Exploring neuroadaptive cellular pathways in chronic morphine exposure: An in-vitro analysis of cabergoline and Mdivi-1 co-treatment effects on the autophagy-apoptosis axis.

The complex impacts of prolonged morphine exposure continue to be a significant focus in the expanding area of addiction studies. This research investigates the effectiveness of a combined treatment using Cabergoline and Mdivi-1 to counteract the neuroadaptive changes caused by in vitro morphine treatment. The impact of Methadone, Cabergoline, and a combination of Cabergoline and Mdivi-1 on the cellular and molecular responses associated with Morphine-induced changes was studied in human Neuroblastoma (SK-N-MC) and Glioblastoma (U87-MG) cell lines that were exposed to prolong Morphine treatment. Cabergoline and Mdivi-1 combined treatment effectively influenced the molecular alterations associated with neuroadaptation in chronic morphine-exposed neural cells. This combination therapy normalized autophagy and reduced oxidative stress by enhancing total-antioxidant capacity, mitigating apoptosis, restoring BDNF expression, and balancing apoptotic elements. Our research outlines morphine's dual role in modulating mitochondrial dynamics via the dysregulation of the autophagy-apoptosis axis. This emphasizes the significant involvement of DRP1 activity in neurological adaptation processes, as well as disturbances in the dopaminergic pathway during in vitro chronic exposure to morphine in neural cells. This study proposes a novel approach by recommending the potential effectiveness of combining Cabergoline and Mdivi-1 to modulate the neuroadaptations caused by morphine. Additionally, we identified BDNF and PCNA in neural cells as potential neuroprotective markers for assessing the effectiveness of drugs against opioid toxicity, emphasizing the need for further validation. The study uncovers diverse effects observed in pretreated morphine glioblastoma cells under treatment with Cabergoline and methadone. This highlights the potential for new treatments in the DRD2 pathway and underscores the importance of investigating the interplay between autophagy and apoptosis to advance research in managing cancer-related pain. The study necessitates an in-depth investigation into the relationship between autophagy and apoptosis, with a specific emphasis on protein interactions and the dynamics of cell signaling.

Suicide gene therapy using allogeneic adipose tissue-derived mesenchymal stem cell gene delivery vehicles in recurrent glioblastoma multiforme: a first-in-human, dose-escalation, phase I clinical trial.

BACKGROUND: Glioblastoma multiforme (GBM) is associated with remarkably poor prognosis, and its treatment is challenging. This investigation aimed to evaluate the safety of suicide gene therapy using allogeneic adipose tissue-derived mesenchymal stem cells (ADSCs) carrying herpes simplex virus-thymidine kinase (HSV-TK) gene for the first time in patients with recurrent GBM. METHODS: This study was a first-in-human, open-label, single-arm, phase I clinical trial with a classic 3 + 3 dose escalation design. Patients who did not undergo surgery for their recurrence were included and received this gene therapy protocol. Patients received the intratumoral stereotactic injection of ADSCs according to the assigned dose followed by prodrug administration for 14 days. The first dosing cohort (n = 3) received 2.5 × 105 ADSCs; the second dosing cohort (n = 3) received 5 × 105 ADSCs; the third dosing cohort (n = 6) received 10 × 105 ADSCs. The primary outcome measure was the safety profile of the intervention. RESULTS: A total of 12 patients with recurrent GBM were recruited. The median follow-up was 16 (IQR, 14-18.5) months. This gene therapy protocol was safe and well tolerated. During the study period, eleven (91.7%) patients showed tumor progression, and nine (75.0%) died. The median overall survival (OS) was 16.0 months (95% CI 14.3-17.7) and the median progression-free survival (PFS) was 11.0 months (95% CI 8.3-13.7). A total of 8 and 4 patients showed partial response and stable disease, respectively. Moreover, significant changes were observed in volumetric analysis, peripheral blood cell counts, and cytokine profile. CONCLUSIONS: The present clinical trial, for the first time, showed that suicide gene therapy using allogeneic ADSCs carrying the HSV-TK gene is safe in patients with recurrent GBM. Future phase II/III clinical trials with multiple arms are warranted to validate our findings and further investigate the efficacy of this protocol compared with standard therapy alone. TRIAL REGISTRATION: Iranian Registry of Clinical Trials (IRCT), IRCT20200502047277N2. Registered 8 October 2020, https://www.irct.ir/ .

