Judo for older adults: the coaches' knowledge and needs of education.

This study aimed to explore the views of judo coaches on their perceived knowledge (PK) and needs for education (NE) for training older practitioners. In total, 470 international (Europe = 48%, Americas = 22%, Africa = 23%, Asia = 5% and Oceania = 2%) judo coaches (IJF: level 1 = 55,3%, level 2 = 33%; judo black belt: 3,4 ± 1,7 dan; F = 15%; university education: 68% >BA) responded an online survey encompassing demographic information and 35 items relevant to training older adults (Aging process; Safety and First Aid; Organization & Environment; Physiology and Fitness; Psychology & Mental Health; Teaching & Training) to be rated on a 7-point Likert scale for PK and NE. Non parametric statistics (p > 0.05) was applied to ascertain differences and relationships between PK and NE, respectively. A bivariate go-zone plot was used to highlight items with the lowest PK and the highest NE mean values. The coaches reported high PK (4.5 ± 0.3 pt) and NE (4.7 ± 0.1 pt) values, with significant higher PK values emerging for high education levels and judo experience. In considering their unique needs and special role, the judo coaches presented valuable insights to develop a sustainable educational curriculum tailored to train older judo practitioners.

Educational Needs for Coaching Judo in Older Adults: The EdJCO Focus Groups.

Judo coaches are urged to develop specific competencies and skills for addressing the special needs of older practitioners. Thus, the purpose of this study was to investigate the experts' opinions on judo training in late adulthood to develop sound educational programs for coaches of older judo practitioners. Overall, eighty-eight experts from an international consortium of judo and educational partners participated in national focus groups. During the focus groups, experts discussed five themes and generated statements pertinent to educate coaches to support older judo practitioners (e.g., benefits; necessary knowledge; risks; training groups definition; tools; and tests for monitoring training plans). The initial list of 262 statements was synthesized, validated, analyzed, and organized into a final list of 55 statements and six macro-areas: aging process (n = 10); safety and first aid (n = 6); physiology and fitness (n = 12); psychology and mental health (n = 11); organization and environment (n = 5); adapted judo teaching and training (n = 11). The present international eminence-based study, harmonizing diverse intercultural perspectives, highlighted the specific needs of older judo practitioners. The results of this study will contribute to the structure of a sound educational program for coaches of older judo practitioners to enhance the quality of older adults' sports experiences by linking safety, enjoyment, social interactions, and learning principles.

A calorimetric and structural analysis of cooperativity in the thermal unfolding of the PDZ tandem of human Syntenin-1.

Syntenin-1 is a multidomain protein containing a central tandem of two PDZ domains flanked by two unnamed domains. Previous structural and biophysical studies show that the two PDZ domains are functional both isolated and in tandem, occurring a gain in their respective binding affinities when joined through its natural short linker. To get insight into the molecular and energetic reasons of such a gain, here, the first thermodynamic characterization of the conformational equilibrium of Syntenin-1 is presented, with special focus on its PDZ domains. These studies include the thermal unfolding of the whole protein, the PDZ-tandem construct and the two isolated PDZ domains using circular dichroism, differential scanning fluorimetry and differential scanning calorimetry. The isolated PDZ domains show low stability (ΔG < 10 kJ·mol-1) and poor cooperativity compared to the PDZ-tandem, which shows higher stability (20-30 kJ·mol-1) and a fully cooperative behaviour, with energetics similar to that previously described for archetypical PDZ domains. The high-resolution structures suggest that this remarkable increase in cooperativity is associated to strong, water-mediated, interactions at the interface between the PDZ domains, associated to nine conserved hydration regions. The low Tm value (45 °C), the anomalously high unfolding enthalpy (>400 kJ·mol-1), and native heat capacity values (above 40 kJ·K-1·mol-1), indicate that these interfacial buried waters play a relevant role in Syntenin-1 folding energetics.

The role of ultrasound and FDG-PET/CT to detect extracranial artery involvement in patients with suspected large vessel vasculitis.

