Role of endocannabinoids in regulating drug dependence

This review will discuss the latest knowledge of how the endocannabinoid system might be involved in treating addiction to the most common illicit drugs. Experimental models are providing increasing evidence for the pharmacological management of endocannabinoid signaling not only to block the direct reinforcing effects of cannabis, opioids, nicotine and ethanol, but also for preventing relapse to the various drugs of abuse, including opioids, cocaine, nicotine, alcohol and metamphetamine. Preclinical and clinical studies suggest that the endocannabinoid system can be manipulated by the CBI receptor antagonist SR141716A, that might constitute a new generation of compounds for treating addiction across different classes of abused drugs

A Practical Approach to Fatigue Management in Colorectal Cancer.

Cancer-related fatigue is serious and complex, as well as one of the most common symptoms experienced by patients with colorectal cancer, with the potential to compromise quality of life, activities of daily living, and ultimately survival. There is a lack of consensus about the definition of cancer-related fatigue; however, definitions have been put forward by the European Association for Palliative Care (EAPC) and the National Comprehensive Cancer Network (NCCN). Numerous cancer- and treatment-related factors can contribute to fatigue, including disease progression, comorbidities, medical complications such as anemia, side effects of other medications, and a number of physical and psychologic factors. This underlines the importance of tackling factors that may contribute to fatigue before reducing the dose of treatment. NCCN guidelines and the EAPC have proposed approaches to managing fatigue in cancer patients; however, relatively few therapeutic agents have been demonstrated to reduce fatigue in randomized controlled trials. It is recognized that physical activity produces many beneficial physiologic modifications to markers of physical performance that can help to counteract various causes of fatigue. In appropriately managed and monitored patients with colorectal cancer, emerging evidence indicates that exercise programs may have a favorable influence on cancer-related fatigue, quality of life, and clinical outcomes, and therefore may help patients tolerate chemotherapy. This review assesses fatigue in patients with colorectal cancer and proposes updates to a treatment algorithm that may help clinicians manage this common problem

Short-term effects of focal muscle vibration on motor recovery after acute stroke: a pilot randomized sham-controlled study

Repetitive focal muscle vibration (rMV) is known to promote neural plasticity and long-lasting motor recovery in chronic stroke patients. Those structural and functional changes within the motor network underlying motor recovery occur in the very first hours after stroke. Nonetheless, to our knowledge, no rMV-based studies have been carried out in acute stroke patients so far, and the clinical benefit of rMV in this phase of stroke is yet to be determined. The aim of this randomized double-blind sham-controlled study is to investigate the short-term effect of rMV on motor recovery in acute stroke patients. Out of 22 acute stroke patients, 10 were treated with the rMV (vibration group–VG), while 12 underwent the sham treatment (control group–CG). Both treatments were carried out for 3 consecutive days, starting within 72 h of stroke onset; each daily session consisted of three 10-min treatments (for each treated limb), interspersed with a 1-min interval. rMV was delivered using a specific device (Cro®System, NEMOCO srl, Italy). The transducer was applied perpendicular to the target muscle's belly, near its distal tendon insertion, generating a 0.2–0.5 mm peak-to-peak sinusoidal displacement at a frequency of 100 Hz. All participants also underwent a daily standard rehabilitation program. The study protocol underwent local ethics committee approval (ClinicalTrial.gov NCT03697525) and written informed consent was obtained from all of the participants. With regard to the different pre-treatment clinical statuses, VG patients showed significant clinical improvement with respect to CG-treated patients among the NIHSS (p < 0.001), Fugl-Meyer (p = 0.001), and Motricity Index (p < 0.001) scores. In addition, when the upper and lower limb scales scores were compared between the two groups, VG patients were found to have a better clinical improvement at all the clinical end points. This study provides the first evidence that rMV is able to improve the motor outcome in a cohort of acute stroke patients, regardless of the pretreatment clinical status. Being a safe and well-tolerated intervention, which is easy to perform at the bedside, rMV may represent a valid complementary non-pharmacological therapy to promote motor recovery in acute stroke patients

