Intrathecal injection of human placental mesenchymal stem cells derived exosomes significantly improves functional recovery in spinal cord injured rats.

BACKGROUND: Spinal cord injury (SCI) due to lack of restoration of damaged neuronal cells is associated with sensorimotor impairment. This study was focused on using the human placental mesenchymal stem cells- exosome (HPMSCs- Exosomes) in an animal model of severe SCI under myelogram procedure. METHODS AND RESULTS: Intrathecal injection of exosomes was performed in the acute phase of SCI in female rats. The improved functional recovery of the animals was followed for 6 weeks in control (saline, n = 6) and HPMSCs- EXO (HPMSCs-Exosomes, n = 6) groups. Pathological changes and glial scar size were evaluated. The Immunohistochemistry (IHC) of GFAP and NF200 factors as well as the apoptosis assay was investigated in the tissue samples from the injury site. The results demonstrated that HPMSCs-exosomes can improve motor function by attenuating apoptosis of neurons at the injury site, decreasing GFAP expression and increasing NF200 in the HPMSCs-EXO group. Also, HPMSCs-exosomes by preventing the formation of cavities causes preservation of tissue in SCI rats. CONCLUSIONS: These findings demonstrate the effectiveness of HPMSC-Exosomes as a therapeutic method to improve functional recovery, reduce pathological changes associated with injury, and prevent chronicity after SCI. The neuroprotective and anti-apoptotic potential of HPMSCs- Exosomes may be a promising therapeutic approach for SCI. Another result was the importance of intrathecal injection of exosomes in the acute phase, which accelerated the healing process. Furthermore, the myelogram can be a feasible and suitable method to confirm the accuracy of intrathecal injection and examine the subarachnoid space in the laboratory animals.

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/ .

Global and Regional DNA methylation silencing of PPARγ Associated with Glioblastoma Multiforme Pathogenesis.

BACKGROUND: The relationship between peroxisome proliferator-activated receptor gamma (PPARγ) expression level and epigenetic modifications occurring in glioblastoma multiforme (GBM) pathogenesis is largely unknown. Herein, we examine the association of PPARγ expression with its promoter and genomic global DNA methylation status, as well as DNA methyltransferases (DNMTs) gene expression in GBM patients. METHODS: We examined the patterns of promoter methylation and PPARγ expression in 26 GBM tissues and 13 adjacent non-tumor tissues by methylation-specific PCR (MSP), real-time PCR, and ELISA, respectively. Also, we examined the genomic global 5-methyl cytosine levels and DNMTs gene expression using ELISA and real-time PCR methods, respectively. RESULTS: We found that hypermethylation on a specific region of the PPARγ promoter is significantly associated with the downregulation of the PPARγ gene and protein level in GBM patients. Interestingly, the amount of 5-methyl cytosine level was significantly reduced in GBM patients and positively correlated with PPARγ protein expression. Furthermore, the expression level of DNMT1, DNMT3A, and 3B were upregulated in GBM patients and the average expression level of all three DNMTs was positively correlated with tumor area. Also, we found that tumors from cortical regions exhibited a higher global DNA hypomethylation and PPARγ hypermethylation was related to the increase in GBM risk. CONCLUSION: Our study demonstrated that global DNA methylation and PPARγ epigenetic silencing is associated with the GBM risk. Our data provide a novel molecular mechanistic insight into epigenetic silencing of PPARγ in GBM patients that may be relevant as a key tumor marker for GBM pathogenesis.

Safety and feasibility of autologous olfactory ensheathing cell and bone marrow mesenchymal stem cell co-transplantation in chronic human spinal cord injury: a clinical trial.

