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Most Americans are living with state-sanctioned cannabis jurisdiction permitting medicinal, and often, recreational use. Yet, cannabis and its cannabinoids remain on schedule-I of the controlled substances act (CSA), imposing hurdles to much needed research and promulgating outdated ‘War on Drugs’ policies and their disproportionate impact on minorities. Recent advances by the current government to decriminalize past federal cannabis possession convictions and the encouragement to State Governors to follow suit are within the current political climate and public opinion but fall short during times of an ever- faster expansion of cannabis legislation and access by the individual states. Opposing views on federal cannabis legalization have precipitated an indeterminate situation between federal and state legislation prompting inconsistent decision-making, social injustice, and health inequities across the country. The latter can be exemplified by the inconsistencies of qualifying conditions and availability of cannabis for medicinal use. Now, under the new 118th U.S. Congress, it becomes ever more important to re-focus on legislative opportunities such as the ‘Marijuana Opportunity Reinvestment and Expungement (MORE) Act of 2021’ which had been previously passed by the House of Representatives on April 1st, 2022, under the 117th Congress (2021-22). This bill aims to de-schedule and decriminalize use, possession, distribution, sale, and production of medical cannabis on the federal level. Through establishing cannabis business equity and loan programs, it seeks to promote social justice for communities disproportionately affected by the ‘War on Drugs’. This health policy research brief provides a comprehensive view of stakeholder perspectives and positions, as well as potential benefits and drawbacks - all with a historical perspective.

Objetivo. Describir las características epidemiológicas, fenotípicas y genéticas de aislamientos clínicos portadores de optrA identificados en la vigilancia de resistencia antimicrobiana por el laboratorio del Instituto Nacional de Salud de Colombia. Métodos. Entre octubre de 2014 y febrero 2019, se recibieron 25 aislamientos de Enterococcus spp. resistentes al linezolid. La identificación y sensibilidad antimicrobiana se determinó con Vitek 2 y la concentración inhibitoria mínima (CIM) al linezolid se estableció con E-test. El gen optrA se detectó mediante PCR. La diversidad genética de aislamientos positivos para optrA se analizó con Diversilab®. Se seleccionaron seis aislamientos para llevar a cabo la secuenciación del genoma completo. Resultados. Se confirmó el gen optrA en 23/25 aislamientos de E. faecalis de siete departamentos de Colombia. Los aislamientos presentaron una CIM al linezolid entre 8 y >256µg/mL. La tipificación por Diversilab® indicó una amplia variabilidad genética. Todos los aislamientos analizados mediante secuenciación del genoma completo, presentaron genes de resistencia fexA, ermB, lsaA, tet(M), tet(L) y dfrG además de optrA y fueron negativos para otros mecanismos de resistencia al linezolid. Se identificaron tres secuencias tipos y tres variantes de optrA: ST16 (optrA-2), ST476 (optrA-5) y ST618 (optrA-6). El entorno genético de los aislamientos optrA-2 (ST16) presentó el segmento impB, fex, optrA, asociado a plásmido, mientras que en dos aislamientos (optrA-6 y optrA-5) se encontró el elemento cromosómico transferible Tn6674-like. Conclusión. Los aislamientos clínicos positivos para optrA presentan una alta diversidad genética, con diferentes clones y variantes de optrA relacionados con dos tipos de estructuras y diferentes elementos genéticos móviles.

La cuenca del río Claro en Antioquia, Colombia, es una región con gran importancia biológica, dado que alberga ecosistemas singulares, y una gran diversidad de especies de plantas, las cuales tienen un gran potencial de uso para las comunidades de la región. No obstante, hasta la fecha no se ha realizado una lista de las plantas útiles para la cuenca y este conocimiento aún permanece disperso. A fin de compilar, catalogar y dar a conocer este conocimiento, se construyó un listado de las especies nativas con el reporte de usos en información secundaria y primaria, con lo cual se generó un insumo de conocimiento que permita orientar esfuerzos de investigación y uso sostenible de la biodiversidad. Con este propósito, se consultaron fuentes tales como herbarios en los que reposan especímenes debidamente preservados y referencias de literatura especializada. Asimismo, se realizaron talleres con las comunidades para indagar sobre los usos locales, y posteriormente se categorizaron los tipos de uso. Se registraron 650 especies de la cuenca del río Claro con usos reportados en literatura, de las cuales 31 son endémicas de Colombia. En cuanto a los usos locales, se registraron 58 especies.

En este texto se aborda el cultivo de caña de azúcar en Colombia y su relación con el acaparamiento y la concentración de la tierra. Con ese objetivo, incorporo el concepto de acumulación por desposesión, que contribuye de manera significativa a comprender la desigualdad de la distribución de la tierra. El análisis del problema involucra la utilización de métodos cuantitativos y espaciales para comparar zonas geográficas que tienen caña de azúcar con aquellos que no la tienen, en aras de determinar el impacto de este cultivo en relación con el acceso a la tierra en Colombia. Abstract: In this text, I discuss the cultivation of sugar cane cultivation in Colombia and its relation to land grabbing and land concentration. Fur such purpose I use the concept of accumulation by dispossession, which contributes significantly to understand the inequality of land distribution in Colombia. The analysis of the problem involves quantitative and spatial methods for comparing geographical areas that have Sugarcane crops with those that do not have them, in order to determine the impact of such crop on land access in Colombia. Keywords: land concentration, land grabbing, accumulation by dispossession, biofuel, sugar cane.

