luca , Cuomo Vincenzo , Trabace Luigia 
Published: October 2002

Abstract(‐)‐(3aS,8aS,1S)‐1,2,3,3a,8,8a‐hexahydro‐1,3a,8‐trimethylpyrrolo[2,3‐b]indol‐5‐ol‐2′‐ethylphenylcarbamate N‐oxide hydrochloride (CHF2819) is a novel, orally active acetylcholinesterase inhibitor (AChEI) for Alzheimer's disease (AD). CHF2819 appears as a selective inhibitor of AChE, being 115 times more potent against this enzyme than butyrylcholinesterase (BuChE). Moreover, CHF2819 appears more selective for inhibiting central (brain) than peripheral (heart) AChE. In vivo studies show that CHF2819 significantly increases acetylcholine (ACh) levels in young adult rat hippocampus in a dose‐dependent manner. Moreover, aged animals exhibit a marked increase in hippocampal concentrations of this neurotransmitter after the administration of CHF2819. This compound attenuates scopolamine‐induced amnesia in a passive avoidance task. Furthermore, CHF2819 induces a significant decrease in dopamine (DA) levels and a significant elevation of hippocampal extracellular concentrations of 5‐hydroxytryptamine (5‐HT), while it does not modify noradrenaline (NA) levels. Oral administration of CHF2819 does not affect hippocampal extracellular glutamate (Glu), aspartate (Asp), γ‐aminobutyric acid (GABA), taurine (Tau), arginine (Arg), and citrulline (Cit) concentrations of young adult rats. Functional observational battery (FOB) screening demonstrates that CHF2819 (1.5 and 4.5 mg/kg p.o.) does not affect activity, excitability, autonomic, neuromuscular, and sensorimotor domains, as well as physiological endpoints. However, this compound induces involuntary motor movements in a dose‐dependent manner. In conclusion, the neurochemical and behavioral profile of CHF2819 suggests that this orally active novel AChEI could be of clinical interest for the treatment of Alzheimer‐type dementia associated with multiple neurotransmitter abnormalities in the brain. In particular, CHF2819 might be a useful therapeutic drug for AD patients in which the cognitive impairment is accompanied by a depressive syndrome. Drug Dev. Res. 56:354–368, 2002. © 2002 Wiley‐Liss, Inc.
Oxidative imbalance and lipid peroxidation in Alzheimer's disease
Authors: Praticò Domenico 
Published: October 2002

AbstractAlzheimer's disease (AD) is a growing serious public health problem worldwide. Clinically, AD is a progressive neurodegenerative disorder characterized by a global cognitive decline. There is significant evidence that reactive oxygen species‐mediated reactions, particularly of neuronal lipids, are extensive in those AD brain areas directly involved in the disease processes. Traditional views claim that oxidative‐mediated tissue injury in the AD brain is the result of neurodegeneration. In recent years, numerous investigations have pointed to the functional importance of oxidative imbalance as a crucial event in mediating AD pathogenesis. The availability of specific and sensitive markers to monitor in vivo oxidative imbalance, in combination with studies performed in living patients with clinical diagnosis of AD, are helping to elucidate these issues. Here, I summarize some of the most recent research on the relevance that oxidative imbalance and lipid peroxidation have in AD. The evidence accumulated so far clearly indicates that oxidative imbalance is an early event during the evolution of this devastating disease. This new concept implies that this phenomenon may play a more important role in AD pathogenesis than previously anticipated. Drug Dev. Res. 56:446–451, 2002. © 2002 Wiley‐Liss, Inc.
The case for iron chelation and/or antioxidant therapy in Alzheimer's disease
Authors: Malecki Elise A. , Connor James R. 
Published: October 2002

AbstractIron is involved in the pathogenesis of Alzheimer's disease by multiple mechanisms. We discuss the role of iron in catalysis of reactive oxygen and nitrogen species, protein physical chemistry, and inflammation. Strategies to deal with iron and its effects have a place in the prevention and treatment of Alzheimer's disease. Therapies utilizing these strategies include iron chelators and antioxidants. Drug Dev. Res. 56:526–530, 2002. © 2002 Wiley‐Liss, Inc.
Patterns of cortisol reactivity in African‐American neonates from low‐income environments
Authors: Keenan Kate , Gunthorpe Dana , Young Desia 
Published: October 2002

