Search

This study used data from 3 sites to examine the invariance and psychometric characteristics of the Brief Symptom Inventory-18 across Black, Hispanic, and White mothers of 5th graders (N = 4,711; M = 38.07 years of age, SD = 7.16). Internal consistencies were satisfactory for all subscale scores of the instrument regardless of ethnic group membership. Mean and covariance structures analysis indicated that the hypothesized 3-factor structure of the instrument was not robust across ethnic groups. It provided a reasonable approximation to the data for Black and White women but not for Hispanic women. Tests for differential item functioning (DIF) were therefore conducted for only Black and White women. Analyses revealed no more than trivial instances of nonuniform DIF but more substantial evidence of uniform DIF for 3 of the 18 items. After having established partial strong factorial invariance of the instrument, latent factor means were found to be significantly higher for Black than for White women on all 3 subscales (somatization, depression, anxiety). In conclusion, the instrument may be used for mean comparisons between Black and White women.

New applications such as the use of High Brightness Light Emitting Diodes (HB-LED's) for general lighting have brought about significant demand for thin dielectric materials laminated to metal substrates such as aluminum and copper. Conventional FR-4 printed wiring laminates have limited thermal performance due to the poor thermal conductivity. To maximize thermal performance, it is necessary to minimize the thermal resistance of the laminate structure. To accomplish this, the thermal conductivity of the dielectric must be maximized and the dielectric thickness must be minimized. This paper summarizes the results of a benchmark study comparing the thermal performance of DuPont CooLam™ and three competitive structures measuring Junction-to-Case Thermal Resistance (RΘ jc ) and using thermal impedance as a figure of merit for comparing thermal performance of substrates, a primary metric commonly used in the LED packaging industry. To ensure uniform and unbiased results all test samples were fabricated by the same PWB fabricator and the testing was conducted by an independent laboratory.

We compared the scores on self-management and associated psychosocial scales of patients with epilepsy at two clinics in Houston, TX, USA, to determine if there were systematic differences associated with socioeconomic status (SES). Patients of low SES reported higher scores on overall, information, and safety management (P

Nitric oxide (NO) is an important messenger both systemically and in the CNS. In digital Ca2+ imaging and patch-clamp experiments, clinically available nitroso compounds that generate NO are shown to inhibit responses mediated by the NMDA subtype of the glutamate receptor on rat cortical neurons in vitro. A mechanism of action for this effect was investigated by using the specific NO-generating agent S-nitrosocysteine. We propose that free sulfhydryl groups on the NMDA receptor-channel complex react to form one or more S-nitrosothiols in the presence of NO. If vicinal thiol groups react in this manner, they can form a disulfide bond(s), which is thought to constitute the redox modulatory site of the receptor, resulting in a relatively persistent blockade of NMDA responses. These reactions with NO can afford protection from NMDA receptor-mediated neurotoxicity. Our results demonstrate a new pathway for NO regulation of physiological function that is not via cGMP, but instead involves reactions with membrane-bound thiol groups on the NMDA receptor-channel complex.

We interviewed 732 smokers (from five US upper Midwestern states) via telephone in 2006 to examine young adult smoking patterns. We first defined two groups of intermittent smokers—low (who smoked for 1–14 days in the past 30 days) and high (who smoked for 15–29 days in the past 30 days), and then analyzed differences between these two groups and daily smokers. Low intermittent smokers were much less likely to consider themselves smokers, feel addicted, or smoke with friends than high intermittent smokers. Daily smokers were more likely to feel addicted and have trouble quitting smoking than high intermittent smokers. Implications, limitations, and ideas for future studies will be discussed.

Nitride program charge effects on random telegraph noise (RTN) in SONOS flash cells are investigated. We measure and simulate RTN amplitudes in floating gate flash, planar SONOS, and FinFET SONOS cells. We find that a planar SONOS has a wide spread in RTN amplitude after programming while a floating gate flash cell has identical RTN amplitude in erase and program states. The spread of program-state RTN amplitudes in a planar SONOS is attributed to a current-path percolation effect caused by random discrete nitride charges. The program-state RTN spread can be significantly reduced in FinFET SONOS.

