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.

COVID-19 in pregnancy: A cross-sectional study on clinical features, disease severity, and health outcome.

Assessing the impact of coronavirus disease 2019 (COVID-19) reveals unique challenges for pregnant women, who experience distinct clinical manifestations and health outcomes compared to their non-pregnant counterparts. We aimed to evaluate the clinical features, disease severity, and health outcomes of COVID-19 in pregnant women and compare them to those of non-pregnant women. In this population-based study, we included all women diagnosed with COVID-19 across the province of Tehran during the first two years of the epidemic. Descriptive statistics, the chi-squared test, and the logistic regression model were applied. Overall, 79,338 non-pregnant women and 3,249 pregnant women diagnosed with COVID-19 were included. Pregnant women were most commonly in the age group of 25-34 years (54%, n = 1758), while the age group of 34-44 years had the highest representation among non-pregnant women (56%, n = 44,492). After accounting for age and comorbidities, pregnancy was associated with an increased risk of requiring intensive care (odds ratio [OR] 1.38, confidence interval [CI] 1.223-1.564). However, the probability of dying due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was lower in pregnant women compared to non-pregnant women (OR 0.55, CI 0.394-0.793). Cough (41%) and fever (30%) were the most frequent clinical presentations in pregnant women, whereas cough (57%) and muscle ache (38%) were the most common symptoms in non-pregnant women. Furthermore, diarrhea (P < 0.001) and skin lesions (P < 0.001) were reported more frequently by pregnant patients than non-pregnant patients. A significant prevalence of diabetes (P < 0.001), hypertension (P < 0.001), cancers (P < 0.001), and chronic hematological diseases (P < 0.001) was observed in pregnant patients. In conclusion, COVID-19-infected pregnant women exhibit different clinical manifestations and a more severe clinical course but have better health outcomes compared to their non-pregnant counterparts.

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.

Migrant Health and COVID-19 Pandemic: A Cross-sectional Study of Characteristics, Clinical Features, and Health Outcome from Iran.

BACKGROUND: As the pandemic unfolds, major concerns remain with those in disadvantaged positions who may be disproportionately affected. This paper aimed to present the characteristics of COVID-19 immigrant patients and investigate whether they were disproportionately affected by COVID-19 pandemic. METHODS: A cross-sectional study was performed using data on 589,146 patients diagnosed with COVID-19 in Iran. Descriptive analyses were used to summarize the study population's characteristics. Chi-squared test and logistic regression model were applied. RESULTS: After accounting for possible confounding covariates, being an immigrant was significantly associated with increased risk of death due to COVID-19 (OR 1.64, CI 1.568-1.727). When compared to Iranian-born patients, the prevalence of low blood oxygen levels on admission was higher among immigrant patients (53.9% versus 47.7%, P value < 0.001). Moreover, greater proportions of immigrants who were diagnosed with COVID-19 were admitted to an ICU (17% versus 15.8%, P value < 0.001). Patients aged 65 and above were the largest age category in both populations. However, there was a significant difference between the age profiles of patients, with children under the age of eighteen presenting 16% of immigrant patients vs 6.6% of Iranian-born patients (P value < 0.001). In both groups, more men were affected by COVID-19 than women, yet the sex bias was more prominent for migrant patients (P value < 0.001). CONCLUSION: The evidence from this study revealed that immigrant patients infected with COVID-19 were more likely to suffer from severe health outcome of the disease compared to Iranian-born patients.

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.

The most places at risk surrounding the COVID-19 treatment hospitals in an urban environment- case study: Tehran city.

Investigations on the spatial patterns of COVID-19 spreading indicate the possibility of the virus transmission by moving infected people in an urban area. Hospitals are the most susceptible locations due to the COVID-19 contaminations in metropolises. This paper aims to find the riskiest places surrounding the hospitals using an MLP-ANN. The main contribution is discovering the influence zone of COVID-19 treatment hospitals and the main spatial factors around them that increase the prevalence of COVID-19. The innovation of this paper is to find the most relevant spatial factors regarding the distance from central hospitals modeling the risk level of the study area. Therefore, eight hospitals with two service areas for each of them are computed with [0-500] and [500-1000] meters distance. Besides, five spatial factors have been considered, consist of the location of patients' financial transactions, the distance of streets from hospitals, the distance of highways from hospitals, the distance of the non-residential land use from the hospitals, and the hospital patient number. The implementation results revealed a meaningful relation between the distance from the hospitals and patient density. The RMSE and R measures are 0.00734 and 0.94635 for [0-500 m] while these quantities are 0.054088 and 0.902725 for [500-1000 m] respectively. These values indicate the role of distance to central hospitals for COVID-19 treatment. Moreover, a sensitivity analysis demonstrated that the number of patients' transactions and the distance of the non-residential land use from the hospitals are two dominant factors for virus propagation. The results help urban managers to begin preventative strategies to decrease the community incidence rate in high-risk places.