The human brain is constantly exposed to air pollutants, some of which might be disruptive or even lethal to certain neurons implicated in abstract features of cognitive function. In this review, we present new evidence from behavioral and neural studies in humans, suggesting a link between indoor fine particulate matter and decision-making behavior. To illustrate this relationship, we use qualitative sources, such as historical documents of the Vietnam War to develop hypotheses of how aerial transmission of pollutants might obstruct alternative choices during the evaluation of policy decisions. We first describe the neural circuits driving decision-making processes by addressing how neurons and their cognate receptors directly evaluate and transduce physical phenomena into sensory perceptions that allow us to decide the best course of action among competing alternatives. We then raise the possibility that indoor air pollutants might also impact cell-signaling systems outside the brain parenchyma to further obstruct the computational analysis of the social environment. We also highlight how particulate matter might be pathologically integrated into the brain to override control of sensory decisions, and thereby perturb selection of choice. These lines of research aim to extend our understanding of how inhalation of airborne particulates and toxicants in smoke, for example, might contribute to cognitive impairment and negative health outcomes.

espanolEn este articulo abordo la relacion entre el acaparamiento de tierras, el cultivo de palma de aceite y el paramilitarismo en Colombia desde la optica de la acumulacion primitiva. Para el efecto, hago un analisis de tres casos concretos: el Bajo Atrato en Choco, Mapiripan en Meta y Las Pavas en el sur de Bolivar, todos en Colombia, en los que se han presentado hechos de violencia que incluyen desplazamiento forzado y despojo de tierras, con subsecuentes proyectos de cultivo de palma de aceite a gran escala. La discusion trae a colacion el mercado internacional de agrocombustibles y la necesidad del Estado colombiano de copar territorios que antes le resultaban hostiles EnglishIn this paper I examine the connections between the hogging of lands, the oil palm tree cultivations, and the para-militarism in Colombia through the lens of the primitive accumulation. To do so, I analyze three concrete cases: the Bajo Atrato en Choco [a river basin], Mapiripan in Meta Province, and Las Pavas in the South Bolivar Province. These three Colombian locations have undergone violent events including forced displacement and land deprivation, with subsequent projects for growing oil palm trees on a broad scale. The discussion brings into contention the agricultural biofuel international market and the need by the Colombian State to take some territories that were previously hostile

Mammalian cells accumulate DNA lesions when they undergo phases of the cell cycle or during normal cellular activity. In this regard, several DNA repair signaling pathways have evolved to maintain genome stability and avoid the potential acquisition of mutations. To define and further characterize the expression of DNA double-strand breaks in humans and mice, we used immunocytochemistry to localize a DNA damage signal within the spatial confines of the cell nucleus. We show that DNA double-strand breaks are abundantly expressed in postmitotic neurons of the human and mouse brain. Notably, DNA double-strand breaks are present in human hypothalamic and mouse striatal and hippocampal cells, with stable expression of the nuclear signal detected throughout the mammalian brain. Analysis of the mouse tongue, heart, and testis shows that expression of DNA double-strand breaks is only demonstrated in circumscribed populations of peripheral cells. These data suggest that levels of DNA double-strand breaks are tissue-specific with the tongue, heart and testicular tissue having different thresholds of DNA repair and DNA damage from those outlined at the brain level. Anat Rec, 301:1251-1257, 2018. © 2018 Wiley Periodicals, Inc.

Patients who harbor brain arteriovenous malformations are at risk for intracranial hemorrhage. These malformations are often seen in inherited vascular diseases such as hereditary hemorrhagic telangiectasia. However, malformations within the brain also sporadically occur without a hereditary-coding component. Here, we review recent insights into the pathophysiology of arteriovenous malformations, in particular, certain signaling pathways that might underlie endothelial cell pathology. To better interpret the origins, determinants and consequences of brain arteriovenous malformations, we present a clinical case to illustrate the phenotypic landscape of the disease. We also propose that brain arteriovenous malformations might share certain signaling dimensions with those of anorectal hemorrhoids. This working hypothesis provides casual anchors from which to understand vascular diseases characterized by arteriovenous lesions with a hemorrhagic- or bleeding-risk component. Anat Rec, 2017. © The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists. Anat Rec, 300:1973-1980, 2017. © 2017 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.

