A study of excitotoxicity as pathological process responsible for spinal cord injury: insight from an in vitro rat spinal cord model with a focus on neuroprotection

Excitotoxicity is considered to be a major contributor to pathophysiological mechanisms responsible for spinal cord damage after acute injury. Hyperactivation of poly(ADP-ribose) polymerase (PARP) is the chief effector of neuronal death which leads to cell energy depletion and DNA damage with the manifestation of non-apoptotic cell death termed parthanatos. Glutamate mediated excitotoxicity is also one important component of post-traumatic degeneration following spinal cord injury (SCI). Kainate (1 h), a potent non-degradable analog of glutamate, was used to induce excitotoxic injury in our in vitro model. The neonatal rat isolated spinal cord preparation allowed investigating changes in locomotor network activity after application of this excitotoxic agent with or without potential neuroprotective drugs. Synaptic transmission, cumulative depolarization, fictive locomotion and disinhibited bursting were studied in order to observe the functional properties of locomotor network and related to network hictology. Our results showed that the locomotor network was very sensitive to excitotoxic damage and excitotoxicity grew gradually leaving a time window in which neuroprotection might be attempted to preserve the circuits which are still capable of expressing basic rhythmogenesis. Our result confirmed that PARP-1 overactivity is closely related to neuronal loss after kainate induced excitotoxicity. Application of PJ-34 (60 \ub5M; PARP-1 selective inhibitor) blocked PARP-1 activation and preserved dorsal, central and ventral grey matter with maintained reflex activity. Fictive locomotion was restored in more than half of the preparations when the excitotoxic stimulus was moderate. Histological damage by 50 \ub5M kainate (moderate injury) was widely prevented by PJ-34. At the same time, this drug strongly increased spontaneous network discharges which occured synchronously on ventral roots and persisted for 24 h even after PJ-34 washout. Neurochemical experiments showed that PJ-34 induced up to 33% inhibition of synaptosomal glutamate uptake with no effect on GABA uptake. However, chemically or electrically induced fictive locomotion was present 24 h after PJ-34 application and neurons and glia remain unchanged. The other PARP-1 inhibitor, PHE, failed to recover locomotor network function, while basic network rhythmicity persisted and appeared to be a moderate histological neuroprotector. Riluzole, by inhibiting glutamate release and neuronal excitability, could prevent neuronal loss 24 h later, but this drug per se (applied for 24 h) exerted strong and persistant neurodepressant effects on network synaptic transmission from which recovery was very slow and partial. Although, the number of pyknotic cells in the grey matter was decreased by riluzole application after kainate washout, no fictive locomotion was observed. Three hours application of riluzole was not sufficient enough to contrast the deleterious effect of kainate on locomotor activity. In conclusion, the divergence between histological and functional outcome in case of PARP-1 inhibition, proposes a narrow borderline between loss of fictive locomotion and neuronal preservation and suggests that protecting the motoneurons is not enough to ensure the persistence of fictive locomotion. It is also discovered that PJ-34 plays the role of a partial blocker of glutamate uptake. Despite the increased network discharges induced by PJ-34, there was no neurotoxic consequence due to this drug. In general, in order to protect the damaged spinal locomotor network, the neuroprotective strategy should be directed toward identified biomedical targets which play the most important role in cell death mechanism. On the other hand, neuroprotection should be applied at the early stages after the insult. Survival of premotoneurons in the grey matter is as important as motoneuron protection in order to achieve the goal of locomotor function preservation

EXPLORING THE INFLUENCE OF DIFFERENT FACTORS IN DESIGNING A GAMIFIED ONLINE COMMUNITY FOR GIRLS

In this thesis, an improved framework is proposed for categorizing existing gamified systems. Related works and real world examples of gamification are discussed and some areas where insufficient research exists. In order to address the identified research problems, an experimental gamified system was designed and implemented for sharing articles related to different aspects of life. The participants of the study were recruited among the users of an existing Iranian lifestyle site for female users. Therefore, the gender of the users was considered in the design. A wide range of gamification elements were implemented in the system to test the effectiveness of specific design features and gamification elements’ parameters in increasing user motivation, for example, the contingency of rewards and the use of sound and animation in badges. A detailed questionnaire was used to answer the research questions. The results suggest specific combinations of gamification elements and their parameters that can be successfully applied by designers of social sites for similar audience

