bluuebunny/crossref_metadata_2025 huggingface dataset:
Using hierarchical clustering methods to classify motor activities of COPD patients from wearable sensor data
Authors: Sherrill Delsey M , Moy Marilyn L , Reilly John J , Bonato Paolo
Published: June 2005

Background

Advances in miniature sensor technology have led to the development of wearable systems that allow one to monitor motor activities in the field. A variety of classifiers have been proposed in the past, but little has been done toward developing systematic approaches to assess the feasibility of discriminating the motor tasks of interest and to guide the choice of the classifier architecture.

Methods

A technique is introduced to address this problem according to a hierarchical framework and its use is demonstrated for the application of detecting motor activities in patients with chronic obstructive pulmonary disease (COPD) undergoing pulmonary rehabilitation. Accelerometers were used to collect data for 10 different classes of activity. Features were extracted to capture essential properties of the data set and reduce the dimensionality of the problem at hand. Cluster measures were utilized to find natural groupings in the data set and then construct a hierarchy of the relationships between clusters to guide the process of merging clusters that are too similar to distinguish reliably. It provides a means to assess whether the benefits of merging for performance of a classifier outweigh the loss of resolution incurred through merging.

Results

Analysis of the COPD data set demonstrated that motor tasks related to ambulation can be reliably discriminated from tasks performed in a seated position with the legs in motion or stationary using two features derived from one accelerometer. Classifying motor tasks within the category of activities related to ambulation requires more advanced techniques. While in certain cases all the tasks could be accurately classified, in others merging clusters associated with different motor tasks was necessary. When merging clusters, it was found that the proposed method could lead to more than 12% improvement in classifier accuracy while retaining resolution of 4 tasks.

Conclusion

Hierarchical clustering methods are relevant to developing classifiers of motor activities from data recorded using wearable systems. They allow users to assess feasibility of a classification problem and choose architectures that maximize accuracy. By relying on this approach, the clinical importance of discriminating motor tasks can be easily taken into consideration while designing the classifier.
Consumer access to health information on the internet: health policy implications
Authors: Scott W Guy , Scott Helen M , Auld Terry S
Published: June 2005

Background

Providers of health care usually have much better information about health and health care interventions than do consumers. The internet is an important and rapidly evolving source of global health-related information and could provide a means of correcting for asymmetric information. However, little is known about who accesses this information and how it is used in New Zealand.

The aims of this research were to: determine the nature of the health information sought, how respondents use the information, how helpful they perceive the information to be, and the self-assessed value of such information.

Methods

The researchers conducted an anonymous five minute telephone and mall intercept survey of randomly selected Wellington residents who had searched for health-related information on the internet. Investigators entered the data into an Excel spreadsheet and transferred it to SPSS for data cleaning, data exploration and statistical analysis. Search time costs were based on the opportunity cost of income foregone and respondents were asked to provide a money value for the information found.

Results

Eighty-three percent of respondents accessed the internet from home, and 87% conducted the search for themselves. Forty-five percent of people were looking for general health and nutrition information, 42% for data about a specific illness and 40% for a medicine.

After finding the information, 58% discussed it with a family member/ friend/ workmate, 36% consulted a general practitioner, 33% changed their eating or drinking habits, and 13% did nothing. Respondents found the information very quick to find and useful. It took them on average 0.47 hours and cost $12 (opportunity cost of time) to find the information. The average value of the data found was $60 and the net benefit to the consumer was $48 ($60 – $12).

Conclusion

The results of this research could assist providers of health information via the internet to tailor their websites to better suit users' needs. Given the high perceived value of internet health information (greater than the average general practitioner fee) and the fact that some of the information found may be unreliable or even unsafe a valuable public health policy initiative would be to provide an improved New Zealand health information website containing information on how to evaluate data sourced from the world-wide-web and links to a range of useful and trustworthy health information sites.
Rheumatoid arthritis is an independent risk factor for multi-vessel coronary artery disease: a case control study
Authors: Warrington Kenneth J , Kent Peter D , Frye Robert L , Lymp James F , Kopecky Stephen L , Goronzy Jörg J , Weyand Cornelia M
Published: June 2005

The risk for cardiovascular (CV) disease is increased in rheumatoid arthritis (RA) but data on the burden of coronary atherosclerosis in patients with RA are lacking. We conducted a retrospective case-control study of Olmsted County (MN, USA) residents with RA and new-onset coronary artery disease (CAD) (n = 75) in comparison with age-and sex-matched controls with newly diagnosed CAD (n = 128). Angiographic scores of the first coronary angiogram and data on CV risk factors and CV events on follow-up were obtained by chart abstraction. Patients with RA were more likely to have multi-vessel coronary involvement at first coronary angiogram compared with controls (P = 0.002). Risk factors for CAD including diabetes, hypertension, hyperlipidemia, and smoking history were not significantly different in the two cohorts. RA remained a significant risk factor for multi-vessel disease after adjustment for age, sex and history of hyperlipidemia. The overall rate of CV events was similar in RA patients and controls; however, there was a trend for increased CV death in patients with RA. In a nested cohort of patients with RA and CAD (n = 27), we measured levels of pro-inflammatory CD4+CD28null T cells by flow cytometry. These T cells have been previously implicated in the pathogenesis of CAD and RA. Indeed, CD4+CD28null T cells were significantly higher in patients with CAD and co-existent RA than in controls with stable angina (P = 0.001) and reached levels found in patients with acute coronary syndromes. Patients with RA are at increased risk for multi-vessel CAD, although the risk of CV events was not increased in our study population. Expansion of CD4+CD28null T cells in these patients may contribute to the progression of atherosclerosis.
Relationship between the tissue-specificity of mouse gene expression and the evolutionary origin and function of the proteins
Authors: Freilich Shiri , Massingham Tim , Bhattacharyya Sumit , Ponstingl Hannes , Lyons Paul A , Freeman Tom C , Thornton Janet M
Published: June 2005

