The Relationship between the Clinical Course of SARS-CoV-2 Infections and Expression of Bruton's Tyrosine Kinase.

OBJECTIVES: The Bruton tyrosine kinase (BTK), an important element for the production of several inflammatory cytokines, may play a role in the pathogenesis of COVID-19. The aim of this study was to investigate the level of BTK gene expression in COVID-19 cases based on the severity and the outcome of the disease. METHODS: In this study, 33 hospitalized patients with COVID-19 were recruited and were divided into two groups based on the severity of the disease: "mild to moderate" and "severe to critical". A blood sample was taken from each patient, peripheral blood mononuclear cells (PBMCs) were extracted, and BTK gene expression was measured. The level of BTK gene expression was compared based on the demographic data, laboratory results, and the severity and outcome of the disease. RESULTS: Among 33 patients, 22 (66.7%) were male. Nearly half of the cases had at least one underlying disease. According to the severity of the disease, 12 patients were in the "mild to moderate" group, and 21 were in the "severe to critical" group; eight (24.2%) eventually died. Age, weight, and BMI had no significant relationship with BTK expression. BTK expression was significantly lower in "severe to critical" and ICU-admitted cases and in subjects with low O2 saturation. There was no significant difference in BTK expression between cured and dead patients (p=0.117). CONCLUSION: BTK gene expression in PBMCs had an inverse relationship with the severity of the disease of COVID-19. However, no correlation between BTK expression and disease outcome was observed.

Mycobacterium genavense infections in immunocompromised patients with HIV: A clinical case report.

Key Clinical Message: It is essential to consider non-tuberculosis mycobacterium in HIV-positive patients with fever, abdominal pain, weight loss, and splenomegaly. Abstract: Mycobacterium genavense is an opportunistic slow-growing nontuberculous mycobacterium in patients with immunocompromised backgrounds, especially HIV-positive patients. In this study, we present two cases of Mycobacterium genovese infection in HIV-positive patients with a good clinical response to accurate treatment.

Breast Tuberculosis in Iran: A Comprehensive Review.

ABSTRACT: Tuberculosis (TB) remains a significant global health concern and kills millions of people every year. While TB can affect any organ in the body, breast TB is relatively uncommon. This study presents a comprehensive review of literature spanning 23 years, with a focus on cases of breast TB in Iran. Among the 96 cases found, the majority (89.6%) fell within the age range of 20-60, with a striking prevalence among women (98.9%). Common symptoms included pain and palpable mass, each presenting in approximately 60.4% of cases. Notably, only a quarter of patients had a confirmed history of exposure to a known TB case. Left breast involvement was more prevalent (58.3%), with ipsilateral lymph node enlargement observed in 40.6% of cases. Given the clinical presentation of breast TB, which often leads to misdiagnosis, a significant proportion of cases (68.7%) were diagnosed through excisional biopsy. Following a standard 6-month regimen of anti-TB drugs, relapse occurred in only 4.2% of cases. This study highlights the need for heightened awareness and vigilance in diagnosing breast TB, especially in regions with a high burden. Although breast TB poses diagnostic challenges, with prompt identification and treatment, the prognosis is generally favorable, with a low incidence of relapse.

Broadening the phenotype and genotype spectrum of novel mutations in pontocerebellar hypoplasia with a comprehensive molecular literature review.

