Safety and tolerability of natural and synthetic cannabinoids in adults aged over 50 years:A systematic review and meta-analysis

BackgroundCannabinoid-based medicines (CBMs) are being used widely in the elderly. However, their safety and tolerability in older adults remains unclear. We aimed to conduct a systematic review and meta-analysis of safety and tolerability of CBMs in adults of age ≥50 years.Methods and findingsA systematic search was performed using MEDLINE, PubMed, EMBASE, CINAHL PsychInfo, Cochrane Library, and ClinicalTrials.gov (1 January 1990 to 3 October 2020). Randomised clinical trials (RCTs) of CBMs in those with mean age of ≥50 years for all indications, evaluating the safety/tolerability of CBMs where adverse events have been quantified, were included. Study quality was assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) criteria and Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. Two reviewers conducted all review stages independently. Where possible, data were pooled using random-effects meta-analysis. Effect sizes were calculated as incident rate ratio (IRR) for outcome data such as adverse events (AEs), serious AEs (SAEs), and death and risk ratio (RR) for withdrawal from study and reported separately for studies using tetrahydrocannabinol (THC), THC:cannabidiol (CBD) combination, and CBD. A total of 46 RCTs were identified as suitable for inclusion of which 31 (67%) were conducted in the United Kingdom and Europe. There were 6,216 patients (mean age 58.6 ± 7.5 years; 51% male) included in the analysis, with 3,469 receiving CBMs. Compared with controls, delta-9-tetrahydrocannabinol (THC)-containing CBMs significantly increased the incidence of all-cause and treatment-related AEs: THC alone (IRR: 1.42 [95% CI, 1.12 to 1.78]) and (IRR: 1.60 [95% CI, 1.26 to 2.04]); THC:CBD combination (IRR: 1.58 [95% CI,1.26 to 1.98]) and (IRR: 1.70 [95% CI,1.24 to 2.33]), respectively. IRRs of SAEs and deaths were not significantly greater under CBMs containing THC with or without CBD. THC:CBD combination (RR: 1.40 [95% CI, 1.08 to 1.80]) but not THC alone (RR: 1.18 [95% CI, 0.89 to 1.57]) significantly increased risk of AE-related withdrawals. CBD alone did not increase the incidence of all-cause AEs (IRR: 1.02 [95% CI, 0.90 to 1.16]) or other outcomes as per qualitative synthesis. AE-related withdrawals were significantly associated with THC dose in THC only [QM (df = 1) = 4.696, p = 0.03] and THC:CBD combination treatment ([QM (df = 1) = 4.554, p = 0.033]. THC-containing CBMs significantly increased incidence of dry mouth, dizziness/light-headedness, and somnolence/drowsiness. Study limitations include inability to fully exclude data from those ConclusionsThis pooled analysis, using data from RCTs with mean participant age ≥50 years, suggests that although THC-containing CBMs are associated with side effects, CBMs in general are safe and acceptable in older adults. However, THC:CBD combinations may be less acceptable in the dose ranges used and their tolerability may be different in adults over 65 or 75 years of age

Anti-inflammatory activity of hydroalcoholic extract of mimosa pudica whole plant in rats

Background: Mimosa pudica is a traditionally used folk medicine to treat various disorders like infections, anxiety, depression, bleeding disorders, convulsions, rheumatoid arthritis, muscular pain, asthma, snake bite etc. We evaluated the anti-inflammatory activity of hydroalcoholic extract of Mimosa pudica whole plant (HAEMPWP) in rats.Methods: HAEMPWP was prepared using Soxhlets apparatus. Acute toxicity tests were done with HAEMPWP given orally to albino rats in increasing doses up to 3200 mg/ kg body weight. The anti-inflammatory action was evaluated by Carrageenan induced paw edema method. Thirty albino rats were grouped into five groups and each contained six rats. Group I (control group) received distilled water orally. Group II (standard) received Aspirin orally dissolved in distilled water. Groups III, IV and V received HAEMPWP in doses of 200 mg/kg, 400 mg/kg and 800mg/kg orally dissolved in distilled water. Data analysis was done by one way ANOVA and unpaired t test using SPSS 16 for windows.Results: HAEMPWP showed a significant anti-inflammatory activity as compared to control. There was no statistically significant dose dependent increase in the anti-inflammatory activity.Conclusions: HAEMPWP possesses significant anti-inflammatory activity and could be an effective treatment option for various inflammatory conditions