Objective. We assessed the price variability of cigarettes by brand, neighborhood characteristics (racial/ethnic and youth composition, number of schools, and number of stores), and store type. Methods. Trained research staff purchased three different brands of cigarettes (premium, menthol, and discount—all produced by the same company) at 214 stores in one metropolitan area. We assessed associations between price and neighborhood/store characteristics through multivariate regression, using four price variables as dependent variables—the price of each brand of cigarettes and the mean price across the three brands. Results. We found that the price of cigarettes varied by neighborhood and store characteristics, although this variability differed by brand. For the same brand, the maximum price was 1.7 to 1.8 times higher than the lowest price. We found a positive association between the percentage of a neighborhood that was nonwhite and the price of discount and premium cigarettes as well as the overall mean price of cigarettes, but not with the price of the menthol brand. We found a negative association between the percentage of youth in a neighborhood and the price of premium cigarettes as well as the mean price, but not with the price of the other two brands. In addition, we found a greater likelihood of higher discount brand prices at independent vs. chain-operated stores. Conclusions. Our findings showed that cigarette prices do vary by brand, the youth and racial/ethnic composition in a neighborhood, and store type, suggesting that the tobacco industry might vary its marketing strategies based on brand as well as neighborhood and store characteristics.

Hyperactivation of NMDA-type glutamate receptors (NMDARs) results in excitotoxicity, contributing to damage in stroke and neurodegenerative disorders. NMDARs are generally comprised of NR1/NR2 subunits but may contain modulatory NR3 subunits. Inclusion of NR3 subunits reduces the amplitude and dramatically decreases the Ca2+permeability of NMDAR-associated channels in heterologous expression systems and in transgenic mice. Since excessive Ca2+influx into neurons is a crucial step for excitotoxicity, we asked whether NR3A subunits are neuroprotective. To address this question, we subjected neurons genetically lacking NR3A to various forms of excitotoxic insult. We found that cultured neurons prepared from NR3A knock-out (KO) mice displayed greater sensitivity to damage by NMDA application than wild-type (WT) neurons.In vivo, neonatal, but not adult, WT mice contain NR3A in the cortex, and neonatal NR3A KO mice manifested more damage than WT after hypoxia–ischemia. In adult retina, one location where high levels of NR3A normally persist into adulthood, injection of NMDA into the eye killed more retinal ganglion cells in adult NR3A KO than WT mice. These data suggest that endogenous NR3A is neuroprotective. We next asked whether we could decrease excitotoxicity by overexpressing NR3A. We found that cultured neurons expressing transgenic (TG) NR3A displayed greater resistance to NMDA-mediated neurotoxicity than WT neurons. Similarlyin vivo, adult NR3A TG mice subjected to focal cerebral ischemia manifested less damage than WT mice. These data suggest that endogenous NR3A protects neurons, and exogenously added NR3A increases neuroprotection and could be potentially exploited as a therapeutic.

Energy-filtered transmission electron microscopy (EFTEM) was used to determine the distribution of lithium ions in solid polymer electrolytes for lithium batteries. The electrolytes of interest are mixtures of bis(trifluoromethane)sulfonimide lithium salt and symmetric poly(styrene-block-ethylene oxide) copolymers (SEO). In contrast to current solid and liquid electrolytes, the conductivity of SEO/salt mixtures increases with increasing molecular weight of the copolymers. EFTEM results show that the salt is increasingly localized in the middle of the poly(ethylene oxide) (PEO) lamellae as the molecular weight of the copolymers is increased. Calculations of the inhomogeneous local stress field in block copolymer microdomains, modeled using self-consistent field theory, provide a quantitative explanation for this observation. These stresses, which increase with increasing molecular weight, interfere with the ability of PEO chains to coordinate with lithium cations near the walls of the PEO channels where ion mobility is expected to be low.