El presente artículo tiene como objeto el estudio de una función considerada fundamental dentro del amplio proceso de la organización y la admi-nistración de las elecciones: el empadronamiento electoral. Lo anterior, con el objetivo de aproxi-marse a la cuestión de hasta qué punto influye el carácter (des)centralizado del Estado en los procesos de registro de electo-res. Tras una revisión teórica y algunas precisiones metodológicas, el trabajo aborda los casos de Argentina y Bolivia desde el rol de las provincias y los departamentos. Los resultados sugieren una baja iniciativa y eficacia por parte de las provincias argentinas, y un fuerte protagonismo y eficacia por parte de los departamentos bolivianos. / This paper analyzes a fundamental function within the broader process of organizing and administering elections: voter registration. The objective is to examine the extent to which the (de)centralized character of the state affects voter registration processes. After a theoretical review and some methodological details, the article addresses the cases of provinces and de-partments in Argentina and Bolivia, respectively. The results suggest the Argentinian provinces show weak initiative and are not very effective, and Bolivian departments are strongly pro-active and efficient.

IMPORTANCE: Abnormal peripheral perfusion after septic shock resuscitation has been associated with organ dysfunction and mortality. The potential role of the clinical assessment of peripheral perfusion as a target during resuscitation in early septic shock has not been established. OBJECTIVE: To determine if a peripheral perfusion–targeted resuscitation during early septic shock in adults is more effective than a lactate level–targeted resuscitation for reducing mortality. DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized trial conducted at 28 intensive care units in 5 countries. Four-hundred twenty-four patients with septic shock were included between March 2017 and March 2018. The last date of follow-up was June 12, 2018. INTERVENTIONS: Patients were randomized to a step-by-step resuscitation protocol aimed at either normalizing capillary refill time (n = 212) or normalizing or decreasing lactate levels at rates greater than 20% per 2 hours (n = 212), during an 8-hour intervention period. MAIN OUTCOMES AND MEASURES The primary outcome was all-cause mortality at 28 days. Secondary outcomes were organ dysfunction at 72 hours after randomization, as assessed by Sequential Organ Failure Assessment (SOFA) score (range, 0 [best] to 24 [worst]); death within 90 days; mechanical ventilation–, renal replacement therapy–, and vasopressor-free days within 28 days; intensive care unit and hospital length of stay. RESULTS: Among 424 patients randomized (mean age, 63 years; 226 [53%] women), 416 (98%) completed the trial. By day 28, 74 patients (34.9%) in the peripheral perfusion group and 92 patients (43.4%) in the lactate group had died (hazard ratio, 0.75 [95% CI, 0.55 to 1.02]; P = .06; risk difference, −8.5% [95% CI, −18.2% to 1.2%]). Peripheral perfusion–targeted resuscitation was associated with less organ dysfunction at 72 hours (mean SOFA score, 5.6 [SD, 4.3] vs 6.6 [SD, 4.7]; mean difference, −1.00 [95% CI, −1.97 to −0.02]; P = .045). There were no significant differences in the other 6 secondary outcomes. No protocol-related serious adverse reactions were confirmed. CONCLUSIONS AND RELEVANCE: Among patients with septic shock, a resuscitation strategy targeting normalization of capillary refill time, compared with a strategy targeting serum lactate levels, did not reduce all-cause 28-day mortality., Facultad de Ciencias Médicas

The existence of exoplanets orbiting low mass-stars is one of the most significant discoveries of our time. Especially intriguing to us is the possibility that Earth-sized exoplanets within a habitable zone might harbor life-forms that resemble our own RNA/DNA-based species. We further narrow this theoretical possibility with the following question: if alien life does indeed exist elsewhere, would extraterrestrial life be burdened with earthly diseases? Given that the chemistry of the universe is subject to specific rules, restraints, and predictable outcomes, we argue that cancer-signaling pathways might be programmed into the life cycle of habitable exoplanets. This hypothetical prediction is also based on evolutionary convergence, the repeated emergence of biological similarity that occurs when disparate life-forms adapt to comparable selection pressures. The possibility that mutations and nucleotide base rearrangements that drive cancer growth might be fixed in the chemical hardware of alien life provides us with the opportunity to wonder and consider the origins, evolution, and ubiquity of disease beyond Earth.

Introducción: Las instituciones que responden a emergencias en salud pública requieren respuestas coordinadas para mitigar y controlar los efectos a partir de la evaluación del riesgo. Con el fin de medir el cumplimiento en cada uno de los procesos a nivel local y nacional, se realizó una evaluación del sistema, en el escenario de un simulacro de casos de cólera. Metodología: Se realizó una evaluación de procesos con metodología mixta mediante la observación y análisis de las actividades definidas en la gestión del riesgo en salud pública ante eventos, brotes y epidemias. La información se recolectó a partir de estrategias de observación con listas de verificación, entrevistas semi-estructuradas notas de campo y la metodología de lecciones aprendidas (reflexión después de la acción). Se realizó análisis descriptivo de los datos obtenidos de las listas de verificación y se identificaron textos significantes que se agruparon en categorías de análisis. Resultados: En el componente cuantitativo se observó un cumplimiento general > 80%. Por escenario se observó un mayor cumplimiento en las actividades desarrolladas en la Institución Prestadora de Servicios de salud (IPS), en el Laboratorio de Salud Pública Departamental (LSPD) y el Sistema de Gestión del Riesgo del Instituto Nacional de Salud (INS), el menor cumplimiento se observó en el proceso de comunicación del riesgo. En el componente cualitativo, se identificaron fortalezas y debilidades en categorías previamente definidas (participación, coordinación, desempeño, comunicación y recursos). Todos los hallazgos constituyen puntos claves de mejora. Conclusiones: Esta evaluación permitió conocer el cumplimiento en cada proceso de la gestión del riesgo en salud pública a niveles nacional y local, identificando oportunidades de mejora en los procesos.

