Drogodependencias: XX Curso de Actualización para Postgraduados en Farmacia

El consumo de drogas es un fenómeno multicausal en el que incide una serie de factores del ámbito personal, familiar, social, y cultural. En los últimos años, asistimos a cambios tanto en la oferta de drogas como en los patrones de consumo. Así, mientras en los años 80 y primeros 90 la droga emblemática era la heroína, hoy en día su consumo se ha estabilizado, e incluso ha disminuido. Las nuevas formas de estar en sociedad afectan a grupos de jóvenes aceptablemente integrados en su medio familiar y social. A día de hoy, debe considerarse el consumo de otras drogas, fundamentalmente las llamadas drogas de síntesis, y la adopción de nuevos patrones en el consumo de algunas ya establecidas, como es el alcohol. En este marco se está haciendo frente al fenómeno del consumo de drogas desde diferentes perspectivas que se extienden desde la investigación científica hasta la prevención, la reducción de daños y la asistencia al drogodependiente. Entre las estrategias del nuevo Plan Nacional Sobre Drogas (PND) destaca la de normalizar las redes asistenciales a drogodependientes, integrándolas de forma coordinada en los sistemas públicos de salud y sistemas sociales. Se pretende que los diferentes recursos que formen parte del denominado sistema de asistencia e integración social de drogodependientes se caractericen por su profesionalización, interdisciplinariedad y fácil accesibilidad. En este sentido, hay que destacar la participación activa de algunos profesionales farmacéuticos en distintos programas de actuación, prevención y reducción de daños producidos por drogas. Por otra parte, se están realizando esfuerzos importantes en la investigación básica y clínica dirigidos a desentrañar los mecanismos que operan en la adicción a drogas. Los capítulos que componen este texto son el resultado del trabajo coordinado entre investigadores, docentes, farmacéuticos comunitarios, psicólogos, psiquiatras y otros profesionales implicados en la problemática de las drogodependencias. Su lectura permitirá conocer la actual situación respecto al consumo de drogas, los mecanismos neurobiológicos implicados en la drogadicción, la farmacología y la toxicología de las diferentes drogas, los riesgos asociados a su consumo, y los recursos disponibles que atienden a la población drogodependiente. Agradecemos la participación de los profesionales que asisten desde diferentes ámbitos a las personas afectadas directa o indirectamente por los problemas derivados del consumo de drogas, que ha hecho posible integrar aspectos básicos y prácticos de un tema tan complejo como es el de las drogodependencias

Knowledge of diversity of wild palms (arecaceae) in the Republic of Benin: finding gaps in the national inventory by combining field and digital accessible knowledge

—Despite efforts by researchers worldwide to assess the biodiversity of plant groups, many locations on Earth remain poorly surveyed, resulting in inadequate or biased knowledge. Robust estimates of inventory completeness could help alleviate the problem. This study aimed to identify areas representing gaps in current knowledge of African palms, with a focus on Benin (West Africa). We assessed the completeness of knowledge of African palms, targeting geographic distance and climatic difference from well-known sites. Data derived from intensive fieldwork were combined with independent data available online. Inventory completeness indices were calculated and coupled with other criteria. Results showed a high overall value for inventory completeness, as well as an even distribution of well-known areas across the country. However, poorly-known areas were identified, which were in remote locations with low accessibility. This study illustrates how biodiversity survey and inventory efforts can be guided by existing knowledge. We strongly recommend the combination of digital accessible knowledge and fieldwork, coupled with expert knowledge, to obtain a better picture of inventory completeness in tropical ecosystems

The Intrinsic Shape Distribution of a Sample of Elliptical Galaxies

We apply the dynamical modeling approach of Statler (1994b) to 13 elliptical galaxies from the Davies and Birkinshaw (1988) sample of radio galaxies to derive constraints on their intrinsic shapes and orientations. We develop an iterative Bayesian algorithm to combine these results to estimate the parent shape distribution from which the sample was drawn, under the assumption that this parent distribution has no preferred orientation. In the process we obtain improved estimates for the shapes of individual objects. The parent shape distribution shows a tendency toward bimodality, with peaks at the oblate and prolate limits. Under minimal assumptions about the galaxies' internal dynamics, 35% of the objects would be strongly triaxial (0.2 < T < 0.8). However, the parent distribution is sensitive to the assumed orbit populations in the galaxies. Dynamical configurations in which all galaxies rotate purely about either their long or short axes can be ruled out because they would require the sample to have a strong orientation bias. Configurations in which the mean motion about the short or long axis is either ``disklike''---dropping off away from the symmetry planes---or ``spheroidlike''---remaining roughly constant at a given radius---are equally viable. Spheroidlike rotation in the long-axis or short-axis tube orbits significantly lowers the abundance of prolate or oblate galaxies, respectively. If rotation in ellipticals is generally disklike, then triaxiality is rare; if spheroidlike, triaxiality is common