The prevalence of restless legs syndrome (RLS) in patients with multiple sclerosis (MS): a systematic review and meta-analysis-an update.

INTRODUCTION: The prevalence of restless legs syndrome (RLS) is reported to vary in patients with multiple sclerosis (MS) in studies which are conducted in different populations. The goal of this systematic review and meta-analysis is to update the prevalence of RLS in MS cases. METHODS: We searched PubMed, Scopus, EMBASE, CINAHL, Web of Science, Google Scholar, and gray literature including references from identified studies and conference abstracts which were published up to June 2021. Data on the total number of participants, first author, country, disease duration, number of controls, mean patient age, male and female numbers, mean EDSS, and number of cases and/or controls with RLS were extracted from the included studies. RESULTS: The literature search revealed 855 articles; after deleting duplicates, 530 remained. For the meta-analysis, 75 studies were included (Fig. 1). In six articles, the authors did not differentiate between CIS and MS cases when reporting RLS cases. In total, 15,411 MS/CIS patients were evaluated and 4309 had RLS. The pooled prevalence of RLS was 28% (95% CI: 24-33%). The pooled prevalence of RLS in men was 22% (95% CI: 17-26%), and the pooled prevalence of RLS in women was 30% (95% CI: 25-35%). The pooled prevalence of RLS in controls was 8% (95% CI: 6-10%). CONCLUSION: The results of this systematic review and meta-analysis show that the pooled prevalence of RLS is 28% in MS cases and 8%. The pooled prevalence is higher in women than men (30% vs 22%).

Toward children's cognitive development from the perspective of neurolaw: implications of Roper v Simmons.

After reaching the age of criminal responsibility, children are deemed capable of having committed criminal offenses. In this regard, the level of criminal responsibility depends on cognitive development and the type of offense committed. Cognitive development is a process of the growth of perception, thinking and reasoning in children. This concept is frequently referred to in cognitive neuroscience literature. Recently, the U.S. Supreme Court's decision in Roper v Simmons has substantially changed attitudes toward juvenile delinquency, considering the fact that cognitive development continues until early adulthood. The present study attempts to scrutinize this case and explain cognitive development by its factors from an interdisciplinary perspective, combining methods and theories from neuroscience and criminal law.

Systematic Analysis of Protein-Protein and Gene-Environment Interactions to Decipher the Cognitive Mechanisms of Autism Spectrum Disorder.

Autism spectrum disorder (ASD), a heterogeneous neurodevelopmental disorder resulting from both genetic and environmental risk factors, is manifested by deficits in cognitive function. Elucidating the cognitive disorder-relevant biological mechanisms may open up promising therapeutic approaches. In this work, we mined ASD cognitive phenotype proteins to construct and analyze protein-protein and gene-environment interaction networks. Incorporating the protein-protein interaction (PPI), human cognition proteins, and connections of autism-cognition proteins enabled us to generate an autism-cognition network (ACN). With the topological analysis of ACN, important proteins, highly clustered modules, and 3-node motifs were identified. Moreover, the impact of environmental exposures in cognitive impairment was investigated through chemicals that target the cognition-related proteins. Functional enrichment analysis of the ACN-associated modules and chemical targets revealed biological processes involved in the cognitive deficits of ASD. Among the 17 identified hub-bottlenecks in the ACN, PSD-95 was recognized as an important protein through analyzing the module and motif interactions. PSD-95 and its interacting partners constructed a cognitive-specific module. This hub-bottleneck interacted with the 89 cognition-related 3-node motifs. The identification of gene-environment interactions indicated that most of the cognitive-related proteins interact with bisphenol A (BPA) and valproic acid (VPA). Moreover, we detected significant expression changes of 56 cognitive-specific genes using four ASD microarray datasets in the GEO database, including GSE28521, GSE26415, GSE18123 and GSE29691. Our outcomes suggest future endeavors for dissecting the PSD-95 function in ASD and evaluating the various environmental conditions to discover possible mechanisms of the different levels of cognitive impairment.