The complex neuronal circuitry of the cerebellum is embedded within its lamina, folia, and lobules, which together play an important role in sensory and motor function. Studies in mouse models have demonstrated that both cerebellar lamination and lobule/fissure development are under genetic control. The cerebellar vermis of C57BL/6 mice exhibits spontaneous malformations of neuronal migration of posterior lobules (VIII-IX; molecular layer heterotopia); however, the extent to which other inbred mice also exhibit these malformations is unknown. Using seven different inbred mouse strains and two first filial generation (F1) hybrids, we show that only the C57BL/6 strain exhibits heterotopia. Furthermore, we observed heterotopia in consomic and recombinant inbred strains. These data indicate that heterotopia formation is a weakly penetrant trait requiring homozygosity of one or more C57BL/6 alleles outside of chromosome 1 and the sex chromosomes. Additional morphological analyses showed no relationship between heterotopia formation and other features of lobule/fissure organization. These data are relevant toward understanding normal cerebellar development and disorders affecting cerebellar foliation and lamination.

Ketamine is one of several clinically important drugs whose therapeutic efficacy is due in part to their ability to act upon ion channels prevalent in nearly all biological systems. In studying eukaryotic and prokaryotic organisms in vitro, we show that ketamine short-circuits the growth and spatial expansion of three microorganisms, Stachybotrys chartarum, Staphylococcus epidermidis and Borrelia burgdorferi, at doses efficient at reducing depression-like behaviors in mouse models of clinical depression. Although our findings do not reveal the mechanism(s) by which ketamine mediates its antifungal and antibacterial effects, we hypothesize that a function of L-glutamate signal transduction is associated with the ability of ketamine to limit pathogen expansion. In general, our findings illustrate the functional similarities between fungal, bacterial and human ion channels, and suggest that ketamine or its metabolites not only act in neurons, as previously thought, but also in microbial communities colonizing human body surfaces.

This review discusses the biology and behavior of Propionibacterium acnes (P. acnes), a dominant bacterium species of the skin biogeography thought to be associated with transmission, recurrence and severity of disease. More specifically, we discuss the ability of P. acnes to invade and persist in epithelial cells and circulating macrophages to subsequently induce bouts of sarcoidosis, low-grade inflammation and metastatic cell growth in the prostate gland. Finally, we discuss the possibility of P. acnes infiltrating the brain parenchyma to indirectly contribute to pathogenic processes in neurodegenerative disorders such as those observed in Parkinson's disease (PD).

Cortical function emerges from the intrinsic properties of neocortical neurons and their synaptic connections within and across lamina. Neurodevelopmental disorders affecting migration and lamination of the neocortex result in cognitive delay/disability and epilepsy. Molecular layer heterotopia (MLH), a dysplasia characterized by over-migration of neurons into layer I, are associated with cognitive deficits and neuronal hyperexcitability in humans and mice. The breadth of different inbred mouse strains that exhibit MLH and inheritance patterns of heterotopia remain unknown. A neuroanatomical survey of numerous different inbred mouse strains, 2 first filial generation (F1) hybrids, and one consomic strain (C57BL/6J-Chr 1A/J/NaJ) revealed MLH only in C57BL/6 mice and the consomic strain. Heterotopia were observed in numerous genetically-engineered mouse lines on a congenic C57BL/6 background. These data indicate that heterotopia formation is a weakly penetrant trait requiring homozygosity of one or more C57BL/6 alleles outside of chromosome 1. These data are relevant toward understanding neocortical development and disorders affecting neocortical lamination.

The brain has long been thought to lack a lymphatic drainage system. Recent studies, however, show the presence of a brain-wide paravascular system appropriately named the glymphatic system based on its similarity to the lymphatic system in function and its dependence on astroglial water flux. Besides the clearance of cerebrospinal fluid and interstitial fluid, the glymphatic system also facilitates the clearance of interstitial solutes such as amyloid-β and tau from the brain. As cerebrospinal fluid and interstitial fluid are cleared through the glymphatic system, eventually draining into the lymphatic vessels of the neck, this continuous fluid circuit offers a paradigm shift in osteopathic manipulative medicine. For instance, manipulation of the glymphatic-lymphatic continuum could be used to promote experimental initiatives for nonpharmacologic, noninvasive management of neurologic disorders. In the present review, the authors describe what is known about the glymphatic system and identify several osteopathic experimental strategies rooted in a mechanistic understanding of the glymphatic-lymphatic continuum.