A Comparative In Vitro Study of the Effects of Irsha and Chlorhexidine Mouthwashes and Acyclovir on HSV-1

Objective: Being able to cause disease in human, herpes simplex viruses (HSVs) clinically demonstrate themselves as intra-oral, extra-oral or recurrent lesions. The existing acyclovir has the selective anti-herpetic drug to control HSV infections. Due to emerged resistance to this drug and limitations of using it in especial situations, there is a need for alternative treatments such as available mouthwashes. This study aimed to compare two mouthwashes (Irsha and Chlorhexidine) with Acyclovir on HSV-1 in vitro.Methods: In this experimental research, we used MTT (Thiazolyl Blue Tetrazolium Bromide) colorimetric test to determine the cytotoxicity level of three solutions consecutively, antiseptic and nonalcoholic Irsha mouth wash (blue-colored), chlorhexidine 0.2% mouthwash, and acyclovir and absorbed wavelengths were recorded by Eliza Reader. After infecting the cells with different dilutions of HSV-1 in different concentrations of Irsha and chlorhexidine mouthwashes, we analyzed their antiherpetic effects on Vero cells. By using suitable statistical tests in version 15 of SPSS the results  were then analyzed.Results: The results showed that in the concentrations of 0.38% for Irsha and 0.003% for chlorhexidine these mouthwashes kill 50% of Vero cells (CC50). After determining CC50, we  detected the antiviral effects of Irsha and chlorhexidine mouthwashes and acyclovir solutions. We observed a significant difference between 0.5% concentration of Irsha mouthwash and other concentrations of it.   The least logarithm of virus titration was observed in 0.002% concentration of/ chlorhexidine  mouthwash.  Both  tested  acyclovir  concentrations  (1250  µgr  Mililiter   and   2500µg/mL         Mililiter µgr/                 ) had a similar effect on decreasing virus titreConclusion: According to our results, anti-herpetic effect of Irsha is less than chlorhexidine and anti-herpetic effect of Acyclovir and Chlorhexidine is stronger than Irsha

Hypermongone C Accelerates Wound Healing through the Modulation of Inflammatory Factors and Promotion of Fibroblast Migration

The physiology of wound healing is dependent on the crosstalk between inflammatory mediators and cellular components of skin regeneration including fibroblasts and endothelial cells. Therefore, strategies to promote healing must regulate this crosstalk to achieve maximum efficacy. In light of the remarkable potential of natural compounds to target multiple signaling mechanisms, this study aims to demonstrate the potential of hypermongone C, a polycyclic polyprenylated acylphloroglucinol (PPAP), to accelerate wound closure by concurrently enhancing fibroblast proliferation and migration, promoting angiogenesis, and suppressing pro-inflammatory cytokines. This compound belongs to a family of plants (Hypericum) that traditionally have been used to treat injuries. Nevertheless, the exact biological evidence to support the claims is still missing. The results were obtained using a traditional model of cell scratch assay and endothelial cell tube formation, combined with the analysis of protein and gene expression by macrophages. In summary, the data suggest that hypermongone C is a multi-targeting therapeutic natural compound for the promotion of tissue repair and the regulation of inflammation

Correlation between Biological Classification and Stromal Reaction in Breast Cancer

