The interactive effects of verapamil and CB1 cannabinoid receptor antagonist/inverse agonist, AM251 on passive avoidance learning and memory in rat.

There are reports regarding the effects of intracellular Ca2+ and synthesis and release of endocannabinoids. The secretion of endocannabinoids depends on the L-type calcium channel. The present study evaluated the involvement of the cannabinoid CB1 receptors in the effect of L-type calcium channel blocker verapamil on passive avoidance learning (PAL) in adult male rats. In this study, we examined the effects of an acute administration of the cannabinoid CB1 receptors antagonist/inverse agonist AM251 following a chronic administration of the Ca2+ channel blocker verapamil on PAL. Male Wistar rats were administered verapamil (10, 25 and 50 mg/kg) or saline intraperitoneally (i.p) daily for 13 days (n = 10/group). After this treatment period, a learning test (acquisition) was performed, and a retrieval test was performed the following day. The results indicated that chronic systemic administration of verapamil (in a dose-dependent manner) impaired memory acquisition and retrieval. Pre-training acute administration of a selective CB1 antagonist/inverse agonist, AM251 (5 mg/kg, i.p.) did not change memory acquisition and retrieval. Co-administration of the verapamil and AM251 significantly reversed verapamil-induced amnesia, suggesting a functional interaction between AM251 and verapamil. The results indicated the interactive effects of cannabinoid CB1 receptors and L-type calcium channel in passive avoidance learning and AM251 can counter the effects of verapamil on memory.

Clinical and chest CT features as a predictive tool for COVID-19 clinical progress: introducing a novel semi-quantitative scoring system.

OBJECTIVE: Proposing a scoring tool to predict COVID-19 patients' outcomes based on initially assessed clinical and CT features. METHODS: All patients, who were referred to a tertiary-university hospital respiratory triage (March 27-April 26, 2020), were highly clinically suggestive for COVID-19 and had undergone a chest CT scan were included. Those with positive rRT-PCR or highly clinically suspicious patients with typical chest CT scan pulmonary manifestations were considered confirmed COVID-19 for additional analyses. Patients, based on outcome, were categorized into outpatient, ordinary-ward admitted, intensive care unit (ICU) admitted, and deceased; their demographic, clinical, and chest CT scan parameters were compared. The pulmonary chest CT scan features were scaled with a novel semi-quantitative scoring system to assess pulmonary involvement (PI). RESULTS: Chest CT scans of 739 patients (mean age = 49.2 ± 17.2 years old, 56.7% male) were reviewed; 491 (66.4%), 176 (23.8%), and 72 (9.7%) cases were managed outpatient, in an ordinary ward, and ICU, respectively. A total of 439 (59.6%) patients were confirmed COVID-19 cases; their most prevalent chest CT scan features were ground-glass opacity (GGO) (93.3%), pleural-based peripheral distribution (60.3%), and multi-lobar (79.7%), bilateral (76.6%), and lower lobes (RLL and/or LLL) (89.1%) involvement. Patients with lower SpO2, advanced age, RR, total PI score or PI density score, and diffuse distribution or involvement of multi-lobar, bilateral, or lower lobes were more likely to be ICU admitted/expired. After adjusting for confounders, predictive models found cutoffs of age ≥ 53, SpO2 ≤ 91, and PI score ≥ 8 (15) for ICU admission (death). A combination of all three factors showed 89.1% and 95% specificity and 81.9% and 91.4% accuracy for ICU admission and death outcomes, respectively. Solely evaluated high PI score had high sensitivity, specificity, and NPV in predicting the outcome as well. CONCLUSION: We strongly recommend patients with age ≥ 53, SpO2 ≤ 91, and PI score ≥ 8 or even only high PI score to be considered as high-risk patients for further managements and care plans. KEY POINTS: • Chest CT scan is a valuable tool in prioritizing the patients in hospital triage. • A more accurate and novel 35-scale semi-quantitative scoring system was designed to predict the COVID-19 patients' outcome. • Patients with age ≥ 53, SpO2 ≤ 91, and PI score ≥ 8 or even only high PI score should be considered high-risk patients.

