Cost-Effectiveness analysis of endovascular versus open repair in patients with abdominal aortic aneurysm in Iran: A Cross-Sectional study.

OBJECTIVES: Abdominal aortic aneurysm is one of the most important cardiovascular diseases, especially in the elderly. People with this disease are at risk of rupture of the abdominal aorta and death. The present study was conducted with the aim of analyzing the cost effectiveness of endovascular repair compared to open surgery in abdominal aortic aneurysm patients in Iran. METHODS: A Markov chain model was developed based on the use of endovascular repair and open surgery. The base-case patient was defined as a 65-year-old man presenting with abdominal aortic aneurysm diameter greater than 5 cm. The determination of costs was from the perspective of the public sector provider. QALY was used to calculate the effectiveness. Incremental cost-effectiveness ratio (ICER) and TreeAge software were used for cost-effectiveness analysis. The follow-up period was 10 years and the willingness to pay (WTP) was determined as three times the Gross domestic product (GDP) per capita. RESULT: At the end of year 10, the endovascular aneurysm repair (EVAR) strategy gained 1,318,313,559 Iranian Rial (IRR) (67885.29$) in cost and 3.57 QALYs in effectiveness. In contrast, the use of the open surgery repair (OSR) strategy gained 1,186,761,858 IRR (61111.16$) in cost and 3·32 QALYs in effectiveness. The incremental cost-effectiveness ratio, comparing EVAR versus OSR, was 53, 346, 3757 IRR (178.36$) per QALYs, which is lower than the proposed WTP, indicating that EVAR is more expensive and more effective. Based on the Monte Carlo simulation test, EVAR is the preferred strategy in 58.6% of the population. CONCLUSION: Endovascular repair has a relative superiority compared to open surgery, and the probability of the effectiveness of endovascular repair compared to open surgery does not change with increasing willingness to pay.

TGN020 application against aquaporin 4 improved multiple sclerosis by inhibiting astrocytes, microglia, and NLRP3 inflammasome in a cuprizone mouse model.

In multiple sclerosis (MS), activation of the astrocytes and microglia induces a cascading inflammatory response. Overexpression of the aquaporin 4 (AQP4) in the glia is a trigger for this reaction. This study aimed to block AQP4 by injecting TGN020 to alleviate the symptoms of MS. Total of 30 male mice were randomly divided into control (intact), cuprizone model of MS (fed with 0.2% cuprizone for 35 days), and TGN020-treated (received daily intraperitoneal injections of 200 mg/kg TGN020 with cuprizone intake) groups. Astrogliosis, M1-M2 microglia polarization, NLRP3 inflammasome activation, and demyelination were investigated in the corpus callosum by immunohistochemistry, real-time PCR, western blot, and luxol fast blue staining. The Rotarod test was performed for a behavior assessment. AQP4 inhibition caused a significant decrease in the expression of the astrocyte-specific marker, GFAP. It also changed the microglia polarization from M1 to M2 indicated by a significant downregulation of iNOS, CD86, MHC-ІІ, and upregulation of arginase1, CD206, and TREM-2. In addition, western blot data showed a significant decrease in the NLRP3, caspase1, and IL-1b proteins in the treatment group, which indicated inflammasome inactivation. The molecular changes following the TGN020 injection resulted in remyelination and motor recovery enhancement in the treatment group. In conclusion, the results draw the attention to the role of AQP4 in the cuprizone model of MS.

The role of inflammasome complex in ischemia-reperfusion injury.

Ischemia-reperfusion injury refers to a temporary interruption of blood flow in a tissue. Restoration of blood flow initiates the inflammation in tissue causing ischemic damage through the activation of a multiprotein complex termed inflammasome. The complex contains a receptor, mainly a member of nucleotide oligomerization domain-like receptors, that receives danger signals. The receptor is oligomerized as a response to danger signals and then the apoptosis-associated speck-like protein containing a caspase recruitment domain and procaspase protein are added to the oligomerized receptors to form the inflammasome complex. In the next step, the isolated procaspase is converted into an active caspase molecule that initiates the inflammation through the release of interleukin-1ß and interleukin-18. The inflammasome has an important role in the pathogenesis of ischemia-reperfusion injury in different tissues. Here, we summarized the role of inflammasome in the pathogenesis of ischemia-reperfusion of brain, liver, kidney, and heart. Moreover, we highlighted the expression of inflammasome components, the mechanisms involved in activation of the complex, and its inhibition as an optimistic therapeutic technique in ischemia-reperfusion injuries.

