Therapeutic potential of pluripotent stem cell-derived dopaminergic progenitors in Parkinson's disease: a systematic review protocol.

BACKGROUND: Parkinson's disease (PD) is the second most common age-dependent neurodegenerative disease that causes motor and cognitive disabilities. This disease is associated with a loss of dopamine content within the putamen, which stems from the degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). Several approved drugs are available that can effectively treat symptoms of PD. However, long-term medical management is often complicated and does not delay or halt disease progression. Alternatively, cell replacement strategies can address these shortcomings and provide dopamine where it is needed. Although using human pluripotent stem cells (hPSCs) for treatment of PD is a promising alternative, no consensus in the literature pertains to efficacy concerns of hPSC-based therapy for PD. This systematic review aims to investigate the efficacy of primate PSC-derived DA progenitor transplantation to treat PD in preclinical studies. METHODS: This is a systematic review of preclinical studies in animal models of PD. We intend to use the following databases as article sources: MEDLINE (via PubMed), Web of Science, and SCOPUS without any restrictions on language or publication status for all related articles published until the end of April 2021. Two independent reviewers will select the titles and abstracts, extract data from qualifying studies, and assess the risk of bias using the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk of bias tool and the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES) checklist. Apomorphine-induced rotation test (APO-IR) and amphetamine-induced rotation test (AMP-IR) are defined as the primary outcomes. The standardized mean difference (SMD) by Hedges' g method (r) and odds ratio (OR) and related 95% confidence interval (CI) will be calculated to determine the size effect of the treatment. The heterogeneity between studies will be calculated by "I2 inconsistency of values and Cochran's Q statistical test," where I2 > 50% and/or p < 0.10 suggests high heterogeneity. Meta-analyses of random effects will be run when appropriate. DISCUSSION: This study will present an overview of preclinical research on PSCs and their therapeutic effects in PD animal models. This systematic review will point out the strengths and limitations of studies in the current literature while encouraging the funding of new studies by public health managers and governmental bodies.

Mesenchymal stem cells derived from perinatal tissues for treatment of critically ill COVID-19-induced ARDS patients: a case series.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a fatal complication of coronavirus disease 2019 (COVID-19). There are a few reports of allogeneic human mesenchymal stem cells (MSCs) as a potential treatment for ARDS. In this phase 1 clinical trial, we present the safety, feasibility, and tolerability of the multiple infusions of high dose MSCs, which originated from the placenta and umbilical cord, in critically ill COVID-19-induced ARDS patients. METHODS: A total of 11 patients diagnosed with COVID-19-induced ARDS who were admitted to the intensive care units (ICUs) of two hospitals enrolled in this study. The patients were critically ill with severe hypoxemia and required mechanical ventilation. The patients received three intravenous infusions (200 × 106 cells) every other day for a total of 600 × 106 human umbilical cord MSCs (UC-MSCs; 6 cases) or placental MSCs (PL-MSCs; 5 cases). FINDINGS: There were eight men and three women who were 42 to 66 years of age. Of these, six (55%) patients had comorbidities of diabetes, hypertension, chronic lymphocytic leukemia (CLL), and cardiomyopathy (CMP). There were no serious adverse events reported 24-48 h after the cell infusions. We observed reduced dyspnea and increased SpO2 within 48-96 h after the first infusion in seven patients. Of these seven patients, five were discharged from the ICU within 2-7 days (average: 4 days), one patient who had signs of acute renal and hepatic failure was discharged from the ICU on day 18, and the last patient suddenly developed cardiac arrest on day 7 of the cell infusion. Significant reductions in serum levels of tumor necrosis factor-alpha (TNF-α; P < 0.01), IL-8 (P < 0.05), and C-reactive protein (CRP) (P < 0.01) were seen in all six survivors. IL-6 levels decreased in five (P = 0.06) patients and interferon gamma (IFN-γ) levels decreased in four (P = 0.14) patients. Four patients who had signs of multi-organ failure or sepsis died in 5-19 days (average: 10 days) after the first MSC infusion. A low percentage of lymphocytes (< 10%) and leukocytosis were associated with poor outcome (P = 0.02). All six survivors were well with no complaints of dyspnea on day 60 post-infusion. Radiological parameters of the lung computed tomography (CT) scans showed remarkable signs of recovery. INTERPRETATION: We suggest that multiple infusions of high dose allogeneic prenatal MSCs are safe and can rapidly improve respiratory distress and reduce inflammatory biomarkers in some critically ill COVID-19-induced ARDS cases. Patients that develop sepsis or multi-organ failure may not be good candidates for stem cell therapy. Large randomized multicenter clinical trials are needed to discern the exact therapeutic potentials of MSC in COVID-19-induced ARDS.