STUDY DESIGN: This is a phase I clinical trial. OBJECTIVES: Our objective was to assess the safety and feasibility of autologous mucosal olfactory ensheathing cell (OEC) and bone marrow mesenchymal stem cell (MSC) co-transplantation in people with chronic, complete (American Spinal Injury Association (ASIA) Impairment Scale (AIS) classification A) spinal cord injury (SCI). SETTING: This study was performed at Shohada Tajrish Hospital, Tehran, Iran. METHODS: Three individuals with the traumatic SCI of the thoracic level were enrolled. They received the autologous OEC and MSC combination through the lumbar puncture. All adverse events and possible functional outcomes were documented performing pre- and post-operative general clinical examination, magnetic resonance imaging (MRI), neurological assessment based on the International Standard of Neurological Classification for SCI, and functional evaluation using Spinal Cord Independence Measure version III (SCIM III). RESULTS: No serious safety issue was recorded during the 2 years of follow-up. MRI findings remained unchanged with no neoplastic tissue formation. AIS improved from A to B in one of the participants. SCIM III evaluation also showed some degrees of progress in this participant's functional ability. The two other research participants had negligible or no improvement in their sensory scores without any changes in the AIS and SCIM III scores. No motor recovery was observed in any of the participants. CONCLUSIONS: Overall, this 2-year trial was not associated with any adverse findings, which may suggest the safety of autologous OEC and bone marrow MSC combination for the treatment of human SCI.

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.

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.

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.

Neuroregenerative effects of olfactory ensheathing cells transplanted in a multi-layered conductive nanofibrous conduit in peripheral nerve repair in rats.

BACKGROUND: The purpose of this study was to evaluate the efficacy of a multi-layered conductive nanofibrous hollow conduit in combination with olfactory ensheathing cells (OEC) to promote peripheral nerve regeneration. We aimed to harness both the topographical and electrical cues of the aligned conductive nanofibrous single-walled carbon nanotube/ poly (L-lactic acid) (SWCNT/PLLA) scaffolds along with the neurotrophic features of OEC in a nerve tissue engineered approach. RESULTS: We demonstrated that SWCNT/PLLA composite scaffolds support the adhesion, growth, survival and proliferation of OEC. Using microsurgical techniques, the tissue engineered nerve conduits were interposed into an 8 mm gap in sciatic nerve defects in rats. Functional recovery was evaluated using sciatic functional index (SFI) fortnightly after the surgery. Histological analyses including immunohistochemistry for S100 and NF markers along with toluidine blue staining (nerve thickness) and TEM imaging (myelin sheath thickness) of the sections from middle and distal parts of nerve grafts showed an increased regeneration in cell/scaffold group compared with cell-free scaffold and silicone groups. Neural regeneration in cell/scaffold group was very closely similar to autograft group, as deduced from SFI scores and histological assessments. CONCLUSIONS: Our results indicated that the tissue engineered construct made of rolled sheet of SWCNT/PLLA nanofibrous scaffolds and OEC could promote axonal outgrowth and peripheral nerve regeneration suggesting them as a promising alternative in nerve tissue engineering.

Hyperbaric Oxygen Therapy as an Alternative Therapeutic Option for Radiation-Induced Necrosis Following Radiotherapy for Intracranial Pathologies.

BACKGROUND: Radiotherapy (RT) is a feasible adjuvant therapeutic option for managing intracranial pathologies. One of the late complications of RT that frequently develops within months following RT is radiation necrosis (RN). Corticosteroids are the first-line therapeutic option for RNs; however, in case of unfavorable outcomes or intolerability, several other options, including bevacizumab, laser interstitial thermal therapy, surgery, and hyperbaric oxygen therapy (HBOT). Our goal was to investigate the feasibility and efficacy of the application of HBOT in RNs following RT and help physicians make decisions based on the latest data in the literature. METHODS: We provide a comprehensive review of the literature on the current issues of utilization of HBOT in RNs. RESULTS: We included 11 studies with a total of 46 patients who underwent HBOT. Most of the cases were diagnosed with brain tumors or arteriovenous malformations. Improvement was achieved in most of the cases. DISCUSSION: HBOT is a noninvasive therapeutic intervention that can play a role in adjuvant therapy concurrent with RT and chemotherapy and treating RNs. HBOT resolves the RN through 3 mechanisms, including angiogenesis, anti-inflammatory modulation, and cellular repair. Previous studies demonstrated that HBOT is a feasible and well-tolerated therapeutic option that has shown promising results in improving clinical and radiological outcomes in intracranial RNs. Complications of HBOT are usually mild and reversible. CONCLUSIONS: HBOT is a feasible and effective therapeutic option in steroid-refractory RNs and is associated with favorable outcomes and a low rate of side effects.