Ketamine exerts powerful anesthetic, psychotic, and antidepressant effects in both healthy volunteers and clinically depressed patients. Although ketamine targets particular glutamate receptors, there is a dearth of evidence for additional, alternative molecular substrates for the behavioral actions of this N-methyl-D-aspartate (NMDA) receptor antagonist drug. Here, we provide behavioral and molecular evidence for the actions of ketamine using a new vertebrate model for psychiatric disorders: the zebrafish. Subanesthetic doses of ketamine produced a variety of abnormal behaviors in zebrafish that were qualitatively analogous to those previously measured in humans and rodents treated with drugs that produce transient psychosis. In addition, we revealed that the transcription factor Phox2b is a molecular substrate for the actions of ketamine, particularly during periods of hypoxic stress. Finally, we also show that SIRT1, a histone deacetylase widely recognized for its link to cell survival is also affected by hypoxia crises. These results establish a relevant assay system in which the effects of psychotomimetic drugs can rapidly be assessed, and provide a plausible and novel neuronal mechanism through which ketamine affects critical sensory circuits that monitor breathing behavior.

Clinical depression is a chronic, recurrent mood disorder that causes significant disability and disease burden throughout the world. Not surprisingly, there is an enormous demand for finding (a) appropriate medications and devices for treating the clinical symptoms and (b) the underlying molecular mechanisms of the disease. Currently, most therapeutic treatments of depression indirectly target the serotonin and norepinephrine systems of the brain, as these neurotransmitters have long been considered promising and mechanistically relevant to the etiology of mood disorders. However, selective serotonin reuptake inhibitors such as sertraline, fluoxetine and paroxetine do not always substantially improve clinical outcome, and when they do show efficacy, it takes weeks of treatment to achieve an appreciable clinical effect. These observations suggest that a serotonin and norepinephrine hypothesis of depression is incomplete at best, and that novel, rapid onset therapeutic options for depression must be considered. In this review, we highlight several potential new drugs for clinical depression based on recent discoveries about the neurotransmitter glutamate and its family of receptors. Moreover, we discuss the possibility that glutamate-based antidepressant drugs might affect covalent histone modifications including acetylation in areas of the brain (e.g., pre-frontal cortex, hippocampus) thought to be relevant for the pathogenesis of affective disorders. If so, histone hyperacetylation and thus chromatin remodeling might be important regulatory mechanisms underlying the effects of ketamine and other N-Methyl-D-Aspartate receptor antagonist drugs. Chromatin remodeling may represent a non-serotonin/norepinephrine therapeutic strategy for treatment of clinical depression, a strategy that may also be appropriate in the context of drug discovery and drug development.

Mesenchymal stem cells (MSCs) have been exploited as cellular vectors to treat a wide array of diseases but the mechanisms responsible for their therapeutic effect remain indeterminate. Previously, we reported that MSCs inhibit bleomycin (BLM)-induced inflammation and fibrosis within the lungs of mice. Interrogation of the MSC transcriptome identified interleukin 1 receptor antagonist (IL1RN) as a potential mediator of this effect. Fractionation studies indicated that MSCs are the principal source of IL1RN in murine bone marrow and that its expression is restricted to a unique subpopulation of cells. Moreover, MSC-conditioned media was shown to block proliferation of an IL-1α-dependent T cell line and inhibit production of TNF-α by activated macrophages in vitro . Studies conducted in mice revealed that MSC administration was more effective than recombinant IL1RN delivered via adenoviral infection or osmotic pumps in inhibiting BLM-induced increases in TNF-α, IL-1α, and IL1RN mRNA in lung, IL1RN protein in bronchoalveolar lavage (BAL) fluid, and trafficking of lymphocytes and neutrophils into the lung. Therefore, MSCs protect lung tissue from BLM-induced injury by blocking TNF-α and IL-1, two fundamental proinflammatory cytokines in lung. Identification of IL1RN-expressing human MSC subpopulations may provide a novel cellular vector for treating chronic inflammatory diseases in humans.

Silent information regulator-1 (SIRT1) deacetylase, a sensor of intermittent energy restriction, is inextricably intertwined with circadian regulation of central and peripheral clock genes. The purpose of this study was to identify SIRT1-specific target genes that are expressed in a circadian rhythm pattern and driven, in part, by specific components of foodstuffs. Using human cells and rats fed with a resveratrol diet we show that SIRT1 binds to, and transcriptionally regulates, a gene locus encoding the G protein-coupled receptor (GPR), GPR50 in the brain. GPR50 is the mammalian orthologue of the melatonin1c membrane-bound receptor which has been identified as a genetic risk factor for bipolar disorder and major depression in women. In general, our findings support and expand the notion that circadian clock signaling components and dietary interventions are adaptively linked, and suggest that the brain may be particularly sensitive to metabolic events in response to light-dark cycles.