Atorvastatin Prevents the Neuron Loss in the Hippocampal Dentate Gyrus Region through its Anti-Oxidant and Anti-Apoptotic Activities.

BACKGROUND: Atorvastatin is a member of statins, which has shown positive vascular effects, anti-oxidant, anti-platelet, and anti-apoptotic properties. OBJECTIVE: In this study, we hypothesized that atorvastatin could prevent the neurons lost in the hippocampal dentate gyrus region after transient global Ischemia/Reperfusion (I/R) through its anti- oxidant and anti-apoptotic activities. METHOD: Twenty-four male Wistar rats, 12-13 weeks old and weighing 250-300 g, were divided randomly into four groups: control, I/R, vehicle (I/R treated with NaCl) and experiment (I/R treated with atorvastatin, 10 mg/kg); rats were sacrificed 96 hours after I/R. Quantitative expression of genes (caspase 8, p53, bax, bcl2, cytochrome c) was studied. The MDA level, SOD, CAT, and GPx activities were measured with biochemical tests. To detect apoptotic cells, TUNEL and Nissl staining were performed. Mitochondria were prepared from the hippocampus rats and used for the quantification of mitochondrial ROS, ATP level, GSH content, membrane potential, cytochrome c release, and determination of mitochondrial swelling. RESULTS: Atorvastatin attenuated the overexpression of bax, cytochrome C, p53, and caspase8 mRNAs and induced expression of bcl-2 mRNA (P<0.001). Atorvastatin treatment increased anti-oxidant enzyme levels (P<0.01). Treatment with atorvastatin reduced the number of TUNEL-positive cells. It could decrease the cytochrome c release (P<0.01), inhibit the decrease of MMP (P<0.001) and increase the ATP level (P<0.001) in hippocampal mitochondria compared with the I/R group. CONCLUSION: Atorvastatin treatment in I/R rats decreases oxidative stress, production of ROS, apoptosis rate in neuronal cells, and improves the mitochondrial function. Hence, atorvastatin has a proper neuronal protective effect against the I/R injury in the brain.

The Effect of Vitamin D Replacement on Patient with Subclinical Hypothyroidism: A Pilot Randomized Clinical Trial.

BACKGROUND: Subclinical hypothyroidism (SCH) is characterized by an elevated Thyroid Stimulating Hormone (TSH) with a normal T4. The prevalence of Vitamin D deficiency in patients SCH is high. Some studies suggested that Vitamin D supplements could be reduced serum concentration of TSH so improve SCH and prevent overt hypothyroidism. This study aims to explore the effect of vitamin D replacement on subclinical hypothyroidism. MATERIALS AND METHODS: Fifty-nine patients, diagnosed with both subclinical hypothyroidism and Vitamin D deficiency by the Endocrinology outpatient clinics between January 2018 and March 2019, were included in this trial. The patients with overt hypothyroidism, cardiovascular risk factors, or positive TPO antibody, abnormal T4, and pregnant women were excluded from this study. The 40 subjects were investigated who received vitamin D supplements for two months. Analyses were conducted through paired-samples t-test and independent-samples t-test using SPSS 24 (Armonk, NY: IBM Corp). RESULTS: The mean serum levels of TSH was decreased from 6.89 mIU/l in the pre-test to 3.34 mIU/l in the post-test, and the difference was found to be statistically significant at P<0.001. CONCLUSION: We found that the TSH mean level significantly dropped through the use of vitamin D supplements. Thus, it is recommended that all the patients with subclinical hypothyroidism be screened and treated with vitamin D supplements.

Impact of Physical Activity on the Incidence of Vascular Diseases in Adults with Type 2 Diabetes Mellitus.