Author(s): Kita-Matsuo, Hiroko; Barcova, Maria; Prigozhina, Natalie; Salomonis, Nathan; Wei, Karen; Jacot, Jeffrey G; Nelson, Brandon; Spiering, Sean; Haverslag, Rene; Kim, Changsung; Talantova, Maria; Bajpai, Ruchi; Calzolari, Diego; Terskikh, Alexey; McCulloch, Andrew D; Price, Jeffrey H; Conklin, Bruce R; Chen, HS Vincent; Mercola, Mark | Abstract: BackgroundDevelopmental, physiological and tissue engineering studies critical to the development of successful myocardial regeneration therapies require new ways to effectively visualize and isolate large numbers of fluorescently labeled, functional cardiomyocytes.Methodology/principal findingsHere we describe methods for the clonal expansion of engineered hESCs and make available a suite of lentiviral vectors for that combine Blasticidin, Neomycin and Puromycin resistance based drug selection of pure populations of stem cells and cardiomyocytes with ubiquitous or lineage-specific promoters that direct expression of fluorescent proteins to visualize and track cardiomyocytes and their progenitors. The phospho-glycerate kinase (PGK) promoter was used to ubiquitously direct expression of histone-2B fused eGFP and mCherry proteins to the nucleus to monitor DNA content and enable tracking of cell migration and lineage. Vectors with T/Brachyury and alpha-myosin heavy chain (alphaMHC) promoters targeted fluorescent or drug-resistance proteins to early mesoderm and cardiomyocytes. The drug selection protocol yielded 96% pure cardiomyocytes that could be cultured for over 4 months. Puromycin-selected cardiomyocytes exhibited a gene expression profile similar to that of adult human cardiomyocytes and generated force and action potentials consistent with normal fetal cardiomyocytes, documenting these parameters in hESC-derived cardiomyocytes and validating that the selected cells retained normal differentiation and function.Conclusion/significanceThe protocols, vectors and gene expression data comprise tools to enhance cardiomyocyte production for large-scale applications.

LEDs are the ideal components to support Global Care activities and to enhance the quality of life by adaptive light solutions. Rapid developments in brightness levels and color quality of LED mean that we can expect many further innovations in entirely new areas of application. Designers and architects are making full use of the light sources, creating extravagant lighting systems that catch the eye. Public authorities are looking for more and more long-life eco-friendly LED lighting systems for street lighting and architectural illumination. This presentation will discuss the success factors of LED in different SSL exterior and interior applications and how to make the best use of LED with optimized system design and lighting design according to market trends and standardization. Article not available.

Objective To explore the social ecological predictors of the transition to overweight in youth, as shown in results from the Teens Eating for Energy and Nutrition at Schools study. Design Longitudinal data from a school-based intervention trial. Participants Adolescents who were involved in the Teens Eating for Energy and Nutrition at Schools intervention study who reported a healthful weight at baseline in 1998 (n=1,728). Main outcome measure Transition to overweight status (body mass index ≥85th percentile) at follow-up in eighth grade. Statistical analysis Generalized linear mixed model regression. Results Factors in the social, environmental, individual, and behavioral domains had significant unadjusted relationships with a transition to overweight status. In the multivariate analysis, adolescents who perceived themselves to be overweight at baseline were 2.3 times more likely to be overweight at follow-up compared to those with a normal weight self-perception. Compared to nondieters, current dieters were 2.6 times more likely to be overweight at follow-up, and boys were nearly three times more likely to transition to overweight status at follow-up compared with girls. Conclusions Individual factors, primarily related to a self-perception of being overweight, were the strongest predictors of transitioning to overweight as adolescents progressed from seventh through eighth grade. A better understanding of the relationship between weight concern and transition to overweight is needed.