Efficacy and Safety of Vaccines After Conventional Treatments for Survival of Gliomas: A Systematic Review and Meta-Analysis.

Background: Malignant gliomas are known with poor prognosis and low rate of survival among brain tumors. Resection surgery is followed by chemotherapy and radiotherapy in treatment of gliomas which is known as the conventional treatment. However, this treatment method results in low survival rate. Vaccination has been suggested as a type of immunotherapy to increase survival rate of glioma patients. Different types of vaccines have been developed that are mainly classified in two groups including peptide vaccines and cell-based vaccines. However, there are still conflicts about which type of vaccines is more efficient for malignant glioma treatment. Methods: Phase Ⅰ/Ⅱ clinical trials which compared the efficacy and safety of various vaccines with conventional treatments were searched in databases through November 2022. Overall survival (OS) rate, progression free survival (PFS), and OS duration were used for calculation of pooled risk ratio (RR). In addition, fatigue, headache, nausea, diarrhea, and flu-like syndrome were used for evaluating the safety of vaccines therapy in glioma patients. Results: A total of twelve articles were included in the present meta-analysis. Comparison of OS rate between vaccinated groups and control groups who underwent only conventional treatments showed a significant increase in OS rate in vaccinated patients (I2 = 0%, RR = 11.17, 95% CI: 2.460-50.225). PFS rate was better in vaccinated glioma patients (I2 = 83%, RR = 2.87, 95% CI: 1.63-5.03). Assessment of safety demonstrated that skin reaction (I2 = 0.0%, RR = 3.654; 95% CI: 1.711-7.801, p-value = 0.0058) and flu-like syndrome were significantly more frequent adverse effects win vaccinated groups compared to the control group. Subgroup analysis also showed that vaccination leads to better OS duration in recurrent gliomas than primary gliomas, and in LGG than HGG (p-value = 0). On the other hand, personalized vaccines showed better OS duration than non-personalized vaccines (p-value = 0). Conclusion: Vaccination is a type of immunotherapy which shows promising efficacy in treatment of malignant glioma patients in terms of OS, PFS and duration of survival. In addition, AFTV, peptide, and dendritic cell-based vaccines are among the most efficient vaccines for gliomas. Personalized vaccines also showed considerable efficacy for glioma treatments.

Epidemiology of malignant gliomas in Iran: first report of Iranian National Population-based Cancer Registry, 2009-2017.

OBJECTIVE: Malignant gliomas constitute the most common type of primary malignant brain tumors. Most previous studies have evaluated the epidemiology of malignant gliomas in developed countries. Hence, there is a lack of evidence in this regard from developing countries. This study is the first epidemiological report on the status of malignant glioma in Iran between 2009 and 2017. METHODS: Data from the Iranian National Population-based Cancer Registry (covering 98% of the Iranian population) on CNS tumors recorded from 2009 to 2017 were used for analysis. Age-adjusted incidence rates were calculated by sex, tumor histology, tumor site, and year of diagnosis. Trend analysis of incidence rates was also performed. Survival data were recorded and the Cox proportional hazards model was used to evaluate underlying risk factors. RESULTS: A total of 8484 patients were diagnosed with malignant glioma between 2009 and 2017 in Iran. The overall age-adjusted incidence rate of malignant gliomas over the 9-year period was 1.71 per 100,000 persons. The most common histology of malignant gliomas was glioblastoma (81.4%). A significant increase in the incidence of malignant gliomas was found between 2009 and 2012. The median overall survival was 13.0 (95% CI 12.6-13.5) months over the study period. Older age groups, higher tumor grade, male sex, the first half of the study period, and receiving no treatment were significantly associated with worse prognoses. CONCLUSIONS: This study is the latest epidemiological report on the status of malignant gliomas in Iran. Although the overall incidence rate was lower than the rates in developed countries, several findings were consistent with those in prior reports.

