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Showing papers by "State University of New York System published in 2008"


Journal ArticleDOI
TL;DR: Ecological momentary assessment holds unique promise to advance the science and practice of clinical psychology by shedding light on the dynamics of behavior in real-world settings.
Abstract: Assessment in clinical psychology typically relies on global retrospective self-reports collected at research or clinic visits, which are limited by recall bias and are not well suited to address how behavior changes over time and across contexts. Ecological momentary assessment (EMA) involves repeated sampling of subjects’ current behaviors and experiences in real time, in subjects’ natural environments. EMA aims to minimize recall bias, maximize ecological validity, and allow study of microprocesses that influence behavior in real-world contexts. EMA studies assess particular events in subjects’ lives or assess subjects at periodic intervals, often by random time sampling, using technologies ranging from written diaries and telephones to electronic diaries and physiological sensors. We discuss the rationale for EMA, EMA designs, methodological and practical issues, and comparisons of EMA and recall data. EMA holds unique promise to advance the science and practice of clinical psychology by shedding ligh...

4,286 citations


Journal ArticleDOI
TL;DR: There is cross-national variability in the prevalence of suicidal behaviours, but strong consistency in the characteristics and risk factors for these behaviours.
Abstract: Background Suicide is a leading cause of death worldwide; however, the prevalence and risk factors for the immediate precursors to suicide – suicidal ideation, plans and attempts – are not wellknown, especially in low- and middle-income countries. Aims To report on the prevalence and risk factors for suicidal behaviours across 17 countries. Method A total of 84 850 adults were interviewed regarding suicidal behaviours and socio-demographic and psychiatric risk factors. Results The cross-national lifetime prevalence of suicidal ideation, plans, and attempts is 9.2% (s.e.=0.1), 3.1% (s.e.=0.1), and 2.7% (s.e.=0.1). Across all countries, 60% of transitions from ideation to plan and attempt occur within the first year after ideation onset. Consistent cross-national risk factors included being female, younger, less educated, unmarried and having a mental disorder. Interestingly, the strongest diagnostic risk factors were mood disorders in high-income countries but impulse control disorders in low- and middle-income countries. Conclusion There is cross-national variability in the prevalence of suicidal behaviours, but strong consistency in the characteristics and risk factors for these behaviours. These findings have significant implications for the prediction and prevention of suicidal behaviours.

2,050 citations


Journal ArticleDOI
TL;DR: In this article, a new approach for parameterizing dissolved organic matter (DOM) ultraviolet-visible absorption spectra is presented, where two distinct spectral slope regions (275-295 nm and 350-400 nm) within log-transformed absorption spectras were used to compare DOM from contrasting water types, ranging from wetlands (Great Dismal Swamp and Suwannee River) to photobleached oceanic water (Atlantic Ocean).
Abstract: A new approach for parameterizing dissolved organic matter (DOM) ultraviolet-visible absorption spectra is presented. Two distinct spectral slope regions (275–295 nm and 350–400 nm) within log-transformed absorption spectra were used to compare DOM from contrasting water types, ranging from wetlands (Great Dismal Swamp and Suwannee River) to photobleached oceanic water (Atlantic Ocean). On the basis of DOM size-fractionation studies (ultrafiltration and gel filtration chromatography), the slope of the 275–295-nm region and the ratio of these slopes (SR; 275–295-nm slope : 350–400-nm slope) were related to DOM molecular weight (MW) and to photochemically induced shifts in MW. Dark aerobic microbial alteration of chromophoric DOM (CDOM) resulted in spectral slope changes opposite of those caused by photochemistry. Along an axial transect in the Delaware Estuary, large variations in SR were measured, probably due to mixing, photodegradation, and microbial alteration of CDOM as terrestrially derived DOM transited through the estuary. Further, SR varied by over a factor of 13 between DOM-rich wetland waters and Sargasso Sea surface waters. Currently, there is no consensus on a wavelength range for log-transformed absorption spectra. We propose that the 275–295-nm slope be routinely reported in future DOM studies, as it can be measured with high precision, it facilitates comparison among dissimilar water types including CDOM-rich wetland and CDOM-poor marine waters, and it appears to be a good proxy for DOM MW.

2,002 citations


Journal ArticleDOI
24 Jan 2008-Nature
TL;DR: Several facets of these kinds of C–H functionalization reactions are discussed and a perspective on how this methodology has affected the synthesis of complex natural products and potential pharmaceutical agents are provided.
Abstract: Novel reactions that can selectively functionalize carbon-hydrogen bonds are of intense interest to the chemical community because they offer new strategic approaches for synthesis. A very promising 'carbon-hydrogen functionalization' method involves the insertion of metal carbenes and nitrenes into C-H bonds. This area has experienced considerable growth in the past decade, particularly in the area of enantioselective intermolecular reactions. Here we discuss several facets of these kinds of C-H functionalization reactions and provide a perspective on how this methodology has affected the synthesis of complex natural products and potential pharmaceutical agents.