OBJECTIVE: To assess the accuracy of ultrasound (US) versus fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) to identify extracranial involvement in large vessel vasculitis (LVV). METHODS: A retrospective observational study of patients with suspected LVV. All patients underwent US exam within 24 h per protocol. FDG-PET/CT was performed according to clinician criteria. The gold standard for LVV diagnosis was clinical confirmation after 6 months. RESULTS: Of the 113 patients included (74.3% female, mean age 74 years), 37 (32.7%) were diagnosed with LVV after 6 months. The sensitivity and specificity of US were 86.5% and 96.1%, respectively. Only 12 (42.9%) of 28 patients undergoing a FDG-PET/CT per clinician criteria showed positive findings. The sensitivity and specificity of FDG-PET/CT for LVV were 61.1% and 90%, respectively. Taking FDG-PET/CT as the reference, US showed extracranial inflammation in 10/12 (83.3%) and detected 2 (12.5%) additional cases of extracranial involvement with negative FDG-PET/CT. Conversely, FDG-PET/CT was positive in two patients with negative US (one isolated aortitis and one aortoiliac involvement). CONCLUSIONS: US and FDG-PET/CT are both valid tools to detect extracranial involvement. The presence of US extracranial artery inflammation is consistent with FDG-PET/CT examination, although a negative US scan does not rule out extracranial involvement.

Identificación de aberraciones cromosómicas en una población infantil costarricense con discapacidad intelectual idiopática / Identification of chromosomal aberrations in a Costa Rican children population with idiopathicintellectual disability

Resumen La prevalencia mundial de la discapacidad intelectual (DI) es del 3 %. Una de las causas más comunes de DI de origen genético son las aberraciones cromosómicas, las cuales resultan fácilmente detectables mediante un cariotipo. Sin embargo, muchas de estas pasan desapercibidas durante el análisis citogenético convencional debido a su tamaño. Estas pequeñas alteraciones se pueden localizar en los subtelómeros y se ha observado que, cuando es así, constituyen una razón importante de DI en pacientes que carecen de un diagnóstico de causalidad. En este estudio de tipo observacional, se utilizó la técnica MLPA con el objetivo de determinar la frecuencia de aberraciones cromosómicas submicroscópicas en los subtelómeros en una población infantil con DI de origen desconocido. Se examinaron 70 muestras de forma exitosa y se obtuvo un caso con una microduplicación en el subtelómero 17p, para una frecuencia del 1,4 %. También, se realizó el análisis citogenético en 33 muestras y se encontró un caso con una aberración cromosómica detectable al microscopio, para una frecuencia del 3 %. El porcentaje de aberraciones cromosómicas subteloméricas fue menor al esperado en comparación con estudios similares. Finalmente, se concluyó que el cariotipo y la técnica MLPA se complementan para el abordaje de personas con DI de origen desconocido.

Abstract The prevalence of intellectual disability (ID) in the global population is 3%. One of the most frequent cause of ID are chromosome aberrations, which are easily detected by a karyotype. However, many of these maygoundetected during a conventional cytogenetic analysis because of their length.These small alterations can be localized in the subtelomeres and it has been observed that when localized there, they are an important cause of ID in patients without a causality diagnostic. In this observational study, we use the MLPA technique for the purpose of identifying the frequency of submicroscopicsubtelomere chromosomal aberrations in a population of people with ID of unknown origin. 70 samples were successfully analyzed with MLPA and we found one case with a microduplication in the 17p subtelomere for a frequency of 1,4%. Also,the karyotype was performed in 33cases, and we foundone case with a chromosome aberration that can be detect by microscope for a frequency of 3%. The subtelomeric chromosome aberration frequency was lower than expected as we compare our results with similar studies. Finally, with this work we conclude that the karyotype and the MLPA technique complement each other for approaching people with ID of unknown origin.

