Effectiveness of Levetiracetam versus phenytoin in preventing seizure in traumatic brain injury patients: A systematic review and meta-analysis.

OBJECTIVE: Traumatic brain injury (TBI) and the subsequent Post-traumatic seizure (PTS) is a growing public health concern. Generally, anti-seizure drugs (ASDs) are recommended for PTS prophylaxis and treatment. This meta-analysis aimed to review the current state of knowledge and the evidence for the efficacy and safety of Levetiracetam (LEV) on the incidence of seizure in TBI patients compared to Phenytoin (PHT). METHODS: A search was carried out based on PubMed, MEDLINE, Europe PMC database, and Cochrane Library up to November 2023. A total of 16 studies (3 randomized clinical trials, 10 retrospective cohort studies, and 3 prospective cohort studies) including 5821 TBI patients included in our meta-analysis. We included studies comparing LEV and PHT after brain injury in both adults and children. Risk of bias assessment was done for randomized controlled trials (RCTs) with a risk-of-bias tool (RoB-2) and the Newcastle-Ottawa Scale (NOS) was used to assess the quality of cohort studies. Two RCTs in our meta-analysis had a high risk of bias, therefore we applied sensitivity analysis to evaluate the robustness of our results. RESULTS: The most commonly reported dosage for LEV was 500 mg twice daily and for PHT it was 5 mg/kg. There was no significant difference between LEV and PHT groups in reducing the early seizure incidence (OR = 0.85; 95% CI = [0.60, 1.21]; p = 0.375, fixed-effect, I2 = 21.75%). The result of sensitivity analysis for late seizure showed no significant difference between LEV and PHT in reducing the late seizure occurrence after TBI (OR = 0.87; 95% CI = [0.21, 3.67]; p = 0.853, fixed-effect, I2 = 0%). The mortality in TBI patients treated with LEV was not statistically significant compared to the PHT group (OR = 1.11; 95% CI = [0.92, 1.34], p = 0.266). The length of stay in the hospital was not significantly different between the LEV and PHT groups (MD = -1.33; 95% CI = [-4.55, 1.90]; p = 0.421). However, in comparison to PHT, LEV shortened the length of ICU stay (MD = -2.25; 95% CI = [-3.58, -0.91]; p =0.001). In terms of adverse effects, more patients in the PHT group have experienced adverse events compared to LEV but the difference was not significant (OR = 0.69; 95% CI = [0.44, 1.08]; p = 0. 11). CONCLUSION: The results of our meta-analysis showed LEV and PHT have similar effects on the occurrence of early and late seizures in TBI patients. Therefore, none of the drugs is superior to the other in reducing PTS. However, treating TBI patients with LEV did not shorten the length of hospital stay in comparison to PHT but reduced the length of ICU stay significantly. The analysis showed that patients in the LEV experienced fewer side effects than in the PHT group, while it was not sufficiently clear whether all reported side effects were related to the drug alone or other factors. The mortality was similar between the LEV and PHT groups. Finally, we recommend more high-quality randomized controlled trials to confirm the current findings before making any recommendations in practice.

Signaling crosstalk between mesenchymal stem cells and tumor cells: Implications for tumor suppression or progression.

Mesenchymal stem cells (MSCs) have been extensively used in various therapeutic applications over the last two decades, particularly in regenerative medicine and cancer treatment. MSCs have the ability to differentiate into mesodermal and non-mesodermal lineages, which makes them a popular choice in tissue engineering and regenerative medicine. Studies have shown that MSCs have inherent tumor-suppressive properties and can affect the behavior of multiple cells contributing to tumor development. Additionally, MSCs possess a tumor tropism property and have a hypoimmune nature. The intrinsic features of MSCs along with their potential to undergo genetic manipulation and be loaded with various anticancer therapeutics have motivated researchers to use them in different cancer therapy approaches without considering their complex dynamic biological aspects. However, despite their desirable features, several reports have shown that MSCs possess tumor-supportive properties. These contradictory results signify the sophisticated nature of MSCs and warn against the potential therapeutic applications of MSCs. Therefore, researchers should meticulously consider the biological properties of MSCs in preclinical and clinical studies to avoid any undesirable outcomes. This manuscript reviews preclinical studies on MSCs and cancer from the last two decades, discusses how MSC properties affect tumor progression and explains the mechanisms behind tumor suppressive and supportive functions. It also highlights critical cellular pathways that could be targeted in future studies to improve the safety and effectiveness of MSC-based therapies for cancer treatment. The insights obtained from this study will pave the way for further clinical research on MSCs and development of more effective cancer treatments.