Heat shock proteins are ubiquitous members of a family of molecular chaperones that protect various cell populations from injury. Up-regulation of heat shock proteins, particularly the 70 kDa species, bind selectively to denatured or partially damaged polypeptides that would otherwise perturb cell function and initiate cell death programs. In this regard, induction of heat shock proteins provides protection from cerebral ischemia in animal models of stroke. Endothelial cells, in particular, are intimately involved in the above protective event as these cells mount a stress response with induction of the 70 kDa heat shock protein. However, the coupling of heat shock proteins and the neurovascular response are not yet known. Here we show that blood content is an important factor in this stress response as rats devoid of blood content do not display a heat shock response in the microvasculature of the hippocampal formation. This lack of stress response, however, is reversed when rats are reperfused with exogenous rat or human blood content. We propose a new ischemic-sensing role for blood that serves to integrate information about protein-damaging conditions and heat shock protein levels in the neurovascular network. Further characterization of this sensing role could represent an attractive new approach to treatment of global ischemia and other microvascular pathologies.

Myocyte enhancer factor 2A (MEF-2A) is a calcium-regulated transcription factor that promotes cell survival during nervous system development. To define and further characterize the distribution pattern of MEF-2A in the adult mammalian brain, we used a specific polyclonal antiserum against human MEF-2A to identify nuclear-localized MEF-2A protein in hippocampal and frontal cortical regions. Western blot and immunocytochemical analyses showed that MEF-2A was expressed not only in laminar structures but also in blood vessels of rat and human brains. MEF-2A was colocalized with doublecortin (DCX), a microtubule-associated protein expressed by migrating neuroblasts, in CA1 and CA2 boundaries of the hippocampus. MEF-2A was expressed heterogeneously in additional structures of the rat brain, including the striatum, thalamus, and cerebellum. Furthermore, we found a strong nuclear and diffuse MEF-2A labeling pattern in spinal cord cells of rat and human material. Finally, the neurovasculature of adult rats and humans not only showed a strong expression of MEF-2A but also labeled positive for hyperpolarization-activated, cyclic nucleotide-regulated (HCN) channels. This study further characterizes the distribution pattern of MEF-2A in the mammalian nervous system, demonstrates that MEF-2A colocalizes with DCX in selected neurons, and finds MEF-2A and HCN1 proteins in the neurovasculature network. Synapse 59:513–520, 2006. © 2006 Wiley-Liss, Inc.

The effects of HSV-1 amplicon and polyethyleneimine (PEI)-mediated transfection of dominant negative FGF receptor-1 mutant FGFR1(TK-) into the rat brain substantia nigra (SN) were examined in vivo to model the reduced FGF signaling documented to occur in Parkinson's disease. The number of SN neurons that expressed tyrosine hydroxylase (TH) was significantly reduced following HSV-1 FGFR1(TK-) intranigral delivery and similar changes were observed after PEI-mediated FGFR1(TK-) transfections. Further, we also observed a significantly lower striatal dopamine content following the PEI transfection of FGFR1(TK-). Thus, we conclude that reduced FGF signaling in the SN of Parkinsonian patients could play a role in the impaired dopaminergic transmission associated with the degenerative disease.

A large number of individuals afflicted with psychiatric disorders, particularly depression with psychotic features, do not respond to conventional drug therapy. An option for this phenomenon is to augment a standard selective serotonin (5-HT) reuptake inhibitor with an atypical antipsychotic agent. In this regard, fluoxetine and olanzapine have been used concomitantly for treatment-resistant depression and bipolar depression. Although highly efficacious in terms of producing superior improvement of symptoms across a variety of psychological measures, the motor patterns, endocrine profiles, and intracellular signaling pathways affected by drug augmentation have not been determined. Here we show that fluoxetine (10 mg/kg) plus olanzapine (5 mg/kg) given to rats for 7 consecutive days (i.e., subchronic treatment) alters motor activity and diminishes spontaneous behaviors as measured by spatial position and angular path analyses. In addition, the same drug combination pattern sensitizes peak adrenal corticosterone secretion without altering serum glucose levels. We also show that subchronic fluoxetine and olanzapine exposure suppresses the induction of two immediate-early gene transcription factors (e.g., pCREB and FOS) that are associated with long-lasting changes in synaptic efficacy and structural modifications in the prefrontal cortex, piriform cortex, and hippocampus. These results suggest that fluoxetine plus olanzapine can interact in a fashion not predicted by the currently accepted model of fluoxetine monotherapy and provide insight into the synergistic actions of drug augmentation in patients with treatment-resistant depression. Synapse 50:353–364, 2003. © 2003 Wiley-Liss, Inc.

Several nutrient-signaling pathways that extend life span have been described in model organisms. Thus, parallel and redundant signaling pathways that are similar across species might be subject to experimental manipulation. Here, we develop a PCR-based technique for testing the hypothesis that mitotic accumulation of extra-chromosomal ribosomal DNA circles might also determine life span in human cells. Using resveratrol, a phytochemical that counters age-related signs, we find treatment-dependent subcellular accumulations of extra-chromosomal 5S ribosomal DNA in human cell lines. These data suggest an association between DNA circles and intrinsic aging and demonstrate the utility of a PCR-based technique for studying the accumulation of dysfunctional molecules that promote senescence.