Estudios genético-moleculares de miotonías hereditarias en la población costarricense / Molecular-genetic studies of inherited myotonic conditions in Costa Rica

Resumen Introducción: las miotonías hereditarias son enfermedades del músculo esquelético, clínica y genéticamente heterogéneas, caracterizadas por presentar miotonía (retraso en la relajación muscular). Se dividen en distróficas y no distróficas, las cuales son causadas por mutaciones en el ADN. Objetivo: describir los hallazgos más relevantes sobre algunas miotonías hereditarias en Costa Rica. Metodología: se realizaron estudios genético-moleculares en individuos afectados con una condición miotónica y sus familiares en riesgo genético. Resultados: la mutación de la distrofia miotónica tipo 1 (DM1) se encontró en 246 individuos. Nuestros estudios contribuyeron a mejorar la correlación entre el tamaño de la mutación y la edad de inicio de los síntomas, además, se demostró el papel modificador de algunos otros factores genéticos en la DM1. De las familias de 18 pacientes negativos para la mutación DM1, en ocho se logró identificar una mutación en genes que proporcionan la información para formar canales iónicos. Los análisis de función ayudaron a mostrar que esas mutaciones ocasionan cambios estructurales y estos modifican las propiedades de los canales, provocando una pérdida o ganancia de su función. Conclusiones: este trabajo permitió la clasificación clínica correcta de muchos pacientes, así como explorar las bases genéticas y moleculares de la variabilidad clínica de estas enfermedades, mediante la búsqueda de factores modificadores de la DM1 y los estudios funcionales de mutaciones causantes de canalopatías hereditarias, aspecto clave para asesorar a pacientes y familias y abordar la enfermedad de la forma más adecuada.

Abstract Introduction: Hereditary myotonias are a clinically and genetically heterogeneous group of skeletal muscle diseases characterized by myotonia (delayed muscle relaxation). Clinically, they are classified as dystrophic and non-dystrophic myotonias, which are caused by mutations in the DNA. Aim: Describe the most relevant findings on some hereditary myotonias in Costa Rica. Methodology: Genetic-molecular studies of these diseases were carried out in individuals affected with a myotonic condition and their relatives at genetic risk. Results: The mutation for myotonic dystrophy type 1 (DM1) was found in 246 individuals. We have seen an improvement in the correlations between the size of the mutation and the age of onset of symptoms, in addition we have demonstrated the modifying role of some genetic factors in DM1. Of 18 patients who were negative for the mutation causing DM1, in eight families, a mutation was identified in genes, that provide the instructions for producing proteins called ion channels. Analyzes at the functional level helped to show that these mutations cause structural changes that modify the properties of these channels, causing a loss or gain of channel function. Conclusions: Our studies have allowed a correct clinical classification for many patients with these pathologies, in addition to explore the genetic and molecular basis of the clinical variability of these diseases, by searching for DM1 modifying factors and functional studies of new mutations that cause hereditary channelopathies, which is key to provide genetic counseling to patients and families and treating the disease in the most appropriate way.

Prevalence of post-COVID-19 in patients with fibromyalgia: a comparative study with other inflammatory and autoimmune rheumatic diseases.

OBJECTIVES: To determine the prevalence and characteristics of post-COVID-19 (PC) in fibromyalgia (FM) patients. METHODS: Retrospective, multi-centric, observational study, comparing a group of FM patients (FM group) with another group of patients with other rheumatic diseases (RD group). COVID-19 diagnosis was established by positive polymerase chain reaction or antigen during acute infection or by positive antibodies thereafter. We considered PC diagnosis when symptoms remain after COVID-19. We collected the principal characteristics of COVID-19, the severity of fatigue, waking unrefreshed and cognitive impairment, and persistent symptoms. The American College of Rheumatology (ACR) criteria and the Combined Index of Severity in Fibromyalgia (ICAF) were collected in the FM group. RESULTS: RD group (n = 56) had more pneumonia (p = 0.001) and hospital admissions (p = 0.002), but the FM group (n = 78) had a higher number of symptoms (p = 0.002). The percentage of patients with PC was similar between groups (FM group 79.5%; RD group 66.1%, p = 0.081). FM group had more PC symptoms (p = 0.001), more impairment after COVID-19 (p = 0.002) and higher severity of fatigue, waking unrefreshed and cognitive impairment (p <  0.0001). Only loss of smell was more frequent in the FM group (p = 0.005). The FM group with PC (n = 29) showed more severity of the Combined Index of Severity in Fibromyalgia (ICAF) total score and physical factor after COVID-19, while emotional, coping factors and the ACR criteria did not change. CONCLUSIONS: The prevalence of PC in FM patients is similar to RD patients. In FM patients, the presence of PC does not appear to impact the severity of FM.

