The roles of the kynurenine pathway in COVID-19 neuropathogenesis.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the highly contagious respiratory disease Corona Virus Disease 2019 (COVID-19) that may lead to various neurological and psychological disorders that can be acute, lasting days to weeks or months and possibly longer. The latter is known as long-COVID or more recently post-acute sequelae of COVID (PASC). During acute COVID-19 infection, a strong inflammatory response, known as the cytokine storm, occurs in some patients. The levels of interferon-γ (IFN-γ), interferon-ß (IFN-ß), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) are particularly increased. These cytokines are known to activate the enzyme indoleamine 2,3-dioxygenase 1 (IDO-1), catalysing the first step of tryptophan (Trp) catabolism through the kynurenine pathway (KP) leading to the production of several neurotoxic and immunosuppressive metabolites. There is already data showing elevation in KP metabolites both acutely and in PASC, especially regarding cognitive impairment. Thus, it is likely that KP involvement is significant in SARS-CoV-2 pathogenesis especially neurologically.

Transferrin decorated-nanostructured lipid carriers (NLCs) are a promising delivery system for rapamycin in Alzheimer's disease: An in vivo study.

Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by progressive cognitive impairment and memory loss. The mammalian target of rapamycin (mTOR) signaling pathway could regulate learning and memory. The effect of rapamycin (Rapa) on mTOR activity could slow or prevent the progression of AD by affecting various essential cellular processes. Previously, we prepared transferrin (Tf) decorated-nanostructured lipid carriers (NLCs) for rapamycin (150 ± 9 nm) to protect the drug from chemical and enzymatic degradation and for brain targeted delivery of rapamycin. Herein, the effect of Tf-NLCs compared to untargeted anionic-NLCs and free rapamycin, were studied in amyloid beta (Aß) induced rat model of AD. Behavioral test revealed that the Rapa Tf-NLCs were able to significantly improve the impaired spatial memory induced by Aß. Histopathological studies of hippocampus also showed neural survival in Rapa Tf-NLCs treated group. The immunosuppressive, and delayed wound healing adverse effects in the rapamycin solution treated group were abolished by incorporating the drug into NLCs. The Aß induced oxidative stress was also reduced by Rapa Tf-NLCs. Molecular studies on the level of Aß, autophagy (LC3) and apoptotic (caspase-3) markers, and mTOR activity revealed that the Rapa Tf-NLCs decreased the Aß level and suppressed the toxic effects of Aß plaques by modulating the mTOR activity and autophagy, and decreasing the apoptosis level. As a conclusion, the designed Tf-NLCs could be an appropriate and a safe brain delivery system for rapamycin and make this drug more efficient in AD for improving memory and neuroprotection.

Impact of oxygen-calcium-generating and bone morphogenetic protein-2 nanoparticles on survival and differentiation of bone marrow-derived mesenchymal stem cells in the 3D bio-printed scaffold.

Although stem cell therapy is a major area of interest in tissue engineering, providing proper oxygen tension, good viability, and cell differentiation remain challenges in tissue-engineered scaffolds. In this study, an osteogenic scaffold was fabricated using the 3D bio-printing technique. The bio-ink contained alginate hydrogel, encapsulated human bone marrow-derived mesenchymal stem cells (hBM-MSCs), calcium peroxide nanoparticles (CPO NPs) as an oxygen generating biomaterial, and bone morphogenic protein-2 nanoparticles (BMP2 NPs) as an osteoinductive growth factor. CPO NPs were synthesized with the hydrolysis-precipitation method, and their concentrations in the bio-ink were optimized. Scaffolds containing CPO 3% (w/w) were preferred, because they generated sufficient oxygen gas for 20 days, increased mechanical strength after 20 days, and had sufficient stability. The CPO NPs effect on the viability of embedded hBM-MSCs under hypoxic conditions was analyzed. Live/Dead staining results represented a 22% improvement in CPO 3% scaffold viability on day 7. Therefore, CPO NPs constituted a promising survival factor. BMP2 NPs were prepared with the double emulsification technique. The incorporation of both BMP2 and CPO NPs resulted in the upregulation of Runt-related transcription factor 2, Collagen type I alpha 1, and the osteocalcin genes compared to internal references in osteogenic media. Overall, the proposed 3D bio-printed osteogenic scaffold in this study has moved scientific research one step forward toward successful stem cell therapy and helped improve host tissue healing by biological activity enhancement, especially for low oxygen pressure tissues.

