Granule Cell Dispersion in Human Temporal Lobe Epilepsy: Proteomics investigation of neurodevelopmental migratory pathways

Granule cell dispersion (GCD) is a common pathological feature observed in the hippocampus of patients with Mesial Temporal Lobe Epilepsy (MTLE). Pathomechanisms underlying GCD remain to be elucidated, but one hypothesis proposes aberrant reactivation of neurodevelopmental migratory pathways, possibly triggered by febrile seizures. This study aims to compare the proteomes of basal and dispersed granule cells in the hippocampus of eight MTLE patients with GCD to identify proteins that may mediate GCD in MTLE. Quantitative proteomics identified 1882 proteins, of which 29% were found in basal granule cells only, 17% in dispersed only and 54% in both samples. Bioinformatics analyses revealed upregulated proteins in dispersed samples were involved in developmental cellular migratory processes, including cytoskeletal remodelling, axon guidance and signalling by Ras homologous (Rho) family of GTPases (P<0.01). The expression of two Rho GTPases, RhoA and Rac1, was subsequently explored in immunohistochemical and in situ hybridisation studies involving eighteen MTLE cases with or without GCD, and three normal post mortem cases. In cases with GCD, most dispersed granule cells in the outer-granular and molecular layers have an elongated soma and bipolar processes, with intense RhoA immunolabelling at opposite poles of the cell soma, while most granule cells in the basal granule cell layer were devoid of RhoA. A higher density and percentage of cells expressing RhoA was observed in cases with GCD than without GCD (P<0.004). In GCD cases, the density and percentage of cells expressing RhoA was significantly higher in the inner molecular layer than granule cell layer (P<0.026), supporting proteomic findings. In situ hybridisation studies using probes against RHOA and RAC1 mRNAs revealed fine peri- and nuclear puncta in granule cells of all cases. The density of cells expressing RHOA mRNAs were significantly higher in the inner molecular layer of cases with GCD than without GCD(P=0.05). In summary, our study has found limited evidence for ongoing adult neurogenesis in the hippocampus of patients with MTLE, but evidence of differential dysmaturation between dispersed and basal granule cells has been demonstrated, and elevated expression of Rho GTPases in dispersed granule cells may contribute to the pathomechanisms underpinning GCD in MTLE

Drug and Alcohol Studies (Volume 6: Current trends, continuing issues and new challenges)

VOLUME SIX: CURRENT TRENDS, CONTINUING ISSUES AND NEW CHALLENGES Toward a Global View of Alcohol, Tobacco, Cannabis and Cocaine Use Louisa Degenhardt et al Findings from the WHO World Mental Health Surveys Global Burden of Disease and Injury and Economic Cost Attributable to Alcohol Use and Alcohol-Use Disorders Jürgen Rehm et al Cannabis Supply and Demand Reduction Thoroddur Bjarnason, Andreea Steriu and Anna Kokkevi Evidence from the ESPAD Study of Adolescents in 31 European Countries Gender and Alcohol Consumption: Patterns from the Multinational Genacis Project Richard Wilsnack et al. Drugs and Development Merrill Singer The Global Impact of Drug Use and Trafficking on Social and Economic Development 'Idle and Disorderly' Khat Users in Western Uganda Susan Beckerleg Harm Reduction Axel Klein The Right Policy Approach for Africa? Alcohol Use and Its Consequences in South India K. Mohindra et al Views from a Marginalized Tribal Population Not Good Enough to Be Pregnant Sheigla Murphy and Marsha Rosenbaum Is Cannabis a Contributory Cause of Psychosis? Louisa Degenhardt and Wayne Hall Key Findings in A Report on Global Illicit Drug Markets, 1998-2007 Peter Reuter and Franz Trautmann Medicine and the Epidemic of Incarceration in the United States Josiah Rich, Sarah Wakeman and Samuel Dickman Waking up to Sleepiness Simon Williams et al Modafinil, the Media and the Pharmaceuticalization of Everyday/Night Life The Promotion and Marketing of OxyContin Art Van Zee Commercial Triumph, Public Health Tragedy Is Deep Brain Stimulation a Prospective 'Cure' for Addiction? Wayne Hall and Adrian Carter 'Executive Summary and Recommendations' and 'Introduction' in Our Invisible Addicts: First Report of the Older Persons' Substance Misuse Working Group of the Royal College of Psychiatrists Royal College of Psychiatrist

Drug and Alcohol Studies (Volume 1: Historical and Cultural Studies)