Xylazine spreads across the US: A growing component of the increasingly synthetic and polysubstance overdose crisis.

BACKGROUND: Sharp exacerbations of the US overdose crisis are linked to polysubstance use of synthetic compounds. Xylazine is a veterinary tranquilizer, long noted in the street opioid supply of Puerto Rico, and more recently Philadelphia. Yet its national trends, geographic distribution, and health risks are poorly characterized. METHODS: In this sequential mixed-methods study, xylazine was increasingly observed by ethnographers in Philadelphia among drug-sellers and people who inject drugs (PWID). Subsequently, we systematically searched for records describing xylazine-present overdose mortality across the US and assessed time trends and overlap with other drugs. RESULTS: In 10 jurisdictions - representing all four US Census Regions - xylazine was increasingly present in overdose deaths, rising from 0.36% of deaths in 015m 6.7% in 2020. The highest xylazine prevalence data was observed in Philadelphia, (25.8% of deaths), followed by Maryland (19.3%) and Connecticut (10.2%). Illicitly-manufactured-fentanyls were present in 98.4% of xylazine-present-overdose-deaths - suggesting a strong ecological link - as well as cocaine (45.4%), benzodiazepines (28.4%), heroin (23.3%), and alcohol (19.7%). PWID in Philadelphia described xylazine as a sought-after adulterant that lengthens the short duration of fentanyl injections. They also linked it to increased risk of soft tissue infection and naloxone-resistant overdose. CONCLUSIONS: Xylazine is increasingly present in overdose deaths, linked to the proliferation of illicitly-manufactured-fentanyls. Ethnographic accounts associate it with profound risks for PWID. Nevertheless, many jurisdictions do not routinely test for xylazine, and it is not comprehensively tracked nationally. Further efforts are needed to provide PWID with services that can help minimize additional risks associated with a shifting drug supply.

Potency-Enhancing Synthetics in the Drug Overdose Epidemic: Xylazine ("Tranq"), Fentanyl, Methamphetamine, and the Displacement of Heroin in Philadelphia and Tijuana.

Multiple transformations-referred to as "waves" in a panoply of recent public health and law enforcement publications-have rendered North American drug markets increasingly toxic since the early 2010s. The introduction of exceptionally potent synthetic sedatives and stimulants is initiating a new generation of drug injectors into co-use of opioids and methamphetamine, catapulting rates of deadly overdoses and infectious diseases. Drawing on extensive participant-observation research in Philadelphia (2007-present) and Tijuana (2018-present), we document the experience of street-based drug users across these two North American cities to focus on regional shifts in narcotics supplies and endpoint user preferences. We link the dramatic proliferation of fentanyl, methamphetamine, xylazine, and Mexican white powder heroin to: 1) pre-existing drug supply networks on the western and eastern coasts of the North American subcontinent; 2) material characteristics of local heroin supplies in pre-fentanyl opiate markets (Mexican black tar vs. Colombian off-white powder heroin); and 3) racialized repression/incarceration of drug sellers and users on both sides of the Mexico-US border. The article combines economic and medical anthropology to develop an ethnographically-informed political economy approach to an urgent public health challenge among street-based drug users with the highest overdose mortality rates in the US Northeastern Rust Belt and the Northwestern Mexican borderland metroplex anchored by Tijuana. It foregrounds street users' experiences in real time amidst rapidly shifting narcotics supply chains, linking market-driven logics of profit-seeking to the war on drugs' prohibitionist policy context, highlighting increasing toxic impacts on vulnerable sectors across regions.