Background: Breast cancer is the most common cancer and a major cause of death from cancer in women. Understanding the factors, which can predict directly and indirectly the final fate of patients, can be useful in clinical decision-making and treatment choices.Materials and Methods: In a retrospective descriptive-analytic study, 108 pathological samples of patients with primary breast cancer collected during 2011-2017 from the department of pathology in Imam Hossein Hospital (Tehran Iran). Classified regarding the association of stromal reactions in tumor tissue including necrosis rate, lymphocyte infiltrating rate, and tumor desmoplasia with different types of breast tumors including four groups of Basal like, HER2/neu, Luminal B, and Luminal A based on biological biomarkers.Results: Mean age of the patients was 50.84±13.25 years. No significant relationship was found between age and type of groups. Majority of patients (60%) were in the pathological grade 2. A significant relationship was observed between three groups of Luminal B, and Basal-like with Grade 2 (p<0.05). Most patients suffered from intermediate desmoplasia which was significant only between three groups of Luminal B, HER2/neu and Basal-like (p<0.05). In terms of tumor necrosis, the majority of patients in the HER2/neu and Basal-like groups indicated non-extensive necrosis, which was significant (p>0.05). In both groups of Luminal A and Luminal B, most patients had no necrosis while the relationship between necrosis and pathological type of tumor was significant only in the Luminal B group (p>0.05). No significant relationship was found between the number of lymphocytes and the type of tumor.Conclusion: This study indicated the relationship between pathological types of breast cancers based on biomarkers with pathological grade, necrosis ratio and tumor desmoplasia. Determination of the pathological type of tumor based on the status of biological markers (HER-2/neu PR, ER, Ki67) in patients with breast cancer is recommended for making decision about therapeutic plan

Health technology assessment of Bevacizumab compare with combination of Bevacizumab with Erlotinib for treatment of patients with metastatic colorectal cancer

Introduction: Effective and efficient treatment for patients with metastatic colorectal cancer that can increase survival rate with limited side effects, is important. The purpose of this study was health technology assessment of Bevacizumab compare with combination of Bevacizumab with Erlotinib for treatment of patients with metastatic colorectal cancer. Methods and Results:In the present investigation first a systematic review on finding the studies was conducted. To reach this goal a comprehensive search in PubMed, Cochrane Library, Scopus, CRD, American Society of Clinical Oncology and European Society for Medical Oncology databases using the PICO based keywords was performed. Then, a retrieved study by means of two independent and expert reviewer during several steps (based on title, abstract and full-text, excluding of duplicated or unrelated cases) was chosen and non-qualified studies was exiled from the study. After that, 20 chosen randomized trial studies were evaluated by two experienced evaluators by Cochrane tool in terms of types of Bias. Eventually obtained data from the investigation was meta-analyzed by Revman5.3 software and safety, effectiveness and economical evaluation of the device were studied based on this data. To calculate the expenses of Bevacizumab and Erlotinib, Cost-effectiveness Analysis with the perspective of the service provider in the public sector was performed. In total, three randomized controlled trials with 682 patients met the inclusion criteria.  The combination of Bevacizumab with Erlotinib for maintenance therapy of patients with metastatic colorectal cancer improved progression free survival by 0.19 and overall survival by 0.22. Degree three and four side effects of developed during treatment were limited and manageable. The combination of the two drugs was cost effective from the perspective of the service provider. Conclusions:Based on current evidence, prescribing the combination of Bevacizumab and Erlotinib in the maintenance treatment of metastatic colorectal cancer patients is cost effective from the perspective of service provider in the public sector, and the use of this combination in the health system is economically viable

Psychological well-being in times of COVID-19: Associated factors and levels in the general population

The COVID-19 pandemic and living under social distancing restrictions have been hypothesized to impact well-being and mental health in the general population. This study investigated the general Norwegian adult population's well-being after implementing and lifting strict social distancing restrictions. The study was conducted through digital surveys; during the implementation of strict social distancing restrictions in March 2020 (T1) and 3 months later, when the preponderance of strict distancing restrictions was discontinued (T2). Well-being was measured at T2. Four thousand nine hundred twenty-one individuals participated, and a sensitivity analysis was conducted to ensure that the sample reflects the true Norwegian adult population. Hierarchical regression analyses show that contemporaneous employment status and positive metacognitions at T2 were associated with higher well-being. Negative metacognitions and the use of unhelpful coping strategies at T2 had a contemporaneous association with lower mental well-being. Negative metacognitions at T1 were associated with lower well-being scores, while positive metacognitions at T1 were positively associated with higher well-being. An indirect association between social distancing and lower well-being was found through heightened depressive symptoms. These results contribute to understanding how social distancing restrictions relate to general well-being, which may further contribute to designing proper strategies to strengthen mental health and well-being during challenging and unavoidable societal conditions.publishedVersio