Five consecutive epidemiological waves of COVID-19: a population-based cross-sectional study on characteristics, policies, and health outcome.

BACKGROUND: This study was conducted with the intension of providing a more detailed view about the dynamics of COVID-19 pandemic. To this aim, characteristics, implemented public health measures, and health outcome of COVID-19 patients during five consecutive waves of the disease were assessed. METHODS: This study was a population-based cross-sectional analysis of data on adult patients who were diagnosed with COVID-19 during five waves of the disease in Iran. Chi-squared test, One-way ANOVA, and Logistic Regression analysis were applied. A detailed literature review on implemented public health policies was performed by studying published documents and official websites responsible for conveying information about COVID-19. RESULTS: Data on 328,410 adult patients was analyzed. Main findings indicated that the probability of dying with COVID-19 has increased as the pandemic wore on, showing its highest odd during the third wave (odds ratio: 1.34, CI: 1.283-1.395) and has gradually decreased during the next two waves. The same pattern was observed in the proportion of patients requiring ICU admission (P < 0.001). First wave presented mainly with respiratory symptoms, gastrointestinal complaints were added during the second wave, neurological manifestations with peripheral involvement replaced the gastrointestinal complaints during the third wave, and central nervous system manifestations were added during the fourth and fifth waves. A significant difference in mean age of patients was revealed between the five waves (P < 0.001). Moreover, results showed a significant difference between men and women infected with COVID-19, with men having higher rates of the disease at the beginning. However, as the pandemic progressed the proportion of women gradually increased, and ultimately more women were diagnosed with COVID-19 during the fifth wave. Our observations pointed to the probability that complete lockdowns were the key measures that helped to mitigate the virus spread during the first twenty months of the pandemic in the country. CONCLUSION: A changing pattern in demographic characteristics, clinical manifestations, and severity of the disease has been revealed as the pandemic unfolded. Reviewing COVID-19-related public health interventions highlighted the importance of immunization and early implementation of restrictive measures as effective strategies for reducing the acute burden of the disease.

Parkinson's disease and COVID-19: a systematic review and meta-analysis.

BACKGROUND: Patients with Parkinson's disease (PD) are at higher risk of COVID-19 infection as most of them are at older age. The goal of this study is to update the pooled prevalence of COVID-19 infection in patients with PD. METHODS: Two researchers systematically searched PubMed, Scopus, EMBASE, Web of Science, Google Scholar, and also gray literature including references of the included studies which were published before September 2021. We extracted data regarding the total number of participants, first author, publication year, the country of origin, mean age, number with COVID-19, symptoms, hospitalization, and death. RESULTS: We found 1693 articles by literature search; after deleting duplicates, 798 remained. Thirty articles remained for meta-analysis. The pooled prevalence of COVID-19 infection in PD cases was 5% (95%CI: 4-6%) (I2 = 98.1%, P < 0.001). The pooled prevalence of fever in cases with PD was 4% (95%CI: 2-6%) (I2 = 96%, P < 0.001). The pooled prevalence of cough in cases with PD was 3% (95%CI: 2-4%) (I2 = 95.9%, P < 0.001). The pooled prevalence of hospitalization in cases with COVID-19 infection was 49% (95%CI: 29-52%) (I2: 93.5%, P < 0.001). The pooled prevalence of mortality in COVID-19 cases was 12% (95%CI: 10-14%) (I2 = 97.6%, P < 0.001). CONCLUSION: The results of this systematic review and meta-analysis show that the pooled prevalence of COVID-19 infection in PD cases is 5% besides hospitalization and mortality rates which are 49% and 12%.

Urban and sub-urban disparities in health outcomes among patients with COVID-19; a cross-sectional study of 234 418 patients in Iran.