A Simple Cuff Technique for Murine Left Lung Transplantation.

Over the past decade, our laboratory has made significant progress in developing and refining vascularized mouse lung transplantation models using an efficient and highly reliable "cuff technique" of transplantation. This article describes a sophisticated and comprehensive method for orthotopic lung transplantation in a vascularized orthotopic lung model, representing the most physiologic and clinically relevant model of mouse lung transplantation to date. The transplantation process consists of two distinct stages: donor harvest and subsequent implantation into the recipient. The method has been successfully mastered, and with several months of sufficient training, a skilled practitioner can perform the procedure in approximately 90 min from skin-to-skin. Surprisingly, once individuals overcome the initial learning curve, the survival rate during the perioperative period approaches nearly 100%. The mouse model allows for the use of multiple commercially available transgenic and mutant strains of mice, enabling the study of tolerance and rejection. Additionally, the unique features of this model make it a valuable tool for investigating tumor biology and immunology.

Nanotechnology and bioengineering approaches to improve the potency of mesenchymal stem cell as an off-the-shelf versatile tumor delivery vehicle.

Targeting actionable mutations in oncogene-driven cancers and the evolution of immuno-oncology are the two prominent revolutions that have influenced cancer treatment paradigms and caused the emergence of precision oncology. However, intertumoral and intratumoral heterogeneity are the main challenges in both fields of precision cancer treatment. In other words, finding a universal marker or pathway in patients suffering from a particular type of cancer is challenging. Therefore, targeting a single hallmark or pathway with a single targeted therapeutic will not be efficient for fighting against tumor heterogeneity. Mesenchymal stem cells (MSCs) possess favorable characteristics for cellular therapy, including their hypoimmune nature, inherent tumor-tropism property, straightforward isolation, and multilineage differentiation potential. MSCs can be loaded with various chemotherapeutics and oncolytic viruses. The combination of these intrinsic features with the possibility of genetic manipulation makes them a versatile tumor delivery vehicle that can be used for in vivo selective tumor delivery of various chemotherapeutic and biological therapeutics. MSCs can be used as biofactory for the local production of chemical or biological anticancer agents at the tumor site. MSC-mediated immunotherapy could facilitate the sustained release of immunotherapeutic agents specifically at the tumor site, and allow for the achievement of therapeutic concentrations without the need for repetitive systemic administration of high therapeutic doses. Despite the enthusiasm evoked by preclinical studies that used MSC in various cancer therapy approaches, the translation of MSCs into clinical applications has faced serious challenges. This manuscript, with a critical viewpoint, reviewed the preclinical and clinical studies that have evaluated MSCs as a selective tumor delivery tool in various cancer therapy approaches, including gene therapy, immunotherapy, and chemotherapy. Then, the novel nanotechnology and bioengineering approaches that can improve the potency of MSC for tumor targeting and overcoming challenges related to their low localization at the tumor sites are discussed.

Bioengineering strategies to enhance the interleukin-18 bioactivity in the modern toolbox of cancer immunotherapy.

Cytokines are the first modern immunotherapeutic agents used for activation immunotherapy. Interleukin-18 (IL-18) has emerged as a potent anticancer immunostimulatory cytokine over the past three decades. IL-18, structurally is a stable protein with very low toxicity at biological doses. IL-18 promotes the process of antigen presentation and also enhances innate and acquired immune responses. It can induce the production of proinflammatory cytokines and increase tumor infiltration of effector immune cells to revert the immunosuppressive milieu of tumors. Furthermore, IL-18 can reduce tumorigenesis, suppress tumor angiogenesis, and induce tumor cell apoptosis. These characteristics present IL-18 as a promising option for cancer immunotherapy. Although several preclinical studies have reported the immunotherapeutic potential of IL-18, clinical trials using it as a monotherapy agent have reported disappointing results. These results may be due to some biological characteristics of IL-18. Several bioengineering approaches have been successfully used to correct its defects as a bioadjuvant. Currently, the challenge with this anticancer immunotherapeutic agent is mainly how to use its capabilities in a rational combinatorial therapy for clinical applications. The present study discussed the strengths and weaknesses of IL-18 as an immunotherapeutic agent, followed by comprehensive review of various promising bioengineering approaches that have been used to overcome its disadvantages. Finally, this study highlights the promising application of IL-18 in modern combinatorial therapies, such as chemotherapy, immune checkpoint blockade therapy, cell-based immunotherapy and cancer vaccines to guide future studies, circumventing the barriers to administration of IL-18 for clinical applications, and bring it to fruition as a potent immunotherapy agent in cancer treatment.