BACKGROUND: Diabetes mellitus (DM) is a common metabolic disease worldwide and has many complications. Vascular events are the major complication of DM, which have an important effect on mortality and disability. Physical activity (PA) enhances the vascular function by several pathways. The aim of this study was to evaluate the relationship between PA and vascular diseases in patients with DM. MATERIALS AND METHODS: This study was performed as a case-control study extracted from a prospective epidemiological research study in Iran. Patients with type 2 DM for more than six months as a case group were compared to sex- and age-matched healthy control subjects. The metabolic equivalent of task score was used to evaluate the level of PA and blood glucose, lipid profile, body mass index, overweight, dyslipidemia, glomerular filtration rate, myocardial infarction, unstable angina, and stroke. RESULTS: Overall, 1242 patients with DM were extracted, and 2484 non-DM subjects were investigated. In the case group, 355 (28.6%) and 887 (71.4%) subjects were men and women, respectively, and 710 (28.6%) men and 1774 (71.4%) women were in the control group. The mean metabolic equivalent of task score was 30 and 40.97 in the DM and non-DM groups, respectively (P˂0.001). The frequency of myocardial infarction, stroke, and cardiac ischemia was 44 (3.5%), 37 (3%), and 267 (21.5%) in the DM group, and 54 (2.2%), 43 (1.7%), and 389 (15.7%) in the non-DM group, respectively. CONCLUSION: The incidence of vascular events associated with PA level in patients with DM and adherence to regular PA reduced vascular events and DM complications.

Autologous bone marrow-derived CD133 cells with core decompression as a novel treatment method for femoral head osteonecrosis: a pilot study.

BACKGROUND: Avascular necrosis (AVN) of femoral head is a progressive bone disease due to ischemia of femoral head; patients experience pain and they can not do normal activity. There is not an effective way to treat the cause of this disease. In recent studies, treatment of this disease using pluripotent stem cell-derived mesenchyme is safe and effective, but this method needs more investigation. In this study, the safety and efficacy of CD133+ cells were evaluated as a novel method of stem cell therapy to treat AVN. METHODS: In this prospective quasi-experimental study, the participants were selected among patients with AVN who were referred to the Royan Cell Therapy Center. Autologous bone marrow-derived CD133+ cells were injected into the necrotic site of the femoral head during core decompression (CD). The Visual Analogue Scale (VAS), Harris Hip Score (HHS), Western Ontario and McMaster Universities Arthritis Index (WOMAC) and walking distance (WD) were measured before and 2, 6 and 12 months after CD. RESULTS: Overall, nine patients (six men and three women) were investigated in this study. Their mean age was 26 years old. All of them significantly improved in VAS, HHS, WOMAC and WD scores and they could do more activity without pain. Also, imaging findings demonstrated significant reductions in joint injuries. Significant complications were not seen in patients. DISCUSSION: This prospective quasi-experimental study demonstrated that, in patients with AVN, a single bone marrow-derived CD133+ cell injection into the necrotic site of the femoral head during CD is safe and effective in providing significant, clinically relevant pain relief and patients could do more activity over 2, 6 and 12 months. This pilot study suggested further clinical trials over an extended assessment period to approve bone marrow-derived CD133+ cell injection to treat AVN.

Intra-articular implantation of autologous bone marrow-derived mesenchymal stromal cells to treat knee osteoarthritis: a randomized, triple-blind, placebo-controlled phase 1/2 clinical trial.

BACKGROUND: The intra-articular implantation of mesenchymal stromal cells (MSCs) as a treatment for knee osteoarthritis (OA) is an emerging new therapy. In this study, patients with knee OA received intra-articular implantations of autologous bone marrow-derived MSCs. We sought to assess the safety and efficacy of this implantation. MATERIALS AND METHODS: This was a phase 1/2 single-center, triple-blind, randomized controlled trial (RCT) with a placebo control. The subjects consisted of patients with knee OA randomly assigned to either an intra-articular implantation of MSCs (40 × 106 cells) or 5 mL normal saline (placebo). Patients were followed up for 6 months after the implantations. The pain level and function improvements for patient-reported outcomes were assessed based on a visual analog scale (VAS), Western Ontario and McMaster Universities Arthritis Index (WOMAC) and its subscales, walking distance, painless walking distance, standing time and knee flexion compared with the placebo group at 3 and 6 months following the implantations. RESULTS: Overall, 43 patients (Kellgren-Lawrence grades 2, 3 and 4) were assigned to either the MSCs (n = 19) or placebo (n = 24) group. Patients who received MSCs experienced significantly greater improvements in WOMAC total score, WOMAC pain and physical function subscales and painless walking distance compared with patients who received placebo. There were no major adverse events attributed to the MSC therapy. CONCLUSION: This randomized, triple-blind, placebo-controlled RCT demonstrated the safety and efficacy of a single intra-articular implantation of 40 × 106 autologous MSCs in patients with knee OA. Intra-articular implantation of MSCs provided significant and clinically relevant pain relief over 6 months versus placebo and could be considered a promising novel treatment for knee OA. We propose that further investigations should be conducted over an extended assessment period and with a larger cohort.