BACKGROUND: Pontocerebellar hypoplasia is an umbrella term describing a heterogeneous group of prenatal neurodegenerative disorders mostly affecting the pons and cerebellum, with 17 types associated with 25 genes. However, some types of PCH lack sufficient information, which highlights the importance of investigating and introducing more cases to further elucidate the clinical, radiological, and biochemical features of these disorders. The aim of this study is to provide an in-depth review of PCH and to identify disease genes and their inheritance patterns in 12 distinct Iranian families with clinically confirmed PCH. METHODS: Cases included in this study were selected based on their phenotypic and genetic information available at the Center for Comprehensive Genetic Services. Whole-exome sequencing (WES) was used to discover the underlying genetic etiology of participants' problems, and Sanger sequencing was utilized to confirm any suspected alterations. We also conducted a comprehensive molecular literature review to outline the genetic features of the various subtypes of PCH. RESULTS: This study classified and described the underlying etiology of PCH into three categories based on the genes involved. Twelve patients also were included, eleven of whom were from consanguineous parents. Ten different variations in 8 genes were found, all of which related to different types of PCH. Six novel variations were reported, including SEPSECS, TSEN2, TSEN54, AMPD2, TOE1, and CLP1. Almost all patients presented with developmental delay, hypotonia, seizure, and microcephaly being common features. Strabismus and elevation in lactate levels in MR spectroscopy were novel phenotypes for the first time in PCH types 7 and 9. CONCLUSIONS: This study merges previously documented phenotypes and genotypes with unique novel ones. Due to the diversity in PCH, we provided guidance for detecting and diagnosing these heterogeneous groups of disorders. Moreover, since certain critical conditions, such as spinal muscular atrophy, can be a differential diagnosis, providing cases with novel variations and clinical findings could further expand the genetic and clinical spectrum of these diseases and help in better diagnosis. Therefore, six novel genetic variants and novel clinical and paraclinical findings have been reported for the first time. Further studies are needed to elucidate the underlying mechanisms and potential therapeutic targets for PCH.

Hematocytological Clues of Peripheral Blood in Different Clinical Presentations of COVID-19.

Background: To gain insight into the pathogenesis and clinical course of COVID-19 from a historical perspective, we reviewed paraclinical diagnostic tools of this disease and prioritized the patients with a more severe form of disease admitted to intensive care units (ICUs). The objective was to better predict the course and severity of the disease by collecting more paraclinical data, specifically by examining the relationship between hematological findings and cytological variation of blood neutrophils and monocytes. Methods: This retrospective study was conducted on 112 patients with confirmed COVID-19 admitted to Imam Hossein Hospital (Tehran, Iran) from August to September 2020. Peripheral blood smears of these patients were differentiated according to several cytological variations of neutrophils and monocytes, and the correlation to the severity of the disease was specified. Results: The mean percentages of degenerated monocytes, degenerated granulocytes, and spiky biky neutrophils were significantly different among critical and non-critical patients (P<0.05). Degenerated monocytes and granulocytes were higher in critical patients as opposed to spiky biky neutrophils, which were higher among non-critical ones. Comparing the peripheral blood smears of COVID-19 patients (regarding pulmonary involvement in chest computed tomography [CT] scans [subtle, mild, moderate, and severe groups]), the twisted form of neutrophils was significantly higher in the subtle group than in the mild and moderate groups (P=0.003). Conclusion: Different cytological morphologies of neutrophils and monocytes, including degenerated monocytes, degenerated granulocytes, and spiky biky and twisted neutrophils, could help to predict the course and severity of the disease.

Evaluation of the Cellular Resistance Process in Treated Cells Via Extracorporeal Photopheresis.

Introduction: Extracorporeal photopheresis (ECP) is a therapeutic method applied against some diseases such as cancers. Using 8-methoxypsoralen (8-MOP) and UVA radiation in ECP is associated with achievement in the treatment of patients with leukemic cutaneous T-cell lymphoma (CTCL). Evaluation of cellular resistance versus ECP is the aim of this study. Methods: Data were downloaded from the Gene Expression Omnibus (GEO) database and were analyzed via the GEO2R program. The significant DEGs were assessed via protein-protein interaction (PPI) network analysis by using the STRING database and Cytoscape software. The critical genes were evaluated via gene ontology by using the ClueGO application of Cytoscape software. The identified biological processes were determined and analyzed. Results: Fifty-seven significant DEGs were determined. The main connected component of the PPI network including 32 queried significant DEGs plus 50 first neighbors was constructed. Nineteen histones as critical nodes were assessed via gene ontology, and "nucleosome organization" was pointed out as the crucial biological process. Finally, 15 histones from H2A, H2B, and H3 histone families were identified as the key genes that are involved in the resistance property of the treated cells. Conclusion: In conclusion, 15 members of H2A, H2B, and H3 families (especially H2A family) were considered as the origin of resistance versus ECP treatment. It is concluded that sensitivity to ECP treatment depends on gross molecular events which are involved in the functions of histones.

Assessment of Photosensitizer Concentration Effects on the Efficacy of Photodynamic Therapy.