The protective effects of neural stem cells and neural stem cells-conditioned medium against inflammation-induced prenatal brain injury.

Intrauterine inflammation affects fetal development of the nervous system and may cause prenatal brain injury in offspring. Previously, neural stem cells have been extensively used as a therapeutic choice for nervous system diseases. Recently, the therapeutic ability of conditioned medium, harvested from cultured stem cells, has captured the attention of researchers in the field. Our study aimed to compare the therapeutic effect of neural stem cells (NSCs) or NSC-conditioned medium (NSC-CM) after prenatal brain injury. The animal model was induced by intraperitoneal injection of lipopolysaccharide into the pregnant mice and NSCs or NSC-CM were transplanted into the lateral ventricle of embryos in treatment groups. Inflammation and apoptosis were evaluated postpartum in offspring via measuring the expression of NLRP3 gene and protein, the expression and the activity of caspase-3, and the expression of pro-inflammatory cytokines by real-time PCR, immunohistochemistry, western blotting, ELISA, and colorimetric assay kit. A rotarod test was performed for motor function evaluation. Data showed that although NSC-CM fought against the inflammation and apoptosis and improved the motor function, NSCs acted more efficiently. In conclusion, the results of our study contend that NSCs have a better therapeutic effect than CM in prenatal brain injury.

Intrathecal administration of the extracellular vesicles derived from human Wharton's jelly stem cells inhibit inflammation and attenuate the activity of inflammasome complexes after spinal cord injury in rats.

Activation of inflammasome complexes during spinal cord injury (SCI) lead to conversion of pro-inflammatory cytokines, interleukin-1beta (IL-1ß) and interleukin-18 (IL-18) to their active form to initiates the neuroinflammation. Mesenchymal stem cells (MSCs) showed anti-inflammatory properties through their extracellular vehicles (EVs). We investigated immunomodulatory potential of human Wharton's jelly mesenchymal stem cells derived extracellular vesicles (hWJ-MSC-EVs) on inflammasome activity one week after SCI in rats. The gene expression and protein level of IL-1ß, IL-18, tumor necrosis factor alpha (TNF-α) and caspase1, were assessed by QPCR and western blotting. Immunohistochemistry (IHC) was done to measure the glial fibrillary acidic protein (GFAP) and Nestin expression. Cell death, histological evaluation and hind limb locomotion was studied by TUNEL assay, Nissl staining and Basso, Beattie, Bresnaham (BBB), respectively. Our finding represented that intrathecally administrated of hWJ-MSC-EVs significantly attenuated expression of the examined factors in both mRNA (P < 0.05 and P ≤ 0.01) and protein levels (P < 0.05 and P ≤ 0.01), decreased GFAP and increased Nestin expression (P < 0.05), reduced cell death and revealed the higher number of typical neurons in ventral horn of spinal cord. Consequently, progress in locomotion. We came to the conclusion that hWJ-MSC-EVs has the potential to control the inflammasome activity after SCI in rats. Moreover, EVs stimulated the neural progenitor cells and modulate the astrocyte activity.

Combined use of platelet-rich plasma and adipose tissue-derived mesenchymal stem cells shows a synergistic effect in experimental spinal cord injury.