Management of Glioblastoma Multiforme During the Severe Acute Respiratory Syndrome Coronavirus 2 Pandemic: A Review of the Literature.

BACKGROUND: Patients with glioblastoma multiforme (GBM) and other patients with cancer are at a greater risk of developing severe complications as a result of coronavirus disease 2019 (COVID-19) infection. Therefore, it is crucial to adjust therapeutic approaches to reduce exposure and complications and achieve the most appropriate treatment outcomes. OBJECTIVE: Our goal was to help physicians to make decisions based on the latest data in the literature. METHOD: We provide a comprehensive review of the literature on the current issues of GBM and COVID-19 infection. RESULTS: The mortality of patients with diffuse glioma as a result of COVID-19 infection was 39%, which is higher than in the general population. The statistics showed that 84.5% of patients with diagnosed brain cancer (mostly GBM) and 89.9% of their caregivers received COVID-19 vaccines. The decision to apply different therapeutic approaches must be made individually based on age, tumor grade, molecular profile, and performance status. The advantages and disadvantages of adjuvant radiotherapy and chemotherapy after the surgery should be evaluated carefully. In the setting of the follow-up period, special considerations must be considered to minimize COVID-19 exposure. CONCLUSIONS: The pandemic altered medical approaches worldwide, and the management of patients in an immunocompromised state, such as patients with GBM, is challenging; therefore, special considerations must be considered.

Gliomatosis cerebri with blindness: A case report with literature review.

Cerebral gliomatosis (GC) is a rare diffuse infiltrative growth pattern of glioma with nonspecific clinical manifestations like visual impairment that may involve bilateral temporal lobes. Herpes simplex encephalitis (HSE) and limbic encephalitis (LE) can also lead to temporal lobe involvement. Differentiating these entities is necessary for patients with misleading presentations and imaging findings. To the best of our knowledge, this is the third case of GC presenting with blindness. The patient was a 35 years-old male in a drug rehabilitation center for heroin addiction. He presented with a headache, a single episode of seizure, and a 2-month history of bilateral decrease in visual acuity, which had acutely worsened. Magnetic resonance imaging (MRI) and computed tomography (CT) showed bilateral temporal lobe involvement. Ophthalmological studies showed bilateral papilledema, absence of visual evoked potential, and thickening of the retinal nerve fiber layer. Due to this clinical presentation, normal laboratory data, and suspicious MRI findings, further investigation with magnetic resonance spectroscopy (MRS) was performed. Results showed a greatly increased ratio of choline to creatinine(Cr) or N-acetyl aspartate (NAA), suggesting a neoplastic nature of the disease. Subsequently, the patient was referred for a brain tissue biopsy with a suspicion of malignancy. The pathology results revealed adult-type diffuse glioma with isocitrate dehydrogenase (IDH) mutation. Bilateral blindness, as well as bilateral temporal lobe involvement, each has many different causes. However, as demonstrated in this study, adult-type diffuse glioma must be considered a rare cause of concomitant bilateral temporal lobe involvement and blindness.

Safety and Potential Efficacy of Selective Dorsal Rhizotomy in Adults with Spinal Cord Injury-Induced Spasticity: An Open-Label, Non-Randomized, Single-Arm Trial.