1,843 citations


Journal ArticleDOI
Jennifer Stone1, Jennifer Stone2, Jennifer Stone3, Michael Conlon O'Donovan4, Hugh Gurling5, George Kirov4, Douglas Blackwood6, Aiden Corvin7, Nicholas John Craddock4, Michael Gill7, Christina M. Hultman8, Christina M. Hultman9, Paul Lichtenstein9, Andrew McQuillin5, Carlos N. Pato10, Douglas M. Ruderfer1, Douglas M. Ruderfer3, Douglas M. Ruderfer2, Michael John Owen4, David St Clair11, Patrick F. Sullivan12, Pamela Sklar3, Pamela Sklar2, Pamela Sklar1, Shaun Purcell1, Shaun Purcell3, Shaun Purcell2, Joshua M. Korn2, Joshua M. Korn1, Stuart MacGregor13, Derek W. Morris7, Colm O'Dushlaine7, Mark J. Daly3, Mark J. Daly1, Mark J. Daly2, Peter M. Visscher13, Peter Holmans4, Edward M. Scolnick3, Edward M. Scolnick1, Nigel Williams4, Lucy Georgieva4, Ivan Nikolov4, Nadine Norton4, Hywel Williams4, Draga Toncheva, Vihra Milanova, Emma Flordal Thelander9, Patrick Sullivan12, Elaine Kenny7, John L. Waddington14, Khalid Choudhury5, Susmita Datta5, Jonathan Pimm5, Srinivasa Thirumalai15, Vinay Puri5, Robert Krasucki5, Jacob Lawrence5, Digby Quested16, Nicholas Bass5, David Curtis17, Caroline Crombie11, Gillian Fraser11, Soh Leh Kwan11, Nicholas Walker, Walter J. Muir6, Kevin A. McGhee6, Ben S. Pickard6, P. Malloy6, Alan W Maclean6, Margaret Van Beck6, Michele T. Pato10, Helena Medeiros10, Frank A. Middleton18, Célia Barreto Carvalho10, Christopher P. Morley18, Ayman H. Fanous, David V. Conti10, James A. Knowles10, Carlos Ferreira, António Macedo19, M. Helena Azevedo19, Steve McCarroll2, Steve McCarroll1, Mark J. Daly2, Mark J. Daly3, Mark J. Daly1, Kimberly Chambert3, Kimberly Chambert1, Casey Gates1, Stacey Gabriel1, Scott Mahon1, Kristen Ardlie1 
11 Sep 2008-Nature
TL;DR: A genome-wide survey of rare CNVs in 3,391 patients with schizophrenia and 3,181 ancestrally matched controls provides strong support for a model of schizophrenia pathogenesis that includes the effects of multiple rare structural variants, both genome- wide and at specific loci.
Abstract: Schizophrenia is a severe mental disorder marked by hallucinations, delusions, cognitive deficits and apathy, with a heritability estimated at 73 - 90% ( ref. 1). Inheritance patterns are complex, and the number and type of genetic variants involved are not understood. Copy number variants ( CNVs) have been identified in individual patients with schizophrenia(2-7) and also in neurodevelopmental disorders(8-11), but large- scale genome- wide surveys have not been performed. Here we report a genome- wide survey of rare CNVs in 3,391 patients with schizophrenia and 3,181 ancestrally matched controls, using high- density microarrays. For CNVs that were observed in less than 1% of the sample and were more than 100 kilobases in length, the total burden is increased 1.15- fold in patients with schizophrenia in comparison with controls. This effect was more pronounced for rarer, single- occurrence CNVs and for those that involved genes as opposed to those that did not. As expected, deletions were found within the region critical for velo- cardio- facial syndrome, which includes psychotic symptoms in 30% of patients(12). Associations with schizophrenia were also found for large deletions on chromosome 15q13.3 and 1q21.1. These associations have not previously been reported, and they remained significant after genome- wide correction. Our results provide strong support for a model of schizophrenia pathogenesis that includes the effects of multiple rare structural variants, both genome- wide and at specific loci.

1,465 citations


Journal ArticleDOI
TL;DR: New molecular, cellular, and immunologic techniques used to study host–pathogen interactions have led to a reexamination of the role of infection in chronic obstructive pulmonary disease.
Abstract: New molecular, cellular, and immunologic techniques used to study host–pathogen interactions have led to a reexamination of the role of infection in chronic obstructive pulmonary disease (COPD). There is now considerable evidence that infection plays a major role in the pathogenesis and clinical course of COPD. A vicious circle of infection and inflammation is thought to lead to exacerbations of the disease.

1,087 citations


Journal ArticleDOI
TL;DR: Stem cell self-renewal and differentiation is influenced by the 3D environment within the stem cell niche, and the intimate dynamic relationship between cells and the ECM must be understood to ensure appropriate cell behavior.
Abstract: The extracellular matrix (ECM) regulates cell behavior by influencing cell proliferation, survival, shape, migration and differentiation. Far from being a static structure, the ECM is constantly undergoing remodeling--i.e. assembly and degradation--particularly during the normal processes of development, differentiation and wound repair. When misregulated, this can contribute to disease. ECM assembly is regulated by the 3D environment and the cellular tension that is transmitted through integrins. Degradation is controlled by complex proteolytic cascades, and misregulation of these results in ECM damage that is a common component of many diseases. Tissue engineering strives to replace damaged tissues with stem cells seeded on synthetic structures designed to mimic the ECM and thus restore the normal control of cell function. Stem cell self-renewal and differentiation is influenced by the 3D environment within the stem cell niche. For tissue-engineering strategies to be successful, the intimate dynamic relationship between cells and the ECM must be understood to ensure appropriate cell behavior.

939 citations


Journal ArticleDOI
TL;DR: This article attempts to provide a brief overview of the main determinants of antibody pharmacokinetics and pharmacodynamics.
Abstract: More than 20 monoclonal antibodies have been approved as therapeutic drugs by the US Food and Drug Administration, and it is quite likely that the number of approved antibodies will double in the next 7-10 years. Antibody drugs show several desirable characteristics, including good solubility and stability, long persistence in the body, high selectivity and specificity, and low risk for bioconversion to toxic metabolites. However, many antibody drugs demonstrate attributes that complicate drug development, including very poor oral bioavailability, incomplete absorption following intramuscular or subcutaneous administration, nonlinear distribution, and nonlinear elimination. In addition, antibody administration often leads to an endogenous antibody response, which may alter the pharmacokinetics and efficacy of the therapeutic antibody. Antibodies have been developed for a wide range of disease conditions, with effects produced through a complex array of mechanisms. This article attempts to provide a brief overview of the main determinants of antibody pharmacokinetics and pharmacodynamics. Clinical Pharmacology & Therapeutics (2008); 84, 5, 548-558 doi:10.1038/clpt.2008.170.