Ultrasound in clinically suspect arthralgia: the role of power Doppler to predict rheumatoid arthritis development.

OBJECTIVE: To determine the usefulness of power Doppler (PD) ultrasound (US) to predict rheumatoid arthritis (RA) development in patients with clinically suspect arthralgia (CSA). METHODS: Retrospective analysis of a US unit cohort over a 1-year period. Patients with CSA and no previous diagnosis of inflammatory arthritis (IA) were included for analysis. All underwent bilateral US examination of the hands and/or feet according to the EULAR guidelines. Active US inflammation was defined as PD synovitis and/or tenosynovitis ≥1 at any location. RA diagnosis according to clinician criteria 6 months after the US examination was checked. Univariate and multivariate logistic regression models were employed to investigate possible predictive factors of RA development. RESULTS: A total of 110 CSA patients (80 females, mean age 53.6 years) were included for analysis. After 6 months of follow-up, 14 (12.7%) developed RA and 34 (30.9%) IA. US active inflammation was present in 38 (34.5%) patients (28.2% showed PD synovitis and 18.2% PD tenosynovitis). Multivariate analysis showed that ACPA (OR 1.0003; 95% CI 1.002-1.006) and ESR (OR 1.054; 95% CI 1.016-1.094) were significantly associated with the detection of US active inflammation at baseline. Only PD tenosynovitis was found to be an independent predictive factor of an evolution towards RA (OR 6.982; 95% CI 1.106-44.057) and IA (OR 5.360; 95% CI 1.012-28.390). CONCLUSION: US is able to detect features of subclinical inflammation in CSA patients, especially in those with higher ESR and ACPA values. Only PD tenosynovitis at baseline US assessment was found to be an independent predictor of RA and IA development in CSA patients.

Lysophosphatidic Acid and Several Neurotransmitters Converge on Rho-Kinase 2 Signaling to Manage Motoneuron Excitability.

Intrinsic membrane excitability (IME) sets up neuronal responsiveness to synaptic drive. Several neurotransmitters and neuromodulators, acting through G-protein-coupled receptors (GPCRs), fine-tune motoneuron (MN) IME by modulating background K+ channels TASK1. However, intracellular partners linking GPCRs to TASK1 modulation are not yet well-known. We hypothesized that isoform 2 of rho-kinase (ROCK2), acting as downstream GPCRs, mediates adjustment of MN IME via TASK1. Electrophysiological recordings were performed in hypoglossal MNs (HMNs) obtained from adult and neonatal rats, neonatal knockout mice for TASK1 (task1 -/-) and TASK3 (task3 -/-, the another highly expressed TASK subunit in MNs), and primary cultures of embryonic spinal cord MNs (SMNs). Small-interfering RNA (siRNA) technology was also used to knockdown either ROCK1 or ROCK2. Furthermore, ROCK activity assays were performed to evaluate the ability of various physiological GPCR ligands to stimulate ROCK. Microiontophoretically applied H1152, a ROCK inhibitor, and siRNA-induced ROCK2 knockdown both depressed AMPAergic, inspiratory-related discharge activity of adult HMNs in vivo, which mainly express the ROCK2 isoform. In brainstem slices, intracellular constitutively active ROCK2 (aROCK2) led to H1152-sensitive HMN hyper-excitability. The aROCK2 inhibited pH-sensitive and TASK1-mediated currents in SMNs. Conclusively, aROCK2 increased IME in task3 -/-, but not in task1 -/- HMNs. MN IME was also augmented by the physiological neuromodulator lysophosphatidic acid (LPA) through a mechanism entailing Gαi/o-protein stimulation, ROCK2, but not ROCK1, activity and TASK1 inhibition. Finally, two neurotransmitters, TRH, and 5-HT, which are both known to increase MN IME by TASK1 inhibition, stimulated ROCK2, and depressed background resting currents via Gαq/ROCK2 signaling. These outcomes suggest that LPA and several neurotransmitters impact MN IME via Gαi/o/Gαq-protein-coupled receptors, downstream ROCK2 activation, and subsequent inhibition of TASK1 channels.