Classical NMDA receptors (NMDARs), activated by glycine and glutamate, are heteromultimers comprised of NR1 and NR2 subunits. Coexpression of the novel NR3 family of NMDAR subunits decreases the magnitude of NR1/NR2 receptor-mediated currents or forms glycine-activated channels with the NR1 subunit alone. The second (M2) and third (M3) membrane segments of NR1 and NR2 subunits of classical NMDARs form the core of the channel permeation pathway. Structural information regarding NR1/NR3 channels remains unknown. Using theXenopusoocyte expression system and the SCAM (substituted cysteine accessibility method), we found that M3 segments of both NR1 and NR3A form a narrow constriction in the outer vestibule of the channel, which prevents passage of externally applied sulfhydryl-specific agents. The most internal reactive residue in each M3 segment is the threonine in the conserved SYTANLAAF motif. These threonines appear to be symmetrically aligned. Several NR3A M3 mutations change the behavior of NR1/NR3A channels. Unlike NR1, however, the M3 segment of NR3A does not undergo extensive molecular rearrangement during channel gating by added glycine. Additionally, in the M2 segment, our data suggest that the amino acid at the asparagine (N) site of NR1, but not NR3A, contributes to the selectivity filter of NR1/3A channels. We therefore conclude that NR3A modulates the NR1/NR3A permeation pathway via a novel mechanism of forming a narrow constriction at the outer channel vestibule. This modified channel vestibule may also explain the dominant-negative effect of the NR3 subunit on channel behavior when coexpressed with NR1 and NR2 subunits.

Memantine, an aminodamantane, has recently been approved to treat moderate-to-severe Alzheimer's disease in the US after over 20 years on the market in Europe for treatment of Parkinson's disease. The unique properties of Memantine allow for its selective inhibition of abnormally active NMDA receptor channels while preserving normal glutamate activity and healthy neuronal function. Recently, it has been shown that compounds such as nitroglycerin, used for years for ischemic coronary disease, can also regulate the NMDA receptor channel. Novel compounds have been synthesized in an attempt to combine these activities, in an attempt to synergistically improve upon the activities of both nitrates and aminoadamantanes. We have subjected these compounds to several laboratory tests to compare their ability to affect the function of the NMDA receptor and to dilate blood vessels. These tests provide an initial indication of which of the compounds may have enhanced activity relative to memantine. The results also provide guidance for the synthesis of additional compounds that are likely to have the properties that are being sought.

Most neuroprotective drugs have failed in clinical trials because of side-effects, causing normal brain function to become compromised. A case in point concerns antagonists of the N-methyl-D-aspartate type of glutamate receptor (NMDAR). Glutamate receptors are essential to the normal function of the central nervous system. However, their excessive activation by excitatory amino acids, such as glutamate itself, is thought to contribute to neuronal damage in many neurological disorders ranging from acute hypoxic-ischemic brain injury to chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. The dual role of NMDARs in particular for normal and abnormal functioning of the nervous system imposes important constraints on possible therapeutic strategies aimed at ameliorating neurological diseases. Blockade of excessive NMDAR activity must therefore be achieved without interference with its normal function. In general, NMDAR antagonists can be categorized pharmacologically according to the site of action on the receptor-channel complex. These include drugs acting at the agonist (NMDA) or co-agonist (glycine) sites, channel pore, and modulatory sites, such as the S-nitrosylation site where nitric oxide (NO) reacts with critical cysteine thiol groups. Because glutamate is thought to be the major excitatory transmitter in the brain, generalized inhibition of a glutamate receptor subtype like the NMDAR causes side-effects that clearly limit the potential for clinical applications. Both competitive NMDA and glycine antagonists, even although effective in preventing glutamate-mediated neurotoxicity, will cause generalized inhibition of NMDAR activities and thus have failed in many clinical trials. Open-channel block with the property of uncompetitive antagonism is the most appealing strategy for therapeutic intervention during excessive NMDAR activation as this action of blockade requires prior activation of the receptor. This property, in theory, leads to a higher degree of channel blockade in the presence of excessive levels of glutamate and little blockade at relatively lower levels, for example, during physiological neurotransmission. Utilizing this molecular strategy of action, we review here the logical process that we applied over the past decade to help develop memantine as the first clinically tolerated yet effective agent against NMDAR-mediated neurotoxicity. Phase 3 (final) clinical trials have shown that memantine is effective in treating moderate-to-severe Alzheimer's disease while being well tolerated. Memantine is also currently in trials for additional neurological disorders, including other forms of dementia, glaucoma, and severe neuropathic pain. Additionally, taking advantage of memantine's preferential binding to open channels and the fact that excessive NMDAR activity can be down-regulated by S-nitrosylation, we have recently developed combinatorial drugs called NitroMemantines. These drugs use memantine as a homing signal to target NO to hyperactivated NMDARs in order to avoid systemic side-effects of NO such as hypotension (low blood pressure). These second-generation memantine derivatives are designed as pathologically activated therapeutics, and in preliminary studies appear to have even greater neuroprotective properties than memantine.