Brain targeted delivery of rapamycin using transferrin decorated nanostructured lipid carriers.

Introduction: Recent studies showed that rapamycin, as a mammalian target of rapamycin (mTOR) inhibitor, could have beneficial therapeutic effects for the central nervous system (CNS) related diseases. However, the immunosuppressive effect of rapamycin as an adverse effect, the low water solubility, and the rapid in vivo degradation along with the blood-brain barrier-related challenges restricted the clinical use of this drug for brain diseases. To overcome these drawbacks, a transferrin (Tf) decorated nanostructured lipid carrier (NLC) containing rapamycin was designed and developed. Methods: Rapamycin-loaded cationic and bare NLCs were prepared using solvent diffusion and sonication method and well characterized. The optimum cationic NLCs were physically decorated with Tf. For in vitro study, the MTT assay and intracellular uptake of nanoparticles on U-87 MG glioblastoma cells were assessed. The animal biodistribution of nanoparticles was evaluated by fluorescent optical imaging. Finally, the in vivo effect of NLCs on the immune system was also studied. Results: Spherical NLCs with small particle sizes ranging from 120 to 150 nm and high entrapment efficiency of more than 90%, showed ≥80% cell viability. More importantly, Tf-decorated NLCs in comparison with bare NLCs, showed a significantly higher cellular uptake (97% vs 60%) after 2 hours incubation and further an appropriate brain accumulation with lower uptake in untargeted tissue in mice. Surprisingly, rapamycin-loaded NLCs exhibited no immunosuppressive effect. Conclusion: Our findings proposed that the designed Tf-decorated NLCs could be considered as a safe and efficient carrier for targeted brain delivery of rapamycin which may have an important value in the clinic for the treatment of neurological disorders.

Correction: Brain targeted delivery of rapamycin using transferrin decorated nanostructured lipid carriers.

[This corrects the article DOI: 10.34172/bi.2021.23389.].

Nanostructured lipid carriers containing rapamycin for prevention of corneal fibroblasts proliferation and haze propagation after burn injuries: In vitro and in vivo.

Chemical burns are a major cause of corneal haze and blindness. Corticosteroids are commonly used after corneal burns to attenuate the severity of the inflammation-related fibrosis. While research efforts have been aimed toward application of novel therapeutics. In the current study, a novel drug delivery system based nanostructured lipid carriers (NLCs) were designed to treat corneal alkaline burn injury. Rapamycin, a potent inhibitor of mammalian target of rapamycin pathway, was loaded in NLCs (rapa-NLCs), and the NLCs were characterized. Cell viability assay, cellular uptake of NLCs, and in vitro evaluation of the fibrotic/angiogenic genes suppression by rapa-NLCs were carried out on human isolated corneal fibroblasts. Immunohistochemistry (IHC) assays were also performed after treatment of murine model of corneal alkaline burn with rapa-NLCs. According to the results, rapamycin was efficiently loaded in NLCs. NLCs could enhance coumarin-6 fibroblast uptake by 1.5 times. Rapa-NLCs efficiently downregulated platelet-derived growth factor and transforming growth factor beta genes in vitro. Furthermore, proliferation of fibroblasts, a major cause of corneal haze after injury, reduced. IHC staining of treated cornea with alpha-smooth muscle actin and CD34 + antibodies showed efficient prevention of myofibroblasts differentiation and angiogenesis, respectively. In conclusion, ocular delivery of rapamycin using NLCs after corneal injury may be considered as a promising antifibrotic/angiogenic treatment approach to preserve patient eyesight.

Effectiveness of Acceptance and Commitment Therapy on Anxiety and Depression of Razi Psychiatric Center Staff.

AIM: Considering the key role of human resources as the main operator of organisations, the present research aimed to determine the effectiveness of acceptance and commitment therapy for anxiety and depression of Razi Psychiatric Center staff. MATERIALS AND METHODS: This research follows a quasi-experimental type with pre-test, post-test plans, and control group. Accordingly, 30 people were selected through volunteered sampling among Razi Psychiatric Center staff. Then, they were randomly placed into two groups of 15 (experimental and control) and evaluated using research tools. Research tools consisted of Beck Anxiety and Depression Inventories whose reliability and validity have been confirmed in several studies. Research data were analysed using the analysis of covariance (ANCOVA). RESULTS: The statistical analysis confirmed the difference in the components of anxiety and depression in the experimental group, which had received acceptance and commitment therapy compared to the group that had not received any therapy in this regard (control group) (p < 0.05). CONCLUSION: Acceptance and commitment therapy reduces anxiety and depression.