BACKGROUND: It remains crucial to understand socio-demographic determinants of COVID-19 infection to improve access to care and recovery rates from the disease. This study aimed to investigate the urban and sub-urban disparities associated with COVID-19 in patients visiting healthcare facilities in the province of Tehran, Iran. METHODS: Data from 234 418 patients who were diagnosed with COVID-19 infection from March 2020 to March 2021 in the province of Tehran were used in this analysis. Descriptive statistics were used to describe the characteristics of the study population. Chi-Squared test was applied to examine the association of study variables with residing area. Independent samples t-test was performed to compare mean age of patients in urban and sub-urban areas. Multiple Logistic Regression model was applied to examine the association of study variables with disease outcome. RESULTS: Overall, most patients resided in the urban settings (73%). Mean age of patients was significantly lower in sub-urban areas compared to their counterparts in urban settings (49 ± 23.1 years versus 53 ± 21.1 years, P < 0.001). Positive PCR test results were more common in urban areas (48.5% versus 41.3%, P < 0.001). Yet, sub-urban settings had higher rates of positive chest CT scan reports (62.8% versus 53.4%, P < 0.001). After accounting for age and sex covariates, residing in urban areas was associated with higher likelihood of being admitted to an ICU (OR = 1.27, CI: 1.240-1.305). Yet, a greater vulnerability to fatal outcome of COVID-19 infection was shown in patients living in sub-urban areas (OR = 1.13, CI: 1.105-1.175). CONCLUSIONS: This study revealed a clear disparity in the health outcome of patients infected with COVID-19 between urban and sub-urban areas.

Preoperative Serum Level of Vitamin D is a Possible Protective Factor for Peritumoral Brain Edema of Meningioma: A Cross Sectional Study.

Meningioma is associated with the development of vasogenic edema defined as disrupted blood brain barrier. Vitamin D3 through its own nuclear receptor can regulate the expression of many effective agents on the integrity of the blood brain barrier. This study aimed to investigate the association between preoperative serum levels of 25(OH)D and peritumoral brain edema in patients with meningioma. One hundred and twelve patients with meningioma completed the study. Serum 25(OH)D levels assessment and magnetic resonance imaging (MRI) were done for all patients at the beginning of the study. The percentage of edema index (EI) was used to estimate the extent of peritumoral brain edema through preoperative MRI. The median serum level of 25(OH)D in the patients with the percentage of EI < 100% was significantly higher than those with > 100% (65.58 vs. 37.33, P < 0.001). The median percentage of EI was 24.9. Preoperative serum levels of 25(OH)D had an inverse and significant correlation with the percentage of EI as by increasing each 1 ng/mL of serum 25(OH)D, EI was decreased approximately 4% (95% CI; -5.984 to -1.952, P < 0.001). Vitamin D may be a protective factor for peritumoral brain edema of meningioma.

Altered expression of EGFR and miR-34a derived from serum and tumoral tissue was associated with glioblastoma multiform.

OBJECTIVE: Glioblastoma multiform (GBM) is the most prevalent and invasive brain malignancy in adults. There are ongoing researches to introduce novel and non-invasive potential biomarkers for the early detection of GBM. METHODS: Here we compared the expression of EGFR, miR-34a, and miR-19a between tumoral and adjacent non-cancerous tissues (ANCTs) of 50 GBM patients and also compared their expression levels in serum samples of GBM patients with serum samples of 50 control subjects. RESULTS: The expression level of the EGFR gene was elevated in GBM tissues in comparison to the corresponding ANCTs (P < 0.0001) and also was higher in the serum sample of patients compared with control serum (P < 0.0001). The miR-34a was significantly downregulated in serum samples as well as tissues obtained from GBM patients compared with the corresponding controls (expression ratio = 0.57 and 0.4, P = 0.02 and 0.001 respectively). CONCLUSIONS: Dysregulation of the EGFR gene and miR-34a in serum samples of GBM patients compared with the control subjects promises the emergence of non-invasive biomarkers for early detection of GBM which need confirmative studies with a large sample size.

Sociodemographic determinants and clinical risk factors associated with COVID-19 severity: a cross-sectional analysis of over 200,000 patients in Tehran, Iran.