Aquaporin 4 in Traumatic Brain Injury: From Molecular Pathways to Therapeutic Target.

Traumatic brain injury (TBI) is known as an acute degenerative pathology of the central nervous system, and has been shown to increase brain aquaporin 4 (AQP4) expression. Various molecular mechanisms affect AQP4 expression, including neuronal high mobility group box 1, forkhead box O3a, vascular endothelial growth factor, hypoxia-inducible factor-1 α (HIF-1 α) sirtuin 2, NF-κB, Malat1, nerve growth factor and Angiotensin II receptor type 1. In addition, inhibition of AQP4 with FK-506, MK-801 (indirectly by targeting N-methyl-D-aspartate receptor), inactivation of adenosine A2A receptor, levetiracetam, adjudin, progesterone, estrogen, V1aR inhibitor, hypertonic saline, erythropoietin, poloxamer 188, brilliant blue G, HIF-1alpha inhibitor, normobaric oxygen therapy, astaxanthin, epigallocatechin-3-gallate, sesamin, thaliporphine, magnesium, prebiotic fiber, resveratrol and omega-3, as well as AQP4 gene silencing lead to reduced edema upon TBI. This review summarizes current knowledge and evidence on the relationship between AQP4 and TBI, and the potential mechanisms involved.

Chronic vertebro-jugular arteriovenous Fistula secondary to hemodialysis catheterization: A case report.

Vertebral artery's iatrogenic arteriovenous fistula due to central venous catheterization is an uncommon vascular complication. This report depicts a case of 21-year-old male patient who underwent central venous catheterization for hemodialysis over 10 years ago and was detected with a vertebrojugular arteriovenous fistula. This report depicts a case of 21-year-old male patient who detected with a vertebrojugular arteriovenous fistula after 10 years of hemodialysis through central venous catheterization. The surgical treatment was successfully performed.

Toward a universal influenza virus vaccine: Some cytokines may fulfill the request.

The influenza virus annually causes widespread damages to the health and economy of the global community. Vaccination is currently the most crucial strategy in reducing the number of patients. Genetic variations, the high diversity of pandemic viruses, and zoonoses make it challenging to select suitable strains for annual vaccine production. If new pandemic viruses emerge, it will take a long time to produce a vaccine according to the new strains. In the present study, intending to develop a universal influenza vaccine, new bicistronic DNA vaccines were developed that expressed NP or NPm antigen with one of modified IL-18/ IL-17A/ IL-22 cytokine adjuvants. NPm is a mutant form of the antigen that has the ability for cytoplasmic accumulation. In order to investigate and differentiate the role of each of the components of Th1, Th2, Th17, and Treg cellular immune systems in the performance of vaccines, Treg competent and Treg suppressed mouse groups were used. Mice were vaccinated with Foxp3-FC immunogen to produce Treg suppressed mouse groups. The potential of the vaccines to stimulate the immune system was assessed by IFN-γ/IL-17A Dual FluoroSpot. The vaccine's ability to induce humoral immune response was determined by measuring IgG1, IgG2a, and IgA-specific antibodies against the antigen. Kinetics of Th1, Th2, and Th17 cellular immune responses after vaccination, were assessed by evaluating the expression changes of IL-17A, IFN-γ, IL-18, IL-22, IL-4, and IL-2 cytokines by semi-quantitative real-time RT-PCR. To assess the vaccines' ability to induce heterosubtypic immunity, challenge tests with homologous and heterologous viruses were performed and then the virus titer was measured in the lungs of animals. Evaluation of the data obtained from this study showed that the DNA-vaccines coding NPm have more ability to induces a potent cross-cellular immune response and protective immunity than DNA-vaccines coding NP. Although the use of IL-18/ IL-17A/ IL-22 genetic adjuvants enhanced immune responses and protective immunity, Administration of NPm in combination with modified IL-18 (Igk-mIL18-IgFC) induced the most effective immunity in Treg competent mice group.

Potential of chitosan/alginate nanoparticles as a non-viral vector for gene delivery: Formulation and optimization using D-optimal design.