Background

The combination of complete genome sequence information with expression data enables us to characterize the relationship between a protein's evolutionary origin or functional category and its expression pattern. In this study, mouse proteins were assigned into functional and phyletic groups and the gene expression patterns of the different protein groupings were examined by microarray analysis in various mouse tissues.

Results

Our results suggest that the proteins that are universally distributed in all tissues are predominantly enzymes and transporters. In contrast, the tissue-specific set is dominated by regulatory proteins (signal transduction and transcription factors). An increased tendency to tissue-specificity is observed for metazoan-specific proteins. As the composition of the phyletic groups highly correlates with that of the functional groups, the data were tested in order to determine which of the two factors - function or phyletic age - is dominant in shaping the expression profile of a protein. The observed differences in expression patterns of genes between functional groups were found mainly to reflect their different phyletic origin. The connection between tissue specificity and phyletic age cannot be explained by the recent rate of evolution. Finally, although metazoan-specific proteins tend to be tissue-specific compared with phyletically conserved proteins present in all domains of life, many such 'universal' proteins are also tissue-specific.

Conclusion

The minimal cellular transcriptome of the metazoan cell differs from that of the ancestral unicellular eukaryote: new functions were added (metazoan-specific proteins), whilst other functions became specialized and no longer took place in all cells (tissue-specific pre-metazoan proteins).
Mobility of proteins associated with the plasma membrane by interaction with inositol lipids
Authors: Brough David , Bhatti Farzana , Irvine Robin F.
Published: June 2005

Translocation of a protein to the plasma membrane in response to the generation of polyphosphoinositol lipids is believed to be an important component of cellular regulation, in part because it increases the effective concentration of that protein relative to other proteins in the same membrane by restricting it to a two-dimensional space. However, such a concept assumes that, once translocated, a protein retains the free mobility it had in the cytoplasm, and also that the possible existence of partitioned pools of inositol lipids does not restrict its sphere of influence. We have explored by fluorescence recovery after photobleaching (FRAP) the mobility of four green-fluorescent-protein-tagged proteins, GAP1IP4BP and GAP1m, when they are either cytoplasmic or attached to the plasma membrane, and the PH domain of PI-PLCδ1 and ICAM as representative of, respectively, another inositol-lipid-anchored protein and a single-transmembrane-span-domain protein. The data from GAP1m and the PI-PLCδ1 PH domain show that, when proteins associate with inositol lipids in the plasma membrane, they retain a mobility similar to that in the cytoplasm, and probably also similar to the inositol lipid to which they are attached, suggesting a free diffusion within the plane of the membrane. Moreover, this free diffusion is similar whether they are bound to PtdIns(3,4,5)P3 or to PtdIns(4,5)P2, and no evidence was found by these criteria for restricted pools of PtdIns(4,5)P2. The mobility of GAP1IP4BP, which has been reported to associate with PtdIns(4,5)P2 in the plasma membrane, is much lower, suggesting that it might interact with other cellular components. Moreover, the mobility of GAP1IP4BP is not detectably altered by the generation of either of its two potential regulators, Ins(1,3,4,5)P4 or PtdIns(3,4,5)P3.
N-WASP deficiency impairs EGF internalization and actin assembly at clathrin-coated pits
Authors: Benesch Stefanie , Polo Simona , Lai Frank P. L. , Anderson Kurt I. , Stradal Theresia E. B. , Wehland Juergen , Rottner Klemens
Published: June 2005

WASP and WAVE family proteins promote actin polymerization by stimulating Arp2/3-complex-dependent filament nucleation. Unlike WAVE proteins, which are known to drive the formation of protrusions such as lamellipodia and membrane ruffles, vertebrate cell functions of WASP or N-WASP are less well established. Recent work demonstrated that clathrin-coated pit invagination can coincide with assembly of actin filaments and with accumulation of N-WASP and Arp2/3 complex, but the relevance of their recruitment has remained poorly defined. We employed two-colour total internal reflection microscopy to study the recruitment and dynamics of various components of the actin polymerization machinery and the epidermal growth factor receptor signalling machinery during clathrin-coated pit internalization in control cells and cells genetically deficient for functional N-WASP. We found that clathrin-coated pit endocytosis coincides with the recruitment of N-WASP, Arp2/3 complex and associated proteins, but not of WAVE family members. Actin accumulation at clathrin-coated pits requires the Arp2/3 complex, since Arp2/3 complex sequestration in the cytosol abolished any detectable actin assembly. The absence of N-WASP caused a significant reduction in the frequencies of actin and Arp2/3 complex accumulations at sites of clathrin-coated pit invagination and vesicle departure. Although N-WASP was not essential for Arp2/3-complex-mediated actin assembly at these sites or for EGF receptor-mediated endocytosis, N-WASP deficiency caused a marked reduction of EGF internalization.