BACKGROUND: Defining socio-demographic factors, clinical presentations and underlying diseases associated with COVID-19 severity could be helpful in its management. This study aimed to further clarify the determinants and clinical risk factors of the disease severity in patients infected with COVID-19. METHODS: A multi-centre descriptive study on all patients who have been diagnosed with COVID-19 in the province of Tehran from March 2020 up to Dec 2020 was conducted. Data on socio-demographic characteristics, clinical presentations, comorbidities, and the health outcomes of 205,654 patients were examined. Characteristics of the study population were described. To assess the association of study variables with the disease severity, the Chi-Squared test and Multiple Logistic Regression model were applied. RESULTS: The mean age of the study population was 52.8 years and 93,612 (45.5%) were women. About half of the patients have presented with low levels of blood oxygen saturation. The ICU admission rate was 17.8% and the overall mortality rate was 10.0%. Older age, male sex, comorbidities including hypertension, cancer, chronic respiratory diseases other than asthma, chronic liver diseases, chronic kidney diseases, chronic neurological disorders, and HIV/AIDS infection were risk markers of poor health outcome. Clinical presentations related with worse prognosis included fever, difficulty breathing, impaired consciousness, and cutaneous manifestations. CONCLUSION: These results might alert physicians to pay attention to determinants and risk factors associated with poor prognosis in patients with COVID-19. In addition, our findings aid decision makers to emphasise on vulnerable groups in the public health strategies that aim at preventing the spread of the disease and its mortalities.

The effect of the "segment" of spinal cord injury on the activity of the nucleotide-binding domain-like receptor protein 3 inflammasome and response to hormonal therapy.

Spinal cord injury (SCI) is a common devastating condition that causes neuronal loss and dysfunction. Neuroinflammation takes cardinal roles in the pathogenesis of SCI, and nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome is a mediator of inflammatory reactions occurring in SCI patients. The present study was designed to survey possible relation between thoracic segments whereby injury occurs with the activity of NLRP3 inflammasome complex, and to find the influence of hormonal therapy on the outcomes. Adult male Wistar rats underwent contusion SCI model at three different thoracic segments T1, T6 and T12, then receiving subcutaneous injection of either 10 mg/kg melatonin or 25 µg/kg 17-ß estradiol (E2) every 12 hours until 72 hours post-SCI. Inflammasome activity was assessed before and at the end of hormonal therapy. SCI rats showed decreased locomotor activity and myelination, and increased activity of the NLRP3, apoptosis-associated speck-like protein (ASC) and caspase-1 at gene and protein levels. Release of interleukins (ILs) 18 and 1ß was also augmented after SCI (P < 0.0.5). Hormonal therapy was most effective for targeting mRNA activity at T6 segment. Treatment with either melatonin or E2 caused a decrease in the protein activity of NLRP3 inflammasome at all segments (P < 0.0.5), except for T6 that NLRP3 protein had no response to melatonin. IL-1ß showed decreased activity in response to hormonal therapy at all segments, whilst IL-18 protein had no change at T1 segment. It is understood that although no alteration in the activity of NLRP3 was found for SCI at different segments, the response to hormonal therapy was influenced by segment. SIGNIFICANCE OF THE STUDY: From our results, the NLRP3 inflammasome activity is not influenced by segment, but there are differences in the effect of hormonal therapy on inflammasome activity at different segments in response to melatonin or E2. These findings also provide the beneficial effects of melatonin or E2 on inflammation caused by spinal cord injury in different thoracic segments. Finally, these data can have therapeutic importance for hormone therapy of spinal cord injury.

Changed pattern of hospital admission in stroke during COVID-19 pandemic period in Iran: a retrospective study.

BACKGROUND: Some previous reports have shown a reduced number of admission in stroke cases during the coronavirus disease 2019 (COVID-19) pandemic period. The present study aimed to investigate this changing pattern and the potential causes behind it at an academic neurology and neurosurgery center in Iran. METHODS: Patients admitted to our center with the diagnosis of ischemic and hemorrhagic stroke, between March 1, 2019, Jun 1, 2019, and the similar 3-month period in 2020 (COVID-19 pandemic period), were compared in terms of clinical characteristics and outcome. Poisson regression was also conducted to assess the correlation between daily admissions and the COVID-19 pandemic period. RESULTS: A total of 210 patients with stroke (ischemic and hemorrhagic) in 2019 were compared with 106 patients in 2020. COVID-19 pandemic period was significantly associated with the decline in the number of daily admissions in ischemic stroke (IRR, 0.51 [95% CI, 0.4-0.64]). A significant reduction (P = 0.003) in time from onset to arrival at hospital from median 12 h [IQR, 5-32] in 2019 to median 6 h [IQR, 4-16] in 2020 was found in ischemic stroke cases. National Institute of Health Stroke Scale (NIHSS) was significantly increased (P < 0.001) from median 4 [IQR, 2-7] in 2019 to median 9 [IQR, 4-14] in 2020. Glasgow coma scale (GCS) was significantly decreased from 13.9 (SD, 2) in 2019 to 12.8 (SD, 2.9) in 2020 (P < 0.001). CONCLUSIONS: The present study provided new pieces of evidence regarding the changed pattern of hospital admission in stroke especially the possible reasons for its decline.

