Bolivia shows how Andean nations can be punished by U.S. neoliberal soft power if they refuse to assist in the ‘war on drugs’

For three decades, the U.S. has attempted to impose a neoliberal economic model of free markets, trade and investment to the countries of Latin America. This free market push, however, has not extended to drugs, which the U.S. considers to be a security rather than an economic issue. James F. Siekmeier writes that Andean nations go along with U.S. antidrug policies because of U.S. neoliberal ‘soft power’. Taking Bolivia as an example, he writes that those countries that refuse to participate in the unpopular U.S sponsored ‘war on drugs’ face the withdrawal of U.S. government assistance and trade relations

Development of Antipsychotic Medications with Novel Mechanisms of Action Based on Computational Modeling of Hippocampal Neuropathology

A large number of cellular level abnormalities have been identified in the hippocampus of schizophrenic subjects. Nonetheless, it remains uncertain how these pathologies interact at a system level to create clinical symptoms, and this has hindered the development of more effective antipsychotic medications. Using a 72-processor supercomputer, we created a tissue level hippocampal simulation, featuring multicompartmental neuron models with multiple ion channel subtypes and synaptic channels with realistic temporal dynamics. As an index of the schizophrenic phenotype, we used the specific inability of the model to attune to 40 Hz (gamma band) stimulation, a well-characterized abnormality in schizophrenia. We examined several possible combinations of putatively schizophrenogenic cellular lesions by systematically varying model parameters representing NMDA channel function, dendritic spine density, and GABA system integrity, conducting 910 trials in total. Two discrete “clusters” of neuropathological changes were identified. The most robust was characterized by co-occurring modest reductions in NMDA system function (-30%) and dendritic spine density (-30%). Another set of lesions had greater NMDA hypofunction along with low level GABA system dysregulation. To the schizophrenic model, we applied the effects of 1,500 virtual medications, which were implemented by varying five model parameters, independently, in a graded manner; the effects of known drugs were also applied. The simulation accurately distinguished agents that are known to lack clinical efficacy, and identified novel mechanisms (e.g., decrease in AMPA conductance decay time constant, increase in projection strength of calretinin-positive interneurons) and combinations of mechanisms that could re-equilibrate model behavior. These findings shed light on the mechanistic links between schizophrenic neuropathology and the gamma band oscillatory abnormalities observed in the illness. As such, they generate specific falsifiable hypotheses, which can guide postmortem and other laboratory research. Significantly, this work also suggests specific non-obvious targets for potential pharmacologic agents

Computational multifactoriality in a detailed neural network model resembling centre-surround suppression deficits in schizophrenia

© 2014 Metzner et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise statedPeer reviewe

Book Review: Thomas C. Field, Jr. From Development to Dictatorship: Bolivia and the Alliance for Progress in the Kennedy Era.

This document offers reviews and discussion of Thomas C. Field, Jr.’s book From Development to Dictatorship: Bolivia and the Alliance for Progress in the Kennedy Era. Ithaca: Cornell University Press, 2014. ISBN: 978-0-8014-5260-4 (hardcover, $45.00)

Low-density lipoprotein particle diameter and mortality: the Ludwigshafen Risk and Cardiovascular Health Study

Aims The aim of the study was to examine whether differences in average diameter of low-density lipoprotein (LDL) particles were associated with total and cardiovascular mortality. Methods and results We studied 1643 subjects referred to coronary angiography, who did not receive lipid-lowering drugs. During a median follow-up of 9.9 years, 398 patients died, of these 246 from cardiovascular causes. We calculated average particle diameters of LDL from the composition of LDL obtained by β-quantification. When LDL with intermediate average diameters (16.5-16.8 nm) were used as reference category, the hazard ratios (HRs) adjusted for cardiovascular risk factors for death from any cause were 1.71 (95% CI: 1.31-2.25) and 1.24 (95% CI: 0.95-1.63) in patients with large (>16.8 nm) or small LDL (<16.5 nm), respectively. Adjusted HRs for death from cardiovascular causes were 1.89 (95% CI: 1.32-2.70) and 1.54 (95% CI: 1.06-2.12) in patients with large or small LDL, respectively. Patients with large LDL had higher concentrations of the inflammatory markers interleukin (IL)-6 and C-reactive protein than patients with small or intermediate LDL. Equilibrium density gradient ultracentrifugation revealed characteristic and distinct profiles of LDL particles in persons with large (approximately even distribution of intermediate-density lipoproteins and LDL-1 through LDL-6) intermediate (peak concentration at LDL-4) or small (peak concentration at LDL-6) average LDL particle diameters. Conclusions Calculated LDL particle diameters identify patients with different profiles of LDL subfractions. Both large and small LDL diameters are independently associated with increased risk mortality of all causes and, more so, due to cardiovascular causes compared with LDL of intermediate siz

Multifactorial modeling of impairment of evoked gamma range oscillations in schizophrenia