Chitosan/alginate (Chi/Alg) nanoparticles as a non-viral vector for the Smad4 encoding plasmid were optimized utilizing D-optimal design based on the nanoparticles/plasmid ratio, Chi/Alg MW, and preparation method type. Following the optimization and validation of the best formula, morphology studies and FTIR measurements were performed to evaluate the optimized Chi/Alg/S NPs. Toxicity (MTT assay) and transfection studies were performed for the best formula in comparison with Lipofectamine 2000, and Polyethyleneimine (PEI) and evaluated using Green Fluorescence Protein (GFP) assay, Flow cytometry, and RT-PCR. The model predicted a particle size of 111 nm, loading efficacy (LE) of 43%, cumulative release (CMR) of 39%, the ζ-potential of +50 mV, and PDI of 0.13. The predicted point condition was as follows: NP ratio = 13, Chi/Alg MW ratio = 2.35, and preparation method type = 1. Microscopic findings revealed that the shape of nanoparticles was spherical. The Chi/Alg/S nanoparticles showed no toxicity and transfection efficacy of 29.9% was observed in comparison with Lipofectamine (35.5%) and PEI (30.9%).

Aquaporin 4 and brain-related disorders: Insights into its apoptosis roles.

Brain-related disorders are leading global health problems. Various internal and external factors are involved in the progression of brain-related disorders. Inflammatory pathways, oxidative stresses, apoptosis, and deregulations of various channels are critical players in brain-related disorder pathogenesis. Among these players, aquaporins (AQP) have critical roles in various physiological and pathological conditions. AQPs are water channel molecules that permit water to cross the hydrophobic lipid bilayers of cellular membranes. AQP4 is one of the important members of AQP family. AQPs are involved in controlling apoptosis pathways in brain-related disorders. In this regard, several reports have evaluated the pathological effects of AQP4 by targeting the apoptosis-related processes in brain-related disorders. Here, for the first time, we highlight the impact of AQP4 on apoptosis-related processes in brain-related disorders.

Neuroprotective effects of probiotics bacteria on animal model of Parkinson's disease induced by 6-hydroxydopamine: A behavioral, biochemical, and histological study.

Parkinson's disease (PD) is an age-associated, progressive, and common neurodegenerative disorder. It is characterized by dopaminergic neuron degeneration in the substantia nigra pars compacta. The involvement of oxidative stress, inflammation, and dysbiosis in PD has been confirmed and probiotics also have the ability to regulate the mentioned mechanisms. Here, we assessed probiotics supplementation effects on experimental model of PD. Thirty Male Wistar rats were divided into three groups for a 14-day treatment. It was shown that a mixture of probiotics containing Lactobacillus acidophilus, Bifidobacterium bifidum, Lactobacillus reuteri, and Lactobacillus fermentum could improve rotational behavior, cognitive function, lipid peroxidation, and neuronal damage in the group received probiotic supplementation compared to the other groups (P < 0001, P < .001, and P = .026, respectively). Taken together, these findings revealed that probiotics supplementation could be an appropriate complementary treatment for PD.

Co-expression of Interleukin-17A molecular adjuvant and prophylactic Helicobacter pylori genetic vaccine could cause sterile immunity in Treg suppressed mice.

The increasing clinical significance of Helicobacter pylori (H. pylori) in human stomach cancer has led to global efforts to eradicate this pathogen. Recent studies have confirmed the importance of some cytokines such as Interleukin-18 (IL-18), Interleukin-8 (IL-8), Interleukin-17A (IL-17A) and Interleukin-22 (IL-22) in the pathogenesis of the so-called bacterium. This study was designed to compare the effects of Type 1T helper (Th1), Type 2T helper (Th2) cells, Regulatory T cells (Treg) and T helper 17 (Th17) modulatory effects on the efficacy of designed H. pylori vaccine by incorporating some molecular adjuvants in Treg competent and Treg suppressed groups. A bicistronic vector was used for simultaneous expression of codon-optimized Outer inflammatory protein a (OipA) gene and modified mice IL-18, IL-17A, IL-22 and Foxp3 (forkhead box P3) cytokines from four cassettes. Immunization of mice groups was performed using produced plasmids intradermally. Specific IgG1 and IgG2 and IgA antibody titers produced in mice were confirmed by enzyme-linked immunosorbent assay (ELISA) in sera and intestine obtained four weeks after the last immunization. After being stimulated with a mixture of both anti-CD28 mAb and H. pylori lysate, frequencies of single Interferon-Gamma (IFN-γ), single IL-17 and dual IFN-γ/IL-17-secreting T-cells were documented using dual-color FluoroSpot. The kinetics of Th1, Th2 and Th17 in the immunized animals was determined by relative quantification of IL-17A, IL-22, IFN-γ, IL-8, IL-2 and IL-4 specific mRNAs. Four weeks after bacterial challenge, quantitative colony count in the isolated and homogenized stomachs was utilized to assess the level of protective immunity among all groups. The results of immunologic assays showed that the highest cell-mediated immunity cytokines were produced in IL-17 receiving group in which the Treg responses were suppressed previously by the administration of the Foxp3 as an immunogen. In addition, potent clearance of Helicobacter pylori infection was seen in this group as well.