A description of spatial-temporal patterns of the novel COVID-19 outbreak in the neighbourhoods' scale in Tehran, Iran.

Background: Analyzing and monitoring the spatial-temporal patterns of the new coronavirus disease (COVID-19) pandemic can assist local authorities and researchers in detecting disease outbreaks in the early stages. Because of different socioeconomic profiles in Tehran's areas, we will provide a clear picture of the pandemic distribution in Tehran's neighbourhoods during the first months of its spread from February to July 2020, employing a spatial-temporal analysis applying the geographical information system (GIS). Disease rates were estimated by location during the 5 months, and hot spots and cold spots were highlighted. Methods: This study was performed using the COVID-19 incident cases and deaths recorded in the Medical Care Monitoring Centre from February 20, to July 20, 2020. The local Getis-Ord Gi* method was applied to identify the hotspots where the infectious disease distribution had significantly clustered spatially. A statistical analysis for incidence and mortality rates and hot spots was conducted using ArcGIS 10.7 software. Results: The addresses of 43,000 Tehrani patients (15,514 confirmed COVID-19 cases and 27,486 diagnosed as probable cases) were changed in its Geo-codes in the GIS. The highest incidence rate from February to July 2020 was 48 per 10,000 and the highest 5-month incidence rate belonged to central and eastern neighbourhoods. According to the Cumulative Population density of patients, the higher number is estimated by more than 2500 people in the area; however, the lower number is highlighted by about 500 people in the neighborhood. Also, the results from the local Getis-Ord Gi* method indicate that COVID-19 has formed a hotspot in the eastern, southeast, and central districts in Tehran since February. We also observed a death rate hot spot in eastern areas. Conclusion: Because of the spread of COVID-19 disease throughout Tehran's neighborhoods with different socioeconomic status, it seems essential to pay attention to health behaviors to prevent the next waves of the disease. The findings suggest that disease distribution has formed a hot spot in Tehran's eastern and central regions.

The expression level of cannabinoid receptors type 1 and 2 in the different types of astrocytomas.

Astrocytomas, the most prevalent primary brain tumors, can be divided by histology and malignancy levels into four following types: pilocytic astrocytoma (grade I), diffuse fibrillary astrocytoma (grade II), anaplastic astrocytoma (grade III), and glioblastoma multiforme (grade IV). For high grade astrocytomas (grade III and grade IV), blood vessels formation is considered as the most important property. The distribution of cannabinoid receptors type 1 (CB1) and cannabinoid receptor type 2 (CB2) in blood vessels and tumor tissue of astrocytoma is still controversial. Asrocytoma tissues were collected from 45 patients under the condition of tumor-related neurosurgical operation. The expression of CB1 and CB2 receptors was assessed using immunofluorescence, quantitative real-time RT-PCR and western blotting. The results indicated an increased expression of CB1 receptors in tumor tissue. There was a significant difference in the mount of CB2 receptors in blood vessels. More was observed in the grade III and glioblastoma (grade IV) than astrocytoma of grade II and control. This study suggested that, the expression increase of cannabinoid receptors is an index for astrocytoma malignancy and can be targeted as a therapeutic approach for the inhibition of astrocytoma growth among patients.

COVID-19-related strokes in adults below 55 years of age: a case series.