EVROPSKA EKONOMSKA ZAJEDNICA I IZVOZNE MOGUĆNOSTI MESNE INDUSTRIJE JUGOSLAVIJE

Rad obrađuje specifičnosti međunarodnih regionalnih ekonomskih grupacija i njihovih tržišta, konkretno se zadržavajući na tržištu EEZ i mogućnostima eksporta mesa iz Jugoslavije u zemlje Zajednice. Analizom čimbenika koji utječu na tokove razmjene kao i analizom potrošnje i proizvodnje mesa u EEZ dolazi se do zaključaka da se plasmanske mogućnosti Jugoslavije smanjuju i da bi se stočarstvo i mesna industrija trebala okrenuti prema širenju tržišta, osobito prema tržištima zemalja u razvoju. Dakako, to ne znači zapuštanje tako interesantnog tržišta kao što je EEZ, ali bi se u strategiji nastupa prema tom tržištu valjalo više orijentirati na primjenu modernih tržišnih postulata kako bi plasman na to tržište bio djelotvorniji. To će reći da se zalažemo za integralnu primjenu marketinških funkcija u poslovnoj politici organizacija udruženog rada - proizvođača mesa i prerađevina od mesa namijenjenih svjetskom tržištu

Metabolic effects of breaking prolonged sitting with standing or light walking in older South Asians and White Europeans: a randomized acute study

Background: Prolonged sitting is common in older adults and associated with insulin resistance and poor cardiometabolic health. We investigate whether breaking prolonged sitting with regular short bouts of standing or light walking improves postprandial metabolism in older white European and South Asian adults and whether effects are modified by ethnic group. Methods: Thirty South Asian (15 women) and 30 white European (14 women) older adults (65-79 years) undertook three experimental conditions in random order. 1) Prolonged sitting: continuous sitting during a 7.5 h observation period consuming two standardised mixed meals. 2) Standing breaks: sitting interrupted with 5 mins of standing every 30 mins (accumulating 60 mins of standing over the observation period). 3) Walking Breaks: sitting interrupted with 5 mins of self-paced light walking every 30 mins (accumulating 60 mins of walking). Blood samples (glucose, insulin, triglycerides) and blood pressure were sampled regularly throughout each condition. Results: Compared with prolonged sitting, walking breaks lowered postprandial insulin by 16.3 mU/l, (95% CI 19.7, 22.0) with greater reductions (p = 0.029) seen in South Asians (22.4 mU/l; 12.4, 32.4) than White Europeans (10.3 mU/l; 5.9, 14.7). Glucose (0.3 mmol/l; 0.1, 0.5) and blood pressure (4 mmHg; 2, 6), but not triglycerides, were lower with walking breaks, with no ethnic differences. Standing breaks did not improve any outcome. Conclusions: Breaking prolonged sitting with short bouts of light walking, but not standing, resulted in clinically meaningful improvements in markers of metabolic health in older adults, with South Asians gaining a greater reduction in postprandial insulin

Genetic predisposition to increased blood cholesterol and triglyceride lipid levels and risk of Alzheimer disease: a Mendelian randomization analysis.

BACKGROUND: Although altered lipid metabolism has been extensively implicated in the pathogenesis of Alzheimer disease (AD) through cell biological, epidemiological, and genetic studies, the molecular mechanisms linking cholesterol and AD pathology are still not well understood and contradictory results have been reported. We have used a Mendelian randomization approach to dissect the causal nature of the association between circulating lipid levels and late onset AD (LOAD) and test the hypothesis that genetically raised lipid levels increase the risk of LOAD. METHODS AND FINDINGS: We included 3,914 patients with LOAD, 1,675 older individuals without LOAD, and 4,989 individuals from the general population from six genome wide studies drawn from a white population (total n=10,578). We constructed weighted genotype risk scores (GRSs) for four blood lipid phenotypes (high-density lipoprotein cholesterol [HDL-c], low-density lipoprotein cholesterol [LDL-c], triglycerides, and total cholesterol) using well-established SNPs in 157 loci for blood lipids reported by Willer and colleagues (2013). Both full GRSs using all SNPs associated with each trait at p<5×10-8 and trait specific scores using SNPs associated exclusively with each trait at p<5 × 10-8 were developed. We used logistic regression to investigate whether the GRSs were associated with LOAD in each study and results were combined together by meta-analysis. We found no association between any of the full GRSs and LOAD (meta-analysis results: odds ratio [OR]=1.005, 95% CI 0.82-1.24, p = 0.962 per 1 unit increase in HDL-c; OR=0.901, 95% CI 0.65-1.25, p=0.530 per 1 unit increase in LDL-c; OR=1.104, 95% CI 0.89-1.37, p=0.362 per 1 unit increase in triglycerides; and OR=0.954, 95% CI 0.76-1.21, p=0.688 per 1 unit increase in total cholesterol). Results for the trait specific scores were similar; however, the trait specific scores explained much smaller phenotypic variance. CONCLUSIONS: Genetic predisposition to increased blood cholesterol and triglyceride lipid levels is not associated with elevated LOAD risk. The observed epidemiological associations between abnormal lipid levels and LOAD risk could therefore be attributed to the result of biological pleiotropy or could be secondary to LOAD. Limitations of this study include the small proportion of lipid variance explained by the GRS, biases in case-control ascertainment, and the limitations implicit to Mendelian randomization studies. Future studies should focus on larger LOAD datasets with longitudinal sampled peripheral lipid measures and other markers of lipid metabolism, which have been shown to be altered in LOAD. Please see later in the article for the Editors' Summary