We conclude that the assembly of WASP subfamily proteins and associated factors at sites of clathrin-coated pit invagination amplifies actin accumulations at these sites promoting efficient internalization of ligands via clathrin-mediated endocytosis.
The apoptosis/autophagy paradox: autophagic vacuolization before apoptotic death
Authors: González-Polo Rosa-Ana , Boya Patricia , Pauleau Anne-Laure , Jalil Abdelali , Larochette Nathanael , Souquère Sylvie , Eskelinen Eeva-Liisa , Pierron Gérard , Saftig Paul , Kroemer Guido
Published: June 2005

Autophagic cell death is morphologically characterized by an accumulation of autophagic vacuoles. Here, we show that inactivation of LAMP2 by RNA interference or by homologous recombination leads to autophagic vacuolization in nutrient-depleted cells. Cells that lack LAMP2 expression showed an enhanced accumulation of vacuoles carrying the marker LC3, yet a decreased colocalization of LC3 and lysosomes, suggesting that the fusion between autophagic vacuoles and lysosomes was inhibited. While a fraction of mitochondria from starved LAMP2-expressing cells colocalized with lysosomal markers, within autophagolysosomes, no such colocalization was found on removal of LAMP2 from the experimental system. Of note, LAMP1 depletion had no such effects and did not aggravate the phenotype induced by LAMP2-specific small interfering RNA. Serum and amino acid-starved LAMP2-negative cells exhibited an accumulation of autophagic vacuoles and then succumbed to cell death with hallmarks of apoptosis such as loss of the mitochondrial transmembrane potential, caspase activation and chromatin condensation. While caspase inhibition retarded cell death, it had no protective effect on mitochondria. Stabilization of mitochondria by overexpression of Bcl-2 or the mitochondrion-targeted cytomegalovirus protein vMIA, however, blocked all signs of apoptosis. Neither caspase inhibition nor mitochondrial stabilization antagonized autophagic vacuolization in LAMP2-deficient cells. Altogether, these data indicate that accumulation of autophagic vacuoles can precede apoptotic cell death. These findings argue against the clear-cut distinction between type 1 (apoptotic) and type 2 (autophagic) cell death.
A surprisingly large RNase P RNA in Candida glabrata
Authors: KACHOURI RYM , STRIBINSKIS VILIUS , ZHU YANGLONG , RAMOS KENNETH S. , WESTHOF ERIC , LI YONG
Published: June 2005

We have found an extremely large ribonuclease P (RNase P) RNA (RPR1) in the human pathogen Candida glabrata and verified that this molecule is expressed and present in the active enzyme complex of this hemiascomycete yeast. A structural alignment of the C. glabrata sequence with 36 other hemiascomycete RNase P RNAs (abbreviated as P RNAs) allows us to characterize the types of insertions. In addition, 15 P RNA sequences were newly characterized by searching in the recently sequenced genomes Candida albicans, C. glabrata, Debaryomyces hansenii, Eremothecium gossypii, Kluyveromyces lactis, Kluyveromyces waltii, Naumovia castellii, Saccharomyces kudriavzevii, Saccharomyces mikatae, and Yarrowia lipolytica; and by PCR amplification for other Candida species (Candida guilliermondii, Candida krusei, Candida parapsilosis, Candida stellatoidea, and Candida tropicalis). The phylogenetic comparative analysis identifies a hemiascomycete secondary structure consensus that presents a conserved core in all species with variable insertions or deletions. The most significant variability is found in C. glabrata P RNA in which three insertions exceeding in total 700 nt are present in the Specificity domain. This P RNA is more than twice the length of any other homologous P RNAs known in the three domains of life and is eight times the size of the smallest. RNase P RNA, therefore, represents one of the most diversified noncoding RNAs in terms of size variation and structural diversity.
Stability of Bortezomib 1-mg/mL Solution in Plastic Syringe and Glass Vial
Authors: André Pascal , Cisternino Salvatore , Chiadmi Fouad , Toledano Audrey , Schlatter Joël , Fain Olivier , Fontan Jean-Eudes
Published: June 2005

BACKGROUND:

The proteasome inhibitor bortezomib (BTZ), used in antineoplastic chemotherapy, must be diluted in NaCl 0.9% for injection and stored for no more than 3 hours in a syringe or 8 hours in a vial. Better information on its stability could improve storage.

OBJECTIVE:

To assess the stability of BTZ solution (1 mg/mL) in syringes and vials.

METHODS:

BTZ 1-mg/mL solutions were prepared by adding sterile NaCl 0.9% to Velcade vials containing 3.5 mg of lyophilized BTZ. Syringes were filled with 1 mL of solution and stored in the dark at 5 °C or 60 °C; others were not protected from light and stored at 22 °C. Velcade vials containing 1 mL of solution were stored at 5 °C in the dark. Samples were taken at various times over 23 days and assayed in duplicate. An HPLC method for assaying the stability of BTZ was validated. Appearance and pH were recorded.

RESULTS:

There was no color change or precipitation in the samples, and the pH was stable. Oxidation, light, and storage temperature all affected the chemical stability of BTZ. The mean concentrations of BTZ in syringes stored for 2, 3, and 5 days at 60, 22, and 5 °C were >95% of the initial concentration. The mean concentration of BTZ in vials stored for 5 days at 5 °C was >95% of the initial concentration.