Relationship of problematic cannabis use among youth in Spain with perceived risk, environmental factors and sociodemographic factors. / Relación del consumo problemático de cannabis en la población joven de España con el riesgo percibido, los factores ambientales y los factores sociodemográficos.

The relationship of problematic cannabis consumption with perceived risk, socioenvironmental and sociodemographic factors among youth in Spain is not well known. The aims of this study are: 1) to describe the patterns of cannabis consumption (problematic and non-problematic) in Spanish youth, and 2) to explore whether problematic cannabis consumption is related to perceived risk, environmental factors and individual sociodemographic characteristics. A cross-sectional design based on data from the 2015/16 Spanish Household Survey on Alcohol and Drugs (EDADES) was performed. Individuals between 15 and 35 years old having used cannabis during the last year with a complete Cannabis Abuse Screening Test (CAST) were included (N = 1,674). Problematic consumption (CAST >= 7) was considered as dependent variable. Perceived risk, environmental factors (availability of the substance and exposure to consumption situations) and sociodemographic factors were taken as independent variables. Descriptive analyses of consumption patterns were performed and univariable and multivariable Poisson regression models were done. All analyses were stratified by gender. Problematic cannabis consumption was more frequent among men (38.9 %) than among women (23.2 %). While among men, problematic use was related to environmental factors and educational level, among women it was associated with perceived risk and unemployment. Problematic cannabis consumption among Spanish youth is associated with different types of gender-related factors. Due to its representativeness at the population level and the validity of the measures, these results might have important implications on the development of prevention strategies targeted at problematic cannabis consumption.

La relación entre el consumo problemático de cannabis, el riesgo percibido y los factores socioambientales y sociodemográficos no es clara actualmente. Los objetivos del estudio son: describir los patrones de consumo de cannabis (problemático y no problemático) en la población joven de España y explorar como el consumo problemático se relaciona con el riesgo percibido, y los factores ambientales y sociodemográficos. Se llevó a cabo un diseño transversal basado en datos de la edición de 2015/2016 de la Encuesta Domiciliaria sobre Alcohol y Drogas (EDADES). La encuesta incluyó participantes de entre 15 y 35 años que habían consumido cannabis en al menos una ocasión durante el último año y que completaron el Cannabis Abuse Screening Test (CAST) (N = 1674). Se consideró el consumo problemático (CAST >= 7) como variable dependiente. Como variables independientes se consideraron el riesgo percibido, los factores ambientales (disponibilidad de la sustancia y exposición a situaciones de consumo) y los factores sociodemográficos. Se llevaron a cabo análisis descriptivos de los patrones de consumo y se realizaron modelos univariables y multivariables de Poisson. Todos los análisis se estratificaron por género. El consumo problemático fue más frecuente en hombres (38,9 %) que en mujeres (23,2 %). Mientras en hombres el consumo problemático se relacionó con factores ambientales y nivel educativo, en mujeres se asoció con riesgo percibido y desempleo. Dada la representatividad de los datos y la validez de las medidas, estos resultados podrían tener importantes implicaciones para el desarrollo de medidas preventivas contra el consumo problemático de cannabis.

Coronavirus disease 2019 (COVID-19) in autoimmune and inflammatory conditions: clinical characteristics of poor outcomes.