Microglial activation, tau and amyloid deposition in TREM2 p.R47H carriers and mild cognitive impairment patients: a multi-modal/multi-tracer PET/MRI imaging study with influenza vaccine immune challenge

BACKGROUND: Microglia are increasingly understood to play an important role in the pathogenesis of Alzheimer's disease. The rs75932628 (p.R47H) TREM2 variant is a well-established risk factor for Alzheimer's disease. TREM2 is a microglial cell surface receptor. In this multi-modal/multi-tracer PET/MRI study we investigated the effect of TREM2 p.R47H carrier status on microglial activation, tau and amyloid deposition, brain structure and cognitive profile. METHODS: We compared TREM2 p.R47H carriers (n = 8; median age = 62.3) and participants with mild cognitive impairment (n = 8; median age = 70.7). Participants underwent two [18F]DPA-714 PET/MRI scans to assess TSPO signal, indicative of microglial activation, before and after receiving the seasonal influenza vaccination, which was used as an immune stimulant. Participants also underwent [18F]florbetapir and [18F]AV1451 PET scans to assess amyloid and tau burden, respectively. Regional tau and TSPO signal were calculated for regions of interest linked to Braak stage. An additional comparison imaging healthy control group (n = 8; median age = 45.5) had a single [18F]DPA-714 PET/MRI. An expanded group of participants underwent neuropsychological testing, to determine if TREM2 status influenced clinical phenotype. RESULTS: Compared to participants with mild cognitive impairment, TREM2 carriers had lower TSPO signal in Braak II (P = 0.04) and Braak III (P = 0.046) regions, despite having a similar burden of tau and amyloid. There were trends to suggest reduced microglial activation following influenza vaccine in TREM2 carriers. Tau deposition in the Braak VI region was higher in TREM2 carriers (P = 0.04). Furthermore, compared to healthy controls TREM2 carriers had smaller caudate (P = 0.02), total brain (P = 0.049) and white matter volumes (P = 0.02); and neuropsychological assessment revealed worse ADAS-Cog13 (P = 0.03) and Delayed Matching to Sample (P = 0.007) scores. CONCLUSIONS: TREM2 p.R47H carriers had reduced levels of microglial activation in brain regions affected early in the Alzheimer's disease course and differences in brain structure and cognition. Changes in microglial response may underlie the increased Alzheimer's disease risk in TREM2 p.R47H carriers. Future therapeutic agents in Alzheimer's disease should aim to enhance protective microglial actions

Association of blood lipids with Alzheimer's disease: A comprehensive lipidomics analysis

Introduction: The aim of this study was to (1) replicate previous associations between six blood lipids and Alzheimer’s disease (AD) (Proitsi et al 2015) and (2) identify novel associations between lipids, clinical AD diagnosis, disease progression and brain atrophy (left/right hippocampus/entorhinal cortex). Methods: We performed untargeted lipidomic analysis on 148 AD and 152 elderly control plasma samples and used univariate and multivariate analysis methods. Results: We replicated our previous lipids associations and reported novel associations between lipids molecules and all phenotypes. A combination of 24 molecules classified AD patients with .70% accuracy in a test and a validation data set, and we identified lipid signatures that predicted disease progression (R2 5 0.10, test data set) and brain atrophy (R2 0.14, all test data sets except left entorhinal cortex). We putatively identified a number of metabolic features including cholesteryl esters/triglycerides and phosphatidylcholines. Discussion: Blood lipids are promising AD biomarkers that may lead to new treatment strategies