Effects of cannabinoid and vanilloid receptor agonists and their interaction on learning and memory in rats.

Despite previous findings on the effects of cannabinoid and vanilloid systems on learning and memory, the effects of the combined stimulation of these 2 systems on learning and memory have not been studied. Therefore, in this study, we tested the interactive effects of cannabinoid and vanilloid systems on learning and memory in rats by using passive avoidance learning (PAL) tests. Forty male Wistar rats were divided into the following 4 groups: (1) control (DMSO+saline), (2) WIN55,212-2, (3) capsaicin, and (4) WIN55,212-2 + capsaicin. On test day, capsaicin, a vanilloid receptor type 1 (TRPV1) agonist, or WIN55,212-2, a cannabinoid receptor (CB1/CB2) agonist, or both substances were injected intraperitoneally. Compared to the control group, the group treated with capsaicin (TRPV1 agonist) had better scores in the PAL acquisition and retention test, whereas treatment with WIN55,212-2 (CB1/CB2 agonist) decreased the test scores. Capsaicin partly reduced the effects of WIN55,212-2 on PAL and memory. We conclude that the acute administration of a TRPV1 agonist improves the rats' cognitive performance in PAL tasks and that a vanilloid-related mechanism may underlie the agonistic effect of WIN55,212-2 on learning and memory.

Validation of the self-reported diagnosis of diabetes mellitus, hypercholesterolemia, and hypertension in Iran; STEPS 2016.

Purpose: As a part of STEPwise approach to risk factor Surveillance (STEPS) study, our aim was to evaluate the validity of the self-reported diagnosis of diabetes (DM), hypertension (HTN), and hypercholesterolemia (Hyper-Chol) in the Iranian population. Methods: Using systematic proportional to size cluster sampling, 27,232 participants were included in our study. We calculated the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) to assess the validity of self-reported diagnoses. Furthermore, logistic regression was employed to examine the relationship between the validity of self-reported diagnoses and sociodemographic and lifestyle factors. All analyses were performed using STATA version 14. Results: The PPV for self-report of DM, HTN, and Hyper-Chol were estimated to be 69%, 74% and 80%, and NPV measured up to 95%, 84%, and 50%, respectively. Positive/negative self-reports were more accurate among older (younger) individuals. Age had a negative correlation with the validity of self-reported Hyper-Chol but a positive correlation with the validity of self-reported DM and hypertension HTN. Additionally, an increase in BMI was associated with an increase/decrease in PPV and a decrease/increase in NPV across all diseases. Conclusion: Self-report studies hold value in situations where direct in-person interaction is not feasible, either due to prohibitive costs or restrictions imposed by infectious diseases (COVID-19). Self-report surveys are valuable tools in studying the epidemiology of diseases; however, the type of the disease, the study purpose, either finding sick people or healthy people, the age subgroups, and socioeconomic status should be taken into consideration.

Effectiveness of coenzyme Q10 on learning and memory and synaptic plasticity impairment in an aged Aß-induced rat model of Alzheimer's disease: a behavioral, biochemical, and electrophysiological study.