Dengue Fever as an Emerging Infection in Southeast Iran.

Dengue fever (DF) is a mosquito-borne acute viral disease presenting with hemorrhagic manifestations in severe cases. Southeast Iran is in close proximity to Pakistan, an endemic country for DF. This cross-sectional study was conducted in the Sistan and Baluchestan province in the southeast of Iran to investigate possibility of DF (immunoglobulin M [IgM], immunoglobulin G [IgG], and nonstructural protein 1 [NS1] antigen tests) in 60 clinically suspected patients (April 2013 to August 2015). NS1 protein was detected in 5% (N = 3), at least one of the antibodies (IgM and/ or IgG) was detected in 11% (N = 7) of the samples. Five patients identified as of acutely infected. There was a simultaneous presence of NS1 protein and IgG or IgM antibodies in 4% (N = 2) of patients. Previous studies show establishment of potential vectors in this area. These evidences support the hypothesis that DF can be a health concern in Southeast Iran with potential future outbreaks.

Management of Substance Use Disorder in Military Services: A Comprehensive Approach.

BACKGROUND: Historically, substance misuse has been a serious problem faced by worldwide military personnel. Some research showed that military personnel have higher rates of unhealthy substance use than their age peers in the general population. These problems have serious consequences and may lead to significant military difficulties in the field of readiness, discipline, and mental or physical health. In this review, we gathered various methods for prevention, diagnosis, and treatment of substance use disorders and suggested a comprehensive plan for Iran Armed Forces to improve existing services. MATERIALS AND METHODS: This article is a narrative review study, which was carried out on 2016. A careful literature review was performed between January 1970 and April 2016 on several national and international databases. Articles were screened according to the following inclusion criteria: (1) review articles about prevention and treatment protocols, (2) executive guidance, (3) cohort articles about risk factors of addiction, and (4) randomized controlled trials about prevention or treatment of substance use disorders in army service members. After screening by title and abstract, 130 articles selected of 832 founded articles, and after quality assessment, finally, 63 articles included in the review. RESULTS: There is a necessity to manage substance use disorder through prevention, screening, and then referral to proper services for diagnosis and treatment. Urinalysis programs for screening are cost-effective and should be considered as a main method. Effective treatment includes both behavioral and pharmacological methods. CONCLUSIONS: The ideal prevention program will include multiple and mutually reinforcing evidence-based universal, selective, and indicated attempts at both the individual and environmental levels. The implementation of screening and treatment strategies needs strict rules and national guideline for the comprehensive management of substance use disorders in army.

Removal of a Broken Instrument from a Tooth with Apical Periodontitis Using a Novel Approach.

UNLABELLED: Instrument breakage during treatment can lead to serious complications and carries the risk of treatment failure. When a file breaks in the canal, bypassing or removal can be difficult and the long-term prognosis of the tooth may be compromised. Sometimes surgery may be indicated for removal of the broken segment. Often some part of the root cannot be cleaned because of blockage by the broken file. This report presents a specific approach in non- surgical removal of a broken file from a maxillary lateral incisor with a buccal sinus tract and a broken instrument in the apical third which was partially over extended into the periapical lesion. The broken file was accessed through the sinus tract and pushed into the canal. The canal was cleaned and shaped, filled with mineral trioxide aggregate (MTA). CONCLUSION: A sinus tract can be a specific path to reach the root tip and get access to remove the foreign materials pushed beyond the root canal space.

Predictors of Change in Substance Abuse Status in Soldiers.