Spinal cord injury (SCI) as a crippling disability causes tissue degeneration via neuron loss and fiber disruption. Some researchers have tried to reverse or minimize these changes. Platelet-rich plasma (PRP) is a biological product derived from peripheral blood containing a variety of growth factors. PRP has been extensively used in regenerative medicine. On the other hand, via secreting neuroprotective growth factors, mesenchymal stem cells (MSCs) have shown a promising potential in repairing central nervous system deficits. This study investigated the therapeutic effect of the combined use of MSCs and PRP in a rat model of SCI. We used real time-PCR method for evaluation of Bcl-2, Bax and caspase 3 expressions, TUNEL test for apoptotic cell death assessment, and neurofilament NF200 immunohistochemistry for examination of axonal regeneration. The results showed that co-treatment with MSCs and PRP efficiently alleviated the evaluated categories. Significant differences were observed in expression of Bcl-2 and caspase3, but not Bax, apoptotic index and the number of NF200 positive axons (for all P ≤ 0.01) between co-treatment animals compared with those treated with only MSCs or PRP. In conclusion, this study showed that combination of MSCs and PRP synergistically promotes their therapeutic effects in the SCI.

Intranasal administration of conditioned medium derived from mesenchymal stem cells-differentiated oligodendrocytes ameliorates experimental autoimmune encephalomyelitis.

In multiple sclerosis, myelin sheaths around the axons are degenerated due to uncontrolled inflammation in the central nervous system. Oligodendrocytes (OLs) are myelin-forming cells that secrete trophic factors necessary for myelin protection. Beneficial features of conditioned medium (CM) derived from different stem cells are nowadays under investigation in treating neurodegenerative diseases. Here, we used the differentiation capacity of Wharton's jelly mesenchymal stem cells (WJMSCs) to obtain OLs. Then, the study aimed to evaluate the status of inflammation and myelination in male experimental autoimmune encephalomyelitis (EAE) mice after intranasal administration of CM derived from OLs (OL-CM). Inflammation was studied by evaluating gliosis, inflammatory cell infiltration and expression of inflammation indicators including NLRP3 inflammasome, interleukin-1ß, interleukin-18, glial fibrillary acidic protein, and ionized calcium binding adaptor molecule 1. Remyelination was studied by luxol fast blue staining and evaluating the expression of myelin indicators including myelin basic protein and oligodendrocyte transcription factor. In addition, we followed the trend of body weight and functional recovery during the 28-day study. ELISA assay revealed that OL-CM contained brain-derived neurotrophic factor, glial cell-derived neurotrophic factor, and ciliary neurotrophic factor. Data showed that OL-CM moderated inflammation, augmented remyelination, and gained normal body weight. Notably, these anti-inflammatory and regenerative effects of OL-CM improved neurological functions in EAE mice. In conclusion, the current study offered a new choice for treating multiple sclerosis using noninvasive intranasal administration of CM harvested from easily achievable WJMSCs-differentiated OLs.

The Therapeutic Potential of Conditioned Medium from Human Breast Milk Stem Cells in Treating Spinal Cord Injury.

STUDY DESIGN: Experimental animal study. PURPOSE: This study investigated the therapeutic effects of human breast milk stem cell (BMSC)-conditioned medium (BMSC-CM) in a model of spinal cord injury (SCI) in male Sprague-Dawley rats. OVERVIEW OF LITERATURE: SCI is one of the leading causes of disability in addition to sensory and motor impairment. So far, there have been no successful treatments for SCI. Given the positive outcomes associated with using stem cells and their derivatives as a treatment for various diseases, there is a growing interest in using them as an SCI treatment. Recent research has demonstrated that CM from stem cells has therapeutic advantages. METHODS: Human BMSCs were isolated and characterized, and CM was subsequently collected. Animals received an intrathecal administration of BMSC-CM after SCI. The activity of caspase-3 was measured to assess apoptosis, and levels of tumor necrosis factor-α and interleukin-1ß were measured to assess inflammation. Also, sensory and locomotor performances were assessed after SCI and BMSC-CM administration. RESULTS: Administration of CM from BMSC reduced apoptosis and inflammation at the site of injury in a rat model of SCI (p<0.05). Motor, sensory, locomotor, and sensorimotor performances were significantly improved in rats that received BMSC-CM after SCI. CONCLUSIONS: Intrathecal administration of BMSC-CM improved recovery in a rat model of SCI.

Schwann cell transplantation exerts neuroprotective roles in rat model of spinal cord injury by combating inflammasome activation and improving motor recovery and remyelination.