Observation of an Excited Bc+ State

Using pp collision data corresponding to an integrated luminosity of 8.5 fb-1 recorded by the LHCb experiment at center-of-mass energies of s=7, 8, and 13 TeV, the observation of an excited Bc+ state in the Bc+π+π- invariant-mass spectrum is reported. The observed peak has a mass of 6841.2±0.6(stat)±0.1(syst)±0.8(Bc+) MeV/c2, where the last uncertainty is due to the limited knowledge of the Bc+ mass. It is consistent with expectations of the Bc∗(2S31)+ state reconstructed without the low-energy photon from the Bc∗(1S31)+→Bc+γ decay following Bc∗(2S31)+→Bc∗(1S31)+π+π-. A second state is seen with a global (local) statistical significance of 2.2σ (3.2σ) and a mass of 6872.1±1.3(stat)±0.1(syst)±0.8(Bc+) MeV/c2, and is consistent with the Bc(2S10)+ state. These mass measurements are the most precise to date

Analysis of mortality metrics associated with a comprehensive range of disorders in Denmark, 2000 to 2018: A population-based cohort study

Background: The provision of different types of mortality metrics (e.g., mortality rate ratios [MRRs] and life expectancy) allows the research community to access a more informative set of health metrics. The aim of this study was to provide a panel of mortality metrics associated with a comprehensive range of disorders and to design a web page to visualize all results. Methods and findings: In a population-based cohort of all 7,378,598 persons living in Denmark at some point between 2000 and 2018, we identified individuals diagnosed at hospitals with 1,803 specific categories of disorders through the International Classification of Diseases-10th Revision (ICD-10) in the National Patient Register. Information on date and cause of death was obtained from the Registry of Causes of Death. For each of the disorders, a panel of epidemiological and mortality metrics was estimated, including incidence rates, age-of-onset distributions, MRRs, and differences in life expectancy (estimated as life years lost [LYLs]). Additionally, we examined models that adjusted for measures of air pollution to explore potential associations with MRRs. We focus on 39 general medical conditions to simplify the presentation of results, which cover 10 broad categories: circulatory, endocrine, pulmonary, gastrointestinal, urogenital, musculoskeletal, hematologic, mental, and neurologic conditions and cancer. A total of 3,676,694 males and 3,701,904 females were followed up for 101.7 million person-years. During the 19-year follow-up period, 1,034,273 persons (14.0%) died. For 37 of the 39 selected medical conditions, mortality rates were larger and life expectancy shorter compared to the Danish general population. For these 37 disorders, MRRs ranged from 1.09 (95% confidence interval [CI]: 1.09 to 1.10) for vision problems to 7.85 (7.77 to 7.93) for chronic liver disease, while LYLs ranged from 0.31 (0.14 to 0.47) years (approximately 16 weeks) for allergy to 17.05 (16.95 to 17.15) years for chronic liver disease. Adjustment for air pollution had very little impact on the estimates; however, a limitation of the study is the possibility that the association between the different disorders and mortality could be explained by other underlying factors associated with both the disorder and mortality. Conclusions: In this study, we show estimates of incidence, age of onset, age of death, and mortality metrics (both MRRs and LYLs) for a comprehensive range of disorders. The interactive data visualization site (https://nbepi.com/atlas) allows more fine-grained analysis of the link between a range of disorders and key mortality estimates.publishedVersio

New insights into the protein aggregation pathology in myotilinopathy by combined proteomic and immunolocalization analyses

Introduction: Myofibrillar myopathies are characterized by progressive muscle weakness and impressive abnormal protein aggregation in muscle fibers. In about 10 % of patients, the disease is caused by mutations in the MYOT gene encoding myotilin. The aim of our study was to decipher the composition of protein deposits in myotilinopathy to get new information about aggregate pathology. Results: Skeletal muscle samples from 15 myotilinopathy patients were included in the study. Aggregate and control samples were collected from muscle sections by laser microdissection and subsequently analyzed by a highly sensitive proteomic approach that enables a relative protein quantification. In total 1002 different proteins were detected. Seventy-six proteins showed a significant over-representation in aggregate samples including 66 newly identified aggregate proteins. Z-disc-associated proteins were the most abundant aggregate components, followed by sarcolemmal and extracellular matrix proteins, proteins involved in protein quality control and degradation, and proteins with a function in actin dynamics or cytoskeletal transport. Forty over-represented proteins were evaluated by immunolocalization studies. These analyses validated our mass spectrometric data and revealed different regions of protein accumulation in abnormal muscle fibers. Comparison of data from our proteomic analysis in myotilinopathy with findings in other myofibrillar myopathy subtypes indicates a characteristic basic pattern of aggregate composition and resulted in identification of a highly sensitive and specific diagnostic marker for myotilinopathy. Conclusions: Our findings i) indicate that main protein components of aggregates belong to a network of interacting proteins, ii) provide new insights into the complex regulation of protein degradation in myotilinopathy that may be relevant for new treatment strategies, iii) imply a combination of a toxic gain-of-function leading to myotilin-positive protein aggregates and a loss-of-function caused by a shift in subcellular distribution with a deficiency of myotilin at Z-discs that impairs the integrity of myofibrils, and iv) demonstrate that proteomic analysis can be helpful in differential diagnosis of protein aggregate myopathies