BACKGROUND: Coronavirus infection is a novel respiratory disease affecting people across the world. Although the majority of patients present with fever, dyspnea, cough, or myalgia, various signs and symptoms have been reported for this disease. Recently, neurological symptoms have been noticed in patients with COVID-19 with unknown etiology. However, the occurrence of strokes in young and middle aged patients with COVID-19 is not fully explained. METHODS: In this series, six patients younger than 55 years of age with diagnosis of stroke and a confirmed diagnosis of COVID-19 were evaluated for symptoms, lab data, imaging findings, and outcomes from March 2020 to the end of April 2020 from all stroke cases in a tertiary academic hospital. Patients older than 55 and all others who had evidence of cardiac abnormalities (arrhythmia/valvular) were excluded. RESULTS: Fever, myalgia, cough, and dyspnea were the most common clinical symptoms noted in 66.66% (4/6), 66.66% (4/6), 50% (3/6), and 50% (3/6) of the patients, respectively. The mean ± standard deviation (SD) of National Institutes of Health Stroke Scale (NIHSS) for the patient was 10.16 ± 7.13 (ranged 5-24). The most involved area was middle cerebral artery (MCA) (five in MCA versus one in basal ganglia) and the majority of our patients had a low lung involvement score (mean ± SD: 13.16 ± 6.49 out of 24). Finally, one patient was deceased and rest discharged. CONCLUSION: Stroke may be unrelated to age and the extent of lung involvement. However, different factors may play roles in co-occurrence of stroke and COVID-19 and its outcome. Future studies with long-term follow-up and more cases are needed to assess prognostic factors.

Non-steroidal anti-inflammatory drugs in management of COVID-19; A systematic review on current evidence.

BACKGROUND: Since there is still no definitive conclusion regarding which non-steroidal anti-inflammatory drugs (NSAIDs) are most effective and safe in viral respiratory infections, we decided to evaluate the efficacy and safety of various NSAIDs in viral respiratory infections so that we can reach a conclusion on which NSAID is best choice for coronavirus disease 2019 (COVID-19). METHODS: A search was performed in Medline (via PubMed), Embase and CENTRAL databases until 23 March 2020. Clinical trials on application of NSAIDs in viral respiratory infections were included. RESULTS: Six clinical trials were included. No clinical trial has been performed on COVID-19, Severe Acute Respiratory Syndrome and Middle East Respiratory Syndrome infections. Studies show that ibuprofen and naproxen not only have positive effects in controlling cold symptoms, but also do not cause serious side effects in rhinovirus infections. In addition, it was found that clarithromycin, naproxen and oseltamivir combination leads to decrease in mortality rate and duration of hospitalisation in patients with pneumonia caused by influenza. CONCLUSION: Although based on existing evidence, NSAIDs have been effective in treating respiratory infections caused by influenza and rhinovirus, since there is no clinical trial on COVID-19 and case-reports and clinical experiences are indicative of elongation of treatment duration and exacerbation of the clinical course of patients with COVID-19, it is recommended to use substitutes such as acetaminophen for controlling fever and inflammation and be cautious about using NSAIDs in management of COVID-19 patients until there are enough evidence. Naproxen may be a good choice for future clinical trials.

Mortality Risk Factors among Hospitalized COVID-19 Patients in a Major Referral Center in Iran.

The Coronavirus Disease 2019 (COVID-19) pandemic has killed many people worldwide since December 2019, and Iran has been among the most affected countries. In this retrospective study, we aimed to determine the prognostic factors associated with mortality in COVID-19 patients by analyzing 396 survived and 63 non-survived patients in Shahid Modarres Hospital, Tehran, Iran, from January 30th until April 5th, 2020. As the results, the BMI > 35 (p = 0.0003), lung cancer (p = 0.007), chronic kidney disease (p = 0.002), Immunocompromised condition (p = 0.003), and diabetes (p = 0.018) were more frequently observed in the expired group. The history of statins use was more common in the discharged group (p = 0.002), while there was no significant difference in the drug history of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, nonsteroidal anti-inflammatory drugs, aspirin, and/or steroids, and in the past-year influenza vaccination. Multivariable regression demonstrated rising odds of in-hospital death related with age (odds ratio (OR) = 1.055, p = 0.002), levels of C-reactive protein (CRP) (OR = 2.915, p < 0.001), creatinine (OR = 1.740, p = 0.023), lymphocyte count (OR = 0.999, p = 0.008), and magnesium level (OR = 0.032, p < 0.001) on admission. In conclusion, the patients with older age and higher BMI with lymphopenia, hypomagnesemia, elevated CRP and/or raised creatinine on admission are at higher risk of mortality due to the COVID-19 infection, which requires the physicians to use timely and strong therapeutic measures for such patients.