Concomitant use of mesenchymal stem cells and neural stem cells for treatment of spinal cord injury: A combo cell therapy approach.

TREATMENT: with neural stem cells (NSCs) provides a hope to recover the neural damage and compensate for the lost neural structures for restoration of interrupted neural communications above and below the site of injury. However, cell-based therapy approach suffers from many biological barriers and technical caveats which severely hamper the prognosis. The biochemically-rich microenvironment at the site of spinal cord injury (SCI), the continuing neuro-degenerative process and infiltrating immune cells offer a serious barrier to the donor cells. We hypothesized that mesenchymal stem cells (MSCs) concomitantly delivered with NSCs would significantly enhance the effectiveness of cell-based therapy for SCI. In a rodent model of SCI (n = 15 animals/group), MSCs labeled with PKH67 (green fluorescence dye) were delivered on day1 after SCI whereas the same animals were treated with NSCs during the subacute phase on day3 (group-5). In comparison with untreated control (group-1), sham group (without cell treatment; group-2), MSCs alone (group-3) and NSCs alone treated animals (group-4), the combined cell treated animals (group-5) showed significantly higher homing of cells at the site of injury during in vivo imaging. Caspase-3 activity was lower in group-5 (P < 0.05 vs all groups) with concomitant reduction in the pro-inflammatory cytokines IL-1ß and IL-6 (P < 0.05 vs all groups). All cell therapy groups showed significant improvement in neurological function as compared to group-2, however, it was highest in group-5 (P < 0.05 vs all groups). In conclusion, combined treatment with (NSCs + MSCs) enhances NSCs survival and functional recovery in SCI and is superior to the treatment with either of NSCs or MSCs alone.

Evaluation of the Persian Version of Maslach Burnout Inventory-Human Services Survey among Iranian Nurses: Validity and Reliability.

BACKGROUND: Nursing is a critical job in the health care system. However, nurses suffering from poor job conditions suffer from job dissatisfaction, eventually causing burnout. This is a very important concern for the health care system because the turnover of nurses leads to a waste of money and time of this system. Therefore, nurse managers need to find a way to measure and reduce the burnout. The Maslach Burnout Inventory-Human Services Survey (MBI-HSS) is a famous inventory to measure the job burnout in human services. This study aimed to measure the validity and reliability of the Persian version of MBI-HSS. MATERIALS AND METHODS: This study was conducted in two hospitals of Fasa University of Medical Sciences, Fars Province, Iran, in July 2017. Nurses participated with their own discretion in this study and filled the MBI-HSS themselves. The questionnaire consisted of 22 items comprising three dimensions. Exploratory factor analysis and Cronbach's alpha were performed in this study using Stata software, version 12. RESULTS: Overall, 200 nurses were included in this study, with a mean age of 29.48 ± 6 years. The result of the exploratory factor analysis showed that the weight of each item in its own dimension was greater than 0.4 or another dimension. Also, the Cronbach's alpha for 3 dimensions was greater than 0.7. CONCLUSIONS: Our study showed that the Persian version of MBI-HSS has sufficient validity and reliability, similar to that of the original version, for the measurement of burnout in Persian speakers of human services workers.

Cytotoxic and Apoptogenic Effects of Cyanidin-3-Glucoside on the Glioblastoma Cell Line.

OBJECTIVE: Glioblastoma multiforme (GBM) is the most prevalent and aggressive primary cerebral tumor. The median survival time is 15 months despite maximum treatment because the tumor is resistant to most therapeutic modalities. Several studies have indicated chemopreventive and chemotherapeutic activity of cyanidin-3-glucoside (C3G) as an anthocyanin component. We aimed to illustrate the cytotoxic and apoptogenic effects of C3G in the U87 cell line (human GBM cell line). METHODS: Cytotoxic activity was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide tetrazolium assay after treatment with C3G at different concentrations in the U87 cell line. Cisplatin was used as a positive control for 24 and 48 hours. The percentage of apoptotic cells was determined using an Annexin V/propidium iodide assay, and the expression of bax, bcl2, and p53 genes was assessed using real-time polymerase chain reaction. RESULTS: Treatment of U87 cells with 40 µg/mL of C3G resulted in 32% apoptotic cells after 24 hours. To further confirm that C3G treatment induced apoptosis in U87 cells, RNA expression of bax, bcl2, and p53 genes was investigated after treatment. Real-time polymerase chain reaction indicated that the expression of bax and p53 increased, whereas the expression of bcl2 decreased. CONCLUSIONS: C3G had an apoptogenic effect in the GBM cell line. New information regarding the therapeutic effects of C3G in GBM could ultimately lead to the production of new drugs.