RATIONALE: Aging is the major risk factor for Alzheimer's disease (AD), and cognitive and memory impairments are common among the elderly. Interestingly, coenzyme Q10 (Q10) levels decline in the brain of aging animals. Q10 is a substantial antioxidant substance, which has an important role in the mitochondria. OBJECTIVE: We assessed the possible effects of Q10 on learning and memory and synaptic plasticity in aged ß-amyloid (Aß)-induced AD rats. METHODS: In this study, 40 Wistar rats (24-36 months old; 360-450 g) were randomly assigned to four groups (n = 10 rats/group)-group I: control, group II: Aß, group III: Q10; 50 mg/kg, and group IV: Q10+Aß. Q10 was administered orally by gavage daily for 4 weeks before the Aß injection. The cognitive function and learning and memory of the rats were measured by the novel object recognition (NOR), Morris water maze (MWM), and passive avoidance learning (PAL) tests. Finally, malondialdehyde (MDA), total antioxidant capacity (TAC), total thiol group (TTG), and total oxidant status (TOS) were measured. RESULTS: Q10 improved the Aß-related decrease in the discrimination index in the NOR test, spatial learning and memory in the MWM test, passive avoidance learning and memory in the PAL test, and long-term potentiation (LTP) impairment in the hippocampal PP-DG pathway in aged rats. In addition, Aß injection significantly increased serum MDA and TOS levels. Q10, however, significantly reversed these parameters and also increased TAC and TTG levels in the Aß+Q10 group. CONCLUSIONS: Our experimental findings suggest that Q10 supplementation can suppress the progression of neurodegeneration that otherwise impairs learning and memory and reduces synaptic plasticity in our experimental animals. Therefore, similar supplemental Q10 treatment given to humans with AD could possibly provide them a better quality of life.

Chest CT Scan Features to Predict COVID-19 Patients' Outcome and Survival.

Background: Providing efficient care for infectious coronavirus disease 2019 (COVID-19) patients requires an accurate and accessible tool to medically optimize medical resource allocation to high-risk patients. Purpose: To assess the predictive value of on-admission chest CT characteristics to estimate COVID-19 patients' outcome and survival time. Materials and Methods: Using a case-control design, we included all laboratory-confirmed COVID-19 patients who were deceased, from June to September 2020, in a tertiary-referral-collegiate hospital and had on-admission chest CT as the case group. The patients who did not die and were equivalent in terms of demographics and other clinical features to cases were considered as the control (survivors) group. The equivalency evaluation was performed by a fellowship-trained radiologist and an expert radiologist. Pulmonary involvement (PI) was scored (0-25) using a semiquantitative scoring tool. The PI density index was calculated by dividing the total PI score by the number of involved lung lobes. All imaging parameters were compared between case and control group members. Survival time was recorded for the case group. All demographic, clinical, and imaging variables were included in the survival analyses. Results: After evaluating 384 cases, a total of 186 patients (93 in each group) were admitted to the studied setting, consisting of 126 (67.7%) male patients with a mean age of 60.4 ± 13.6 years. The PI score and PI density index in the case vs. the control group were on average 8.9 ± 4.5 vs. 10.7 ± 4.4 (p value: 0.001) and 2.0 ± 0.7 vs. 2.6 ± 0.8 (p value: 0.01), respectively. Axial distribution (p value: 0.01), cardiomegaly (p value: 0.005), pleural effusion (p value: 0.001), and pericardial effusion (p value: 0.04) were mostly observed in deceased patients. Our survival analyses demonstrated that PI score ≥ 10 (p value: 0.02) and PI density index ≥ 2.2 (p value: 0.03) were significantly associated with a lower survival rate. Conclusion: On-admission chest CT features, particularly PI score and PI density index, are potential great tools to predict the patient's clinical outcome.

Electrophysiological study of the interactive role of the cannabinoid breakdown inhibitors and L-type calcium channels on granular neurons in the hippocampal dentate gyrus in rats.