The effects of acupuncture and electroacupuncture on Parkinson's disease: Current status and future perspectives for molecular mechanisms.

Among the progressive neurodegenerative disorders, Parkinson's disease (PD) is the second most common. Different factors have critical role in pathophysiology of PD such as apoptosis pathways, inflammatory cytokines, oxidative stress, and neurotransmitters and its receptors abnormalities. Acupuncture and electroacupuncture were considered as nondrug therapies for PD. Although numerous studies has been conducted for assessing the mechanism underlying electroacupuncture and acupuncture, various principal aspects of these treatment procedures remain not well-known. There have also been few investigations on the molecular mechanism of acupuncture and electroacupuncture therapy effects in PD. This review evaluates the effects of electroacupuncture and acupuncture on the molecular mechanism in PD.

A retrospective analysis of rectal and bladder dose for gynecological brachytherapy treatments with GZP6 HDR afterloading system.

AIM: The aim of this work is to evaluate rectal and bladder dose for the patients treated for gynecological cancers. BACKGROUND: The GZP6 high dose rate brachytherapy system has been recently introduced to a number of radiation therapy departments in Iran, for treatment of various tumor sites such as cervix and vagina. MATERIALS AND METHODS: Our analysis was based on dose measurements for 40 insertions in 28 patients, treated by a GZP6 unit between June 2009 and November 2010. Treatments consisted of combined teletherapy and intracavitary brachytherapy. In vivo dosimetry was performed with TLD-400 chips and TLD-100 microcubes in the rectum and bladder. RESULTS: The average of maximum rectal and bladder dose values were found to be 7.62 Gy (range 1.72-18.55 Gy) and 5.17 Gy (range 0.72-15.85 Gy), respectively. It has been recommended by the ICRU that the maximum dose to the rectum and bladder in intracavitary treatment of vaginal or cervical cancer should be lower than 80% of the prescribed dose to point A in the Manchester system. In this study, of the total number of 40 insertions, maximum rectal dose in 29 insertions (72.5% of treatment sessions) and maximum bladder dose in 18 insertions (45% of treatments sessions) were higher than 80% of the prescribed dose to the point of dose prescription. CONCLUSION: In vivo dosimetry for patients undergoing treatment by GZP6 brachytherapy system can be used for evaluation of the quality of brachytherapy treatments by this system. This information could be used as a base for developing the strategy for treatment of patients treated with GZP6 system.

Air kerma strength characterization of a GZP6 Cobalt-60 brachytherapy source.

BACKGROUND: Task group number 40 (TG-40) of the American Association of Physicists in Medicine (AAPM) has recommended calibration of any brachytherapy source before its clinical use. GZP6 afterloading brachytherapy unit is a (60)Co high dose rate (HDR) system recently being used in some of the Iranian radiotherapy centers. AIM: In this study air kerma strength (AKS) of (60)Co source number three of this unit was estimated by Monte Carlo simulation and in air measurements. MATERIALS AND METHODS: Simulation was performed by employing the MCNP-4C Monte Carlo code. Self-absorption of the source core and its capsule were taken into account when calculating air kerma strength. In-air measurements were performed according to the multiple distance method; where a specially designed jig and a 0.6 cm(3) Farmer type ionization chamber were used for the measurements. Monte Carlo simulation, in air measurement and GZP6 treatment planning results were compared for primary air kerma strength (as for November 8th 2005). RESULTS: Monte Carlo calculated and in air measured air kerma strength were respectively equal to 17240.01 µGym(2) h(-1) and 16991.83 µGym(2) h(-1). The value provided by the GZP6 treatment planning system (TPS) was "15355 µGym(2) h(-1)". CONCLUSION: The calculated and measured AKS values are in good agreement. Calculated-TPS and measured-TPS AKS values are also in agreement within the uncertainties related to our calculation, measurements and those certified by the GZP6 manufacturer. Considering the uncertainties, the TPS value for AKS is validated by our calculations and measurements, however, it is incorporated with a large uncertainty.