BACKGROUND: Despite the abundant literature on the use of selective dorsal rhizotomy (SDR) in spastic cerebral palsy, no investigation has evaluated its use in adult patients with chronic spinal cord injury (SCI)-induced spasticity. The present investigation aimed to evaluate the safety and potential efficacy of SDR in chronic SCI-induced spasticity for the first time. METHODS: In this open-label, single-arm, non-randomized clinical trial, all patients were assigned to the single study intervention arm and underwent SDR. The primary outcome measure was the safety profile of SDR. Secondary outcome measures were Modified Ashworth Scale, Penn Spasm Frequency Scale, visual analog scale for spasticity, Spinal Cord Injury Spasticity Tool, Spinal Cord Independence measure version III, and Short Form 36 Health Survey Questionnaire. RESULTS: Six patients with cervical SCI and 4 with thoracic SCI were allocated to the single study intervention arm. No adverse event attributable to the SDR was found. Moreover, all secondary outcome measures of the study improved significantly over the study period (P < 0.001). Multiple regression analysis also found a significant association between level of injury and changes in average Modified Ashworth Scale scores (P = 0.041), Spinal Cord Injury Spasticity Tool score (P = 0.013), and Spinal Cord Independence measure version III total (P = 0.002) and mobility domain scores (P = 0.004) at 12-month postoperatively. CONCLUSIONS: This clinical trial indicated that SDR is a safe and potentially effective procedure in patients with severe and intractable SCI-induced spasticity. However, future clinical trials with larger sample sizes and adequate power are required to validate our findings regarding efficacy.

Case report: Stem cell-based suicide gene therapy mediated by the herpes simplex virus thymidine kinase gene reduces tumor progression in multifocal glioblastoma.

Introduction: The prognosis for glioblastoma multiforme (GBM), a malignant brain tumor, is poor despite recent advancements in treatments. Suicide gene therapy is a therapeutic strategy for cancer that requires a gene to encode a prodrug-activating enzyme which is then transduced into a vector, such as mesenchymal stem cells (MSCs). The vector is then injected into the tumor tissue and exerts its antitumor effects. Case presentation: A 37-year-old man presented to our department with two evident foci of glioblastoma multiforme at the left frontal and left parietal lobes. The patient received an injection of bone marrow-derived MSCs delivering the herpes simplex virus thymidine kinase (HSV-tk) gene to the frontal focus of the tumor, followed by ganciclovir administration as a prodrug for 14 days. For follow-up, the patient was periodically assessed using magnetic resonance imaging (MRI). The growth and recurrence patterns of the foci were assessed. After the injection on 09 February 2019, the patient's follow-up appointment on 19 December 2019 MRI revealed a recurrence of parietal focus. However, the frontal focus had a slight and unremarkable enhancement. On the last follow-up (18 March 2020), the left frontal focus had no prominent recurrence; however, the size of the left parietal focus increased and extended to the contralateral hemisphere through the corpus callosum. Eventually, the patient passed away on 16 July 2020 (progression-free survival (PFS) = 293 days, overall survival (OS) = 513 days). Conclusion: The gliomatous focus (frontal) treated with bone marrow-derived MSCs carrying the HSV-TK gene had a different pattern of growth and recurrence compared with the non-treated one (parietal). Trial registration: IRCT20200502047277N2. Registered 10 May 2020-Retrospectively registered, https://eng.irct.ir/trial/48110.

Effects of Preoperative Use of Povidone-Iodine-Impregnated Dressing on Postoperative Rate of Surgical Site Infection in Patients Undergoing Posterolateral Lumbar Spinal Fusion Surgery: A Randomized, Nonblinded, Active-Controlled Trial.

BACKGROUND AND OBJECTIVES: No study has evaluated the efficacy of using preoperative antiseptic dressings in reducing the rate of surgical site infection (SSI) in spine surgery thus far. To investigate the efficacy of the use of preoperative povidone-iodine-impregnated antiseptic dressings in patients undergoing instrumented posterolateral lumbar spinal fusion. METHODS: This was a randomized, nonblinded, active-controlled, parallel-group clinical trial. Patients were randomly assigned to the 2 study groups, including treatment and control. Patients in the treatment group received povidone-iodine-impregnated antiseptic dressing applied to the anticipated incision site 12 hours before the operation. The control group merely received the standard perioperative care with no additional intervention or placebo. Patients were followed up for 90 days, and SSIs were recorded. RESULTS: A total of 200 patients were included in this study (100 in each arm). Three cases of SSI were observed in the treatment group compared with 12 in the control one. A significant reduction in the postoperative rate of SSI was observed in the treatment group compared with the control one (P = .029). In addition to study intervention (P = .029), body mass index (P = .005), smoking status (P = .005), duration of the procedure (P = .003), American Society of Anesthesiologists class (P = .002), and diabetes mellitus (P < .001) were significantly associated with the postoperative rate of SSI. CONCLUSION: To the best of our knowledge, this study for the first time showed that preoperative use of antiseptic dressings is significantly effective in reducing the rate of SSI in instrumented posterior lumbar spinal fusion surgery. Future studies are warranted to evaluate the efficacy of different preparations or the effectiveness of the present one in patients undergoing spine procedures with other surgical characteristics.