OBJECTIVE: To describe clinical characteristics of patients with rheumatic and musculoskeletal diseases (RMDs) and immunosuppressive therapies with Coronavirus disease 2019 (COVID-19) at an academic rheumatology center in Madrid and to identify baseline variables associated with a severe infection requiring hospitalization. METHODS: We identified SARS-CoV-2 positive cases by polymerase chain reaction performed at our center within an updated RMDs database in our clinic. Additional RMDs patients were identified when they contacted the clinic because of a positive infection. Data extraction included diagnosis, demographics, immunosuppressive treatment, comorbidities, and laboratory tests. Comparisons between patients with or without hospitalization were performed. Multivariate logistic regression was used to analyze associations between baseline variables and need for hospitalization. RESULTS: A total of 62 patients with COVID-19 and underlying RMDs were identified by April 24, 2020. Median age was 60.9 years, and 42% men. Forty-two patients required hospitalization; these were more frequently men, older and with comorbidities. There were no statistically significant between-group differences for rheumatologic diagnosis and for baseline use of immunosuppressive therapy except for glucocorticoids that were more frequent in hospitalized patients. Total deaths were 10 (16%) patients. In multivariate analysis, male sex (odds ratio [OR], 8.63; p = 0.018), previous lung disease (OR, 27.47; p = 0.042), and glucocorticoids use (> 5 mg/day) (OR, 9.95; p = 0.019) were significantly associated to hospitalization. CONCLUSION: Neither specific RMD diagnoses or exposures to DMARDs were associated with increased odds of hospitalization. Being male, previous lung disease and exposure to glucocorticoids were associated with higher odds of hospitalization in RMDs patients.

The Textures of Heroin: User Perspectives on "Black Tar" and Powder Heroin in Two U.S. Cities.

Since the 1990s, U.S. heroin consumers have been divided from the full range of available products: east of the Mississippi River, Colombian-sourced powder heroin (PH) dominates the market while, to the west, Mexican-sourced "black tar" (BTH) is the main heroin available. By conducting qualitative research in two exemplar cities, Philadelphia (PH) and San Francisco (BTH), we compare users' experiences of heroin source-types, markets, health consequences, and consumption preferences. The strict division of heroin markets may be changing with novel forms of powder heroin appearing in San Francisco. Our researchers and interviewees perceived vein loss stemming from the injection of heroin alone to be a particular problem of BTH while, among the Philadelphia sample, those who avoided the temptations of nearby cocaine sales displayed healthier injecting sites and reported few vein problems. Abscesses were common across both sites, the Philadelphia sample generally blaming missing a vein when injecting cocaine and the San Francisco group finding several explanations, including the properties of BTH. Consumption preferences revealed a "connoisseurship of potency," with knowledge amassed and deployed to obtain the strongest heroin available. We discuss the reasons that their tastes take this narrow form and its relationship to the structural constraints of the heroin market.

Heroin-related overdose: The unexplored influences of markets, marketing and source-types in the United States.

Heroin overdose, more accurately termed 'heroin-related overdose' due to the frequent involvement of other drugs, is the leading cause of mortality among regular heroin users. (Degenhardt et al., 2010) Heroin injectors are at greater risk of hospital admission for heroin-related overdose (HOD) in the eastern United States where Colombian-sourced powder heroin is sold than in the western US where black 'tar' heroin predominates. (Unick et al., 2014) This paper examines under-researched influences on HOD, both fatal and non-fatal, using data from a qualitative study of injecting drug users of black tar heroin in San Francisco and powder heroin in Philadelphia Data were collected through in-depth, semi-structured interviews carried out in 2012 that were conducted against a background of longer-term participant-observation, ethnographic studies of drug users and dealers in Philadelphia (2007-12) and of users in San Francisco (1994-2007, 2012). Our findings suggest three types of previously unconsidered influences on overdose risk that arise both from structural socio-economic factors and from the physical properties of the heroin source-types: 1) retail market structure including information flow between users; 2) marketing techniques such as branding, free samples and pricing and 3) differences in the physical characteristics of the two major heroin source forms and how they affect injecting techniques and vascular health. Although chosen for their contrasting source-forms, we found that the two cities have contrasting dominant models of drug retailing: San Francisco respondents tended to buy through private dealers and Philadelphia respondents frequented an open-air street market where heroin is branded and free samples are distributed, although each city included both types of drug sales. These market structures and marketing techniques shape the availability of information regarding heroin potency and its dissemination among users who tend to seek out the strongest heroin available on a given day. The physical characteristics of these two source-types, the way they are prepared for injecting and their effects on vein health also differ markedly. The purpose of this paper is to examine some of the unexplored factors that may lead to heroin-related overdose in the United States and to generate hypotheses for further study.