Inflammasome activation in the traumatic central nervous system (CNS) injuries is responsible for propagation of an inflammatory circuit and neuronal cell death resulting in sensory/motor deficiencies. NLRP1 and NLRP3 are known as activators of inflammasome complex in the spinal cord injury (SCI). In this study, cell therapy using Schwann cells (SCs) was applied for targeting NLRP inflammasome complexes outcomes in the motor recovery. These cells were chosen due to their regenerative roles for CNS injuries. SCs were isolated from sciatic nerves and transplanted to the contusive SCI-induced Wistar rats. NLRP1 and NLRP3 inflammasome complexes and their related pro-inflammatory cytokines were assayed in both mRNA and protein levels. Neuronal cell survival (Nissl staining), motor recovery and myelination (Luxol fast blue/LFB) were also evaluated. The groups were laminectomy, SCI, vehicle and treatment. The treatment group received Schwann cells, and the vehicle group received solvent for the cells. SCI caused increased expressions for both NLRP1 and NLRP3 inflammasome complexes along with their related pro-inflammatory cytokines, all of which were abrogated after administration of SCs (except for IL-18 protein showing no change to the cell therapy). Motor deficits in the hind limb, neuronal cell death and demyelination were also found in the SCI group, which were counteracted in the treatment group. From our findings we conclude promising role for cell therapy with SCs for targeting axonal demyelination and degeneration possibly through attenuation of the activity for inflammasome complexes and related inflammatory circuit.

The role of fibromodulin in cancer pathogenesis: implications for diagnosis and therapy.

Fibromodulin (FMOD) is known as one of very important extracellular matrix small leucine-rich proteoglycans. This small leucine-rich proteoglycan has critical roles in the extracellular matrix organization and necessary for repairing of tissue in many organs. Given that the major task of FMOD is the modulation of collagen fibrillogenesis. However, recently observed that FMOD plays very important roles in the modulation of a variety of pivotal biological processes including angiogenesis, regulation of TGF-ß activity, and differentiation of human fibroblasts into pluripotent cells, inflammatory mechanisms, apoptosis and metastatic related phenotypes. Besides these roles, FMOD has been considered as a new tumor-related antigen in some malignancies such as lymphoma, leukemia, and leiomyoma. Taken together, these findings proposed that FMOD could be introduced as diagnostic and therapeutic biomarkers in treatment of various cancers. Herein, for first time, we highlighted the various roles of FMOD in the cancerous conditions. Moreover, we summarized the diagnostic and therapeutic applications of FMOD in cancer therapy.

The therapeutic effect of platelet-rich plasma on the experimental autoimmune encephalomyelitis mice.

The use of growth factors is considered to be one of the promising therapeutic strategies for multiple sclerosis (MS). Various studies have shown that platelet-rich plasma (PRP), a bioproduct of concentrated platelets, contains a variety of growth factors such as insulin-like growth factor 1 (IGF-1), platelet-derived growth factor (PDGF), epithelial growth factor (EGF), and transforming growth factor ß (TGF-ß). The therapeutic roles of PRP, with regard to a wide range of growth factors, on the nervous system have been shown in a limited number of studies. This study aimed to investigate the therapeutic effect of PRP in experimental autoimmune encephalomyelitis (EAE) mouse model of MS. PRP was prepared and intrathecally injected into the EAE mice. The EAE scoring test, the modified neurological severity score (mNSS) test, luxol fast blue and hematoxylin and eosin staining, real-time PCR, and western blotting were used for studying the effect of PRP on the motosensory function, remyelination, inflammatory cell infiltration, gliosis, and inflammatory cytokines expression. PRP administration in treated animals improved the functional abilities, remyelination, and oligodendrogenesis compared to the EAE mice. Furthermore, high numbers of microglia, astrocytes and infiltrating inflammatory cells and also the expression of proinflammatory cytokines were reversed after PRP therapy. In conclusion, these data suggest the PRP as a potential candidate for MS treatment.

In utero transplantation of neural stem cells ameliorates maternal inflammation-induced prenatal white matter injury.