Many adolescent smokers rely significantly on retail tobacco sources to initiate or maintain their smoking behavior. Though promising, the results from various interventions aimed at curtailing retail tobacco access have been mixed. In the present study, 14 communities were randomly assigned to intervention and control groups in an attempt to determine the long-term effect of local youth access laws and policies on adolescent smoking. The intervention continued for 32 months. Assessments were conducted at baseline (1991) and at years 3, 5, and 7. The intervention was based on a community-organizing approach that mobilized community members to support adoption and enforcement of local ordinances to restrict minors' access to commercial sources of tobacco. The major outcome measure for the study was cross-sectional prevalence of daily tobacco use among all students in grades 8, 9, and 10 in each community, measured by a self-administered student survey. A short-term significant intervention effect was observed and reported previously. That difference between intervention and control communities was maintained through the year 5 assessment but had dissipated by the year 7 assessment, very likely related to adoption of ordinances by control communities. Restricting commercial access to tobacco through local ordinances is effective in reducing adolescent smoking both immediately after the intervention (year 3) and 2 years later (year 5). Longer-term results are still inconclusive, because control communities adopted ordinances similar to those in the intervention communities.

Low-affinity, uncompetitive antagonists with rapid ‘off-rates’, such as memantine offer protection from dementia and other neurological disorders, but break all the old rules of screening for new drugs by high-affinity bind-ing.

Raj K Maturi,1,2 Vincent Chen,3 Dan Raghinaru,3 Laurie Bleau,1 Michael W Stewart4 1Midwest Eye Institute, Indianapolis, IN, USA; 2Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA; 3Jaeb Center for Health Research, Tampa, FL, USA; 4Department of Ophthalmology, Mayo Clinic, Jacksonville, FL, USA Aims: To determine if intravitreal bevacizumab combined with the dexamethasone intravitreal implant0.7mg improves visual acuity and macular thickness more than bevacizumab monotherapy in eyes with macular edema due to branch and central retinal vein occlusions. Methods: Thirty eyes were randomly assigned to receive either combination therapy or bevacizumab monotherapy. All patients received intravitreal bevacizumab at baseline, followed by dexamethasone implants or sham injections1week later. Monthly bevacizumab injections were given if the central subfield thickness (CST) was >250µm, and the combined group received a second implant at month4or5if CST was >250µm. Results: At6months, several secondary endpoints were met. Patients receiving combined therapy required fewer bevacizumab reinjections compared to those receiving monotherapy (two versus three; P=0.02), experienced greater mean reductions in CST from randomization (–56µm versus +45µm; P=0.01), and were more likely to have resolved all edema (CST

A three-dimensional (3-D) shape measurement system that can simultaneously achieve 3-D shape acquisition, reconstruction, and display at 30 frames per second (fps) with 480,000 measurement points per frame is presented. The entire processing pipeline was realized on a graphics processing unit (GPU) without the need of substantial central processing unit (CPU) power, making it achievable on a portable device, namely a laptop computer. Furthermore, the system is extremely inexpensive compared with similar state-of-art systems, making it possible to be accessed by the general public. Specifically, advanced GPU techniques such as multipass rendering and offscreen rendering were used in conjunction with direct memory access to achieve the aforementioned performance. The developed system, implementation details, and experimental results to verify the performance of the proposed technique are presented.

A stereo-phase-based absolute three-dimensional (3D) shape measurement method is provided that requires neither phase unwrapping nor projector calibration. This proposed method can be divided into two steps: (1) obtain a coarse disparity map from the quality map; and (2) refine the disparity map using local phase information. Experiments demonstrated that the proposed method could achieve high-quality 3D measurement even with extremely low-quality fringe patterns. The method is particular well-suited for a number of different applications including in mobile devices such as phones.