Beneficial effects of the combination of BCc1 and Hep-S nanochelating-based medicines on IL-6 in hospitalized moderate COVID-19 adult patients: a randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: In the severe forms of COVID-19 and many other infectious diseases, the patients develop a cytokine storm syndrome (CSS) where pro-inflammatory cytokines such as IL-6 and TNF-α play a key role in the development of this serious process. Selenium and iron are two important trace minerals, and their metabolism is tightly connected to immune system function. Numerous studies highlight the role of selenium and iron metabolism changes in the procedure of COVID-19 inflammation. The immunomodulator effect of nanomedicines that are synthesized based on nanochelating technology has been proved in previous studies. In the present study, the effects of the combination of BCc1(with iron-chelating property) and Hep-S (containing selenium) nanomedicines on mentioned cytokines levels in hospitalized moderate COVID-19 patients were evaluated. METHODS: Laboratory-confirmed moderate COVID-19 patients were enrolled to participate in a randomized, double-blind, placebo-controlled study in two separate groups: combination of BCc1 and Hep-S (N = 62) (treatment) or placebo (N = 60) (placebo). The blood samples were taken before medications on day zero, at discharge, and 28 days after consumption to measure hematological and biochemical parameters and cytokine levels. The clinical symptoms of all the patients were recorded according to an assessment questionnaire before the start of the treatment and on days 3 and discharge day. RESULTS: The results revealed that consumption of the nanomedicines led to a significant decrease in the mean level of IL-6 cytokine, and at the end of the study, there was a 77% downward trend in IL-6 in the nanomedicine group, while an 18% increase in the placebo group (p < 0.05). In addition, the patients in the nanomedicines group had lower TNF-α levels; accordingly, there was a 21% decrease in TNF-α level in the treatment group, while a 31% increase in this cytokine level in the placebo was observed (p > 0.05). On the other hand, in nanomedicines treated groups, clinical scores of coughing, fatigue, and need for oxygen therapy improved. CONCLUSIONS: In conclusion, the combination of BCc1 and Hep-S inhibits IL-6 as a highly important and well-known cytokine in COVID-19 pathophysiology and presents a promising view for immunomodulation that can manage CSS. TRIAL REGISTRATION: Iranian Registry of Clinical Trials RCT20170731035423N2 . Registered on June 12, 2020.

Obesity and posterior spine fusion surgery: A prospective observational study.

OBJECTIVE: Obesity is an important issue in spine surgeries due to its negative effects on the quality of surgery, more complications, and adverse consequences. This study compared the outcomes of obese and non-obese patients undergoing instrumented posterior fusion surgery in the lumbar spine. METHODS: In this prospective observational study conducted in a university hospital, we compared the rate of vertebral fusion, surgical site infection (SSI), pain, and disability in 160 patients undergoing instrumented posterior fusion surgery in the lumbar spine between obese and non-obese patients. RESULTS: A total of 160 patients, 80 in each group, were included. Obesity was associated with a significantly higher prevalence of diabetes, hypertension, coronary artery disease (CAD), and chronic obstructive pulmonary disease (COPD) (P < 0.05). Poor outcomes, including non-fusion, SSI, pain, and disability were significantly higher in the obese group versus the non-obese group (P < 0.05). The multiple regression analysis indicated that obesity is an independent predictor of non-fusion, more pain, disability, and SSI. CONCLUSION: These findings suggest that the association of obesity with postoperative complications may help in the evaluation and selection of patients before surgery and preoperative weight management is important.