Distinct muscle imaging patterns in myofibrillar myopathies

Objective: To compare muscle imaging findings in different subtypes of myofibrillar myopathies (MFM) in order to identify characteristic patterns of muscle alterations that may be helpful to separate these genetic heterogeneous muscular disorders. Methods: Muscle imaging and clinical findings of 46 patients with MFM were evaluated (19 desminopathy, 12 myotilinopathy, 11 filaminopathy, 1 alpha B-crystallinopathy, and 3 ZASPopathy). The data were collected retrospectively in 43 patients and prospectively in 3 patients. Results: In patients with desminopathy, the semitendinosus was at least equally affected as the biceps femoris, and the peroneal muscles were never less involved than the tibialis anterior (sensitivity of these imaging criteria to detect desminopathy in our cohort 100%, specificity 95%). In most of the patients with myotilinopathy, the adductor magnus showed more alterations than the gracilis muscle, and the sartorius was at least equally affected as the semitendinosus (sensitivity 90%, specificity 93%). In filaminopathy, the biceps femoris and semitendinosus were at least equally affected as the sartorius muscle, and the medial gastrocnemius was more affected than the lateral gastrocnemius. The semimembranosus mostly showed more alterations than the adductor magnus (sensitivity 88%, specificity 96%). Early adult onset and cardiac involvement was most often associated with desminopathy. In patients with filaminopathy, muscle weakness typically beginning in the 5th decade of life was mostly pronounced proximally, while late adult onset (> 50 years) with distal weakness was more often present in myotilinopathy. Conclusions: Muscle imaging in combination with clinical data may be helpful for separation of distinct myofibrillar myopathy subtypes and in scheduling of genetic analysis

Extended HI disks in dust-lane elliptical galaxies

We present the results of HI observations of five dust-lane ellipticals with the Australia Telescope Compact Array. Two galaxies (NGC 3108 and NGC 1947) are detected, and sensitive upper limits are obtained for the other three. In the two detected galaxies, the HI is distributed in a regular, extended and warped disk-like structure of low surface brightness. Adding data from the literature, we find that several more dust-lane ellipticals have regular HI structures. This HI is likely to be a remnant of accretions/mergers which took place a considerable time ago, and in which a significant fraction of the gas survived to form a disk. The presence of regular HI structures suggests that some mergers lead to galaxies with extended low surface brightness density gas disks. These gas disk will evolve very slowly and these elliptical galaxies will remain gas rich for a long period of time. (abridged)Comment: 21 pages, 12 separate jpeg figures, at http://www.nfra.nl/~morganti/Papers/dust.ps.gz the full ps version is available. Accepted for publication in A

Therapeutic vaccine in chronically Hiv-1-infected patients

Therapeutic vaccinations aim to re-educate human immunodeficiency virus (HIV)-1specific immune responses to achieve durable control of HIV-1 replication in virally suppressed infected individuals after antiretroviral therapy (ART) is interrupted. In a double blinded, placebocontrolled phase IIa multicenter study, we investigated the safety and immunogenicity of intranodal administration of the HIVACAT T cell Immunogen (HTI)-TriMix vaccine. It consists of naked mRNA based on cytotoxic T lymphocyte (CTL) targets of subdominant and conserved HIV-1 regions (HTI), in combination with mRNAs encoding constitutively active TLR4, the ligand for CD40 and CD70 as adjuvants (TriMix). We recruited HIV-1-infected individuals under stable ART. Study-arms HTI-TriMix, TriMix or Water for Injection were assigned in an 8:3:3 ratio. Participants received three vaccinations at weeks 0, 2, and 4 in an inguinal lymph node. Two weeks after the last vaccination, immunogenicity was evaluated using ELISpot assay. ART was interrupted at week 6 to study the effect of the vaccine on viral rebound. The vaccine was considered safe and well tolerated. Eighteen percent (n = 37) of the AEs were considered definitely related to the study product (grade 1 or 2). Three SAEs occurred: two were unrelated to the study product, and one was possibly related to ART interruption (ATI). ELISpot assays to detect T cell responses using peptides covering the HTI sequence showed no significant differences in immunogenicity between groups. There were no significant differences in viral load rebound dynamics after ATI between groups. The vaccine was safe and well tolerated. We were not able to demonstrate immunogenic effects of the vaccine