CONCLUSIONS:

BTZ stored refrigerated in vials or syringes and protected from light is chemically stable for 5 days after reconstitution.
Polymorphisms of Coagulation Factor Genes a Review
Authors: Ferrer-Antunes Carlos
Published: June 2005

Common genetic variants of coagulation factor genes associated with differences in concentration and/or function of coagulation factors have been studied in search of variability that could explain the individual susceptibility to thrombosis and atherothrombotic diseases. The more outstanding polymorphisms in genes of factors involved in coagulation and fibrinolysis described in the literature (such as fibrinogen, factor XIII, glycoprotein IIb/IIIa, von Willebrand factor, factors VII, VIII and IX, factor V, ATIII and protein C system factors, prothrombin, PAI-1 and fibrinolytic system) are reviewed in the context of factor's structure and function and also in its proposed relevance for thrombotic and atherothrombotic risk definition.
Urinary Microscopy as Seen by Nephrologists
Authors: Fogazzi Giovanni B. , Grignani Simona , Colucci Patrizia
Published: June 2005

Urinary microscopy is a diagnostic tool which is largely used by nephrologists. In the opinion of the authors the best results can be achieved when all the aspects concerning this test are properly taken into account. Thus, from the methodological point of view, proper patient guidance, proper urine collection and handling, adequate microscopic equipment, and knowledge of the factors which can influence the results are all necessary. All the elements of clinical importance have to be known, namely, erythrocytes (with their morphological subtypes), leukocytes, tubular cells, uroepithelial cells (both superficial and deep), lipids, casts, crystals, and microorganisms. Then, the urinary findings have to be interpreted and, whenever possible, also combined into urinary profiles (e.g., the nephritic sediment, the nephrotic sediment). This, combined with other laboratory tests, the pathologic findings, and the clinical data, allows for the definition and management of urinary tract diseases.
Optimized Detection of DNA Point Mutations by Double Gradient Denaturing Gradient Gel
Authors: Cremonesi Laura , Carrera Paola , Cardillo Elena , Fumagalli Antonella , Lucchiari Sabrina , Ferrari Maurizio , Righetti Sabina C. , Righetti Pier Giorgio , Gelfi Cecilia
Published: June 2005

Denaturing gradient gel electrophoresis displays the highest detection rate among mutation scanning methods. In classical denaturing gradient gel electrophoresis the denaturant gradient range and migration times vary for every amplicon to be scanned, greatly affecting the routine application of the method. As an alternative, we developed double gradient denaturing gradient gel electrophoresis where a gradient of pore size is superimposed over the denaturing one, allowing maintenance of the zone-sharpening effect even over prolonged time runs, and adoption of identical run time conditions for all fragments analyzed. Here double gradient denaturing gradient gel electrophoresis has been applied to the analysis of a number of point mutations and polymorphisms located in several exons of three different genes, the cystic fibrosis transmembrane conductance regulator, the β-globin and the p53 genes.
Analytical and Clinical Performance of an Automated Immunoassay System (Immulite®) for Estradiol in Serum
Authors: Rodríguez-Espinosa José , Otal-Entraigas Carles , Gascón-Roche Neus , Mora-Brugués Josefina , Urgell-Rull Eulalia , Bordás-Serrat José-Ramón , Viscasillas-Molins Pere
Published: June 2005

The analytical and clinical performance of a commercial automated immunoassay system (Immulite®) for estradiol (E2) in serum was evaluated. The functional sensitivity for E2 was 0.07 nmol/l, and analytical imprecision (<13 %, <9 % and <7 % at 0.22, 0.51 and 1.51 nmol/l, respectively) for concentrations above this detection limit met published analytical goals. The assay recovery was good and the assay was linear over a wide concentration range. No sample carryover was found, and interferences from common substances present in serum were observed only at very high concentrations. Most of samples from men and postmenopausal women showed E2 concentrations below the detection limit. Longitudinal estradiol profiles from 11 healthy menstruating women showed characteristic menstrual cycle patterns (12 samples per subject obtained during a 30-day period). Longitudinal studies on women during induction of ovulation showed that E2 concentrations are highly correlated with the total number of follicles. Our results demonstrate the reliability of this system for routine use in the clinical laboratory.
Bistable Network Behavior of Layer I Interneurons in Auditory Cortex
Authors: Merriam Elliott B. , Netoff Theoden I. , Banks Matthew I.
Published: June 2005

GABAergic interneurons in many areas of the neocortex are mutually connected via chemical and electrical synapses. Previous computational studies have explored how these coupling parameters influence the firing patterns of interneuronal networks. These models have predicted that the stable states of such interneuronal networks will be either synchrony (near zero phase lag) or antisynchrony (phase lag near one-half of the interspike interval), depending on network connectivity and firing rates. In certain parameter regimens, the network can be bistable, settling into either stable state depending on the initial conditions. Here, we investigated how connectivity parameters influence spike patterns in paired recordings from layer I interneurons in brain slices from juvenile mice. Observed properties of chemical and electrical synapses were used to simulate connections between uncoupled cells via dynamic clamp. In uncoupled pairs, action potentials induced by constant depolarizing currents had randomly distributed phase differences between the two cells. When coupled with simulated chemical (inhibitory) synapses, however, these pairs exhibited a bimodal firing pattern, tending to fire either in synchrony or in antisynchrony. Combining electrical with chemical synapses, prolonging τDecayof inhibitory connections, or increasing the firing rate of the network all resulted in enhanced stability of the synchronous state. Thus, electrical and inhibitory synaptic coupling constrain the relative timing of spikes in a two-cell network to, at most, two stable states, the stability and precision of which depend on the exact parameters of coupling.
Effect of the Temporal Pattern of Contralateral Inhibition on Sound Localization Cues
Authors: Marsat Gary , Pollack Gerald S.
Published: June 2005