884 citations


Journal ArticleDOI
TL;DR: The trial did not meet the predefined criteria for noninferiority but showed similar rates of recurrent stroke with ASA-ERDP and with clopidogrel, and there is no evidence that either of the two treatments was superior to the other in the prevention of recurrent strokes.
Abstract: BACKGROUND: Recurrent stroke is a frequent, disabling event after ischemic stroke. This study compared the efficacy and safety of two antiplatelet regimens--aspirin plus extended-release dipyridamole (ASA-ERDP) versus clopidogrel. METHODS: In this double-blind, 2-by-2 factorial trial, we randomly assigned patients to receive 25 mg of aspirin plus 200 mg of extended-release dipyridamole twice daily or to receive 75 mg of clopidogrel daily. The primary outcome was first recurrence of stroke. The secondary outcome was a composite of stroke, myocardial infarction, or death from vascular causes. Sequential statistical testing of noninferiority (margin of 1.075), followed by superiority testing, was planned. RESULTS: A total of 20,332 patients were followed for a mean of 2.5 years. Recurrent stroke occurred in 916 patients (9.0%) receiving ASA-ERDP and in 898 patients (8.8%) receiving clopidogrel (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11). The secondary outcome occurred in 1333 patients (13.1%) in each group (hazard ratio for ASA-ERDP, 0.99; 95% CI, 0.92 to 1.07). There were more major hemorrhagic events among ASA-ERDP recipients (419 [4.1%]) than among clopidogrel recipients (365 [3.6%]) (hazard ratio, 1.15; 95% CI, 1.00 to 1.32), including intracranial hemorrhage (hazard ratio, 1.42; 95% CI, 1.11 to 1.83). The net risk of recurrent stroke or major hemorrhagic event was similar in the two groups (1194 ASA-ERDP recipients [11.7%], vs. 1156 clopidogrel recipients [11.4%]; hazard ratio, 1.03; 95% CI, 0.95 to 1.11). CONCLUSIONS: The trial did not meet the predefined criteria for noninferiority but showed similar rates of recurrent stroke with ASA-ERDP and with clopidogrel. There is no evidence that either of the two treatments was superior to the other in the prevention of recurrent stroke. (ClinicalTrials.gov number, NCT00153062.)

853 citations


Journal ArticleDOI
TL;DR: A new approach for photoluminescence imaging in vitro and in vivo has been shown utilizing near infrared to near infrared (NIR-to-NIR) up-conversion in nanophosphors, which results in high contrast optical imaging due to absence of an autofluorescence background and decreased light scattering.
Abstract: A new approach for photoluminescence imaging in vitro and in vivo has been shown utilizing near infrared to near infrared (NIR-to-NIR) up-conversion in nanophosphors. This NIR-to-NIR up-conversion process provides deeper light penetration into biological specimen and results in high contrast optical imaging due to absence of an autofluorescence background and decreased light scattering. Aqueous dispersible fluoride (NaYF4) nanocrystals (20−30 nm size) co-doped with the rare earth ions, Tm3+ and Yb3+, were synthesized and characterized by TEM, XRD, and photoluminescence (PL) spectroscopy. In vitro cellular uptake was shown by the PL microscopy visualizing the characteristic emission of Tm3+ at ∼800 nm excited with 975 nm. No apparent cytotoxicity was observed. Subsequent animal imaging studies were performed using Balb-c mice injected intravenously with up-converting nanophosphors, demonstrating the high contrast PL imaging in vivo.

849 citations


Journal ArticleDOI
TL;DR: A novel method to flexibly fit atomic structures into electron microscopy (EM) maps using molecular dynamics simulations is presented, incorporating the EM data as an external potential added to the molecular dynamics force field.