Introduction: Photodynamic therapy (PDT) is an attractive approach in medicine. Due to its noninvasive nature and low side effects, PDT has been developed quickly. In the present study, the gene expression profiles of the human cell line that was treated via PDT in the sub-lethal concentration (LC50) and super-lethal concentration (LC90) of a photosensitizer (PS) from Gene Expression Omnibus (GEO) were extracted and the common differentially expressed genes (DEGs) were investigated. Methods: The gene expression profiles of the treated cells were compared with a control, and the common DEGs were determined. The common DEGs were assessed via protein-protein interaction (PPI) network analysis, and gene ontology enrichment was evaluated. The related biological terms for the common genes were identified. Results: Ninety-four common DEGs were selected to be analyzed. It appeared that the activation and increment of gene expression were prominent processes. Jun, Dusp1, Atf4, and Atf3 as four critical genes were highlighted. "Chromosomal and microsatellite instability in colorectal cancer" was identified as the main class of biological terms related to the assessed DEGs. Conclusion: The major molecular events which happened in both analyses indicated that PDT, independent from the concentration of PS, induced gross molecular changes such as the upregulation of Jun and Dusp1.

Collagen Synthesis as a Prominent Process During the Interval between Two Laser Sessions.

Introduction: Many people suffer from skin photodamage, especially photoaging. The application of a laser to repair damages is a common therapeutic method that is used widely. In the present study, the effectiveness and molecular mechanism of an Er:Glass non-ablative fractional laser on the human skin was assessed via bioinformatics and network analysis. Methods: The gene expression profiles of 17 white female forearm skins which received an Er:Glass non-ablative fractional laser before and after laser treatment in two sessions were extracted from Gene Expression Omnibus (GEO). Data were evaluated via GEO2R and the significant differentially expressed genes (DEGs) were assessed via protein-protein interaction (PPI) network analysis. The central nodes were identified and discussed for the compared set of samples. Results: Five classes of samples were clustered in two categories: first, baseline, 7 and 14 days after the first session of laser treatment, and second, one day after the first laser session, 29 days after the first laser session, and 1 day after the second laser session. The gross cell functions such as cell division and cell cycle and immune response were highlighted as the early affected targets of the laser. Collagen synthesis was resulted after the first laser session. Conclusion: In conclusion, the time interval between laser sessions plays a critical role in the effectiveness of laser therapy. Findings indicate that the gross effect of laser application appears in a short time, and important processes such as collagen synthesis happen later.

The Accuracy of Diagnosis and Genotyping of Leishmania Species Based on Spliced Leader Mini-Exon Gene by Nuclear Magnetic Resonance and Sequencing Assays.

Background: We aimed to evaluate the accuracy of genotyping of Leishmania species by the spliced leader mini-exon gene. Methods: Suspected leishmaniasis patients, referred to Masieh Daneshvary Hospital, Tehran, Iran were included from May 2017 to September 2021. The Leishmania species were genotyped by PCRRFLP based on the SL mini-exon gene and the ITS1 region of SSU-rRNA gene and compared with the sequencing results. The expressed metabolites of metacyclic promastigotes were evaluated by Proton nuclear magnetic resonance (1H-NMR). Results: Out of 66 suspected cases, 36 (54.4%) were positive for Leishmania species based on the PCR assays. In 21 (31.8%) cases, promastigotes grew on culture tubes. Based on the RFLP of SL RNA profile, 13 (19.7%) L. tropica, 9 (13.6%) L. major, 3 (4.5%) L. infantum, and 8 (12.1%) C. fasciculata isolates, isolated from culture media, were identified; however, 3 (4.5%) cases were unidentifiable due to the low number of parasites. Seventeen metabolites were expressed by the metacyclic forms of L. major, L. tropica and C. fasciculata isolates. The top differential metabolites expressed more in C. fasciculata were FAD, p-Methoxybenzyl alcohol and S-b-G-5, 5-G-b-S (A = CH2) (P<0.005) whereas Veratryl glycerols and D-(+)-Mannose were significantly increased in L. major and Betulin, LTyrosine in L. tropica (P<0.01). Conclusion: The invaluable techniques such as sequencing and 1H-NMR confirmed the results of genotyping of Leishmania species based on the SL mini-exon gene. SL mini exon gene can be used as a diagnostic tool to differentiate various Leishmania genotypes and detect contamination of culture media with C. fasciculata.