Eddy covariance methane measurements at a Ponderosa pine plantation in California

Long term methane flux measurements have been mostly performed with plant or soil enclosure techniques on specific components of an ecosystem. New fast response methane analyzers make it possible to use the eddy covariance (EC) technique instead. The EC technique is advantageous because it allows continuous flux measurements integrating over a larger and more representative area including the complete ecosystem, and allows fluxes to be observed as environmental conditions change naturally without disturbance. We deployed the closed-path Fast Methane analyzer (FMA) from Los Gatos Research Ltd and demonstrate its performance for EC measurements at a Ponderosa pine plantation at the Blodgett Forest site in central California. The fluctuations of the CH<sub>4</sub> concentration measured at 10 Hz appear to be small and their standard deviation is comparable to the magnitude of the signal noise (±5 ppbv). Consequently, the power spectra typically have a white noise signature at the high frequency end (a slope of +1). Nevertheless, in the frequency range important for turbulent exchange, the cospectra of CH<sub>4</sub> compare very well with all other scalar cospectra confirming the quality of the FMA measurements are good for the EC technique. We furthermore evaluate the complications of combined open and closed-path measurements when applying the Webb-Pearman-Leuning (WPL) corrections (Webb et al., 1980) and the consequences of a phase lag between the water vapor and methane signal inside the closed path system. The results of diurnal variations of CH<sub>4</sub> concentrations and fluxes are summarized and compared to the monthly results of process-based model calculations

Effect of UV radiation and temperature on the emission of methane from plant biomass and structural components

The recently reported finding that plant matter and living plants produce significant amounts of the important greenhouse gas methane under aerobic conditions has led to an intense scientific and public controversy. Whereas some studies question the up-scaling method that was used to estimate the global source strength, others have suggested that experimental artifacts could have caused the reported signals, and two studies, one based on isotope labeling, have recently reported the absence of CH<sub>4</sub> emissions from plants. Here we show – using several independent experimental analysis techniques – that dry and detached fresh plant matter, as well as several structural plant components, emit significant amounts of methane upon irradiation with UV light and/or heating. Emissions from UV irradiation are almost instantaneous, indicating a direct photochemical process. Long-time irradiation experiments demonstrate that the size of the CH<sub>4</sub> producing reservoir is large, exceeding potential interferences from degassing or desorption processes by several orders of magnitude. A dry leaf of a pure <sup>13</sup>C plant produces <sup>13</sup>CH<sub>4</sub> at a similar rate as dry leaves of non-labeled plants produce non-labeled methane

Methane flux, vertical gradient and mixing ratio measurements in a tropical forest

Measurements of CH<sub>4</sub> mixing ratio, vertical gradients and turbulent fluxes were carried out in a tropical forest (Reserva Biológica Cuieiras), about 60 km north of Manaus, Brazil. The methane mixing ratio and flux measurements were performed at a height of 53 m (canopy height 35 m). In addition, vertical CH<sub>4</sub> gradients were measured within the canopy using custom made air samplers at levels of 2, 16 and 36 m above ground. The methane gradients within the canopy reveal that there is a continuous methane source at the surface. No clear evidence for aerobic methane emission from the canopy was found. The methane fluxes above the canopy are small but consistently upwards with a maximum early in the morning. The measured fluxes are in agreement with the observed CH<sub>4</sub> gradient in the canopy. In the morning hours, a strong canopy venting peak is observed for both CH<sub>4</sub> and CO<sub>2</sub>, but for CO<sub>2</sub> this peak is then superimposed by photosynthetic uptake, whereas the peak lasts longer for CH<sub>4</sub>. Monthly averaged diurnal cycles of the CH<sub>4</sub> mixing ratio show a decrease during daytime and increase during nighttime. The magnitude of the difference in CH<sub>4</sub> mixing ratio between day and night gradually increases throughout the wet season. The fluxes required to explain the nighttime increase are in agreement with the nighttime fluxes measured above the canopy, which implies that the CH<sub>4</sub> increase in the nighttime boundary layer originates from local sources