Journal ArticleDOI
TL;DR: Some important parameters related to crystal nucleation and growth/dissolution including the supersaturation/undersaturation, pH, ionic strength and the ratio of calcium to phosphate activities are discussed.
Abstract: Calcium orthophosphates are the main mineral constituents of bones and teeth, and there is great interest in understanding the physical mechanisms that underlie their growth, dissolution, and phase stability. By definition, all calcium orthophosphates consist of three major chemical elements: calcium (oxidation state +2), phosphorus (oxidation state +5), and oxygen (oxidation state −2).1 The orthophosphate group (PO43−) is structurally different from meta (PO3−), pyro (P2O74−), and poly (PO3)nn−. In this review, only calcium orthophosphates will be discussed. The chemical composition of many calcium orthophosphates includes hydrogen, either as an acidic orthophosphate anion such as HPO42− or H2PO4−, and/or incorporated water as in dicalcium phosphate dihydrate (CaHPO4 · 2H2O).1 Most calcium orthophosphates are sparingly soluble in water, but all dissolve in acids; the calcium to phosphate molar ratios (Ca/P) and the solubilities are important parameters to distinguish between the phases (Table 1) with crystallographic data summarized in Table 2. In general, the lower the Ca/P ratio, the more acidic and soluble the calcium phosphate phase.2 It is now generally recognized that the crystallization of many calcium phosphates involves the formation of metastable precursor phases that subsequently dissolve as the precipitation reactions proceed. Thus, complex intermediate phases can participate in the crystallization process. Moreover, the in vivo presence of small peptides, proteins, and inorganic additives other than calcium and phosphate has a considerable influence on crystallization, making it difficult to predict the possible phases that may form.3 Studies of apatite mineral formation are complicated by the possibility of forming several calcium phosphate phases. The least soluble, hydroxyapatite (HAP), is preferentially formed under neutral or basic conditions. In more acidic solutions, phases such as brushite (DCPD) and octacalcium phosphate (OCP) are often encountered. Even under ideal HAP precipitation conditions, the precipitates are generally nonstoichiometric, suggesting the formation of calcium-deficient apatites. Both DCPD and OCP have been implicated as possible precursors to the formation of apatite. This may occur by the initial precipitation of DCPD and/or OCP followed by transformation to a more apatitic phase. Although DCPD and OCP are often detected during in vitro crystallization, in vivo studies of bone formation rarely show the presence of these acidic calcium phosphate phases. In the latter case, the situation is more complicated, since a large number of ions and molecules are present that can be incorporated into the crystal lattice or adsorbed at the crystallite surfaces. In biological apatite, DCPD and OCP are usually detected only during pathological calcification, where the pH is often relatively low. In normal in vivo calcifications, these phases have not been found, suggesting the involvement of other precursors or the formation of an initial amorphous calcium phosphate phase (ACP) followed by transformation to apatite. Table 1 Ca/P Molar Ratios, Chemical Formulas, and Solubilitiesa of Some Calcium Orthophosphate Minerals1,3,4 Table 2 Crystallographic Data of Calcium Orthophosphates1,4,5 In this review, we will discuss some important parameters related to crystal nucleation and growth/dissolution including the supersaturation/undersaturation, pH, ionic strength and the ratio of calcium to phosphate activities (Table 3). We then focus on the dynamics of crystallization/dissolution in the presence of additive molecules pertinent to biogenic calcium phosphate minerals. Table 3 Crystal Growth Controls and Their Effect on the Bulk Solution and the Crystal Surfaces6 2. Biologically Related Calcium Phosphate Phases 2.1. Structure, Composition, and Phase Stability 2.1.1. Amorphous Calcium Phosphate (ACP) During the synthesis of HAP crystals through the interaction of calcium and phosphate ions in neutral to basic solution, a precursor amorphous phase is formed that is structurally and chemically distinct from HAP.7 However, calculations have shown that the phase consisted of individual or groups of HAP unit cells.8 Chemical analysis of the precursor phase indicated this noncrystalline phase to be a hydrated calcium phosphate (Ca3(PO4)2 · xH2O) with a Ca/P ratio 1.50,8 consisting of roughly spherical Ca9(PO4)6 “Posner’s clusters” (PC) close-packed to form larger spherical particles with water in the interstices.9 PCs appeared to be energetically favored in comparison to alternative candidates including Ca3(PO4)2 and Ca6(PO4)4 clusters.10 The structure of PCs in isolated form is notably different from that in a HAP environment.11 In particular, the chirality feature of PCs found in the HAP environment is suggested to disappear in an isolated form and in aqueous solution. The reconsideration of PCs as possible components in the actual structural model of ACP resulted from the cluster growth model of the HAP crystal.12 Ab initio calculations confirmed that stable isomers exist on the [Ca3(PO4)2]3 potential energy surface (PES).12,13 These isomers correspond to compact arrangements, i.e., arrangements in which the Ca and PO4 are disposed closely together. Their geometries are compatible with the terms “roughly spherical” used in Posner’s hypothesis. The calculations performed on the monomer and dimer PES revealed that the relative energies of the different isomers are governed by a specific bonding pattern in which a calcium atom interacts with two PO43− groups, forming four CaO bonds.12,13 The compact isomers on the trimer PES are energetically favored in comparison to monomer or dimer isomers. This is rationalized by the appearance of a specific bonding pattern for the trimer case in which a calcium forms six CaO bonds with six different PO4 groups. This type of bonding in encountered in HAP.13 It is now generally agreed that, both in vitro and in vivo, precipitation reactions at sufficiently high supersaturation and pH result in the initial formation of an amorphous calcium phosphate with a molar calcium/phosphate ratio of about 1.18–2.50. The chemical composition of ACP is strongly dependent on the solution pH: ACP phases with Ca/P ratios in the range of 1.18:1 precipitated at pH 6.6 to 1.53:1 at pH 11.7 and even as high as 2.5:1.4 Two amorphous calcium phosphates, ACP1 and ACP2, have been reported with the same composition, but differing in morphology and solubility.14,15 The formation of ACP precipitate with little long-range order tends to consist of aggregates of primary nuclei (roughly spherical clusters) with composition Ca9(PO4)65 dependent on the conditions of formation. It hydrolyzes almost instantaneously to more stable phases. These amorphous clusters served as seeds during HAP crystallization via a stepwise assembly process12 and were presumed to pack randomly with respect to each other,16 forming large 300–800 A spheres. Recent experimental studies found that ACP has definite local atomic microcrystalline order rather than a random network structure. NMR of thoroughly dried ACP suggests that the tightly held water resides in the interstices between clusters,17 but these are probably not of intrinsic importance in the structure of ACP. It is well-known that ACP contains 10–20% by weight of tightly bound water, which is removed by vacuum drying at elevated temperature.9 However, drying does not alter the calcium and phosphorus atomic arrangement. The side band intensities of dried ACP suggest that its chemical shift anisotropy is similar to or identical with that of normal ACP.17 ACP has an apatitic short-range structure, but with a crystal size so small that it appears to be amorphous by X-ray analysis. This is supported by extended X-ray absorption fine structure (EXAFS) on biogenic and synthetic ACP samples.18–20 The CaP amorphous phase transforms to HAP microcrystalline in the presence of water. The lifetime of the metastable amorphous precursor in aqueous solution was reported to be a function of the presence of additive molecules and ions, pH, ionic strength, and temperature.21 The transformation kinetics from ACP to HAP, which can be described by a ”first-order” rate law, is a function only of the pH of the mediating solution at constant temperature. The solution-mediated transformation depends upon the conditions which regulate both the dissolution of ACP and the formation of the early HAP nuclei.22 Tropp et al. used 31P NMR to demonstrate that the strength of ACP side bands is due to a characteristic structural distortion of unprotonated phosphate and not to a mixture of protonated and unprotonated phosphates,17 suggesting that ACP could contain substantial amounts of protonated phosphate not in the form of any known phase of calcium phosphate crystals. Yin and Stott suggested that, in the transformation from ACP to HAP, ACP need only dissociate into clusters rather than undergo complete ionic solvation. The cluster with C1 symmetry is the most stable isomer in vacuum. The interaction of Posner’s cluster with sodium ions and especially with protons leads to a considerable stability increase, and surprisingly, the cluster with six protons and six OH− recovers the C3 symmetry and similar atomic arrangement that it has as a structural unit in the HAP crystal. This may be a key factor in the transformation from ACP to HAP crystal.23 In general, ACP is a highly unstable phase that hydrolyzes almost instantaneously to more stable phases. In the presence of other ions and macromolecules or under in vivo conditions, ACP may persist for appreciable periods3 and retain the amporphous state under some specific experimental conditions.24