As endogenous sources of oxidizing and reducing agents have been discovered, redox modulation of protein function has been recognized to be an important mechanism for many cell types. For our purposes, we confine our review of redox modulation to covalent modification of sulfhydryl (thiol) groups on protein cysteine residues with special reference to the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor in the brain. If the cysteine sulfhydryls possess a sufficient redox potential, oxidizing agents can react to form adducts on single sulfhydryl (thiol, -SH) groups; or if two free sulfhydryl groups are vicinal (in close proximity), disulfide bonds may be formed. Reducing agents can regenerate free sulfhydryl (thiol, -SH) groups by donating electron(s). Considering endogenous redox agents, in addition to the usual suspects including glutathione, ascorbate, vitamin E, lipoic acid, and reactive oxygen species, nitric oxide (NO) and its redox-related species have come to the fore. This has occurred largely because of the rediscovery and application to biological systems of work from the early part of the twentieth century showing the organic synthesis of nitrosothiols (RS-NO) (for review, Stamler et al. 1992). NO group donors represent different redox-related species of the NO group, each with its own distinctive chemistry, that lead to entirely different biological effects. NO-related species include nitric oxide (NO-) but also the other redox-related forms of the NO group: with one less electron (NO+, or nitrosonium ion) or one additional electron (NO-, or nitroxyl anion) (Stamler et al. 1992). Evidence suggests that all three of these redox-related forms or their functional equivalents are important pharmacologically and physiologically, participating in distinctive chemical reactions.

The NMDA (N -methyl-D-aspartate) subclass of glutamate receptor1 is essential for the synaptic plasticity thought to underlie learning and memory2,3,4 and for synaptic refinement during development5,6. It is currently believed that the NMDA receptor (NMDAR) is a heteromultimeric channel comprising the ubiquitous NR1 subunit and at least one regionally localized NR2 subunit7,8,9,10,11. Here we report the characterization of a regulatory NMDAR subunit, NR3A (formerly termed NMDAR-L or χ-1), which is expressed primarily during brain development12,13. NR3Aco-immunoprecipitates with receptor subunits NR1 and NR2 in cerebrocortical extracts. In single-channel recordings from Xenopus oocytes, addition of NR3A to NR1 and NR2 leads to the appearance of a smaller unitary conductance. Genetic knockout of NR3A in mice results in enhanced NMDA responses and increased dendritic spines in early postnatal cerebrocortical neurons. These data suggest that NR3A is involved in the development of synaptic elements by modulating NMDAR activity.

Locus control regions (LCRs) are thought to provide a dominant tissue-specific open chromatin domain that allows for proper gene regulation by enhancers/silencers and their associated transcription factors. Expression of the T-cell receptor alpha (TCR alpha) gene is limited to T cells and its locus exists in different chromatin configurations in expressing and nonexpressing cell types. Here we show that eight DNase I-hypersensitive sites in the TCR alpha locus comprise an LCR that confers T-cell compartment-specific expression upon a linked heterologous transgene. Removal of the three 5'-most hypersensitive sites of this LCR, containing TCR alpha enhancers/silencers, abolishes tissue-differential chromatin structure and results in transgene expression in all tissues examined. The remaining five DNase I-hypersensitive sites therefore constitute a novel control element possessing a widely active chromatin-opening function that allows for ubiquitous expression of a linked transgene in all transgenic founder mice. Furthermore, these data show that cis-acting elements without inherent LCR activity can dominantly modulate chromatin structure to determine tissue-specific gene expression in vivo.