The interaction between L-type voltage-dependent Ca2+ channels and the endocannabinoid system (eCs) in synaptic plasticity is controversial. In the present research, the impact of acute administration of URB597, as an endocannabinoid breakdown inhibitor, was evaluated after chronic injection of verapamil, as a Ca2+ channels blocker, on inducing long-term potentiation (LTP) in the rat's hippocampal dentate gyrus (DG). Treatment of male Wistar rats was done using intraperitoneal(i.p) injection of verapamil hydrochloride (n = 8) and saline (n = 10), as the solvent of verapamil once a day within 13 days. Anesthetization was done by i.p injection of urethane and the rats were located in the stereotaxic apparatus for surgery, electrode implantation, and field potential recording. After observing a steady-state baseline response, saline or URB597 were injected (n = 9). Measurement of the population spike (PS) amplitude and slope of field excitatory postsynaptic potentials (fEPSPs) in the DG region was performed as a result of perforant pathway (PP) stimulation. Our treatments could inhibit LTP. Our results indicated that the chronic administration of verapamil produced a significant decrease in the slope of fEPSP and PS amplitude. Also, acute URB597 administration decreased the slope of fEPSP and PS amplitude compared to the saline group. Moreover, URB597 administration in combination with chronic administration of verapamil produced a greater decrease in fEPSP slope and PS amplitude than the saline group. These findings indicated that verapamil and URB597 disrupted LTP induction in the DG. Moreover, an interaction was observed between Ca2+ channels and eCs. Therefore, the eCs possibly play a selective role in synaptic plasticity.

Burden of Transport-Related Injuries in the Eastern Mediterranean Region: A Systematic Analysis for the Global Burden of Disease Study 2017.

BACKGROUND: Transport-related injuries (TIs) are a substantial public health concern for all regions of the world. The present study quantified the burden of TIs and deaths in the Eastern Mediterranean region (EMR) in 2017 by sex and age. METHODS: TIs and deaths were estimated by age, sex, country, and year using Cause of Death Ensemble modelling (CODEm) and DisMod-MR 2.1. Disability-adjusted life years (DALYs), which quantify the total burden of years lost due to premature death or disability, were also estimated per 100000 population. All estimates were reported along with their corresponding 95% uncertainty intervals (UIs). RESULTS: In 2017, there were 5.5 million (UI 4.9-6.2) transport-related incident cases in the EMR - a substantial increase from 1990 (2.8 million; UI 2.5-3.1). The age-standardized incidence rate for the EMR in 2017 was 787 (UI 705.5-876.2) per 100000, which has not changed significantly since 1990 (-0.9%; UI -4.7 to 3). These rates differed remarkably between countries, such that Oman (1303.9; UI 1167.3-1441.5) and Palestine (486.5; UI 434.5-545.9) had the highest and lowest age-standardized incidence rates per 100000, respectively. In 2017, there were 185.3 thousand (UI 170.8-200.6) transport-related fatalities in the EMR - a substantial increase since 1990 (140.4 thousand; UI 118.7-156.9). The age-standardized death rate for the EMR in 2017 was 29.5 (UI 27.1-31.9) per 100000, which was 30.5% lower than that found in 1990 (42.5; UI 36.8-47.3). In 2017, Somalia (54; UI 30-77.4) and Lebanon (7.1; UI 4.8-8.6) had the highest and lowest age-standardized death rates per 100,000, respectively. The age-standardised DALY rate for the EMR in 2017 was 1,528.8 (UI 1412.5-1651.3) per 100000, which was 34.4% lower than that found in 1990 (2,331.3; UI 1,993.1-2,589.9). In 2017, the highest DALY rate was found in Pakistan (3454121; UI 2297890- 4342908) and the lowest was found in Bahrain (8616; UI 7670-9751). CONCLUSION: The present study shows that while road traffic has become relatively safer (measured by deaths and DALYs per 100000 population), the number of transport-related fatalities in the EMR is growing and needs to be addressed urgently.

Investigation of protective effects of coenzyme Q10 on impaired synaptic plasticity in a male rat model of Alzheimer's disease.