Journal ArticleDOI
TL;DR: The history of the areas of multiple criteria decision making (MCDM) and multiattribute utility theory (MAUT) are extended and topics the authors believe to be important for the future of these fields are discussed.
Abstract: This paper is an update of a paper that five of us published in 1992. The areas of multiple criteria decision making (MCDM) and multiattribute utility theory (MAUT) continue to be active areas of management science research and application. This paper extends the history of these areas and discusses topics we believe to be important for the future of these fields.

Journal ArticleDOI
TL;DR: A comparison of the strongest associations with the genome-wide scan of 1868 patients with BP disorder and 2938 controls who completed the scan as part of the Wellcome Trust Case–Control Consortium indicates concordant signals for SNPs within the voltage-dependent calcium channel, L-type, alpha 1C subunit (CACNA1C) gene.
Abstract: We performed a genome-wide association scan in 1461 patients with bipolar (BP) 1 disorder, 2008 controls drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder and the University College London sample collections with successful genotyping for 372,193 single nucleotide polymorphisms (SNPs). Our strongest single SNP results are found in myosin5B (MYO5B; P=1.66 x 10(-7)) and tetraspanin-8 (TSPAN8; P=6.11 x 10(-7)). Haplotype analysis further supported single SNP results highlighting MYO5B, TSPAN8 and the epidermal growth factor receptor (MYO5B; P=2.04 x 10(-8), TSPAN8; P=7.57 x 10(-7) and EGFR; P=8.36 x 10(-8)). For replication, we genotyped 304 SNPs in family-based NIMH samples (n=409 trios) and University of Edinburgh case-control samples (n=365 cases, 351 controls) that did not provide independent replication after correction for multiple testing. A comparison of our strongest associations with the genome-wide scan of 1868 patients with BP disorder and 2938 controls who completed the scan as part of the Wellcome Trust Case-Control Consortium indicates concordant signals for SNPs within the voltage-dependent calcium channel, L-type, alpha 1C subunit (CACNA1C) gene. Given the heritability of BP disorder, the lack of agreement between studies emphasizes that susceptibility alleles are likely to be modest in effect size and require even larger samples for detection.

Journal ArticleDOI
TL;DR: Robust and selective social deficits, repetitive self‐grooming, genetic stability and commercial availability of the BTBR inbred strain encourage its use as a research tool to search for background genes relevant to the etiology of autism, and to explore therapeutics to treat the core symptoms.
Abstract: Autism is a behaviorally defined neurodevelopmental disorder of unknown etiology. Mouse models with face validity to the core symptoms offer an experimental approach to test hypotheses about the causes of autism and translational tools to evaluate potential treatments. We discovered that the inbred mouse strain BTBR T+tf/J (BTBR) incorporates multiple behavioral phenotypes relevant to all three diagnostic symptoms of autism. BTBR displayed selectively reduced social approach, low reciprocal social interactions and impaired juvenile play, as compared with C57BL/6J (B6) controls. Impaired social transmission of food preference in BTBR suggests communication deficits. Repetitive behaviors appeared as high levels of self-grooming by juvenile and adult BTBR mice. Comprehensive analyses of procedural abilities confirmed that social recognition and olfactory abilities were normal in BTBR, with no evidence for high anxiety-like traits or motor impairments, supporting an interpretation of highly specific social deficits. Database comparisons between BTBR and B6 on 124 putative autism candidate genes showed several interesting single nucleotide polymorphisms (SNPs) in the BTBR genetic background, including a nonsynonymous coding region polymorphism in Kmo. The Kmo gene encodes kynurenine 3-hydroxylase, an enzyme-regulating metabolism of kynurenic acid, a glutamate antagonist with neuroprotective actions. Sequencing confirmed this coding SNP in Kmo, supporting further investigation into the contribution of this polymorphism to autism-like behavioral phenotypes. Robust and selective social deficits, repetitive self-grooming, genetic stability and commercial availability of the BTBR inbred strain encourage its use as a research tool to search for background genes relevant to the etiology of autism, and to explore therapeutics to treat the core symptoms.