VOLUME ONE: HISTORICAL AND CULTURAL STUDIES Mr ATOD's Wild Ride David Courtwright What Do Alcohol, Tobacco and Other Drugs Have in Common? Opium, Cocaine and Marijuana in American History David Musto Morality and Medical Science Virginia Berridge Concepts of Narcotic Addiction in Britain, 1820-1926 The Discovery of Addiction Harry Levine Changing Conceptions of Habitual Drunkenness in America Stable Force in a Storm Douglas Kinder and William Walker III Harry J. Aslinger and United States Narcotic Policy, 1930-1962 Alcohol and the State in Nazi Germany, 1933-1945 Hermann Fahrenkrug Coercion and Its Unintended Consequences Alfred McCoy A Study of Heroin Trafficking in South-East and South-West Asia Intoxication and Bad Behaviour Robin Room Understanding Cultural Differences in the Link Slavery from within Mariana Valverde The Invention of Alcoholism and the Question of Free Will Narcotic Use in South-East Asia and afterward Lee Robins, John Helzer and Darlene Davis An Interview Study of 898 Vietnam Returnees New Perspectives on the 'Prohibition Experiment' of the 1920s J. Burnham Opium Smoking in Late Imperial China R. Newman A Reconsideration Between Culture and Nature Pekka Sulkunen Intoxication in Cultural Studies of Alcohol and Drug Us

Drug and Alcohol Studies (Volume 5: Interventions)

VOLUME FIVE: INTERVENTIONS Natural Recovery from Alcohol Problems Harald Klingemann School-Based Programmes to Prevent Alcohol, Tobacco and Other Drug Use Gilbert Botvin and Kenneth Griffin Community Prevention of Alcohol Problems Harold Holder Can Screening and Brief Intervention Lead to Population-Level Reductions in Alcohol-Related Harm? Nick Heather Sharpening the Focus of Alcohol Policy from Aggregate Consumption to Harm and Risk Reduction Tim Stockwell et al A Review of the Efficacy and Effectiveness of Harm Reduction Strategies for Alcohol, Tobacco and Illicit Drugs Alison Ritter and Jacqui Cameron 10 Years of Experience with Needle and Syringe Exchange Programmes in European Prisons Heino Stover and Joachim Nelles Motivational Interviewing William Miller Research, Practice and Puzzles Controlled Drinking after 25 Years Mark Sobell and Linda Sobell How Important Was the Great Debate? Matching Alcoholism Treatment to Client Heterogeneity Project MATCH Research Group Project MATCH Post-Treatment Drinking Outcomes How Can Cognitive Therapy Help? Aaron Beck et al A Medical Treatment for Diacetylmorphine (Heroin) Addiction Vincent Dole and Marie Nyswander A Clinical Trial with Methadone Hydrochloride Is Treatment for Substance Abuse Effective? A. Thomas McLellan et al From Morphine Clinics to Buprenorphine Jerome Jaffe and Charles O'Keeffe Regulating Opioid Agonist Treatment of Addiction in the United States Heroin-Assisted Treatment (HAT) a Decade Later Benedikt Fischer et al A Brief Update on Science and Politic

Drug and Alcohol Studies (Volume 3: Methods and Measurements)

The field of drug and alcohol studies has expanded rapidly in recent years, with estimates of at least a doubling in the number of publications in the past decades. A feature of this wide and multidisciplinary field is the tendency of sub-groups of scholars to operate within their disciplinary silos, paying only token attention to the contributions of others. There are also, naturally, significant differences in approaches of different countries, reflecting different policy frameworks and cultural perspectives. When faced with these challenges to comprehensive study, a publication such as this new six-volume collection - which aims to bring together the various disparate strands of the topic, including key articles written by scholars from across the globe, disciplines and decades - truly proves itself to be a unique and valuable resource for specialist students and researchers in the field. VOLUME THREE: METHODS AND MEASUREMENTS Evaluation of Heroin Maintenance in a Controlled Trial Richard Hartnoll et al Cost-Benefit Analysis of Drug Treatment Services William Cartwright Review of the Literature The National Treatment Outcome Research Study (NTORS) Michael Gossop et al Four to Five-Year Follow-up Results Scientific and Political Challenges in North America's First Randomized Controlled Trial of Heroin-Assisted Treatment for Severe Heroin Addiction Eugenia Oviedo-Joekes et al Rationale and Design of the NAOMI Study Co-Morbidity of Mental Disorders with Alcohol and Other Drug Abuse Darrel A. Regier et al Results from the Epidemiologic Catchment Area (ECA) Study Alcohol Consumption and Injury in Western Australia Richard Midford et al A Spatial Correlation Analysis Using Geographic Information Systems Development of the Alcohol Use Disorders Identification Test (AUDIT) J. Saunders et al WHO Collaborative Project on Early Detection of Persons with Harmful Alcohol Consumption Unravelling the Preventive Paradox for Acute Alcohol Problems Tim Stockwell et al Assessing Alcohol Consumption Lee Strunin Developments from Qualitative Research Methods Measuring Alcohol-Related Consequences in School Surveys Gerhard Gmel et al Alcohol Attributable Consequences or Consequences with Students' Alcohol Attribution Rapid Assessment and Response Studies of Injecting Drug Use Gerry Stimson et al Knowledge Gain, Capacity-Building and Intervention Development in a Multisite Study The Application of Ethnography with Reference to Harm Reduction in Sverdiovsk Russia Robert Power Putting It in Context Nicholas Jenkins et al The Use of Vignettes in Qualitative Interviewing Development of a Rational Scale to Assess the Harms of Drugs of Potential Misuse David Nutt et al The Clinical Utility of Brain SPECT Imaging in Process Addictions Daniel Amen, Kristen Willeumier and Robert Johnso