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.

Intracerebral Administration of Autologous Mesenchymal Stem Cells as HSV-TK Gene Vehicle for Treatment of Glioblastoma Multiform: Safety and Feasibility Assessment.

Widespread investigation has revealed the promising ability of suicidal genes in the treatment of glioma tumors; nevertheless, promoting their effects relies on the ability to apply suitable vehicles and techniques. In this study, the safety and feasibility of using bone marrow-derived mesenchymal stem cells (MSCs) in combination with prodrug for treatment of patients with primary and secondary glioblastoma multiform (GBM) was assessed. Five GBM patients were recruited. Following gross total resection of the tumor and adjuvant radiotherapy and chemotherapy, intracerebral injection of autologous MSCs transduced with lentivirus containing herpes simplex virus thymidine kinase (HSV-TK) was performed followed by intravenous administration of ganciclovir for 2 weeks. The treatment was well tolerated by all patients. Mild-to-moderate fever, headache, and cerebrospinal fluid leukocytosis were evident in three, two, and one patient, respectively. The progression-free survival (PFS) and overall survival (OS) of patients were 95.79 ± 51.40 and 128.85 ± 48.81 weeks, respectively. The 1-year PFS and OS were 60% and 100%, respectively, among our patients, and two patients had more than 3 years of OS and more than 2 years of PFS. It seems that intracerebral administration of bone marrow MSC containing the HSV-TK gene in combination with intravenous ganciclovir would be safe and feasible in the treatment of patients with GBM.

Cauda equina syndrome due to herpes simplex virus type 2-associated meningoradiculitis (Elsberg syndrome) after posterior lumbar spinal fusion surgery: Case report and review of literature.

Elsberg syndrome is a rare but well-defined clinical condition, including acute or subacute lumbosacral meningoradiculitis, which might be accompanied by myelitis and is often associated with herpes simplex virus type 2 (HSV-2) infection. We report the case of an immunocompetent 24-year-old man who presented with perineal pain, saddle hypoesthesia, and urinary retention associated with Elsberg syndrome due to HSV-2 infection 20-day after the posterior lumbar spinal fusion surgery. Lumbar magnetic resonance imaging (MRI) with gadolinium enhancement showed mildly enhanced and swollen right sacral nerve roots. One week after the admission, electromyography and nerve conduction studies (EMG-NCS) demonstrated severe axonal damage and radiculopathy at right S3 and S4 roots. Cerebrospinal fluid (CSF) analysis revealed lymphocytic pleocytosis, elevated protein, positive HSV-2 IgG index, and positive HSV-2 polymerase chain reaction (PCR). The patient was treated with intravenous acyclovir for 14 days and showed a gradual improvement in anal sphincter control and urination. Therefore, according to our findings, surgery might have an immunosuppressing role, and in cases with symptoms of cauda equina syndrome (CES) and systemic infection, in the postoperative setting, viral meningoradiculitis should be considered.

Cluster and Principal Component Analysis of Human Glioblastoma Multiforme (GBM) Tumor Proteome.

BACKGROUND: Glioblastoma Multiforme (GBM) or grade IV astrocytoma is the most common and lethal adult malignant brain tumor. Several of the molecular alterations detected in gliomas may have diagnostic and/or prognostic implications. Proteomics has been widely applied in various areas of science, ranging from the deciphering of molecular pathogen nests of discuses. METHODS: In this study proteins were extracted from the tumor and normal brain tissues and then the protein purity was evaluated by Bradford test and spectrophotometry. In this study, proteins were separated by 2-Dimensional Gel (2DG) electrophoresis method and the spots were then analyzed and compared using statistical data and specific software. Protein clustering analysis was performed on the list of proteins deemed significantly altered in glioblastoma tumors (t-test and one-way ANOVA; P< 0.05). RESULTS: The 2D gel showed totally 876 spots. We reported, 172 spots were exhibited differently in expression level (fold > 2) for glioblastoma. On each analytical 2D gel, an average of 876 spots was observed. In this study, 188 spots exhibited up regulation of expression level, whereas the remaining 232 spots were decreased in glioblastoma tumor relative to normal tissue. Results demonstrate that functional clustering (up and down regulated) and Principal Component Analysis (PCA) has considerable merits in aiding the interpretation of proteomic data. CONCLUSION: 2D gel electrophoresis is the core of proteomics which permitted the separation of thousands of proteins. High resolution 2DE can resolve up to 5,000 proteins simultaneously. Using cluster analysis, we can also form groups of related variables, similar to what is practiced in factor analysis.