We studied the temporal coding properties of identified interneurons in the auditory system of crickets, using information theory as an analytical tool. The ascending neuron 1 (AN1), which is tuned to the dominant carrier frequency (CF) of cricket songs, selectively codes the limited range of amplitude modulation (AM) frequencies that occur in these signals. AN2, which is most sensitive to the ultrasonic frequencies that occur in echolocation calls of insectivorous bats, codes a broader range of AM frequencies, as occur in bat calls. A third neuron, omega neuron 1 (ON1), which is dually tuned to both ranges of carrier frequency, was shown previously to have CF-specific coding properties, allowing it to represent accurately the differing temporal structures of both cricket songs and bat calls. ON1 is a source of contralateral inhibition to AN1 and AN2, enhancing binaural contrast and facilitating sound localization. We used dichotic stimulation to examine the importance of the temporal structure of contralateral inhibition for enhancing binaural contrast. Contralateral inhibition degrades the coding of temporal pattern by AN1 and AN2, but only if the temporal pattern of inhibitory input matches that of excitation. Firing rate is also decreased most strongly by temporally matched contralateral inhibition. This is apparent for AN1 in its mean firing rate; for AN2, high-frequency firing is selectively suppressed. Our results show that the CF-specific coding properties of ON1 allow this single neuron to enhance effectively localization cues for both cricket-like and bat-like acoustic signals.
Treatment with an Amyloid-β Antibody Ameliorates Plaque Load, Learning Deficits, and Hippocampal Long-Term Potentiation in a Mouse Model of Alzheimer's Disease
Authors: Hartman Richard E. , Izumi Yukitoshi , Bales Kelly R. , Paul Steven M. , Wozniak David F. , Holtzman David M.
Published: June 2005

PDAPP transgenic mice overexpress a mutant form of human amyloid precursor protein under control of the platelet-derived growth factor promoter in CNS neurons that causes early onset, familial Alzheimer's disease in humans. These mice, on a mixed genetic background, have been shown to have substantial learning impairments from early ages, as well as an age-dependent decline in learning ability that has been hypothesized to be caused by amyloid-β (Aβ) accumulation. The goals of this study were to determine: (1) whether PDAPP mice on a pure C57BL/6 background develop more severe age-dependent learning deficits than wild-type mice; (2) if so, whether Aβ accumulation accounts for the excessive decline in learning ability; and (3) whether the learning deficits are reversible, even after significant Aβ deposition. At 4-6, 10-12, or 17-19 months of age, PDAPP and littermate wild-type mice on a C57BL/6 background were tested on a 5 week water maze protocol in which the location of the escape platform changed weekly, requiring the mice to repeatedly learn new information. PDAPP mice exhibited impaired spatial learning as early as 4 months (pre-Aβ deposition), and the performance of both wild-type and PDAPP mice declined with age. However, PDAPP mice exhibited significantly greater deterioration with age. Direct evidence for the role of Aβ accumulation in the age-related worsening in PDAPP mice was provided by the observation that systemic treatment over several weeks with the anti-Aβ antibody 10D5 reduced plaque deposition, increased plasma Aβ, improved hippocampal long-term potentiation, and improved behavioral performance in aged PDAPP mice with substantial Aβ burden.
Sortilin Controls Intracellular Sorting of Brain-Derived Neurotrophic Factor to the Regulated Secretory Pathway
Authors: Chen Zhe-Yu , Ieraci Alessandro , Teng Henry , Dall Henning , Meng Chui-Xiang , Herrera Daniel G. , Nykjaer Anders , Hempstead Barbara L. , Lee Francis S.
Published: June 2005

Brain-derived neurotrophic factor (BDNF), after activity-dependent secretion from neurons, modulates critical nervous system functions. Recently, a variant in the humanbdnfgene, resulting in a valine to methionine substitution in the prodomain, has been shown to lead to defective regulated secretion from neurons and memory impairment. Here, we report a novel function for a Vps10p domain protein, sortilin, in controlling BDNF sorting to the regulated secretory pathway. Sortilin interacts specifically with BDNF in a region encompassing the methionine substitution and colocalizes with BDNF in secretory granules in neurons. A truncated form of sortilin causes BDNF missorting to the constitutive secretory pathway without affecting neurotrophin-4 (NT-4) secretion. In addition, sortilin small interfering RNA introduced into primary neurons also led to BDNF missorting from the regulated to the constitutive secretory pathway. Together, these data suggest a mechanism to understand the defect associated with variant BDNF and provide a framework, based on divergent presynaptic regulation of sorting to secretory pathways, to explain how two ligands for tropomyosin-related kinase B, BDNF and NT-4, can mediate diverse biological responses.
NMDA Receptor Subunit-Dependent [Ca2+] Signaling in Individual Hippocampal Dendritic Spines
Authors: Sobczyk Aleksander , Scheuss Volker , Svoboda Karel
Published: June 2005