Drug and Alcohol Studies (Volume 4: Policy approaches)

VOLUME FOUR: POLICY APPROACHES Preface Robert MacCoun and Peter Reuter The Varieties of Drug Control at the Dawn of the 21st Century Comparative Analysis of Alcohol Control Policies in 30 Countries Donald Brand et al A Comparative Study of 38 European Countries Limited Rationality and the Limits of Supply Reduction Jonathan Caulkins and Robert MacCoun The Limited Relevance of Drug Policy Craig Reinerman, Peter Cohen and Hendrien Kaal Cannabis in Amsterdam and San Francisco AIDS and Injecting Drug Use in the United Kingdom, 1987-1993 Gerry Stimson The Policy Response and the Prevention of the Epidemic Treatment of What? Class, Gender and Work Ethics within the Compulsory Institutional Care of Alcohol Abusers in Sweden during the 20th Century Johan Edman From Margin to Mainstream Dagmar Hedrich, Alessandro Pirona and Lucas Wiessing The Evolution of Harm Reduction Responses to Problem Drug Use in Europe What Can We Learn from the Portuguese Decriminalization of Illicit Drugs? Caitlin Elizabeth Hughes and Alex Stevens Effects of Alcohol Tax and Price Policies on Morbidity and Mortality Alexander Wagenaar et al A Systematic Review Alcohol Industry Influences on U.K. Alcohol Policy Benjamin Hawkins et al A New Research Agenda for Public Health Counting the Costs of the War on Drugs Steve Rolles et al Executive Summary The Death Penalty for Drug Offences: Global Overview 2012 Patrick Gallahue et al Towards Revision of the U.N. Drug Control Conventions David Bewley-Taylor Harnessing Like-Mindednes

Drug and Alcohol Studies (Volume 2: Theoretical Studies)

VOLUME TWO: THEORETICAL PERSPECTIVES Excerpt from Drug, Set and Setting: The Basis for Controlled Intoxicant Use N. Zinberg Sociocultural Anthropology and Alcohol and Drug Research Geoffrey Hunt and Judith Barker Towards a Unified Theory Addiction Is a Brain Disease and It Matters Alan Leshner Drug Dependence A. Thomas McLellan et al A Chronic Mental Illness Alcohol Dependence Griffith Edwards and Milton Gross Provisional Description of a Clinical Syndrome Illicit Drugs and the Rise of Epidemiology during the 1960s Alex Mold A Conceptual Framework for Explaining Drug Addiction Nick Heather Addiction as an Excessive Appetite Jim Orford Becoming a Marijuana User Howard Becker The 'Risk Environment' Tim Rhodes A Framework for Understanding and Reducing Drug-Related Harm The Social Basis of Drug Dependency J. Young The Legacy of 'Normalization' Fiona Measham and Michael Shiner ' The Role of Classical and Contemporary Criminological Theory in Understanding Young People's Drug Use Taking Care of Business Edward Preble and John Casey The Heroin User's Life on the Street The Concept of Alcoholism as a Bad Habit R. Reinert Illegal Lemons P. Reuter and J. Caulkins Price Dispersion in Cocaine and Heroin Market

Reproductive success through high pollinator visitation rates despite self incompatibility in an endangered wallflower