Membrane-derived phospholipids control synaptic neurotransmission and plasticity.

Synaptic communication is a dynamic process that is key to the regulation of neuronal excitability and information processing in the brain. To date, however, the molecular signals controlling synaptic dynamics have been poorly understood. Membrane-derived bioactive phospholipids are potential candidates to control short-term tuning of synaptic signaling, a plastic event essential for information processing at both the cellular and neuronal network levels in the brain. Here, we showed that phospholipids affect excitatory and inhibitory neurotransmission by different degrees, loci, and mechanisms of action. Signaling triggered by lysophosphatidic acid (LPA) evoked rapid and reversible depression of excitatory and inhibitory postsynaptic currents. At excitatory synapses, LPA-induced depression depended on LPA1/Gαi/o-protein/phospholipase C/myosin light chain kinase cascade at the presynaptic site. LPA increased myosin light chain phosphorylation, which is known to trigger actomyosin contraction, and reduced the number of synaptic vesicles docked to active zones in excitatory boutons. At inhibitory synapses, postsynaptic LPA signaling led to dephosphorylation, and internalization of the GABAAγ2 subunit through the LPA1/Gα12/13-protein/RhoA/Rho kinase/calcineurin pathway. However, LPA-induced depression of GABAergic transmission was correlated with an endocytosis-independent reduction of GABAA receptors, possibly by GABAAγ2 dephosphorylation and subsequent increased lateral diffusion. Furthermore, endogenous LPA signaling, mainly via LPA1, mediated activity-dependent inhibitory depression in a model of experimental synaptic plasticity. Finally, LPA signaling, most likely restraining the excitatory drive incoming to motoneurons, regulated performance of motor output commands, a basic brain processing task. We propose that lysophospholipids serve as potential local messengers that tune synaptic strength to precedent activity of the neuron.

Cannabinoid agonists rearrange synaptic vesicles at excitatory synapses and depress motoneuron activity in vivo.

Impairment of motor skills is one of the most common acute adverse effects of cannabis. Related studies have focused mainly on psychomotor alterations, and little is known about the direct impact of cannabinoids (CBs) on motoneuron physiology. As key modulators of synaptic function, CBs regulate multiple neuronal functions and behaviors. Presynaptic CB1 mediates synaptic strength depression by inhibiting neurotransmitter release, via a poorly understood mechanism. The present study examined the effect of CB agonists on excitatory synaptic inputs incoming to hypoglossal motoneurons (HMNs) in vitro and in vivo. The endocannabinoid anandamide (AEA) and the synthetic CB agonist WIN 55,212-2 rapidly and reversibly induced short-term depression (STD) of glutamatergic synapses on motoneurons by a presynaptic mechanism. Presynaptic effects were fully reversed by the CB1-selective antagonist AM281. Electrophysiological and electron microscopy analysis showed that WIN 55,212-2 reduced the number of synaptic vesicles (SVs) docked to active zones in excitatory boutons. Given that AM281 fully abolished depolarization-induced depression of excitation, motoneurons can be feasible sources of CBs, which in turn act as retrograde messengers regulating synaptic function. Finally, microiontophoretic application of the CB agonist O-2545 reversibly depressed, presumably via CB1, glutamatergic inspiratory-related activity of HMNs in vivo. Therefore, evidence support that CBs, via presynaptic CB1, induce excitatory STD by reducing the readily releasable pool of SVs at excitatory synapses, then attenuating motoneuron activity. These outcomes contribute a possible mechanistic basis for cannabis-associated motor performance disturbances such as ataxia, dysarthria and dyscoordination.