Ca2+influx through synaptic NMDA receptors (NMDA-Rs) triggers a variety of adaptive cellular processes. To probe NMDA-R-mediated [Ca2+] signaling, we used two-photon glutamate uncaging to stimulate NMDA-Rs on individual dendritic spines of CA1 pyramidal neurons in rat brain slices. We measured NMDA-R currents at the soma and NMDA-R-mediated [Ca2+] transients in stimulated spines (Δ[Ca2+]). Uncaging-evoked NMDA-R current amplitudes were independent of the size of the stimulated spine, implying that smaller spines contain higher densities of functional NMDA-Rs. The ratio of Δ[Ca2+] over NMDA-R current was highly variable (factor of 10) across spines, especially for small spines. These differences were not explained by heterogeneity in spine sizes or diffusional coupling between spines and their parent dendrites. In addition, we find that small spines have NMDA-R currents that are sensitive to NMDA-R NR2B subunit-specific antagonists. With block of NR2B-containing receptors, the range of Δ[Ca2+]/NMDA-R current ratios and their average value were much reduced. Our data suggest that individual spines can regulate the subunit composition of their NMDA-Rs and the effective fractional Ca2+current through these receptors.
Integrin-Mediated Dendrite Branch Maintenance Requires Abelson (Abl) Family Kinases
Authors: Moresco Eva Marie Yang , Donaldson Stephanie , Williamson Anne , Koleske Anthony J.
Published: June 2005

Dendrite arbor structure is a critical determinant of nervous system function that must be actively maintained throughout life, but the signaling pathways that regulate dendrite maintenance are essentially unknown. We report that the Abelson (Abl) and Abl-related gene (Arg) nonreceptor tyrosine kinases are required for maintenance of cortical dendrites in the mouse brain.arg-/-cortical dendrites initially develop normally and are indistinguishable from wild-type dendrites at postnatal day 21. Dendrite branches are not efficiently maintained inarg-/-neurons, leading to a reduction in dendrite arbor size by early adulthood. More severe dendrite loss is observed inabl-/-arg-/-neurons. Elevation of Arg kinase activity in primary cortical neurons promotes axon and dendrite branching. Activation of integrin receptors by adhesion to laminin-1 or Semaphorin 7A also promotes neurite branching in cortical neurons, but this response is absent inarg-/-neurons because of the reduced dynamic behavior of mutant neurite branches. These data suggest that integrin signaling through Abl and Arg support cortical dendrite branch maintenance by promoting dendrite branch dynamics in response to adhesive cues.
Dopamine Cells Respond to Predicted Events during Classical Conditioning: Evidence for Eligibility Traces in the Reward-Learning Network
Authors: Pan Wei-Xing , Schmidt Robert , Wickens Jeffery R. , Hyland Brian I.
Published: June 2005

Behavioral conditioning of cue-reward pairing results in a shift of midbrain dopamine (DA) cell activity from responding to the reward to responding to the predictive cue. However, the precise time course and mechanism underlying this shift remain unclear. Here, we report a combined single-unit recording and temporal difference (TD) modeling approach to this question. The data from recordings in conscious rats showed that DA cells retain responses to predicted reward after responses to conditioned cues have developed, at least early in training. This contrasts with previous TD models that predict a gradual stepwise shift in latency with responses to rewards lost before responses develop to the conditioned cue. By exploring the TD parameter space, we demonstrate that the persistent reward responses of DA cells during conditioning are only accurately replicated by a TD model with long-lasting eligibility traces (nonzero values for the parameter λ) and low learning rate (α). These physiological constraints for TD parameters suggest that eligibility traces and low per-trial rates of plastic modification may be essential features of neural circuits for reward learning in the brain. Such properties enable rapid but stable initiation of learning when the number of stimulus-reward pairings is limited, conferring significant adaptive advantages in real-world environments.
Presynaptic Regulation of Quantal Size by the Vesicular Glutamate Transporter VGLUT1
Authors: Wilson Nathan R. , Kang Jiansheng , Hueske Emily V. , Leung Tony , Varoqui Helene , Murnick Jonathan G. , Erickson Jeffrey D. , Liu Guosong
Published: June 2005

A fundamental question in synaptic physiology is whether the unitary strength of a synapse can be regulated by presynaptic characteristics and, if so, what those characteristics might be. Here, we characterize a newly proposed mechanism for altering the strength of glutamatergic synapses based on the recently identified vesicular glutamate transporter VGLUT1. We provide direct evidence that filling in isolated synaptic vesicles is subject to a dynamic equilibrium that is determined by both the concentration of available glutamate and the number of vesicular transporters participating in loading. We observe that changing the number of vesicular transporters expressed at hippocampal excitatory synapses results in enhanced evoked and miniature responses and verify biophysically that these changes correspond to an increase in the amount of glutamate released per vesicle into the synaptic cleft. In addition, we find that this modulation of synaptic strength by vesicular transporter expression is endogenously regulated, both across development to coincide with a maturational increase in vesicle cycling and quantal amplitude and by excitatory and inhibitory receptor activation in mature neurons to provide an activity-dependent scaling of quantal size via a presynaptic mechanism. Together, these findings underscore that vesicular transporter expression is used endogenously to directly regulate the extent of glutamate release, providing a concise presynaptic mechanism for controlling the quantal efficacy of excitatory transmission during synaptic refinement and plasticity.
Brain-Derived Neurotrophic Factor Is Required for the Establishment of the Proper Number of Dopaminergic Neurons in the Substantia Nigra Pars Compacta
Authors: Baquet Zachary C. , Bickford Paula C. , Jones Kevin R.
Published: June 2005