Post-mitotic neurons are particularly susceptible to DNA double-strand breaks during their relatively long lifespan. Here, we report the anatomical distribution and subcellular localization of a molecule first identified as a DNA damage checkpoint protein. Immunocytochemical analysis of 53BP1 showed that this nuclear molecule is widely expressed in adult human and rat brains. Further, we showed that 53BP1 routinely co-clusters with γ-aminobutyric acid neurons throughout the rat neuraxis. Notably, 53BP1 is only expressed in neuronal cells as the DNA damage checkpoint protein was virtually absent from glial cells. Finally, we found that human neural progenitors showed a differential index of DNA fragmentation at different stages of cellular differentiation. These data provide additional and important anatomical findings for the distribution and phenotype of DNA double-strand breaks in the mammalian brain, and suggest that DNA fragmentation is a spontaneous event routinely occurring in neural progenitors and adult neurons.

Parkin is an intracellular protein that plays a significant role in the etiopathogenesis of autosomal recessive juvenile parkinsonism. Using immunoblot methods, we found Parkin isoforms varying from 54 to 58 kDa in rat, mouse, bird, frog and fruit-fly brains. Immunocytochemical studies carried out in rats, mice and birds demonstrated multiple cell types bearing the phenotype for Parkin throughout telencephalic, diencephalic, mesencephalic and metencephalic brain structures. While in some instances Parkin-containing neurons tended to be grouped into clusters, the majority of these labeled nerve cells were widely scattered throughout the neuraxis. The topographical distribution and organizational pattern of Parkin within major functional brain circuits was comparable in both rats and mice. However, the subcellular localization of Parkin was found to vary significantly as a function of antibody reactivity. A consistent cytoplasmic labeling for Parkin was observed in rodent tissue incubated with a polyclonal antibody raised against the human Parkin protein and having an identical amino-acid sequence with that of the rat. In contrast, rodent tissue alternately incubated with a polyclonal antibody raised against a different region of the same human Parkin protein but having 10 mismatched amino-acid sequence changes with those of the rat and mouse, resulted in nuclear labeling for Parkin in rat but not mouse neurons. This difference in epitope recognition, however, was reversed when mouse brain tissue was heated at 80 degrees C, apparently unmasking target epitopes against which the antisera were directed. Collectively, these results show a high degree of conservation in the cellular identity of Parkin in animals as different as drosophilids and mammals and points to the possibility that the biochemical specificities of Parkin, including analogous functional roles, may have been conserved during the course of evolution.

Addictive drugs like cocaine, ethanol, and morphine activate signal transduction pathways that regulate brain gene expression. Such regulation is modulated by the presence of certain transcription factor proteins present in a given neuron. This article summarizes the effects of several addictive drugs on transcriptional processes contributing to the development of a drug-dependent state. The characterization of drug-induced changes in gene expression shows promise for improving our understanding of drug-addiction phenomena and cellular modes of cocaine, ethanol, and morphine action.

Cocaethylene is a psychoactive metabolite formed during the combined consumption of cocaine and ethanol. In this brief review, we discuss several well-characterized effects of this metabolite with an emphasis on the neurobiological and behavioral correlates of polydrug addiction. Included herein are the descriptions of some of the changes in trans-synaptic transmission and their relationship to pathological behaviors associated with a chronic, drug-dependent state that may be altered by the spatial or temporal dynamics of cocaethylene.

We examined the behavioral and neurochemical effects of cocaethylene treatment in Long-Evans (LE) and Sprague-Dawley (SD) rats. Cocaethylene-induced behaviors were significantly less in LE rats. Cocaethylene caused an inhibition of dopamine synthesis in the caudate nucleus and nucleus accumbens that was equivalent in both rat lines. Serotonin synthesis was also suppressed by cocaethylene treatment, however this phenomenon was less pronounced when compared with the effects on dopamine synthesis.

Fluoxetine is a serotonin re-uptake blocker commonly used to treat endogenous depression. The present experiments were carried out to assess the effects of fluoxetine on c-fos induction throughout the rat brain. In addition, intron-directed in situ hybridization analysis was used to examine fluoxetine regulation of corticotropin-releasing factor heteronuclear gene transcription in the paraventricular nucleus of the hypothalamus. Because the actions of corticotropin-releasing factor are mediated by membrane-bound corticotropin-releasing factor type 1 receptors, we also evaluated the stimulation of such receptors after acute fluoxetine exposure. The immediate-early gene, c-fos, was markedly induced in several telencephalic and diencephalic brain structures. For instance, a strong hybridized signal was apparent 30 min after fluoxetine (10 mg/kg; intraperitoneal) administration in the caudate putamen, septal nucleus, bed nucleus of stria terminalis, anterodorsal preoptic area, paraventricular nucleus, supraoptic nucleus, ventromedial hypothalamus and posterior hypothalamic nucleus. In addition, c-fos-expressing neurons were also evident in discrete amygdaloid nuclei. This nuclear induction was brief in duration, as levels of the immediate-early gene were mostly undetectable 90 min after drug administration. In contrast to the extensive induction of c-fos by fluoxetine throughout the brain parenchyma, elevation of corticotropin-releasing factor heteronuclear RNA levels were confined exclusively to neurosecretory nerve cells of the paraventricular nucleus, with peak levels detected 30 min after fluoxetine exposure. Therefore, the time-course of corticotropin-releasing factor heteronuclear RNA closely paralleled that of c-fos. Significant changes in corticotropin-releasing factor type 1 receptor messenger RNA levels were also observed in the paraventricular nucleus but with a slow incremental biosynthesis of the receptor messenger RNA, as high levels were discernible only 360 min after fluoxetine treatment. Finally, we failed to detect sex-related differences in the acute response to fluoxetine, as both female and male rat brains showed a comparable induction of c-fos, corticotropin-releasing factor heteronuclear RNA and corticotropin-releasing factor type 1 receptor expression within parvocellular neurosecretory nerve cells that govern the stress response. All of these findings are discussed in terms of specific sequences of nuclear events that couple fluoxetine-based serotonin input with changes in gene expression in selective neurons.