The Study of "Dihydropyrimidinase Related Proteins (DRPs)" Expression Changes Influence in Malignant Astrocytoma Brain Tumor.

BACKGROUND: Dihydropyrimidinase Related Proteins (DRPs) have known homologous to the Collapsing Response Mediator Proteins (CRMPs). The DRP gene family has comprised four members, DRP 1, 2, 3, and 4, all out of which have considered to be involved in axonal outgrowth and path-finding. METHODS: The protein has extracted from tumor, normal brain tissues, and then the protein purity has evaluated by Bradford test and spectrophotometric methods. In this study, proteins has separated by Two-Dimensional Gel (2DG) electrophoresis method and then spots have analyzed and compared using statistical data and specific software (Progenesis Same Spots).Spots have identified by pH isoelectric, molecular weights and data banks. RESULTS: The 2D gel has shown 800 spots totally. Two spots have reported for DRP2, and one spot has reported for DRP3 in the human brain proteome, that have differed in pH isoelectric, and Molecular Weights values. CONCLUSION: This protein family has involved in neuronal differentiation and axonal guidance, and abundantly influenced in the developing brain, but their expression persisted into adulthood. DRP2 has regulated by phosphorylation, Glycogen synthase kinase 3, regulate phosphorylation of DRP2 an inactive from, and induced neuronal polarity.

Safety and possible outcome assessment of autologous Schwann cell and bone marrow mesenchymal stromal cell co-transplantation for treatment of patients with chronic spinal cord injury.

BACKGROUND AIMS: Cell replacement therapy has become a promising issue that has raised much hope in the regeneration of central nervous system injury. Evidence indicates that successful functional recovery in patients with spinal cord injury will not simply emphasize a single therapeutic strategy. Therefore, many recent studies have used combination strategies for spinal cord regeneration. METHODS: We assessed the safety and feasibility of a bone marrow mesenchymal stromal cell and Schwann cell combination for the treatment of patients with chronic spinal cord injury. Eight subjects who received a complete traumatic spinal cord injury (American Spinal Injury Association [ASIA] classification A) enrolled in this study. The patients received this autologous combination of cells directly into the injury site. The mean duration of follow-up was approximately 24 months. RESULTS: No magnetic resonance imaging evidence of neoplastic tissue overgrowth, syringomyelia or psuedomeningocele in any of the patients was seen during the study. There was no deterioration in sensory or motor function in any of the patients during the course of the study. Three patients had negligible improvement in ASIA sensory scale. No motor score improvement and no change in ASIA classification was seen. The patients had widely subjective changes in the course of the study such as urination and defecation sensation and more stability and trunk equilibrium in the sitting position. CONCLUSIONS: There were no adverse findings at least 2 years after autologous transplantation of Schwann cell and mesenchymal stromal cell combination into the injured spinal cord. It appears that the use of this combination of cells is safe for clinical application to spinal cord regeneration.

Comparison of the acute physiology and chronic health evaluation score (APACHE) II with GCS in predicting hospital mortality of neurosurgical intensive care unit patients.