Brain-derived neurotrophic factor (BDNF) has been implicated in regulating neuronal survival, differentiation, and synaptic plasticity. Reduced expression of BDNF within the substantia nigra accompanies the deterioration of dopaminergic neurons in Parkinson's disease (PD) patients. Analysis of the effects of long-term BDNF absence from the CNS has been difficult because of the early postnatal lethality ofBDNF-/-mice. Mice with a floxed BDNF allele were bred withWnt1-Cremice to generateWnt-BDNFKOmice that lack BDNF from the midbrain-hindbrain (MHB). These mice are viable but exhibit hindlimb clutching and poor rotarod performance. Tyrosine hydroxylase (TH)-positive neuron numbers in the substantia nigra pars compacta (SNC) were estimated using stereological methods, revealing a persistent ∼23% reduction of these cells at postnatal day 21 (P21) inWnt-BDNFKOmice compared with controls. The diminishment of TH-expressing neurons was present at birth and continued through P120. This deficit appears selective for the dopaminergic population, because at P21, total neuron number within the SNC, defined as neuronal nuclei protein-positive cells, was not significantly reduced. Interestingly, and similar to observations in PD patients, SNC neuron subpopulations are not equally affected. Calbindin- and calretinin-expressing SNC populations show no significant difference betweenWnt-BDNFKOmice and controls. Thus, BDNF depletion from the MHB selectively leads to reduced TH expression in a subpopulation of neurons, but it remains unclear whether these cells are lost.
Making Sense of the Movement for the Restoration of the Ten Commandments of God
Authors: Walliss John
Published: June 2005

In March 2000, approximately 540 members of the Movement for the Restoration of the Ten Commandments of God (MRTCG) died in what initially appeared to be collective suicide. Subsequent police investigations, however, discovered the bodies of an additional 240 members who showed signs of having met a violent end prior to the apparent suicide. As well as discussing the history and apoc-alyptic beliefs of the MRTCG, in this article I focus particularly on the various theories that have been put forward to account for the murder-suicides. In doing so, I argue that although various facile similarities may be drawn between the MRTCG and other recent examples of "cult sui-cides," the MRTCG traversed a radically different "apocalyptic trajectory" prior to its denouement than its most obvious contemporaries. In par-ticular, I will highlight the role of internal factors within the MRTCG in precipitating the deaths.
HIV Incidence Among Injection Drug Users in New York City, 1990 to 2002: Use of Serologic Test Algorithm to Assess Expansion of HIV Prevention Services
Authors: Des Jarlais Don C. , Perlis Theresa , Arasteh Kamyar , Torian Lucia V. , Beatrice Sara , Milliken Judith , Mildvan Donna , Yancovitz Stanley , Friedman Samuel R.
Published: June 2005

Objectives. We sought to estimate HIV incidence among injection drug users (IDUs) in New York City from 1990 to 2002 to assess the impact of an expansion of syringe exchange services. Syringe exchange increased greatly during this period, from 250000 to 3000000 syringes exchanged annually.

Methods. Serum samples were obtained from serial cross-sectional surveys of 3651 IDUs. HIV-positive samples were tested with the Serologic Test Algorithm for Recent HIV Seroconversion (STARHS) assay to identify recent HIV infections and to estimate HIV incidence. Consistency with other incidence studies was used to assess strengths and limitations of STARHS.

Results. HIV incidence declined from 3.55/100 person-years at risk (PYAR) from 1990–1992, to 2.63/100 PYAR from 1993–1995, to 1.05/100 PYAR from 1996–1998, and to 0.77/100 PYAR from 1999–2002 (P<.001). There was a very strong negative linear relationship (r= −.99, P<.005) between the annual numbers of syringes exchanged and estimated HIV incidence. These results were highly consistent with a large number of shorter incidence studies among IDUs conducted during the time period.

Conclusions. STARHS testing of samples from large serial cross-sectional surveys can provide important data for the assessment of community-level HIV prevention.
The Economic Burden of Home Care for Children with HIV and Other Chronic Illnesses
Authors: Wilson Leslie S. , Moskowitz Judith Tedlie , Acree Michael , Heyman Melvin B. , Harmatz Paul , Ferrando Stephen J. , Folkman Susan
Published: June 2005

Objectives. We compared types, amounts, and costs of home care for children with HIV and chronic illnesses, controlling for the basic care needs of healthy children to determine the economic burden of caring for and home care of chronically ill children.

Methods. Caregivers of 97 HIV-positive children, 101 children with a chronic illness, and 102 healthy children were surveyed regarding amounts of paid and unpaid care provided. Caregiving value was determined according to national hourly earnings and a market replacement method.

Results. Chronically ill children required significantly more care time than HIV-positive children (7.8 vs 3.9 hours per day). Paid care accounted for 8% to 16% of care time. Annual costs were $9300 per HIV-positive child and $25 900 per chronically ill child. Estimated national annual costs are $86.5 million for HIV-positive children and $155 to $279 billion for chronically ill children.