AbstractIndividual differences and stability in patterns of salivary cortisol reactivity were examined in 100 African‐American neonates from low‐income environments. A pattern of reactivity was defined by the change from prestressor to poststressor cortisol concentrations and the change following the poststressor during a recovery phase. Cortisol reactivity was measured in response to two stressors: the Neonatal Behavioral Assessment Scale (NBAS; T. B. Brazelton & J. K. Nugent) and the routine hospital heels‐tick procedure. The use of two stressors allowed an examination of whether patterns of reactivity to different stimuli vary and whether there is individual stability in patterns of cortisol reactivity. Cortisol concentrations changed significantly across the three time points. The magnitude of change during the recovery period differed across stressors. Prestressor cortisol values were associated with cortisol reactivity. Both prestressor cortisol concentrations and pattern of cortisol response were significantly associated within individuals. © 2002 Wiley Periodicals, Inc. Dev Psychobiol 41: 265–276, 2002. Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/dev.10048
Sucking, not milk, is important for the rapid learning of nipple‐search odors in newborn rabbits
Authors: Hudson Robyn , Labra‐Cardero Daniela , Mendoza‐Soylovna Adela 
Published: October 2002

AbstractNewborn rabbits are only nursed once a day for 3 to 4 min and are completely dependent on a pheromone on the mother's ventrum for the release of nipple‐search behavior and sucking. However, if the mother's ventrum is perfumed, pups can be conditioned in just one 3‐min nursing session to respond with nipple searching to the novel odorant. To define more precisely the reinforcing properties of the nursing situation supporting such rapid learning, odor conditioning was conducted in independent groups of 2‐day‐old pups after successively eliminating potential reinforcing stimuli such as the doe's behavior, milk ingestion, nipple‐search behavior, or sucking nipples. All experimental groups showed significant conditioning compared to control groups subjected to similar treatments on unscented does, with the strength of conditioning indicating that behavior of the doe, milk consumption, or arousal during performance of the search behavior were not major reinforcers, but rather the opportunity to suck nipples. Thus, this study suggests intraoral stimulation associated with sucking to be an important reinforcer in this paradigm, as for early olfactory learning in other young mammals. © 2002 Wiley Periodicals, Inc. Dev Psychobiol 41: 226–235, 2002. Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/dev.10073
Analysis of N‐cadherin function in limb mesenchymal chondrogenesis in vitro
Authors: Delise Anthony M. , Tuan Rocky S. 
Published: October 2002

AbstractDuring embryonic limb development, cartilage formation is presaged by a crucial mesenchymal cell condensation phase. N‐Cadherin, a Ca2+‐dependent cell–cell adhesion molecule, is expressed in embryonic chick limb buds in a spatiotemporal pattern suggestive of its involvement during cellular condensation; functional blocking of N‐cadherin homotypic binding, by using a neutralizing monoclonal antibody, results in perturbed chondrogenesis in vitro and in vivo. In high‐density micromass cultures of embryonic limb mesenchymal cells, N‐cadherin expression level is high during days 1 and 2, coincident with active cellular condensation, and decreases upon overt chondrogenic differentiation from day 3 on. In this study, we have used a transfection approach to evaluate the effects of gain‐ and loss‐of‐function expression of N‐cadherin constructs on mesenchymal condensation and chondrogenesis in vitro. Chick limb mesenchymal cells were transfected by electroporation with recombinant expression plasmids encoding wild‐type or two mutant extracellular/cytoplasmic deletion forms of N‐cadherin. Expression of the transfected N‐cadherin forms showed a transient profile, being high on days 1–2 of culture, and decreasing by day 3, fortuitously coincident with the temporal profile of endogenous N‐cadherin gene expression. Examined by means of peanut agglutinin (PNA) staining for condensing precartilage mesenchymal cells, cultures overexpressing wild‐type N‐cadherin showed enhanced cellular condensation on culture days 2 and 3, whereas expression of the deletion mutant forms (extracellular/cytoplasmic) of N‐cadherin resulted in a decrease in PNA staining, suggesting that a complete N‐cadherin protein is required for normal cellular condensation to occur. Subsequent chondrogenesis was also affected. Cultures overexpressing the wild‐type N‐cadherin protein showed enhanced chondrogenesis, indicated by increased production of cartilage matrix (sulfated proteoglycans, collagen type II, and cartilage proteoglycan link protein), as well as increased cartilage nodule number and size of individual nodules, compared with control cultures and cultures transfected with either of the two mutant N‐cadherin constructs. These results demonstrate that complete N‐cadherin function, at the levels of both extracellular homotypic binding and cytoplasmic linkage to the cytoskeleton by means of the catenin complex, is required for chondrogenesis by mediating functional mesenchymal cell condensation. © 2002 Wiley‐Liss, Inc.
2D adaptive state‐space filters suitable for parallel processing using state‐space model with general form
Authors: Ishizaki Naoya , Muneyasu Mitsuji , Hinamoto Takao 
Published: October 2002