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Despite a significant increase in efforts to identify biomarkers and endophenotypic measures of psychiatric illnesses, only a very limited amount of computational models of these markers and measures has been implemented so far. Moreover, existing computational models dealing with biomarkers typically only examine one possible mechanism in isolation, disregarding the possibility that other combinations of model parameters might produce the same network behavior (what has been termed “multifactoriality”). In this study we describe a step toward a computational instantiation of an endophenotypic finding for schizophrenia, namely the impairment of evoked auditory gamma and beta oscillations in schizophrenia. We explore the multifactorial nature of this impairment using an established model of primary auditory cortex, by performing an extensive search of the parameter space. We find that single network parameters contain only little information about whether the network will show impaired gamma entrainment and that different regions in the parameter space yield similar network level oscillation abnormalities. These regions in the parameter space, however, show strong differences in the underlying network dynamics. To sum up, we present a first step toward an in silico instantiation of an important biomarker of schizophrenia, which has great potential for the identification and study of disease mechanisms and for understanding of existing treatments and development of novel ones.Peer reviewedFinal Published versio

Current european regulatory perspectives on insulin analogues

Insulin analogues are increasingly considered as an alternative to human insulin in the therapy of diabetes mellitus. Insulin analogues (IAs) are chemically different from human insulin and may have different pharmacokinetic or pharmacodynamic properties. The significance of the modifications of the insulin molecule for the safety profile of IAs must be considered. This review describes the regulatory procedure and the expectations for the scientific content of European marketing authorization applications for innovative IAs submitted to the European Medicines Agency. Particular consideration is given to a potential cancer hazard. Specific regulatory guidance on how to address a possible carcinogenic or tumor promoting effect of innovative IAs in non-clinical studies is available. After marketing authorization, the factual access of patients to the new product will be determined to great extent by health technology assessment bodies, reimbursement decisions and the price. Whereas the marketing authorization is a European decision, pricing and reimbursement are national or regional responsibilities. The assessment of benefit and risk by the European Medicines Agency is expected to influence future decisions on price and reimbursement on a national or regional level. Collaborations between regulatory agencies and health technology assessment bodies have been initiated on European and national level to facilitate the use of the European Medicines Agency's benefit risk assessment as basis on which to build the subsequent health technology assessment. The option for combined or joint scientific advice procedures with regulators and health technology assessment bodies on European level or on a national level in several European Member States may help applicants to optimize their development program and dossier preparation in regard of both European marketing authorization application and reimbursement decisions

Low-Cost Production of Proinsulin in Tobacco and Lettuce Chloroplasts for Injectable or Oral Delivery of Functional Insulin and C-Peptide

Current treatment for type I diabetes includes delivery of insulin via injection or pump, which is highly invasive and expensive. The production of chloroplast-derived proinsulin should reduce cost and facilitate oral delivery. Therefore, tobacco and lettuce chloroplasts were transformed with the cholera toxin B subunit fused with human proinsulin (A, B, C peptides) containing three furin cleavage sites (CTB-PFx3). Transplastomic lines were confirmed for site-specific integration of transgene and homoplasmy. Old tobacco leaves accumulated proinsulin up to 47% of total leaf protein (TLP). Old lettuce leaves accumulated proinsulin up to 53% TLP. Accumulation was so stable that up to ~40% proinsulin in TLP was observed even in senescent and dried lettuce leaves, facilitating their processing and storage in the field. Based on the yield of only monomers and dimers of proinsulin (3 mg/g leaf, a significant underestimation), with a 50% loss of protein during the purification process, one acre of tobacco could yield up to 20 million daily doses of insulin per year. Proinsulin from tobacco leaves was purified up to 98% using metal affinity chromatography without any His-tag. Furin protease cleaved insulin peptides in vitro. Oral delivery of unprocessed proinsulin bioencapsulated in plant cells or injectable delivery into mice showed reduction in blood glucose levels similar to processed commercial insulin. C-peptide should aid in long-term treatment of diabetic complications including stimulation of nerve and renal functions. Hyper-expression of functional proinsulin and exceptional stability in dehydrated leaves offer a low-cost platform for oral and injectable delivery of cleavable proinsulin

Comprehensive review:Computational modelling of Schizophrenia

Computational modelling has been used to address: (1) the variety of symptoms observed in schizophrenia using abstract models of behavior (e.g. Bayesian models - top-down descriptive models of psychopathology); (2) the causes of these symptoms using biologically realistic models involving abnormal neuromodulation and/or receptor imbalance (e.g. connectionist and neural networks - bottom-up realistic models of neural processes). These different levels of analysis have been used to answer different questions (i.e. understanding behavioral vs. neurobiological anomalies) about the nature of the disorder. As such, these computational studies have mostly supported diverging hypotheses of schizophrenia's pathophysiology, resulting in a literature that is not always expanding coherently. Some of these hypotheses are however ripe for revision using novel empirical evidence.Here we present a review that first synthesizes the literature of computational modelling for schizophrenia and psychotic symptoms into categories supporting the dopamine, glutamate, GABA, dysconnection and Bayesian inference hypotheses respectively. Secondly, we compare model predictions against the accumulated empirical evidence and finally we identify specific hypotheses that have been left relatively under-investigated