Journal ArticleDOI
TL;DR: Therapy with telmisartan initiated soon after an ischemic stroke and continued for 2.5 years did not significantly lower the rate of recurrent stroke, major cardiovascular events, or diabetes.
Abstract: BACKGROUND: Prolonged lowering of blood pressure after a stroke reduces the risk of recurrent stroke. In addition, inhibition of the renin-angiotensin system in high-risk patients reduces the rate of subsequent cardiovascular events, including stroke. However, the effect of lowering of blood pressure with a renin-angiotensin system inhibitor soon after a stroke has not been clearly established. We evaluated the effects of therapy with an angiotensin-receptor blocker, telmisartan, initiated early after a stroke. METHODS: In a multicenter trial involving 20,332 patients who recently had an ischemic stroke, we randomly assigned 10,146 to receive telmisartan (80 mg daily) and 10,186 to receive placebo. The primary outcome was recurrent stroke. Secondary outcomes were major cardiovascular events (death from cardiovascular causes, recurrent stroke, myocardial infarction, or new or worsening heart failure) and new-onset diabetes. RESULTS: The median interval from stroke to randomization was 15 days. During a mean follow-up of 2.5 years, the mean blood pressure was 3.8/2.0 mm Hg lower in the telmisartan group than in the placebo group. A total of 880 patients (8.7%) in the telmisartan group and 934 patients (9.2%) in the placebo group had a subsequent stroke (hazard ratio in the telmisartan group, 0.95; 95% confidence interval [CI], 0.86 to 1.04; P=0.23). Major cardiovascular events occurred in 1367 patients (13.5%) in the telmisartan group and 1463 patients (14.4%) in the placebo group (hazard ratio, 0.94; 95% CI, 0.87 to 1.01; P=0.11). New-onset diabetes occurred in 1.7% of the telmisartan group and 2.1% of the placebo group (hazard ratio, 0.82; 95% CI, 0.65 to 1.04; P=0.10). CONCLUSIONS: Therapy with telmisartan initiated soon after an ischemic stroke and continued for 2.5 years did not significantly lower the rate of recurrent stroke, major cardiovascular events, or diabetes. (ClinicalTrials.gov number, NCT00153062.)

Journal ArticleDOI
TL;DR: In un analisis multitemporal mediante tecnicas de teledeteccion and sistemas de informacion geografica (SIG) as discussed by the authors, Tullparaju, Palcacocha, Arhuaycocha, Pacliash, Ocshpalca, 513, Artizon Alto, Quitacoche, and Safuna Alta; estudios batimetricos indican las caracteristicas morfometricas de evolucion of las lagunas in their

Journal ArticleDOI
TL;DR: A new cooperative communication protocol is proposed, which achieves higher bandwidth efficiency while guaranteeing the same diversity order as that of the conventional cooperative schemes, and the tradeoff between the achievable bandwidth efficiency and the corresponding SER is presented.
Abstract: In this paper; we propose a new cooperative communication protocol, which achieves higher bandwidth efficiency while guaranteeing the same diversity order as that of the conventional cooperative schemes. The proposed scheme considers relay selection via the available partial channel state information (CSI) at the source and the relays. In particular, we discuss the multi-node decode-and-forward cooperative scenarios, where arbitrary N relays are available. The source determines when it needs to cooperate with one relay only, and which relay to cooperate with in case of cooperation, i.e., "When to cooperate?" and "Whom to cooperate with?". An optimal relay is the one which has the maximum instantaneous scaled harmonic mean functionof its source-relay and relay-destination channel gains. For the symmetric scenario, we derive an approximate expression of the bandwidth efficiency and obtain an upper bound on the symbol error rate (SER) performance. We show that full diversity is guaranteed and that a significant increase of the bandwidth efficiency is achieved. Moreover, we present the tradeoff between the achievable bandwidth efficiency and the corresponding SER. Finally, the obtained analytical results are verified through computer simulations.

Journal ArticleDOI
13 Jun 2008-Cell
TL;DR: Drosophila lines that have extra centrosomes in approximately 60% of their somatic cells can initiate tumorigenesis in flies, and these flies maintain a stable diploid genome over many generations.

Journal ArticleDOI
TL;DR: The authors analyzes why immigrant religion is viewed as a problematic area in Western Europe in contrast to the United States, where it is seen as facilitating the adaptation process, and argues that the difference, it is argued, is anchored in whether or not religion can play a major role for immigrants and the second generation as a bridge to inclusion in the new society.
Abstract: This article analyzes why immigrant religion is viewed as a problematic area in Western Europe in contrast to the United States, where it is seen as facilitating the adaptation process. The difference, it is argued, is anchored in whether or not religion can play a major role for immigrants and the second generation as a bridge to inclusion in the new society. Three factors are critical: the religious backgrounds of immigrants in Western Europe and the United States; the religiosity of the native population; and historically rooted relations and arrangements between the state and religious groups.

Journal ArticleDOI
TL;DR: It is suggested that parent ratings could be a useful source of information about anxiety symptoms in this population of children with PDD, and some anxiety symptoms such as phobic and social anxiety may be closer to core symptoms of PDD.
Abstract: In addition to the core symptoms, children with Pervasive Developmental Disorders (PDD) often exhibit other problem behaviors such as aggression, hyperactivity, and anxiety, which can contribute to overall impairment and, therefore, become the focus of clinical attention. Limited data are available on the prevalence of anxiety in these children. We examined frequency and correlates of parent-rated anxiety symptoms in a large sample of children with PDD. The goals of this study were to examine the frequency and correlates of parent-rated anxiety symptoms in a sample of 171 medication-free children with PDD who participated in two NIH-funded medication trials. Twenty items of the Child and Adolescent Symptom Inventory (CASI) were used to measure anxiety. Forty three percent of the total sample met screening cut-off criteria for at least one anxiety disorder. Higher levels of anxiety on the 20-item CASI scale were associated with higher IQ, the presence of functional language use, and with higher levels of stereotyped behaviors. In children with higher IQ, anxiety was also associated with greater impairment in social reciprocity. Anxiety is common in PDD and warrants consideration in clinical evaluation and treatment planning. This study suggests that parent ratings could be a useful source of information about anxiety symptoms in this population. Some anxiety symptoms such as phobic and social anxiety may be closer to core symptoms of PDD. Further efforts to validate tools to ascertain anxiety are needed, as are studies to empirically test approaches to treat anxiety in PDD.