Comparing Human Sperm Quality Preserved at Two Different Temperatures; Effect of Trolox, Coenzyme Q10 and Extracellular Adenosine Triphosphate

Cooling method was proposed to maintain the sperm quality for several days. Nevertheless, during this procedure, sperm is encountered to “cold shock”, and its quality decreases time-dependently. This study was designed to improve the in vitro sperm preservation methods. Thirty normal semen samples were examined in Shiraz, Iran, 2017. Fifteen samples were incubated at 22-27 °C and 15 samples were cooled moderately to 4 °C. Each sample was divided into five subgroups; control, solvent, 200 μM Trolox, 40 μM Coenzyme Q10, and 10 mM ATP. ATP was added only 15 minutes before the analysis. Assessments of motility parameters and sperm viability were done every 24 hours. Statistical analysis was performed using SPSS 16 software. The differences between two main groups and subgroups were compared by t test and one-way ANOVA, respectively. The effect of time was analyzed by repeated measurement test. Sperm motility and viability were the same in both groups until 24 hours, except the straight line velocity was greater in the cold group. Even after 48 hours, progressive motility and sperm velocity, but not viability, were still the same. The greatest reduction in progressive motility occurred on the second day; and after 72 hours, sperm quality was better preserved in 22-27 °C. Treatment with Trolox, coenzyme-Q10, and extracellular ATP did not have effect on sperm quality. Cold temperature is recommended for in-vitro sperm preservation up to 24 hours, and 22-27 °C is preferred for longer time storage. The sperm does not need antioxidant therapy for quality maintenance, but the extender media must be supplied with nutrients and antibiotics

A comparison of diet quality indices in a nationally representative cross-sectional study of Iranian households

Background: Iranian diet quality has been evaluated using indices that have not been created based on Iranian dietary guidelines. This study aimed to examine the applicability of two diet quality indices by examining their associations with nutrient adequacy, nutrient intakes and sociodemographics. Methods: Dietary data were collected using three 24-h dietary recalls from Iranian households. Nutrient adequacy was assessed using World Health Organization/Food and Agriculture Organization 2002 (WHO/FAO) cut points. Household diet quality was calculated using the Healthy Eating Index (HEI) and Diet Quality Index-International (DQI-I). Sociodemographics of the household members were assessed. Regression analyses were used to examine associations between diet quality and nutrient adequacy, and between sociodemographics and diet quality. Results: A total of 6935 households were included in the analysis. Higher household diet quality was associated with adequate intake of calcium (HEI: OR 1.11, 95% CI: 1.10, 1.13; DQI-I: OR 1.14, 95% CI: 1.13, 1.16), vitamin C (HEI: OR 1.19, 95% CI: 1.17, 1.20; DQI-I: OR 1.12, 95% CI: 1.11, 1.12) and protein (HEI: OR 1.01, 95% CI: 1.00, 1.02; DQI-I: OR 1.09, 95% CI: 1.08, 1.09). Higher household diet quality was associated with household heads who were older (> 56 years old) (HEI: β 2.06, 95% CI: 1.63, 2.50; DQI-I β 2.90, 95% CI: 2.34, 3.45), higher educated (college/university completed) (HEI: β 4.54, 95% CI: 4.02, 5.06; DQI-I: β 2.11, 95% CI: 1.45, 2.77) and living in urban areas (HEI: β 2.85, 95% CI: 2.54, 3.16; DQI-I: β 0.72, 95% CI: 0.32, 1.12). Conclusions: Based on associations with nutrient adequacy and sociodemographics, the applicability of two diet quality indices for assessing the diet quality of Iranian households was demonstrated. Results also indicated DQI-I may be more applicable than HEI for evaluating Iranian nutrient adequacy. Findings have implications for the design and assessment of diet quality in Iranian populations. Future research should examine the link between these diet quality indices and health outcomes