The use of Drosophila as a model to study the behavioral consequences of stimulant drugs was analyzed in an active preparation of decapitated Drosophila. Application of cocaine and cocaethylene to discrete nerve cord cells regulating motor programs of behavior produced striking patterns of behavioral activity in a concentration-related manner. In general, intense circling behavior and significant wing buzzing activity were distinguishable behavioral markers in flies treated with mM concentrations of cocaine or cocaethylene. The significant changes in motor behavior induced by stimulant drugs in decapitated flies were not reproduced by the application of apomorphine, a direct dopamine (DA) agonist, or octopamine, a naturally occurring transmitter in arthropods. Because both cocaine and cocaethylene interfere with DA reuptake in mammals, we characterized the role of DA receptors mediating increased stereotypy and motor behavior in flies. Coadministration of SCH-23390, a specific D1 receptor antagonist, significantly attenuated the behavior-activating properties of cocaine and cocaethylene in this active experimental preparation. Therefore, the receptor protein mediating the behavioral responses to stimulant drugs in Drosophila is pharmacologically similar to the mammalian D1 subtype. In rats, cocaine- and cocaethylene-induced behavioral activity is complex, with increasing evidence that the D1 receptor interacts significantly with N-methyl-D-aspartate (NMDA) receptor pathways to produce an altered behavioral phenotype. To further characterize additional receptor subtypes targeted by the actions of cocaine and cocaethylene, we pretreated flies with MK-801 and dextromethorphan. Both of these drugs are potent, selective noncompetitive NMDA receptor antagonists. Interestingly, MK-801 and dextromethorphan profoundly reduced the behavior-activating properties of cocaine and cocaethylene in Drosophila. Therefore, as in rats, the NMDA (and D1) receptor pathways in this arthropod represent obligatory targets for the behavioral effects of stimulant drugs.

Cocaethylene is a neuroactive metabolite derived from the concurrent consumption of cocaine and ethanol. The effects of cocaethylene on locomotor activity, stereotypy, and rearing in Long-Evans and Sprague-Dawley rats were compared.A single cocaine injection (molar equivalent of 60 μmol/kg cocaethylene, intraperitoneal) elicited a robust series of motor output behaviors, including locomotion, stereotypy, and rearing over a 30-minute testing period in Long-Evans rats. In contrast, cocaethylene administration, under comparable testing conditions, produced no significant changes in locomotor and investigatory behaviors. Because cocaethylene has relatively little impact on serotonin (5-HT) reuptake as opposed to reuptake of dopamine, we pretreated Long-Evans rats with fluoxetine (10 mg/kg; IP), a selective 5-HT reuptake inhibitor. Fluoxetine profoundly augmented cocaethylene-stimulated behaviors in this rat phenotype. To examine whether other rat strains exhibit a similar response to cocaethylene, Sprague-Dawley rats were injected (IP) with cocaethylene and their behavior patterns monitored over a 30-minute testing period. Cocaethylene produced marked locomotor and exploratory behaviors in this strain, suggesting therefore that Long-Evans and Sprague- Dawley rats differ in their response to cocaethylene. To relate these behavioral differences to possible structural differences in the neuronal density of dopaminergic or serotonergic neurons, Long-Evans and Sprague-Dawley brains were evaluated for tyrosine hydroxylase and 5-HT immunocytochemistry. No gross morphological differences in neuronal architecture or density were found in the ventral tegmental area or dorsal raphe nucleus of the two rat phenotypes. These results indicate that two commonly used rat strains show a differential response to cocaethylene and the neurochemical basis for this behavioral difference may be related to synaptic 5-HT bioavailability.

This radiology case report describes an elderly female patient diagnosed with rectal gastrointestinal stromal tumor (GIST). Although these tumors frequently occur in the gastrointestinal tract (~70%), they are relatively rare in the rectum (~0.1%). Computed tomography (CT) scans showed a tumor invading the rectal wall, radiating laterally into the posterior vaginal wall with well-defined focal necrosis around the lesions. Abdomino-perineal resection and posterior vaginectomy followed by histological and immunocytochemical analyses of biopsied tissue verified further the presence of a high grade GIST using primary antibodies directed against CD 117 and CD 34. These data support the hypothesis that GISTs are pathologically related to mutations in receptors for tyrosine kinase pathways, and suggest that elderly individuals might be at risk for developing ectopic forms of GISTs.