Journal ArticleDOI
11 Apr 2008-Science
TL;DR: It is shown, in an analysis of wide taxonomic and geographic breadth and high spatial resolution, that multitaxonomic rather than single-taxon approaches are critical for identifying areas likely to promote the persistence of most species.
Abstract: Globally, priority areas for biodiversity are relatively well known, yet few detailed plans exist to direct conservation action within them, despite urgent need. Madagascar, like other globally recognized biodiversity hot spots, has complex spatial patterns of endemism that differ among taxonomic groups, creating challenges for the selection of within-country priorities. We show, in an analysis of wide taxonomic and geographic breadth and high spatial resolution, that multitaxonomic rather than single-taxon approaches are critical for identifying areas likely to promote the persistence of most species. Our conservation prioritization, facilitated by newly available techniques, identifies optimal expansion sites for the Madagascar government's current goal of tripling the land area under protection. Our findings further suggest that high-resolution multitaxonomic approaches to prioritization may be necessary to ensure protection for biodiversity in other global hot spots.


Journal ArticleDOI
TL;DR: Size ratio and aneurysm angle are promising new morphological metrics for IA rupture risk assessment because these parameters account for vessel geometry and may bridge the gap between morphological studies and more qualitative location-based studies.
Abstract: Intracranial aneurysms (IA) affect approximately 2 to 5% of the entire population (23, 25) Ruptured IAs typically cause subarachnoid hemorrhage (SAH) and its sequelae, resulting in significant morbidity and mortality Among patients who have SAH, 50 to 60% will die from the initial hemorrhage and a further 20 to 25% will experience complications (30) However, despite their expected common occurrence, only 1% of all IAs actually rupture (25) Although the morbidity and mortality associated with rupture may suggest that an incidentally detected aneurysm should be treated to forestall the catastrophic event of SAH, the two current methods of treatment (open microsurgical aneurysm clip ligation or endovascular aneurysm coil embolization) are not without some risk of major morbidity and mortality (8, 31) Therefore, an accurate metric (or several metrics) to judge the risk of rupture of an aneurysm is critical to aid in generating the best possible treatment algorithm Hemodynamics has been shown to play an important role in IA pathophysiology and rupture Using computational fluid dynamics, Hassan et al (11) suggested that high wall shear stress (WSS) may be responsible for IA growth and rupture in high-flow aneurysms, whereas the predominant factors causing rupture in low-flow aneurysms are high intra-aneurysmal pressure and flow stasis Cebral et al (6) demonstrated that ruptured IAs have unstable flow patterns, smaller impinging jet diameters, and smaller impingement zones Shojima et al (24) found that ruptured IAs have a higher average WSS in the aneurysm sac than unruptured IAs They observed recirculation zones and blood stasis at the apex of ruptured IAs It is important to realize that IA hemodynamics are strongly dependent on the geometry of the aneurysmal sac and its feeding vessel (11, 13, 26) For a given geometry, Cebral et al (5) showed that hemodynamics do not vary significantly with physiological variations of flow rate, blood pressure, and waveform Therefore, suitable parameters characterizing IA geometry can capture the characteristic hemodynamics and potentially predict rupture risk Several past studies have investigated such parameters The most ubiquitous parameter is IA size Although aneurysms exceeding 10 mm in size are considered to be dangerous, several studies have shown that a large percentage of ruptured aneurysms are, in fact, smaller than 10 mm (2, 9, 22, 23, 26, 27, 30) The relationship between IA rupture risk and IA size has yet to be completely elucidated Aneurysm shape has been studied as well, and certain shape parameters show stronger correlation with rupture than IA size Aspect ratio (AR), defined as IA height divided by neck diameter, is the most commonly studied shape parameter Although most findings affirm its importance, they do not converge on a common threshold value (2, 22, 26, 27, 29) Other, more sophisticated, shape parameters such as undulation index (UI), nonsphericity index (NSI), and ellipticity index (EI) have been proposed (22) in an attempt to account for the three-dimensional (3D) nature of IA Such 3D parameters show promise to be better predictors than lower-dimensional parameters such as size or AR, and they are further examined in the current study Previous studies have also investigated additional factors that correlate with IA rupture risk, such as familial preponderance, smoking, hypertension, female sex, connective tissue disorder, aneurysm growth rate, and presence of multiple IAs (15-17, 32) However, these studies have not yielded quantifiable metrics that can be readily integrated into the clinical decision-making process Adding complexity from such diverse variables into our current study would make risk assessment analysis unwieldy Currently, morphometric evaluation, typically using size alone, is the mainstay of applied aneurysm rupture risk assessment in day-to-day clinical practice Our aim is to improve such morphological evaluation and better the accuracy of aneurysm rupture risk assessment, something that is fundamental to the current practice of cerebrovascular neurosurgery A limitation of previous morphology-based rupture risk studies, including those investigating 3D parameters, is that the geometry of the parent artery is typically ignored Parent artery geometry has a significant influence on the resultant IA hemodynamics and, consequently, the rupture risk Castro et al (4) have demonstrated that upstream vessel tortuosity can critically influence intra-aneurysmal hemodynamics Hassan et al (11) observed that a greater parent vessel incidence angle shifts the high WSS area toward the aneurysm dome, where rupture-prone blebs often are present, whereas Hoi et al (13) noted that highly curved parent vessels subject IAs to higher hemodynamic stresses at the inflow zone that might promote growth or rupture Thus, parent vessel geometry should be accounted for when defining morphological parameters for IA rupture risk prediction Furthermore, numerous studies have observed a connection between IA rupture risk and vessel location (3, 4, 9, 21, 26, 30) Because vessel location is strongly related to vessel geometry, this finding affirms the importance of vessel geometry for IA rupture risk Incorporating parent vessel geometry in morphology parameters can, at least to some extent, capture the influence of IA location as well In the current study, we address the above-mentioned issues and define three new morphology parameters that incorporate IA parent vessel geometry We analyze a group of 45 IAs (20 ruptured, 25 unruptured) to evaluate new IA rupture parameters, in comparison with five “traditional” parameters that have been described in earlier studies