AbstractThis paper proposes a realization of a two‐dimensional adaptive state‐space filter for parallel processing using state‐space model with a general form. For the modeling of the filter, a generalized model realized for parallel processing is used and the conventional denominator‐separation type model is extended. Further, the LMS (Least Mean Square) algorithm is used to construct an adaptive algorithm and its processing speed and computational effort are evaluated. By means of this method, the hardware content can be reduced while the processing speed is maintained almost the same as in the complete generalized model. Finally, in order to verify the effectiveness of the present method, an example is presented in which a two‐dimensional adaptive filter is applied to the spatial domain design as a system identification problem. © 2002 Wiley Periodicals, Inc. Electron Comm Jpn Pt 3, 86(1): 46–57, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecjc.10019
Association of prostate cancer with rapid N‐acetyltransferase 1 (NAT1*10) in combination with slow N‐acetyltransferase 2 acetylator genotypes in a pilot case‐control study
Authors: Hein David W. , Leff Matthew A. , Ishibe Naoko , Sinha Rashmi , Frazier Harold A. , Doll Mark A. , Xiao Gong H. , Weinrich Martin C. , Caporaso Neil E. 
Published: October 2002

AbstractN‐acetyltransferase‐1 (NAT1) and N‐acetyltransferase‐2 (NAT2) are important in the metabolism of aromatic and heterocyclic amine carcinogens that induce prostate tumors in the rat. We investigated the association of genetic polymorphisms in NAT1 and NAT2, alone and in combination, with human prostate cancer. Incident prostate cancer cases and controls in a hospital‐based case‐control study were frequency‐matched for age, race, and referral pattern. The frequency of slow acetylator NAT1 genotypes (NAT1*14, *15, *17) was 5.8% in controls but absent in cases. In contrast, in comparison with all other NAT1 genotypes the putative rapid acetylator NAT1 genotype (NAT1*10) was significantly higher in prostate cancer cases than controls (OR, 2.17; 95% CI, 1.08–4.33; P = 0.03). Combinations of NAT1*10 with NAT2 slow acetylator genotypes (OR, 5.08; 95% CI, 1.56–16.5; P = 0.008) or with NAT2 very slow (homozygous NAT2*5) acetylator genotypes (OR, 7.50; 95% CI, 1.55–15.4; P = 0.016) further increased prostate cancer risk. The results of this small pilot study suggest increased susceptibility to prostate cancer for subjects with combinations of NAT1*10 and slow (particularly very slow) NAT2 acetylator genotypes. This finding should be investigated further in larger cohorts and in other ethnic populations. Environ. Mol. Mutagen. 40:161–167, 2002. © 2002 Wiley‐Liss, Inc.
On sampling and experiments
Authors: Thompson Steven K. 
Published: October 2002

AbstractSampling generally concerns how a sample of units is selected from a population, while experiments deal with the effects of a treatment or exposure on units and are concerned with the assignment of treatments to units. Real studies typically involve elements of both, with varying control by investigators over sample selection and treatment assignment aspects. Design and model based approaches in sampling and experiments, and in particular studies which combine both elements, are examined in this article. Within a model based approach design based methods can be used based on a conditioning argument which is necessarily somewhat more complex in the case of experimental studies than in studies involving only sampling. Copyright © 2002 John Wiley & Sons, Ltd.
Accounting for measurement error in uncertainty modeling and decision‐making using indicator kriging andp‐field simulation: application to a dioxin contaminated site
Authors: Saito Hirotaka , Goovaerts Pierre 
Published: October 2002

AbstractIn many environmental studies spatial variability is viewed as the only source of uncertainty while measurement errors tend to be ignored. This article presents an indicator kriging‐based approach to account for measurement errors in the modeling of uncertainty prevailing at unsampled locations. Probability field simulation is then used to assess the probability that the average pollutant concentration within remediation units exceeds a regulatory threshold, and probability maps are used to identify hazardous units that need to be remediated. This approach is applied to two types of dioxin data (composite and single spoon samples) with different measurement errors which were collected at the Piazza Road dioxin site, an EPA Superfund site located in Missouri. A validation study shows that the proportion of contaminated soil cores provides a reasonable probability threshold to identify hazardous remediation units. When a lower probability threshold is chosen, the total remediation costs are unreasonably high while false negatives are unacceptably frequent for a higher probability threshold. The choice of this threshold becomes critical as the sampling density decreases. Copyright © 2002 John Wiley & Sons, Ltd.
Computing the Bayesian highest posterior density credible sets for the lognormal mean
Authors: Dalpatadu Rohan , Gewali L. , Singh A. K. 
Published: October 2002