Acetyl-11-Keto-Beta-Boswellic Acid Has Therapeutic Benefits for NAFLD Rat Models That Were Given a High Fructose Diet by Ameliorating Hepatic Inflammation and Lipid Metabolism.

Acetyl-11-keto-beta-boswellic acid (AKBA), a potent anti-inflammatory compound purified from Boswellia species, was investigated in a preclinical study for its potential in preventing and treating non-alcoholic fatty liver disease (NAFLD), the most common chronic inflammatory liver disorder. The study involved thirty-six male Wistar rats, equally divided into prevention and treatment groups. In the prevention group, rats were given a high fructose diet (HFrD) and treated with AKBA for 6 weeks, while in the treatment group, rats were fed HFrD for 6 weeks and then given a normal diet with AKBA for 2 weeks. At the end of the study, various parameters were analyzed including liver tissues and serum levels of insulin, leptin, adiponectin, monocyte chemoattractant protein-1 (MCP-1), transforming growth factor beta (TGF-ß), interferon gamma (INF-ϒ), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α). Additionally, the expression levels of genes related to the inflammasome complex and peroxisome proliferator-activated receptor gamma (PPAR-ϒ), as well as the levels of phosphorylated and non-phosphorylated AMP-activated protein kinase alpha-1 (AMPK-α1) protein, were measured. The results showed that AKBA improved NAFLD-related serum parameters and inflammatory markers and suppressed PPAR-ϒ and inflammasome complex-related genes involved in hepatic steatosis in both groups. Additionally, AKBA prevented the reduction of the active and inactive forms of AMPK-α1 in the prevention group, which is a cellular energy regulator that helps suppress NAFLD progression. In conclusion, AKBA has a beneficial effect on preventing and avoiding the progression of NAFLD by preserving lipid metabolism, improving hepatic steatosis, and suppressing liver inflammation.

Inverted ILM Flap Technique in Optic Disc Pit Maculopathy.

Purpose: To present the outcome of optic disc pit maculopathy (ODPM) managed successfully with an inverted internal limiting membrane (ILM) flap over the optic disc. A narrative review of ODPM pathogenesis and surgical management techniques are also provided. Case Report: This prospective interventional case series included three eyes of three adult patients (25-39 years old) with unilateral ODPM and a mean duration of unilaterally decreased visual acuity of 7.33 ± 2.40 months (4-12 months). The pars plana vitrectomy with posterior vitreous detachment induction was performed on eyes, followed by an inverted ILM flap insertion over the optic disc and gas tamponade. Patients were followed for 7-16 weeks postoperatively; best-corrected visual acuity (BCVA) improved dramatically in one patient from 2/200 to 20/25. BCVA in other patients improved two and three lines - to 20/50 and 20/30, respectively. A significant anatomical improvement was achieved in all three eyes, and no complication was detected throughout the follow-up period. Conclusion: Vitrectomy with inverted ILM flap insertion over the optic disc is safe and can yield favorable anatomical improvement in patients with ODPM.

A case report of cutaneous infection with Mycobacterium neoaurum.

Cutaneous infection due to Mycobacterium neoaurum in immune-competent individuals had only been reported in limited cases. The point that makes our case very impressive was its cutaneous infection, and presentation in the immune-competent patient. Abstract: Cutaneous infections caused by nontuberculous mycobacteria usually occur in immunocompromised hosts. We report a rare case of cutaneous infection caused by Mycobacterium neoaurum in an immune-competent patient.

Molecular Communication Transmitter Design in Limited-Capacity Storage Regime.

The limited storage capacity at the transmitters of a molecular communication (MC) system can affect the system's performance. One of the reasons for this limitation is the size restriction of the transmitter, which the storage must be replenished so that the transmitter has enough molecules for future transmission. This paper proposes a biologically inspired transmitter model based on neurons for MC whose storage charging and discharging follow differential equations. The proposed transmitter opens its outlet for a specific time in each time frame to exponentially release a portion of stored molecules to code bit-1 and remains silent to code bit-0. We analyze our model based on different transmission parameters. These parameters are the symbol duration, the release time duration, the storage capacity, and the release and replenishment rate of the storage. We find that the storage outlet must be open for a certain period within the time slot duration in order to improve the performance of the proposed system. Additionally, we demonstrate that determining the effect of storage capacity size can be important for practical MC due to the significant differences between the ideal transmitter and the proposed one, which have a limited size. We show that increases in the transmitter storage size can improve the system performance. As a result, taking a closer look at these practical transmitters is essential to solving the problems and challenges of molecular communication systems.