Journal ArticleDOI
TL;DR: In this paper, the Late Palaeozoic Ice Age comprised at least eight discrete glacial intervals (each 1-8 Ma in duration) separated by nonglacial intervals of comparable duration, and illustrate a pattern of increasing climatic austerity and increasingly widespread glacial ice from initial onset until an acme in the late Early Permian.
Abstract: Stratigraphic and sedimentological data from New South Wales and Queensland, eastern Australia, indicate that the Late Palaeozoic Ice Age comprised at least eight discrete glacial intervals (each 1–8 Ma in duration, here termed ‘glaciations’), separated by nonglacial intervals of comparable duration. These events spanned an interval from mid-Carboniferous ( c . 327 Ma) to the early Late Permian ( c . 260 Ma), and illustrate a pattern of increasing climatic austerity and increasingly widespread glacial ice from initial onset until an acme in the late Early Permian, followed by an opposite trend towards the final demise of glaciation in the Late Permian. The alternating glacial–nonglacial motif suggests that the Late Palaeozoic Ice Age was considerably more dynamic than previously thought. These patterns are remarkably consistent with recent interpretations of palaeofloral change, eustatic sea-level fluctuations and CO 2 –climate–glaciation relationships for this interval of time. The detailed record of alternating glacial and nonglacial climate mode disclosed herein may facilitate more closely resolved evaluations of stratigraphic records elsewhere, notably in far-field, ice-distal, northern hemisphere successions.

Journal ArticleDOI
TL;DR: The relationship between access to large amounts of recovery capital and substance misuse maintenance and the concept of negative recovery capital is revealed and the relationships between gender, age, health, mental health, and incarceration are examined.
Abstract: In order to capture key personal and social resources individuals are able to access in their efforts to overcome substance misuse, we introduced the construct of recovery capital into the literature. The purpose of this paper is to further explore the construct and include discussions of implications unexplored in our previous writings. In this paper we reveal the relationship between access to large amounts of recovery capital and substance misuse maintenance and introduce the concept of negative recovery capital. In doing so, we examine the relationships between negative recovery capital and gender, age, health, mental health, and incarceration.

Journal ArticleDOI
23 May 2008-Science
TL;DR: Opaline silica deposits found on Mars are interpreted to have formed under hydrothermal conditions and therefore to be strong indicators of a former aqueous environment, important for understanding the past habitability of Mars.
Abstract: Mineral deposits on the martian surface can elucidate ancient environmental conditions on the planet. Opaline silica deposits (as much as 91 weight percent SiO2) have been found in association with volcanic materials by the Mars rover Spirit. The deposits are present both as light-toned soils and as bedrock. We interpret these materials to have formed under hydrothermal conditions and therefore to be strong indicators of a former aqueous environment. This discovery is important for understanding the past habitability of Mars because hydrothermal environments on Earth support thriving microbial ecosystems.

Journal ArticleDOI
TL;DR: The authors examined organizational characteristics such as ideology, size, age, state sponsorship, alliance connections, and control of territory while controlling for factors that may also influence lethality, including the political system and relative wealth of the country in which the organization is based.
Abstract: Why are some terrorist organizations so much more deadly then others? This article examines organizational characteristics such as ideology, size, age, state sponsorship, alliance connections, and control of territory while controlling for factors that may also influence lethality, including the political system and relative wealth of the country in which the organization is based. Using data from the Memorial Institute for the Prevention of Terrorism's Terrorism Knowledge Base (TKB), we use a negative binomial model of organizational lethality, finding that organizational size, ideology, territorial control, and connectedness are important predictors of lethality while state sponsorship, organizational age, and host country characteristics are not.

Journal ArticleDOI
TL;DR: Sorafenib was associated with a significantly increased risk of all-grade hypertension in patients with cancer with an RR of 6.11 (2.44-15.32], p<0.001) compared with controls.
Abstract: Summary Background Sorafenib is used in patients with advanced renal-cell carcinoma (RCC) or hepatocellular cancer, and its application in other types of cancers is also undergoing extensive clinical assessment. Hypertension is one of the major side-effects of this drug, and reported incidences vary substantially between clinical trials. We did a systematic review and meta-analysis of published clinical trials to establish the incidence of hypertension associated with sorafenib. The aim of this study is to gain a better understanding of the overall risk of hypertension in patients with cancer who receive sorafenib. Methods Databases, including Medline (July, 1966, to July, 2007), and Web of Science, and abstracts presented at the American Society of Clinical Oncology annual meetings from 2004 to 2007 were searched to identify relevant studies. Eligible studies were prospective clinical trials of patients with cancer assigned single-drug sorafenib at 400 mg twice daily with data on hypertension available. Incidence and relative risk (RR) of hypertension were calculated using a random-effects or fixed-effects model, depending on the heterogeneity of the included studies. Findings Nine studies published between January, 2006, and July, 2007, which included a total of 4599 patients with RCC or other solid tumours, were selected from 223 articles screened for analysis. For patients assigned sorafenib, the overall incidence of all-grade and high-grade (ie, grade 3 or 4) hypertension were 23·4% (95% CI 16·0–32·9%) and 5·7% (2·5–12·6%), respectively. No significant difference was noted between patients with RCC or a non-RCC malignancy (all grade: RR 1·03 [95% CI 0·73–1·45], p=0·89; high-grade: RR 1·23 [0·76–1·99], p=0·40) who were assigned sorafenib. Sorafenib was associated with a significantly increased risk of all-grade hypertension in patients with cancer with an RR of 6·11 (2·44–15·32], p Interpretation Patients with cancer assigned sorafenib have a significant risk of developing hypertension. Appropriate monitoring and treatment is strongly recommended to prevent cardiovascular complications.

Journal ArticleDOI
01 Sep 2008-Cytokine
TL;DR: This review will focus on interleukin (IL)-17, the founding member of the newest subclass of cytokines, which has received considerable attention in the last several years due to its central role in the Th17 system.