Response of human glioblastoma cells to hyperthermia: Cellular apoptosis and molecular events.

Glioblastoma multiforme (GBM) also categorized as a grade IV astrocytoma, is an aggressive brain tumor which invades the surrounding brain tissue. Hyperthermia is known to be effective for chemo-radiotherapy to sensitize cancer cells to radiation as a treatment option for patients with GBM. The current study was performed in order to assess and compare the properties of the astrocyte and cancer stem cells isolated from glioblastoma exposed to hyperthermia. Astrocytes and cancer stem cells were isolated from human glioblastoma tissue. Glioblastoma tissues were digested and cultured in culture medium supplemented with B27, basic fibroblast growth factor and epidermal growth factor. The morphology and specific markers were evaluated in astrocyte and cancer stem cell of human glioblastoma through immunocytochemistry and quantitative real-time RT-PCR. The multipotentiality of cancer stem cells was presented using differentiation potential into neurons, oligodendrocytes, and astrocytes. For hyperthermia, cells were exposed to temperatures at 4246 °C for 1 h using a water bath. Cell survival rate by MTT assay and apoptosis using quantitative real-time RT-PCR and western blot were evaluated. Results demonstrated that there were two morphology types in cell culture including epithelioid morphology and fibroblastic morphology. Astrocytes were confirmed via expression of the Glial fibrillary acidic protein (GFAP) protein; whereas, cancer stem cells (CSCs) were round and floating in the culture medium. Immunocytochemical staining indicated that nestin, CD133 and SRY-box 2 (SOX2) antigens were positively expressed in primary neurospheres. Results indicated that cancer stem cells of glioblastoma are multipotent and are able to differentiate into neurons, oligodendrocytes, and astrocytes. The current study obtained evidence via apoptosis evaluation that CSCs are resistant to hyperthermia when compared to astrocytes isolated from glioblastoma. Furthermore, hyperthermia was demonstrated to decrease cell resistance, which may be effective for chemo-radiotherapy to sensitize cancer cells to radiation. Taken together, CSCs of glioblastoma could be used as a powerful tool for evaluating the tumorigenesis process in the brain and developing novel therapies for treatment of GBM.

Protein Supplement and Enhanced Recovery After Posterior Spine Fusion Surgery: A Randomized, Double-blind, Placebo-controlled Trial.

STUDY DESIGN: This was a randomized, double-blind clinical trial study. OBJECTIVE: The objective of this study was to evaluate the effect of protein supplementation on vertebral fusion and enhanced recovery after posterior spine fusion (PSF) surgery. SUMMARY OF BACKGROUND DATA: Nonfusion is one of the most common complications of lumbar spine surgery. It has been shown that protein plays an important role in bone repair; however, its correlation to vertebral fusion following PSF surgery is unknown. PATIENTS AND METHODS: In this randomized, double-blind clinical trial study, the intervention group received a diet with 1.2 g of protein plus high-protein supplement (36 g whey protein), and the control group received a similar diet, except for starch as a placebo from 48 hours before to 1 month after surgery. RESULTS: The intervention group showed a significantly higher rate of vertebral fusion compared with the control group (P=0.019). Surgical site infection and pain were significantly lower in the intervention group. A significant difference was found in the wound healing rate in favor of the intervention group. The rates of decrease in serum high-sensitivity C-reactive protein levels and increase in serum levels of insulin-like growth factor 1, albumin, total protein, and alkaline phosphatase were greater in the intervention group than in the control group (P<0.001). CONCLUSIONS: Increased protein intake improves vertebral fusion and enhances recovery in patients undergoing PSF. This was the first study to investigate the effect of protein on fusion and healing factors; as a result, further clinical trials are needed to confirm the current results.