Process development and validation of expanded regulatory T cells for prospective applications: an example of manufacturing a personalized advanced therapy medicinal product

Background: A growing number of clinical trials have shown that regulatory T (Treg) cell transfer may have a favorable effect on the maintenance of self-tolerance and immune homeostasis in different conditions such as graft-versus-host disease (GvHD), solid organ transplantation, type 1 diabetes, and others. In this context, the availability of a robust manufacturing protocol that is able to produce a sufficient number of functional Treg cells represents a fundamental prerequisite for the success of a cell therapy clinical protocol. However, extended workflow guidelines for nonprofit manufacturers are currently lacking. Despite the fact that different successful manufacturing procedures and cell products with excellent safety profiles have been reported from early clinical trials, the selection and expansion protocols for Treg cells vary a lot. The objective of this study was to validate a Good Manufacturing Practice (GMP)-compliant protocol for the production of Treg cells that approaches the whole process with a risk-management methodology, from process design to completion of final product development. High emphasis was given to the description of the quality control (QC) methodologies used for the in-process and release tests (sterility, endotoxin test, mycoplasma, and immunophenotype). Results: The GMP-compliant protocol defined in this work allows at least 4.11 7 109 Treg cells to be obtained with an average purity of 95.75 \ub1 4.38% and can be used in different clinical settings to exploit Treg cell immunomodulatory function. Conclusions: These results could be of great use for facilities implementing GMP-compliant cell therapy protocols of these cells for different conditions aimed at restoring the Treg cell number and function, which may slow the progression of certain diseases

SARS-COV-2 comorbidity network and outcome in hospitalized patients in Crema, Italy

We report onset, course, correlations with comorbidities, and diagnostic accuracy of nasopharyngeal swab in 539 individuals suspected to carry SARS-COV-2 admitted to the hospital of Crema, Italy. All individuals underwent clinical and laboratory exams, SARS-COV-2 reverse transcriptase-polymerase chain reaction on nasopharyngeal swab, and chest X-ray and/or computed tomography (CT). Data on onset, course, comorbidities, number of drugs including angiotensin converting enzyme (ACE) inhibitors and angiotensin-II-receptor antagonists (sartans), follow-up swab, pharmacological treatments, non-invasive respiratory support, ICU admission, and deaths were recorded. Among 411 SARS-COV-2 patients (67.7% males) median age was 70.8 years (range 5-99). Chest CT was performed in 317 (77.2%) and showed interstitial pneumonia in 304 (96%). Fatality rate was 17.5% (74% males), with 6.6% in 60-69 years old, 21.1% in 70-79 years old, 38.8% in 80-89 years old, and 83.3% above 90 years. No death occurred below 60 years. Non-invasive respiratory support rate was 27.2% and ICU admission 6.8%. Charlson comorbidity index and high Creactive protein at admission were significantly associated with death. Use of ACE inhibitors or sartans was not associated with outcomes. Among 128 swab negative patients at admission (63.3% males) median age was 67.7 years (range 1-98). Chest CT was performed in 87 (68%) and showed interstitial pneumonia in 76 (87.3%). Follow-up swab turned positive in 13 of 32 patients. Using chest CT at admission as gold standard on the entire study population of 539 patients, nasopharyngeal swab had 80% accuracy. Comorbidity network analysis revealed a more homogenous distribution 60-40 aged SARS-COV-2 patients across diseases and a crucial different interplay of diseases in the networks of deceased and survived patients. SARS-CoV-2 caused high mortality among patients older than 60 years and correlated with pre-existing multiorgan impairment. Copyright