Diminution of STING Expression in the Blood of Patients with Severe or Critical COVID-19 Pneumonia.

INTRODUCTION: Cytokine storm and critical COVID-19 pneumonia are caused in at least 10% of patients by inborn errors of or auto-Abs to type I IFNs. The pathogenesis of life-threatening COVID-19 pneumonia in other patients remains unknown. METHODS: This study was conducted at Masih Daneshvari Hospital, Tehran, Iran. In the period of study, 75 confirmed cases of COVID-19 with presentations ranging from mild upper respiratory tract infection to lower respiratory tract infection, including moderate, severe, and critical disease, were recruited. Expression of STING mRNA was measured in peripheral blood mononuclear cells (PBMCs) and compared between patients with different severity and outcome. RESULTS: There was a significant negative correlation between age and STING expression level (p value = 0.010). Patients with "severe to critical" illness had a 20-fold lower STING expression level compared to the "mild to moderate" group (p value = 0.001). Also, the results showed lower expressions of STING in the patients admitted to the ICU (p value = 0.015). Patients who finally died had lower expression of STING at the time of sampling (p value = 0.041). CONCLUSION: STING mRNA expression in PBMCs was significantly lower in older COVID-19 cases, the patients with more severe illness, who needed intensive care, and who eventually died.

Erratum: Inverted ILM Flap Technique in Optic Disc Pit Maculopathy.

[This corrects the article DOI: 10.18502/jovr.v18i2.13189.].

The role of angiotensin I converting enzyme insertion/deletion polymorphism in the severity and outcomes of COVID-19 patients.

The pandemic of coronavirus disease in 2019 has led to a global crisis. COVID-19 shows distinct clinical manifestations of the severity of symptoms. Numerous patients with no associated risk factors demonstrate acute respiratory distress syndrome (ARDS). The role of genetic factors in determining the severity and outcome of the disease remains unresolved. The purpose of this study was to see if a correlation exists between Angiotensin I Converting Enzyme (ACE) insertion/deletion (I/D) polymorphism and the severity of COVID-19 patients' symptoms. 120 COVID-19 patients admitted to Masih Daneshvari Hospital in Tehran with their consent to participate entered the study. Based on the World Health Organization classification, patients were divided into moderate and severe groups, which were primarily affected by O2 saturation levels. The effects of the patients' ACE insertion/deletion polymorphism, background disease, Angiotensin receptor blocker (ARB) drug consumption, and demographic parameters on the severity risk were calculated statistically. The ACE D allele was associated with an increased risk of disease severity (OR = 6.766, p = 0.012), but had no effect on mortality.

National Research Institute of Tuberculosis and Lung Disease (NRITLD) Protocol for the Treatment of Patients with COVID-19.

More than a year after the onset of the coronavirus disease pandemic in 2019, the disease remains a major global health issue. During this time, health organizations worldwide have tried to provide integrated treatment guidelines to control coronavirus disease 2019 (COVID-19) at different levels. However, due to the novel nature of the disease and the emergence of new variants, medical teams' updating medical information and drug prescribing guidelines should be given special attention. This version is an updated instruction of the National Research Institute of Tuberculosis and Lung Disease (NRITLD) in collaboration with a group of specialists from Masih Daneshvari Hospital in Tehran, Iran, which is provided to update the information of caring clinicians for the treatment and care of COVID-19 hospitalized patients.

The Frequency of Epidermal Growth Factor Receptor (EGFR) Mutation in Patients with Lung Adenocarcinoma Referred to a Lung Diseases Hospital; A Cross-Sectional Study from Iran.