Prenatal white matter injury is a serious problem due to maternal inflammation leading to postnatal disabilities. In this study, we used the periventricular leukomalacia (PVL) model as a common prenatal white matter injury by maternal administration of lipopolysaccharide (LPS). Neural stem cells (NSCs) have shown therapeutic ability in neurological disorders through a different mechanism such as immunomodulation. Here, we studied the preventive potential of NSCs following in utero transplantation into the embryonic lateral ventricle in an LPS-induced white matter injury model. Pregnant animals were divided into three groups and received phosphate buffered saline, LPS, or LPS + NSCs. The brains of offspring were obtained and evaluated by real-time polymerase chain reaction (PCR), immunohistochemy, enzyme-linked immunosorbent assay (ELISA), terminal deoxynucleotidyl transferase-mediated biotinylated-dUTP nick-end labeling (TUNEL), and caspase-3 activity assay. The LPS-induced maternal inflammation degenerated the myelin sheath in the offspring periventricular region which was associated with an increased microglial number, oligodendrocytes degeneration, proinflammatory cytokine secretion, and cell apoptosis. The transplanted NSCs homed into the brain and ameliorated the evaluated parameters. The expression of proinflammatory cytokines interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-α (TNF-α), cell apoptosis and caspase-3 activity were inhibited by NSCs. In addition, Olig2 and myelin basic protein immunohistochemy staining showed that prenatal NSCs transplantation augmented the myelination in the periventricular white matter of offspring. In conclusion, we think that prenatal therapeutic strategies, such as in utero NSCs transplantation, may prevent prenatal white matter injury after birth.

Intrathecal transplantation of Wharton's jelly mesenchymal stem cells suppresses the NLRP1 inflammasome in the rat model of spinal cord injury.

After spinal cord injury (SCI) local inflammation is induced following secretion of interleukin-1beta (IL-1ß) and IL-18. It has been described that the secretion of IL-1ß and IL-18 is mediated by a cytoplasmic multiprotein complex, termed inflammasome. Mesenchymal stem cells (MSCs) have been extensively used for treating inflammatory diseases in which they showed immunomodulation characteristics. We utilized the anti-inflammatory potential of Wharton's jelly mesenchymal stem cells (WJ-MSCs) to target inflammasome complex in rat SCI model. Real time-polymerase chain reaction, western blotting, and ELISA assay were done one week after SCI to measure the expression of the inflammasome components including NLRP1, ASC, and active caspase-1 as well as IL-1ß, IL-18, and tumor necrosis factor-α (TNF-α). The histologic alteration and hind-limb locomotion were evaluated three weeks after injury by nissl staining and Basso, Beattie, Bresnahan (BBB), respectively. Our results showed that WJ-MSCs transplantation significantly decreased the SCI-induced expression of the evaluated factors in both mRNA and protein levels. In addition, WJ-MSCs significantly increased the number of normal-appearance neurons in the ventral horn of spinal cord. Noteworthy, these effects resulted in a significant improvement of motor function recovery. We conclude that inflammasome inhibition may be one of the mechanisms for the anti-inflammatory effect of MSCs in the SCI.

Stem cell- and gene-based therapies as potential candidates in Alzheimer's therapy.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, which is associated with impairments of memory, thinking, language, and reasoning. Despite extensive research aiming at the treatment of AD, durable and complete remissions are rare. Hence, new therapeutic approaches are required. Among various therapeutic approaches, stem cells (ie, neural stem cells, mesenchymal stem cells, and embryonic stem cells) and delivery of protective genes such as encoding nerve growth factor, APOE, and glial cell-derived neurotrophic factor have generated promise in AD therapy. Here, we summarized a variety of effective therapeutic approaches (ie, stem cells, and genes) in AD therapy.

Micro-RNAs as critical regulators of matrix metalloproteinases in cancer.

Metastasis is known to be one of the important factors associated with cancer-related deaths worldwide. Several cellular and molecular targets are involved in the metastasis process. Among these targets, matrix metalloproteinases (MMPs) play central roles in promoting cancer metastasis. MMPs could contribute toward tumor growth, angiogenesis, migration, and invasion via degradation of the extracellular matrix and activation of pre-pro-growth factors. Therefore, identification of various cellular and molecular pathways that affect MMPs could contribute toward a better understanding of the metastatic pathways involved in various tumors. Micro-RNAs are important targets that could affect MMPs. Multiple lines of evidence have indicated that deregulation of various micro-RNAs, including miR-9, Let-7, miR-10b, and miR-15b, affects metastasis of tumor cells via targeting MMPs.