Oxidative stress plays a key role in contributing to ß-amyloid (Aß) deposition in Alzheimer's disease (AD). Coenzyme Q10 (Q10) is a powerful antioxidant that buffers the potential adverse consequences of free radicals. In this study, we investigated the neuroprotective effects of Q10 on Aß-induced impairment in hippocampal long-term potentiation (LTP), a widely researched model of synaptic plasticity, which occurs during learning and memory, in a rat model of AD. In this study, 50 adult male Wistar rats were assigned to five groups: control group (saline); sham group; intraventricular PBS injection, Aß group; intraventricular Aß injection, Q10 group; and Q10 via oral gavage and Q10 + Aß group. Q10 was administered via oral gavage, once a day, for 3 weeks before and 3 weeks after the Aß injection. After the treatment period, in vivo electrophysiological recordings were performed to quantify the excitatory postsynaptic potential (EPSP) slope and population spike (PS) amplitude in the hippocampal dentate gyrus. LTP was created by a high-frequency stimulation of the perforant pathway. Following LTP induction, the EPSP slope and PS amplitude were significantly diminished in Aß-injected rats, compared with sham and control rats. Q10 treatment of Aß-injected rats significantly attenuated these decreases, suggesting that Q10 reduces the effects of Aß on LTP. Aß significantly increased serum malondialdehyde levels and total oxidant levels, whereas Q10 supplementation significantly reversed these parameters and increased total antioxidant capacity levels. The present findings suggested that Q10 treatment offers neuroprotection against the detrimental effects of Aß on hippocampal synaptic plasticity via its antioxidant activity.

The interactive role of CB1 receptors and L-type calcium channels in hippocampal long-term potentiation in rats.

Long-term potentiation (LTP) of synaptic responses is a widely researched model of synaptic plasticity that occurs during learning and memory. The cannabinoid system is an endogenous system that modulate this kind of synaptic plasticity. In addition, voltage dependent calcium channels is essential for induction of LTP at some synapses in the hippocampus. However, there is currently debate over the interaction between L-type calcium channels and cannabinoid system on the synaptic plasticity. In this study, we examined the effects of an acute administration of the cannabinoid antagonist AM251 following a chronic administration of the Ca2+ channel blocker verapamil on LTP induction in the hippocampal dentate gyrus(DG) of rats. Male Wistar rats were administered verapamil(10,25,50mg/kg) or saline intraperitoneally(IP) daily for 13days(n=10/group). After this treatment period, animals were anesthetized with an IP injection of urethane; the recording and stimulating electrodes were positioned in the DG and the perforant pathway. After obtaining a steady state baseline response, a single IP injection of saline or AM251(1 or 5mg/kg) was administered. LTP was induced by high-frequency stimulation(HFS). The population spike(PS) amplitude and the slope of excitatory postsynaptic potentials(EPSP) were compared between the experimental groups. The acute administration of the CB1 antagonist AM251 increased LTP induction. The EPSP slopes and PS amplitude in the verapamil and AM251 groups differed after HFS, such that AM251 increased LTP, whereas verapamil decreased LTP induction. These findings suggest that there are functional interactions between the L-type calcium channels and cannabinoid system in this model of synaptic plasticity in the hippocampus.

Interaction between paired-pulse facilitation and long-term potentiation during the stimulation of the cannabinoid and vanilloid systems in the dentate gyrus.

Synaptic plasticity includes short-term and long-term changes in synaptic strength. Short-term plasticity can be used to assess the site mediating the long-lasting forms of synaptic plasticity such as long-term potentiation (LTP). The endogenous endocannabinoid systems can modulate LTP, and similarly, the activation of the vanilloid system has been shown to mediate synaptic plasticity in the hippocampus. In this study, we examined the interaction between short-term and long-term plasticity during the stimulation of the cannabinoid and vanilloid systems in the hippocampus of rats in vivo. Forty male Wistar rats, divided into four groups, were treated with the following compounds: control (saline+dimethyl sulfoxide), WIN55,212-2, capsaicin, and WIN55,212-2+capsaicin. The animals were anesthetized with urethane and then recording and stimulating electrodes were positioned at the dentate gyrus(DG) and perforant pathway(PP), respectively. Population spike (PS) amplitudes were measured before and after the induction of LTP, which was induced with high-frequency stimulation (HFS). The paired-pulse ratio (PPR) was measured before and after the induction of LTP in all groups. We showed that WIN55,212-2 reduced the PS amplitude after HFS, whereas the vanilloid agonist increased the induction of LTP compared with the control treatment. In the present study, we found that in the presence of WIN55,212-2 and capsaicin, the induction of LTP changed the PPR. Additionally, we showed that the co-administration of cannabinoid and vanilloid agonists modulate the PPR. These findings suggest the presynaptic expression of this LTP form, and therefore, this form of LTP is caused by the increase of neurotransmitter release.