Background & Objective: Various studies showed the use of epidermal growth factor receptors (EGFRs) gene mutations in the therapeutic plan of patients with advanced lung cancer. This study aimed to investigate the frequency and types of EGFR gene mutations among Iranian patients with lung adenocarcinoma referred to a specialized lung diseases hospital from 2014 to 2019. Methods: The data of all patients with lung adenocarcinoma referred to the Molecular Department of Masih Daneshvari Hospital Laboratory (National Research Institute of Tuberculosis and Lung Diseases) from 2014 to 2019 for EGFR mutation tests were collected. Patients' characteristics data and information on the frequency and types of EGFR gene mutations were obtained from the hospital information system (HIS). The collected data were analyzed using SPSS 25. Results: A total of 570 individuals (Mean age of 58.74, 51.6% Male) were included in the study; 113 out of 570 patients (19.8%) were diagnosed with gene mutation. In terms of the type of mutation, 65 participants (57%) showed deletion, 48 patients (42.1%) were diagnosed with replacement, and one (0.9%) case demonstrated both. Notably, the mutation rate detected among the female patients was significantly higher than the male ones (P=0.001); in particular, deletion type of mutation was found more among women, although both genders were the same in terms of the replacement frequency. However, the age had no effect on the mutation in this study (P=0.05). Conclusion: Among Iranian patients with lung adenocarcinoma, 19.8% harbored EGFR gene mutation. This mutation was found in association with lung cancer and could affect the patient's therapeutic plan.

Transmission electron microscopy study of suspected primary ciliary dyskinesia patients.

Primary ciliary dyskinesia (PCD) is a rare autosomal recessive condition often presenting with chronic respiratory infections in early life. Transmission electron microscopy (TEM) is used to detect ciliary ultrastructural defects. In this study, we aimed to assess ciliary ultrastructural defects using quantitative methods on TEM to identify its diagnostic role in confirming PCD. Nasal samples of 67 patients, including 37 females and 30 males (20.3 ± 10.7 years old), with suspected PCD symptoms were examined by TEM. The most common presentations were bronchiectasis: 26 (38.8%), chronic sinusitis: 23 (34.3%), and recurrent lower respiratory infections: 21 (31.3%). Secondary ciliary dyskinesia, including compound cilia (41.4%) and extra-tubules (44.3%), were the most prevalent TEM finding. Twelve patients (17.9%) had hallmark diagnostic criteria for PCD (class 1) consisting of 11 (16.4%) outer and inner dynein arm (ODA and IDA) defects and only one concurrent IDA defect and microtubular disorganization. Also, 11 patients (16.4%) had probable criteria for PCD (class 2), 26 (38.8%) had other defects, and 18 (26.9%) had normal ciliary ultrastructure. Among our suspected PCD patients, the most common ultrastructural ciliary defects were extra-tubules and compound cilia. However, the most prevalent hallmark diagnostic defect confirming PCD was simultaneous defects of IDA and ODA.

The Possible Role of Bruton Tyrosine Kinase Inhibitors in the Treatment of COVID-19: A Review.

BACKGROUND: Coronavirus disease 2019 (COVID-19), an acute, sometimes severe respiratory illness caused by a novel coronavirus has led to a vast pandemic with an astonishing spread rate. Its treatment is unknown, its mortality is significant, and its socioeconomic complications are uncontrollable. Although there is still little known about the pathogenesis of the disease, severe cases of COVID-19 are usually associated with cytokine release syndrome and high serum levels of inflammatory cytokines, which are believed to be a major cause of mortality in these patients. Different pathways cause inflammation and the release of cytokines. One of these pathways is the Bruton tyrosine kinase (BTK) pathway, which is essential for the production of several anti-inflammatory cytokines. Theoretically, the inhibition of BTK signaling can reduce cytokine levels and subsequent anti-inflammatory effects. OBJECTIVE: This review aims to investigate the role of the BTK pathway in the pathogenesis of COVID-19 and the possible effects of its inhibition in the treatment of this disease. METHODS: This narrative review provides information regarding the use of BTK inhibitors in patients with COVID-19 and discusses whether clinicians should consider these medications while managing their patients based on the literature. Data were gathered using the PubMed, Scopus, and Web of Science databases. RESULTS: Some data support the use of BTK inhibitors for treating COVID-19. CONCLUSIONS: It is recommended that patients continue their medications in this class if they develop COVID-19 and were receiving these agents before the disease developed. The use of BTK inhibitors might enable patients to experience less severe immune responses to the COVID-19. Well-designed studies are needed to evaluate the effectiveness of BTKis in the management of COVID-19. (Curr Ther Res Clin Exp. 2022; 82:XXX-XXX) © 2022 Elsevier HS Journals.