Embryonic intraventricular transplantation of neural stem cells augments inflammation-induced prenatal brain injury.

OBJECTIVE: Prenatal brain injury results from undesirable circumstances during the embryonic development. Current endeavors for treating this complication are basically excluded to postnatal therapeutic approaches. Neural stem cell therapy has shown great promise for treating neurodevelopmental disorders. To our knowledge, this is the first study that investigates the therapeutic effect of in utero transplantation of neural stem cells (NSCs) in inflammation model of prenatal brain injury. METHODS: To induce prenatal injury, time-mated C57BL6J mice were intraperitoneally injected with 50 µg/kg lipopolysaccharide (LPS(on the day 15 of gestation. In the treatment group, NSCs were transplanted into the lateral ventricle of embryos on day 17 of gestation. The expression of GFAP, Iba-1, Olig2, and NeuN were assessed by real time PCR and immunohistochemistry. Changes in IL-6, TNF-α and IL-10 cytokines level, and caspase 3 activity were evaluated in the cortex of pups. RESULTS: Intrauterine transplanted NSCs homed to the brain cortex of offspring. Brain levels of pro-inflammatory cytokines showed a significant downward trend in the NSCs group. Furthermore, NSCs ameliorated inflammation-induced reactive microgliosis and astrogliosis as well as cellular degeneration. Apoptosis inhibition in the treated group was demonstrated by the decline in the caspase 3 activity and dark neurons. CONCLUSION: This study suggests a promising prospect to initiate the treatment of prenatal brain injury before birth by intrauterine transplantation of NSCs.

Anthropometric Parameters for Access to Sella Turcica Through the Nostril.

The pituitary gland is located in the sella turcica. Pituitary tumors constitute approximately 15% of intracranial benign tumors. "Endo nasal endoscopic trans-sphenoidal" method is an appropriate surgical technique to remove this tumor. In this operation an endoscope enters the nasal cavity through the nostril to reach the floor of the sella turcica. The aim of this study was an anthropometric evaluation of the route of endoscope in this surgery. Two hundred twenty-seven patients (116 women, 111 men) were divided into ≥30, 31 to 61, and ≥61-year age groups. Lateral scanograms of skull were used to measure 3 linear distances and 1 angle. While the mean of the linear variables was significantly higher in men (P <0.001), this difference was not significant in angular measurement between sexes. More detail evaluation of the age groups showed age- and sex-specific differences in measurements. The authors concluded that it needs to consider the anthropometrical indexes in pituitary surgery.

Hyperglycemia decreased medial amygdala projections to medial preoptic area in experimental model of Diabetes Mellitus.

In Wistar rats, reproductive behavior is controlled in a neural circuit of ventral forebrain including the medial amygdala (Me), bed nucleus of the stria terminalis (BNST) and medial preoptic area (MPOA) via perception of social odors. Diabetes Mellitus (DM) is a widespread metabolic disease that affects many organs in a variety of levels. DM can cause central neuropathies such as neuronal apoptosis, dendritic atrophy, neurochemical alterations and also causes reproductive dysfunctions. So we hypothesized damage to the nuclei of this circuit can cause reproductive dysfunctions. Therefore in this project we assessed diabetic effect on these nuclei. For this purpose neuron tracing technique and TUNEL assay were used. We injected HRP in the MPOA and counted labeled cells in the Me and BNST to evaluate the reduction of neurons in diabetic animals. Also, coronal sections were analyzed with the TMB histochemistry method. Animals in this study were adult male Wistar rats (230 ± 8g) divided to control and 10-week streptozotocin-induced diabetic groups. After data analysis by SPSS 16 software, a significant reduction of HRP-labeled neurons was shown in both Me and BNST nuclei in the diabetic group. Moreover, apoptotic cells were significantly observed in diabetic animals in contrast to control the group. In conclusion, these alterations of the circuit as a result of diabetes might be one of the reasons for reproductive dysfunctions.