Conclusions. Informal caregiving represents a substantial economic value to society. The total care burden among chronically ill children is higher than that among children with HIV.
Emergency Contraception in Emergency Departments in Oregon, 2003
Authors: Rosenberg Kenneth D. , DeMunter Jodi K. , Liu Jihong
Published: June 2005

Objectives. We sought to learn about access to emergency contraception (EC) in Oregon emergency departments, both for women who are rape patients and for women who have had consensual unprotected sexual intercourse (“nonrape patients”).

Methods. We interviewed emergency department staff in 54 of Oregon’s 57 licensed emergency departments in February–March 2003 (response rate = 94.7%).

Results. Only 61.1% of Oregon emergency departments routinely offered EC to rape patients. Catholic hospitals were as likely as non-Catholic hospitals to routinely offer EC to rape patients. The hospitals most likely to routinely offer EC to rape patients had a written protocol for the care of rape patients that included offering EC (P = .02) and access to staff with specialized sexual assault training (P=.002). For nonrape patients, 46.3% of emergency departments discouraged the prescribing of EC. Catholic hospitals were significantly less likely than non-Catholic hospitals to provide access to EC for nonrape patients (P=.05).

Conclusions. Oregon emergency departments do not routinely offer EC to women who have been raped or to women who have had consensual unprotected sexual intercourse.
Socioeconomic Position in Childhood and Early Adult Life and Risk of Mortality: A Prospective Study of the Mothers of the 1958 British Birth Cohort
Authors: Power Chris , Hyppönen Elina , Davey Smith George
Published: June 2005

Objectives. We sought to establish whether women’s childhood socioeconomic position influenced their risk of mortality separately from the effects of adult socioeconomic position.

Methods. We examined 11855 British women aged 14 to 49 years, with mortality follow-up over a 45-year period.

Results. Trends according to childhood social class were observed for all-cause mortality, circulatory disease, coronary heart disease, respiratory disease, chronic obstructive pulmonary disease, stroke, lung cancer, and stomach cancer, with higher death rates among members of unskilled manual groups. Associations attenuated after adjustment for adult social class, smoking, and body mass index. No trend was seen for breast cancer or accidents and violence. Adverse social conditions in both childhood and adulthood were associated with higher death rates from coronary heart disease and respiratory disease. Stomach cancer was influenced primarily by childhood conditions and lung cancer by factors in adult life.

Conclusions. Socioeconomic position in childhood was associated with adult mortality in a large sample of British women.
Recent Changes in Soil Chemistry in a Forested Ecosystem of Southern Québec, Canada
Authors: Courchesne François , Côté B. , Fyles J. W. , Hendershot W. H. , Biron P. M. , Roy A. G. , Turmel M.-C.
Published: June 2005

We analyzed the temporal trends of elemental changes in the soil of the Hermine, a 5.1‐ha watershed of the Lower Laurentians, Quebec, Canada, from 1993 to 2002. The forest canopy of the Hermine is dominated by sugar maple (Acer saccharumMarshall) growing on Podzols formed in a shallow (<2 m) anorthositic till. The results show a significant long‐term decrease of SO4concentration in the solution of both the LFH (−1.33 μmol L−1yr−1; α = 0.05) and B (−0.78 μmol L−1yr−1; α = 0.01) horizons. This SO4decline is associated with a reduction in dissolved Ca and Mg in the B (−1.83 and −0.38 μmol L−1yr−1for Ca and Mg, respectively; α = 0.001) and, to a lesser extent, in the LFH horizons (−2.09 and −0.69 μmol L−1yr−1for Ca and Mg, respectively; α = 0.01). Thus, the combined change in dissolved Ca and Mg in the B horizon not only follows that of SO4but it proceeds, on an equivalent basis, at a rate almost three times faster than that of SO4For SO4, the concentration changes in solution are accompanied from 1994 to 2002 by a moderate depletion of the H2O‐soluble SO4pool in the podzolic B horizon of Zones A and C (mean rate for Zones A and C of −3.5 μmol kg−1yr−1; α = 0.05). Indeed, SO4desorption from the B horizon occurs even under constant S deposition levels and seems to respond to changes in atmospheric deposition that occurred decades ago. In the case of exchangeable calcium and magnesium (Caexand Mgex), decreasing trends are present in the FH horizons but they are statistically significant only for Mgexin the B horizons of Zones A and C. A decrease of up to 50% of the Mnexpool is observed in the FH and B horizons, a decline that is partly balanced by an increase in Mn uptake by sugar maple since 1994. A tendency toward acidification is also noted in the solution (mean rate of +3.48 μmol H+L−1yr−1, α = 0.01) and in the solid phase (mean rate of +36.4 μmol H+kg−1yr−1, α = 0.001) of the organic horizons. The increase in exchangeable aluminum (Alex) in the FH horizons of zones B and C (mean rate for zones B and C of +0.16 cmol(+)kg−1yr−1; α = 0.01) could reflect these decreasing pH trends. Finally, a recurrent seasonal pattern in exchangeable cations is observed where Alexincreases at the expense of Caex, Mgex, and exchangeable manganese and potassium (Mnexand Kex) during the growing season. This study shows that long‐term, seasonal, and episodic trends in soil properties create a complex temporal pattern that needs to be recognized and partitioned when assessing the response of soil materials to changes in environmental conditions.