Down-regulation of 14-3-3 zeta sensitizes human glioblastoma cells to apoptosis induction.

Strong 14-3-3 zeta protein expression plays an important role in tumorigenesis, including in the maintenance of cell growth, resistance increase, and the prevention of apoptosis. In this study, we focus on two targets: (1) the expression of 14-3-3 zeta in the different grades of human astrocytoma (II-IV), (2) suppression of 14-3-3 zeta protein expression in glioblastoma derived astrocytes by 14-3-3 zeta shRNA lentiviral particles. The tissues of human astrocytoma were provided from 30 patients (ten of each grade of astrocytoma). Control tissues were obtained from the peritumoral brain zone of those patients with glioblastoma. The protein and mRNA expression levels of each astrocytoma grade were assessed via western blotting and RT-PCR, respectively. Results indicated that 14-3-3 zeta was significantly expressed in glioblastoma multiforme (grade IV) and 14-3-3 zeta expression levels enhanced according to the increase of astrocytoma malignancy. In the cellular study for knock down of the 14-3-3 zeta protein, surgical biopsy of glioblastoma was used to isolate primary astrocyte. Astrocytes were transduced with 14-3-3 zeta shRNA or non-targeted shRNA lentiviral particles. Furthermore, reduction of the 14-3-3 zeta protein expression in the astrocytes evaluated through qRT-PCR and western blot after transduction of 14-3-3 zeta shRNA lentiviral particles. Moreover, apoptosis properties, including DNA fragmentation and ratio increase of Bax/Bcl-2 were observed in astrocytes following reduction of 14-3-3 zeta protein expression. Further observation indicated that the mitochondrial pathway through release of cytochorome c and caspase-3 activity was involved in the apoptosis induction. Hence, this study demonstrates a key role of the 14-3-3 zeta protein in tumorigenesis but also indicates that 14-3-3 zeta can be considered as a target for the astrocytoma treatment specially glioblastoma.

Tumoricidal effect of human olfactory ensheathing cell mediated suicide gene therapy in human glioblastoma cells.

The potential of herpes simplex virus type 1 thymidine kinase (HSV-tk)-expressing olfactory ensheathing cells (OEC) treated with ganciclovir (GCV) to induce cell death in adjacent HSV-tk-negative cells (bystander effect) has been well demonstrated. Although it has been shown that bystander effect occurs through the delivery of phosphorylated GCV, the bystander effect mechanism and the role of gap junctions for human OECs mediated suicide gene therapy in primary astrocytes of human glioblastma remain obscure. In the present study, the efficacy of a new method for the transfer of phosphorylated GCV from OECs into primary astrocytes was evaluated. Surgical biopsy of glioblastoma was used to isolate primary astrocyte. Biopsy of olfactory mucosa was applied to isolate olfactory ensheathing cell. Expression of S100-beta antigen was confirmed immunocytochemically in astrocytes and OECs. OECs were transduced to lentiviral containing thymidine kinase gene (TK) and co-cultured with astrocytes. Fluorescent dye transfer and western blot analysis indicated the expression of connexin43 between olfactory ensheathing cells and astrocytes whereas, expression of the gap junction protein connexin43 was inhibited by the gap junction inhibitor 18α-glycyrrhethinic acid (AGA, 20 µg/ml). Furthermore, co-culture of astrocytes with OEC-TK in the presence of concentration of 30 µg/ml GCV led to a decrease in astrocytes survival rate. Also, apoptosis hallmarks, including DNA fragmentation in cell nuclear, expression increase of Bax to Bcl-2 ratio and increase of caspase3 activation were observed in this study. Our findings suggest that human olfactory ensheathing cells can deliver phosphorylated GCV into the glioblastoma derived astrocytes through gap junction communication for apoptosis induction.