Interactive effects of AM251 and baclofen on synaptic plasticity in the rat dentate gyrus.

Long-term potentiation (LTP), a form of synaptic plasticity, is considered to be a critical cellular mechanism that underlies learning and memory. Cannabinoid CB1 and metabotropic GABAB receptors display similar pharmacological effects and co-localize in certain brain regions. In this study, we examined the effects of co-administration of the CB1 and GABAB antagonists AM251 and baclofen, respectively, on LTP induction in the rat dentate gyrus (DG). Male Wistar rats were anesthetized with urethane. A stimulating electrode was placed in the lateral perforant path (PP), and a bipolar recording electrode was inserted into the DG until maximal field excitatory postsynaptic potentials (fEPSPs) were observed. LTP was induced in the hippocampal area by high-frequency stimulation (HFS) of the PP. fEPSPs and population spikes (PS) were recorded at 5, 30, and 60min after HFS in order to measure changes in the synaptic responses of DG neurons. Our results showed that HFS coupled with administration of AM251 and baclofen increased both PS amplitude and fEPSP slope. Furthermore, co-administration of AM251 and baclofen elicited greater increases in PS amplitude and fEPSP slope. The results of the present study suggest that CB1 receptor activation in the hippocampus mainly modifies synapses onto GABAergic interneurons located in the DG. Our results further suggest that, when AM251 and baclofen are administered simultaneously, AM251 can alter GABA release and thereby augment LTP through GABAB receptors. These results suggest that functional crosstalk between cannabinoid and GABA receptors regulates hippocampal synaptic plasticity.

Vitamin C reverses lead-induced deficits in hippocampal synaptic plasticity in rats.

Lead (Pb) is a neurotoxic metal that is widely distributed in the environment. In experimental animals, chronic exposure to this neurotoxicant resulted in impaired synaptic plasticity and cognitive function. In this study, we examined the protective effects of vitamin C (ascorbic acid) against Pb exposure-induced impairment of long-term potentiation (LTP). Forty-four adult male Wistar rats were divided into six groups and subjected to the following treatments for three months: (1) vehicle (distilled water); (2) Pb; (3) ascorbic acid; (4) Pb+ascorbic acid; (5) Pb (two months) followed by ascorbic acid; and (6) ascorbic acid (one month) followed by Pb. After treatment, the population spike (PS) amplitude and slope of excitatory postsynaptic potentials (EPSP) were measured in the dentate gyrus(DG) of rats in vivo. Following these measurements, blood samples were collected for the following biochemical assays: malondialdehyde (MDA), total antioxidant capacity (TAC), and total oxidant status (TOS). There was a significant increase in plasma MDA and TOS in the Pb-intoxicated group compared to the control group. There was a significant increase in TAC levels in the ascorbic acid group. Our results also show that Pb exposure caused a decrease in the EPSP slope and PS amplitude when compared with the control group, whereas vitamin C increased these parameters. Co-administration of Pb with vitamin C inhibited the effects of Pb. These findings suggested that Pb exposure caused impairment in LTP, that may have been mediated through oxidative damage. Vitamin C ameliorated the Pb-induced impairment of synaptic plasticity in the DG via antioxidant activity.