BACKGROUND: The Glasgow Coma Scale (GCS) is popular, simple, and reliable, and provides information about the level of consciousness in trauma patients. However, a systemic evaluation scale specially in patients with multiple trauma is so important. The revised Acute Physiology and Chronic Health Evaluation system type 2 (APACHE II) is a physiologically based system including physiological variables. This study compares the efficacy of the predicting power for mortality and functional outcome of GCS and APACHEII in patients with multiple trauma in intensive care unit. METHODS: This study included the patients with head injury associated with systemic trauma admitted in the ICU of Shahid Rajaee Hospital in 2007 and 2008. Sensitivity, specificity and correct prediction of outcome by GCS and APACHE II were assessed and compared. RESULTS: This study included 93 patients (79 males, 14 females; mean age 60.5; range 14 to 87 years) with head injury associated with systemic trauma in 2007 and 2008. Mortality increased in the elderly group. The mean survival score using APACHE II was 36.5 and death score was 67.4 . These values using GCS were 10.3 and 6.8, respectively. CONCLUSION: For the assessment of mortality, the GCS score still provides simple, less-time consuming and effective information concerning head injury patients, especially in emergencies; however, for the prediction of mortality in patients with multiple trauma. APACHE II is superior to GCS since it includes the main physiologic parameters of patients.

Accuracy of combined EEG parameters in prediction the depth of anesthesia.

BACKGROUND: The importance of proper qualitative evaluation of EEG parameters during surgery has been recognized since many years. Although none of the characteristics based on the frequency, entropy, and Bi spectral characteristics have been regarded as a good predictor for detection of the depth of anesthesia alone. So it seems necessary to study multiple characteristics together. OBJECTIVES: In this study we tried to introduce the best combination of the mentioned characteristics. MATERIALS AND METHODS: EEG data of 64 patients undergoing general anesthesia with the same anesthesia protocol (total intravenous anesthesia) were recorded in all anesthetic stages in Shohada Tajrish Hospital. Quantitative EEG characteristics are classified into 4 categories: time, frequency, bi spectral and entropy based characteristics. Their sensitivity, specificity and accuracy in determination of the depth of anesthesia are yielded by comparison with recorded reference signal in awake, light anesthesia, deep anesthesia and brain death patients. Then, with combining 2, 3, 4 and 5 of characteristics and using coded algorithm we determined the error degree and introduced the combination yielding the least error. RESULTS: Fifteen vectors (of dimension two to five) which yielded the best results were introduced. Vectors combined of entropy based characteristics obtained 100% specificity and sensitivity during all 4 stages. CONCLUSIONS: The combination entropy based characteristics had high accuracy in predicting the depth of anesthesia. Reevaluation of classic indices cortical status index and BIS seems necessary. The next step is to find a system to simplify the evaluation of this information for technicians.

Presentation of a minimally symptomatic large extradural hematoma in a patient with an arachnoid cyst: a case report and review of the literature.

INTRODUCTION: Hemorrhagic complications of arachnoid cysts have been reported, extensively presenting with subdural or intracystic hematoma after trauma, but presentation with extradural hemorrhage is very rare. In this paper, we report the case of a patient with an arachnoid cyst who developed an extradural hematoma after a subtle head injury. Our patient presented with very mild symptoms in spite of the very large size of the hematoma. CASE PRESENTATION: Our patient was a 23-year-old Iranian man who complained of diffuse progressive headache and vomiting after mild head trauma. A brain computerized scan showed a very large extradural hematoma in the left frontotemporoparietal convexity over a large arachnoid cyst. CONCLUSION: Brain parenchyma containing an arachnoid cyst is vulnerable to trauma and increases the risk of serious hemorrhagic complications. We also suggest that the abnormal shape of the head should be considered as an indication for a computerized tomography scan in cases of mild head injury.

Proteomic analysis in human fibroblasts by continuous exposure to extremely low-frequency electromagnetic fields.

Most people are Exposed to Extremely Low-Frequency Electromagnetic Fields (ELF-EMF). A number of studies have indicated association between exposure to extremely low frequency electromagnetic fields and a variety of cancers. Recently some therapeutic techniques such as repetitive Transcranial Magnetic Stimulation (rTMS) have been used to study localization of brain function, connectively of brain regions and pathophysiology of neuropsychiatric disorders (rTMS utilize low frequency-electromagnetic field). Here, the effect of continuous ELF electromagnetic fields (3 Hz, sinusoidal, 3 h and 4 mT) on the protein expression of human fibroblast cells is investigated via proteomics. The comparison of the 2-DE separated proteins from the exposed and sham (control) cells showed that some protein expressions are affected by radiation. The two proteins that their expression are reduced about 50% are determined as alpha 1 antitrypsin (A1AT) and Transthyretin (TTR). As it is reported that the amounts of these proteins reduced in the pathological conditions it can be concluded that application of ELF-EMF in therapeutic aspects may be to accompanying with their side effects.