Evaluation of medicine prescription pattern using World Health Organization prescribing indicators in Iran: A cross-sectional study.

OBJECTIVE: The objective was to quantify the specialists' prescription pattern in Iran and to point out the prescribing behavioral differences among several specialties. METHODS: A retrospective cross-sectional study was carried out on the claim data. National prescription data were obtained on the basis of the claims that the pharmacies submitted to the insurers during 1 year period of the study. More than 85 million prescriptions were analyzed using "Rx-Analyst" software that is designed and applied by National Committee of Rational Use of Medicines in Iran. Specified medical specialties were considered and the World Health Organization prescription indicators were used to evaluate the physicians' prescribing behavior. FINDINGS: Average items per prescription were ranged from 3.68 in cardiologists' to 2.06 in dermatologists' prescriptions. The highest and the lowest mean price were belonged to neurologists' and ophthalmologists' prescriptions, respectively. In addition, 45% of patients received antibiotics, 41% of patients received injectable form of drugs, and 23% received corticosteroids. A high tendency toward prescribing corticosteroids and antibiotics as well as an injectable form of medicines was observed among general physicians. CONCLUSION: There is an inevitable need to improve prescription habits among different specialties, especially among general practitioners. This causes the policymakers to put more emphasis on priorities such as continuous education.

Management of stroke as described by Ibn Sina (Avicenna) in the Canon of Medicine.

Stroke or cerebrovascular accident (CVA) is caused by a disturbance of the blood supply to the brain and an accruing loss of brain function. The first recorded observations were in 2455 BC and it has been studied intensely by ancient physicians throughout history. In the early medieval period, Ibn Sina (980-1025 AD) called stroke sekteh and described it extensively. Some of Ibn Sina's definitions and his etiology of stroke are based on humoral theories and cannot be compared with medical current concepts, but most of his descriptions concur with current definitions. This review examines the definition and etiology, clinical manifestations, prognosis, differential diagnosis, and interventions for stroke based on Ibn Sina's epic work, Canon of Medicine. The pharmacological effects of medicinal herbs suggested by Ibn Sina for stroke are examined in light of current knowledge.

The protective and therapeutic effects of alpha-solanine on mice breast cancer.

Alpha-solanine, a naturally steroidal glycoalkaloid, is found in leaves and fruits of plants as a defensive agent against fungi, bacteria and insects. Herein, we investigated solanine toxicity in vitro and in vivo, and assessed its protective and the therapeutic effects on a typical animal model of breast cancer. The study conducted in three series of experiments to obtain (i) solanine effects on cell viability of mammary carcinoma cells, (ii) in vivo toxicity of solanine, and (iv) the protective and therapeutic effects of solanine on animal model of breast cancer. Alpha-solanine significantly suppressed proliferation of mouse mammary carcinoma cells both in vitro and in vivo (P<0.05). Under the dosing procedure, 5 mg/kg solanine has been chosen for assessing its protective and therapeutic effects in mice breast cancer. Tumor take rate in the solanine-treated group was zero compared with a 75% rate in its respective control group (P<0.05). The average tumor size and weight were significantly lower in solanine-treated animals than its respective control ones (P<0.05). Proapoptotic Bax protein expression increased in breast tumor by solanine compared with its respective control group (P<0.05). Antiapoptotic Bcl-2 protein expression found to be lower in solanine-treated animals (P<0.05). Proliferative and angiogenic parameters greatly decreased in solanine-treated mice (P<0.05). Data provide evidence that solanine exerts a significant chemoprotective and chemotherapeutic effects on an animal model of breast cancer through apoptosis induction, cell proliferation and angiogenesis inhibition. These findings reveal a new therapeutic potential for solanine in cancer.