PREMISE OF THE STUDY: Self incompatibility (SI) in rare plants presents a unique challenge—SI protects plants from inbreeding depression, but requires a sufficient number of mates and xenogamous pollination. Does SI persist in an endangered polyploid? Is pollinator visitation sufficient to ensure reproductive success? Is there evidence of inbreeding/outbreeding depression? We characterized the mating system, primary pollinators, pollen limitation, and inbreeding/outbreeding depression in Erysimum teretifolium to guide conservation efforts. METHODS: We compared seed production following self pollination and within- and between-population crosses. Pollen tubes were visualized after self pollinations and between-population pollinations. Pollen limitation was tested in the field. Pollinator observations were quantified using digital video. Inbreeding/outbreeding depression was assessed in progeny from self and outcross pollinations at early and later developmental stages. KEY RESULTS: Self-pollination reduced seed set by 6.5× and quadrupled reproductive failure compared with outcross pollination. Pollen tubes of some self pollinations were arrested at the stigmatic surface. Seed-set data indicated strong SI, and fruit-set data suggested partial SI. Pollinator diversity and visitation rates were high, and there was no evidence of pollen limitation. Inbreeding depression (δ) was weak for early developmental stages and strong for later developmental stages, with no evidence of outbreeding depression. CONCLUSIONS: The rare hexaploid E. teretifolium is largely self incompatible and suffers from late-acting inbreeding depression. Reproductive success in natural populations was accomplished through high pollinator visitation rates consistent with a lack of pollen limitation. Future reproductive health for this species will require large population sizes with sufficient mates and a robust pollinator community

Secukinumab versus adalimumab for psoriatic arthritis: comparative effectiveness up to 48 weeks using a matching-adjusted indirect comparison

Secukinumab and adalimumab are approved for adults with active psoriatic arthritis (PsA). In the absence of direct randomized controlled trial (RCT) data, matching-adjusted indirect comparison can estimate the comparative effectiveness in anti-tumor necrosis factor (TNF)-naïve populations. Individual patient data from the FUTURE 2 RCT (secukinumab vs. placebo; N = 299) were adjusted to match baseline characteristics of the ADEPT RCT (adalimumab vs. placebo; N = 313). Logistic regression determined adjustment weights for age, body weight, sex, race, methotrexate use, psoriasis affecting ≥ 3% of body surface area, Psoriasis Area and Severity Index score, Health Assessment Questionnaire Disability Index score, presence of dactylitis and enthesitis, and previous anti-TNF therapy. Recalculated secukinumab outcomes were compared with adalimumab outcomes at weeks 12 (placebo-adjusted), 16, 24, and 48 (nonplacebo-adjusted). After matching, the effective sample size for FUTURE 2 was 101. Week 12 American College of Rheumatology (ACR) response rates were not significantly different between secukinumab and adalimumab. Week 16 ACR 20 and 50 response rates were higher for secukinumab 150 mg than for adalimumab (P = 0.017, P = 0.033), as was ACR 50 for secukinumab 300 mg (P = 0.030). Week 24 ACR 20 and 50 were higher for secukinumab 150 mg than for adalimumab (P = 0.001, P = 0.019), as was ACR 20 for secukinumab 300 mg (P = 0.048). Week 48 ACR 20 was higher for secukinumab 150 and 300 mg than for adalimumab (P = 0.002, P = 0.027), as was ACR 50 for secukinumab 300 mg (P = 0.032). In our analysis, patients with PsA receiving secukinumab were more likely to achieve higher ACR responses through 1 year (weeks 16-48) than those treated with adalimumab. Although informative, these observations rely on a subgroup of patients from FUTURE 2 and thus should be considered interim until the ongoing head-to-head RCT EXCEED can validate these findings. Novartis Pharma AG

On Turing dynamical systems and the Atiyah problem

Main theorems of the article concern the problem of M. Atiyah on possible values of l^2-Betti numbers. It is shown that all non-negative real numbers are l^2-Betti numbers, and that "many" (for example all non-negative algebraic) real numbers are l^2-Betti numbers of simply connected manifolds with respect to a free cocompact action. Also an explicit example is constructed which leads to a simply connected manifold with a transcendental l^2-Betti number with respect to an action of the threefold direct product of the lamplighter group Z/2 wr Z. The main new idea is embedding Turing machines into integral group rings. The main tool developed generalizes known techniques of spectral computations for certain random walk operators to arbitrary operators in groupoid rings of discrete measured groupoids.Comment: 35 pages; essentially identical to the published versio