AbstractContaminant concentration data collected at Superfund sites are typically positively skewed, and the log‐normal distribution is commonly used to model such data distribution. U.S. EPA guidance documents recommend the use of H‐statistics to compute the upper confidence limit (UCL) of the mean of a log‐normal distribution. Recent work reported in the statistical literature has shown that the UCL calculated from the H‐statistics can yield extremely high false positives. In the present article we compute the Bayesian highest posterior density (HPD) credible set of the log‐normal mean. Simulated results using techniques of computational geometry are presented. Several experimental results on environmental data sets reveal that the UCL obtained by using the proposed Bayesian approach is more reasonable than those obtained by using other techniques. Copyright © 2002 John Wiley & Sons, Ltd.
Bootstrap upper bounds for the arithmetic mean of right‐skewed data, and the use of censored data
Authors: Ginevan Michael E. , Splitstone Douglas E. 
Published: October 2002

AbstractEnvironmental contamination data frequently follow an extremely right skewed distribution, which is often approximated by a log‐normal distribution. For the purpose of risk assessment it is of interest to use the sample data to calculate an upper bound on the population arithmetic mean. This article reviews the usual upper bound estimator calculated assuming a log‐normal distribution and shows that, when the log‐normal assumption is not satisfied, this method can result in severe over‐estimation of the upper bound for the arithmetic mean. We then show, using Monte Carlo simulation, that a bootstrap upper bound is a much better approximation to the true upper bound on the population arithmetic mean. Finally, we present a bootstrap procedure for use when the data are left censored by detection/quantification limits and discuss Monte Carlo results that support the use of this procedure when as much as one‐half of the sample consists of censored observations. Copyright © 2002 John Wiley & Sons, Ltd.
An evaluation of the Confidence Removal Goal approach for making remediation decisions at Superfund sites
Authors: Schultz Brad , Singh Ashok K. , Singh Anita 
Published: October 2002

AbstractThe Confidence Removal Goal approach was developed by the Gradient Corporation for the cleanup decisions at the METCOA Superfund Site. The CRG approach is a statistical approach to meet site cleanup goals based on the arithmetic mean of the contaminant concentration distribution. The CRG approach involves computing a threshold value c* (called the CRG value) from observed sample values in cases where the data distribution is log‐normal and the UCL of the population mean calculated for the sample exceeds the Cleanup Goal (CUG). The cleanup would then consist of removing all soils from the site with observed concentrations higher than the CRG value c*. At the METCOA site, the cadmium (Cd) and nickel (Ni) concentrations passed the test of log‐normality, and the UCL of the means exceeded their respective CUG values. The CRG values were then computed for observed Cd and Ni concentrations. In both cases, the CRG values turned out to be much higher than the respective observed maximum concentration. Based on these CRG values, it would appear that no cleanup would be needed at the METCOA site. A Monte Carlo simulation experiment was conducted by two of the authors of this article to investigate the performance of the CRG approach. The simulation experiments showed that the CRG approach had a rather high percentage of false negatives, i.e. it recommended no cleanup a large number of times when the simulation was performed for contaminated site conditions. The present article investigates the performance of the CRG approach for normal, uniform and exponential distributions, in addition to the log‐normal distribution. The CRG approach gives reasonable results for all models considered in this article, except for the log‐normal model, suggesting the inadequacy of the log‐normal distribution for modeling skewed environmental data. Copyright © 2002 John Wiley & Sons, Ltd.
Finite volume evolution Galerkin methods for Euler equations of gas dynamics
Authors: Lukáčová‐Medvid'ová M. , Morton K. W. , Warnecke G. 
Published: October 2002

AbstractThe aim of this paper is a derivation of a new multidimensional high‐resolution finite volume evolution Galerkin method for system of the Euler equations of gas dynamics. Instead of solving one‐dimensional Riemann problems in directions normal to cell interfaces the finite volume evolution Galerkin schemes are based on a genuinely multidimensional approach. The approximate solution at cell interfaces is computed by means of an approximate evolution operator taking all of the infinitely many bicharacteristics explicitly into account. Integrals along the Mach cones are evaluated exactly or by means of numerical quadratures. Second‐order resolution is obtained with a conservative piecewise bilinear recovery and the second‐order midpoint rule for the time integration. A numerical experiment which illustrates the good multidimensional approximation as well as higher‐order resolution is presented. Copyright © 2002 John Wiley & Sons, Ltd.