Parkinson's disease and dementia with Lewy bodies are associated with abnormal neuronal aggregation of ␣-synuclein. However, the mechanisms of aggregation and their relationship to disease are poorly understood. We developed an in vivo multiphoton imaging paradigm to study ␣-synuclein aggregation in mouse cortex with subcellular resolution. We used a green fluorescent protein-tagged human ␣-synuclein mouse line that has moderate overexpression levels mimicking human disease. Fluorescence recovery after photobleaching (FRAP) of labeled protein demonstrated that somatic ␣-synuclein existed primarily in an unbound, soluble pool. In contrast, ␣-synuclein in presynaptic terminals was in at least three different pools: (1) as unbound, soluble protein; (2) bound to presynaptic vesicles; and (3) as microaggregates. Serial imaging of microaggregates over 1 week demonstrated a heterogeneous population with differing ␣-synuclein exchange rates. The microaggregate species were resistant to proteinase K, phosphorylated at serine-129, oxidized, and associated with a decrease in the presynaptic vesicle protein synapsin and glutamate immunogold labeling. Multiphoton FRAP provided the specific binding constants for ␣-synuclein's binding to synaptic vesicles and its effective diffusion coefficient in the soma and axon, setting the stage for future studies targeting synuclein modifications and their effects. Our in vivo results suggest that, under moderate overexpression conditions, ␣-synuclein aggregates are selectively found in presynaptic terminals.

Morphine infusions at steady-state did not mirror clearance maturation in children nursed in our hospital. We suggest that initial infusion rates in children are started at 10 μg · kg(-1) per h in neonates, 15 μg · kg(-1) per h in toddlers and 25 μg · kg(-1) per h in children above the age of 5 years. The large variability associated with infusion rates means that subsequent infusion rates will depend on feedback from pain scores, adjuvant medications and adverse effects.

In the last few years there have been several 'drug panics' over new synthetic drugs such as mephedrone and the substituted cathinones. These new designer stimulants have become increasingly popular as substitutes for 3,4-methylenedioxy-methamphetamine and other 'classic' stimulants. This paper discusses these compounds in the context of the substitutional effects caused by drug prohibition. As drugs are banned, new drugs crop up to replace them. This results in the diversification and proliferation of new drug markets, drugs, drug distributors, and drug consumers. Processes of illegalization are shown to have directly resulted in an explosion of new synthetic stimulant drugs, and irrevocably altered the conventional geographies of drug production, distribution, and consumption. The continuing prohibition of these new substances along with the ones they originally substituted for has had the effect of creating ever-evolving stimulant drug markets, which foster more dangerous conditions for users than the original drug markets themselves.EXTRACTO Au cours des dernières années il y a eu plusieurs 'crises' concernant les nouvelles drogues synthétiques, telles l'éphédrine et les cathinones de synthèse. Ces nouveaux stimulants de synthèse sont devenus de plus en plus populaires comme substituts de la MDMA et des autres stimulants 'classiques'. Cet article discute de ces composés dans le contexte des effets de substitution qui s'expliquent par l'interdiction des drogues. Au fur et à mesure que certaines drogues sont interdites, de nouvelles drogues apparaissent et les remplacent. Il s'ensuit la diversification et la prolifération de nouvelles drogues, de nouveaux marchés, de nouveaux distributeurs et de nouveaux usagers. On montre que les processus d'interdiction entraînent directement une explosion des stimulants synthétiques et modifient irrévocablement les géographies conventionnelles de la production, de la distribution et de la consommation de drogues. L'interdiction continue de ces nouveaux stupéfiants conjointement avec ceux auxquels ils se sont substitués dans un premier temps, a eu l'effet de créer des marchés de stimulants en pleine évolution qui encouragent des conditions plus dangereuses pour les usagers que ne le font les marchés de drogues initiaux.摘要 过去数年来，对诸如中枢神经兴奋剂4-甲基甲基卡西酮(mephedrone)、以及 取代卡西酮(substitutedcathinones)等新的合成毒品，数度产生'毒品恐慌'。这些新的 设计兴奋剂，已逐渐流行成为摇头丸(MDMA)及其他'经典'兴奋剂的替代品。本文 在因禁用毒品而导致的取代作用之脉络下，探讨这些化合物。当毒品被禁止时，新的 毒品出现并取而代之，结果导致新兴毒品市场、毒品、毒品散布者与毒品消费者的分 化与增生。将毒品非法化的过程，证明已直接导致新的合成兴奋剂毒品的爆炸，以及 对药物生产、传播和消费的传统地理造成无法挽回的改变。这些新物品、及其原本取 代之物的持续禁止，已影响了创造不断演化的兴奋剂毒品市场，并且相较于原本的毒 品市场本身而言，导致对使用者更加危险的处境。 RESUME En los últimos años han surgido varios 'pánicos' por las drogas debido a las nuevas drogas sintéticas, tales como mefedrona y catinona de sustitución. Estos nuevos estimulantes de diseño se utilizan cada vez más como sustitutos de MDMA y otros estimulantes 'clásicos'. En este artículo analizamos estos componentes en el contexto de los efectos de sustitución causados por la prohibición de drogas. Cuando se prohíb...

Background In COVID-19 patients, lung ultrasound is superior to chest radiograph and has good agreement with computerized tomography to diagnose lung pathologies. Most lung ultrasound protocols published to date are complex and time-consuming. We describe a new illustrative Point-of-care ultrasound Lung Injury Score (PLIS) to help guide the care of patients with COVID-19 and assess if the PLIS would be able to predict COVID-19 patients’ clinical course. Methods This retrospective study describing the novel PLIS was conducted in a large tertiary-level hospital. COVID-19 patients were included if they required any form of respiratory support and had at least one PLIS study during hospitalization. Data collected included PLIS on admission, demographics, Sequential Organ Failure Assessment (SOFA) scores, and patient outcomes. The primary outcome was the need for intensive care unit (ICU) admission. Results A total of 109 patients and 293 PLIS studies were included in our analysis. The mean age was 60.9, and overall mortality was 18.3%. Median PLIS score was 5.0 (3.0–6.0) vs. 2.0 (1.0–3.0) in ICU and non-ICU patients respectively (p<0.001). Total PLIS scores were directly associated with SOFA scores (inter-class correlation 0.63, p<0.001), and multivariate analysis showed that every increase in one PLIS point was associated with a higher risk for ICU admission (O.R 2.09, 95% C.I 1.59–2.75) and in-hospital mortality (O.R 1.54, 95% C.I 1.10–2.16). Conclusions The PLIS for COVID-19 patients is simple and associated with SOFA score, ICU admission, and in-hospital mortality. Further studies are needed to demonstrate whether the PLIS can improve outcomes and become an integral part of the management of COVID-19 patients.