Background Brugada syndrome (BrS) is associated with loss of sodium channel function. Previous studies showed features consistent with sodium current (I Na ) deficit in patients carrying desmosomal mutations, diagnosed with arrhythmogenic cardiomyopathy ([AC]; or arrhythmogenic right ventricular cardiomyopathy [ARVC]). Experimental models showed correlation between loss of expression of desmosomal protein plakophilin-2 (PKP2) and reduced I Na . We hypothesized that PKP2 variants that reduce I Na could yield a BrS phenotype, even without cardiomyopathic features of AC. Methods and Results We searched for PKP2 variants in genomic DNA of 200 patients with BrS diagnosis, no signs of AC, and no mutations in BrS-related genes SCN5A, CACNa1c, GPD1L, and MOG1 . We identified 5 cases of single amino acid substitutions. One (Q62K) was previously described in AC patients as a variant of unknown significance; 4 were unreported. In a family with multiple cases of syncope and/or suspect ECG, novel variant R635Q cosegregated with the phenotype in all affected relatives and was absent in the nonaffected ones. Mutations were tested in HL-1–derived cells endogenously expressing Na v 1.5 but made deficient in PKP2 (PKP2-KD). Loss of PKP2 caused decreased I Na and Na v 1.5 at site of cell contact. These deficits were restored by transfection of wild-type PKP2 (PKP2-WT) but not of BrS-related PKP2 mutants. Similar results were obtained when cells were cotransfected with PKP2-WT and the BrS-related PKP2 variants, to mimic heterozygosity. Human-induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) from a patient with PKP2 deficit showed drastically reduced I Na . The deficit was restored by transfection of WT but not BrS-related PKP2 variant R635Q. Superresolution microscopy in murine PKP2-deficient cardiomyocytes related I Na deficiency to reduced number of channels at the intercalated disk and increased separation of microtubules from the cell end. Conclusions This is the first systematic retrospective analysis of a patient group to define the coexistence of sodium channelopathy and genetic PKP2 variations. PKP2 mutations may be a molecular substrate leading to the diagnosis of BrS.

To investigate whether calcium and vitamin D reduce the expression of the inflammation marker COX-2 in the normal-appearing colorectal mucosa of sporadic colorectal adenoma patients, we conducted a pilot, randomized, double-blind, placebo-controlled, 2 × 2 factorial clinical trial (n=92) of 2.0 g elemental calcium daily and vitamin D3 800 IU/day, alone and in combination, versus placebo over 6 months. COX-2 expression and colorectal crypt distribution in biopsies of normal-appearing colorectal mucosa were detected by automated immunohistochemistry and quantified by image analysis. COX-2 expression along the entire crypt increased by 4% (p=0.73) in the calcium group and decreased by 3% (p=0.86) and 4% (p=0.73) in the vitamin D3 and joint calcium and vitamin D3 supplementation groups, respectively, relative to the placebo group. The distribution of COX-2 in the colorectal crypts overall or in various regions of the crypt (proliferative zone, differentiation zone, and area closest to contact with colon lumen contents) did not substantially change over follow-up. Our findings did not support the hypothesis that calcium and/or vitamin D3 supplementation can substantially decrease COX-2 expression in the normal appearing colorectal mucosa of sporadic adenoma patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2896.

Excessive activation of NMDA receptors is thought to mediate the calcium-dependent neurotoxicity associated with hypoxic-ischemic brain injury, trauma, epilepsy, and several neurodegenerative diseases. For this reason, various NMDA antagonists have been investigated for their therapeutic potential in these diseases, but heretofore none have proven to be both effective and safe. In the present study, memantine, an adamantane derivative similar to the antiviral drug amantadine, is shown to block the channels activated by NMDA receptor stimulation. From whole-cell and single-channel recording experiments, the mechanism of action of memantine is deduced to be open-channel block, similar to MK-801; however, unlike MK-801, memantine is well tolerated clinically. Compared to MK-801, memantine's safety may be related to its faster kinetics of action with rapid blocking and unblocking rates at low micromolar concentrations. Furthermore, at these levels memantine is an uncompetitive antagonist and should theoretically allow near-normal physiological NMDA activity throughout the brain even in the face of pathologically high focal concentrations of glutamate. These pharmacological properties confer upon memantine a therapeutic advantage against NMDA receptor-mediated neurotoxicity with few side effects compared with other organic NMDA open-channel blockers. Moreover, memantine is increasingly effective against escalating levels of glutamate, such as those observed during a stroke. Low micromolar concentrations of memantine, levels known to be tolerated by patients receiving the drug for the treatment of Parkinson's disease, prevent NMDA receptor-mediated neurotoxicity in cultures of rat cortical and retinal ganglion cell neurons; memantine also appears to be both safe and effective in a rat stroke model. These results suggest that memantine has considerable therapeutic potential for the myriad of clinical entities associated with NMDA receptor-mediated neurotoxicity.

not Available.