BACKGROUND: Military service is a stressful task that influences the life style of army personnel. Several factors can make soldiers less capable of coping with stressful events; so they may try to start drug abuse or increase in the amount or diversity of substance abuse. Understanding factors responsible for this misbehavior among soldiers is crucial for their commanders to modify these factors. OBJECTIVES: This study aimed to determine the predictors of change in substance abuse status in soldiers. PATIENTS AND METHODS: This cross-sectional research was conducted to evaluate the substance abuse status among Iranian soldiers in 2010. The target population was the soldiers who had spent at least 3 months of their military service. Cluster sampling was done from army service garrisons in 12 provinces in Iran. A total of 3960 soldiers were selected with different levels of education and age. Data gathering was done with demographic questionnaires, Texas Christian university (TCU) drug screen II and ASI questionnaire (fifth edition). Four types of dependent variables were defined: "improvement", "without change", "deterioration", and "severe deterioration". Backward ordinal regression analysis was done and P values, OR, and SE were calculated by SPSS19 software. RESULTS: Totally, 6.7% of soldiers improved, 82% remained without change, 6.1% deteriorated, and 5.2% severely deteriorated with regard to their substance abuse. Modifiable predictors were distance from home lower than 200 km (OR =1.54), bad relationship with commanders (OR = 1.88), service place dissatisfaction (OR = 1.39), and always feeling lonely (OR = 1.83). Non-modifiable factors were alcohol use within family and friends (P = 0.000); psychiatric drug use history (OR = 1.72); suicidal attempt history (OR = 1.31); divorce, separation, and extramarital contact (P = 0.001); unemployment (P = 0.019); leisure time dissatisfaction (P = 0.004); living alone (OR = 2.43); and substance abuse onset before age 15 (OR = 1.71). CONCLUSIONS: Considering non-modifiable risk factors, leaders and commanders may recognize more vulnerable soldiers and try to resolve modifiable factors and decrease the risk of getting worse (with respect to substance abuse) about 7.3 times.

A New Adaptive Diffusive Function for Magnetic Resonance Imaging Denoising Based on Pixel Similarity.

Although there are many methods for image denoising, but partial differential equation (PDE) based denoising attracted much attention in the field of medical image processing such as magnetic resonance imaging (MRI). The main advantage of PDE-based denoising approach is laid in its ability to smooth image in a nonlinear way, which effectively removes the noise, as well as preserving edge through anisotropic diffusion controlled by the diffusive function. This function was first introduced by Perona and Malik (P-M) in their model. They proposed two functions that are most frequently used in PDE-based methods. Since these functions consider only the gradient information of a diffused pixel, they cannot remove noise in noisy images with low signal-to-noise (SNR). In this paper we propose a modified diffusive function with fractional power that is based on pixel similarity to improve P-M model for low SNR. We also will show that our proposed function will stabilize the P-M method. As experimental results show, our proposed function that is modified version of P-M function effectively improves the SNR and preserves edges more than P-M functions in low SNR.

Development of a multiplex one step RT-PCR that detects eighteen respiratory viruses in clinical specimens and comparison with real time RT-PCR.

Rapid and accurate diagnosis of viral respiratory infections is crucial for patient management. Multiplex reverse transcriptase polymerase chain reaction (mRT-PCR) is used increasingly to diagnose respiratory infections and has shown to be more sensitive than viral culture and antigen detection. Objective of the present study was to develop a one-step mRT-PCR that could detect 18 respiratory viruses in three sets. The method was compared with real time RT-PCR (rRT-PCR) for its sensitivity and specificity. Clinical specimens from 843 pediatric patients with respiratory symptoms were used in the study. 503 (59.7%) samples were detected positive by mRT-PCR. Of these 462 (54.8%) exhibited presence of a single pathogen and 41 (4.9%) had multiple pathogens. rRT-PCR detected 439 (52.1%) positive samples, where 419 (49.7%) exhibited one virus and 20 (2.4%) showed co-infections. Concordance between mRT-PCR and rRT-PCR was 91.9% and kappa correlation 0.837. Sensitivity and specificity of mRT-PCR were 99.5% and 83.7% while that of rRT-PCR was 86.9% and 99.4% respectively. Rhinovirus (17.2%) was the most frequently detected virus followed by respiratory syncytial virus B (15.4%), H1N1pdm09 (8.54%), parainfluenza virus-3 (5.8%) and metapneumovirus (5.2%). In conclusion, mRT-PCR is a rapid, cost effective, specific and highly sensitive method for detection of respiratory viruses.

Zolpidem dependence, abuse and withdrawal: A case report.

Zolpidem, a nonbenzodiazepine hypnotic, binds to the benzodiazepine binding site on the gamma-aminobutyric acid type A (GABA-A) receptors. Many studies have reported efficacy and safety of zolpidem in treatment of insomnia, low abuse, and dependence capability. However, many cases of zolpidem abuse and dependence were reported around the world. This case showed that zolpidem can exert abuse capability, euphoric mood, tolerance, and withdrawal syndrome.