Mansur ibn Ilyas Shirazi (1380-1422 AD), a pioneer of neuroanatomy.

History of anatomy is as long as the history of medicine itself. Development of this basic science was not possible without the dedicative effort of those physicians and scholars who were committed to discover the mysteries of human anatomy. In this regard, Iranian scholars played an important role in the development of the anatomical sciences despite the religious limitations in their societies. Mansur ibn Ilyas Shirazi is an Iranian physician of fourteenth century who wrote the first color illustrated anatomical book, Mansur's Anatomy. A considerable portion of the book has been dedicated to the central and peripheral nervous system so that he could be considered as one of the pioneers of neuroanatomy.

Update on Immunology of COVID-19 Disease and Potential Strategy for Controlling.

Coronavirus disease 2019 (COVID-19) is caused by a novel form of the coronavirus that caused severe acute respiratory syndrome (SARS). SARS-CoV-2 raised in China and has broadcast to 261 countries globally. SARS-CoV-2 a member of ß-coronavirus family and has an almost matching genome sequence to a bat coronavirus, pointing to the bat as the natural host before it was transmitted to humans. SARS-CoV-2 uses the same receptor, angiotensin-converting enzyme 2 (ACE2) as that used by SARS-CoV and principally infects the respiratory tract. The clinical symptoms of COVID-19 patients include fever, cough and fatigue whilst small populations of patients have gastrointestinal symptoms. The old people and people with underlying metabolic and cardiovascular diseases are more affected to infection and have worse outcomes. These may be associated with acute respiratory distress syndrome (ARDS) and a cytokine storm. In this review, we discuss the pathogenesis and clinical characteristics of disease and the pharmacologic approaches that may control COVID-19.

Blood Purification Techniques, Inflammatory Mediators and Mortality in COVID-19 Patients.

BACKGROUND: Inflammatory mediators are an important component in the pathophysiology of the coronavirus disease 2019 (COVID-19). This study aimed to assess the effects of reducing inflammatory mediators using hemoperfusion (HP) and continuous renal replacement therapy (CRRT) on the mortality of patients with COVID-19. MATERIALS AND METHODS: Twelve patients with confirmed diagnosis of COVID-19 were included. All patients had acute respiratory distress syndrome (ARDS). Patients were divided into three groups, namely, HP, CRRT and HP+CRRT. The primary outcome was mortality and the secondary outcomes were oxygenation and reduction in inflammatory mediators at the end of the study. RESULTS: Patients were not different at baseline in demographics, inflammatory cytokine levels, and the level of acute phase reactants. Half of the patients (3 out of 6) in the HP+CRRT group survived along with the survival of one patient (1 out of 2) in the HP group. All four patients in the CRRT group died. Serum creatinine (SCr), Interleukin-1 (IL1), Interleukin-6 (IL6), Interleukin-8 (IL8), partial pressure of oxygen (PaO2), O2 saturation (O2 sat), and hemodynamic parameters improved over time in HP+CRRT and CRRT groups, but no significant difference was observed in the HP group (All Ps > 0.05). CONCLUSION: Combined HP and CRRT demonstrated the best result in terms of mortality, reduction of inflammatory mediators and oxygenation. Further investigations are needed to explore the role of HP+CRRT in COVID-19 patients.

Delay in the Diagnosis of APECED: A Case Report and Review of Literature from Iran.

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) syndrome is a rare monogenic autosomal recessive disorder caused by biallelic mutations in the AIRE (autoimmune regulator) gene. Patients with APECED present with heterogeneous endocrine and non-endocrine manifestations. In this study, we report an Iranian patient who presented with Addison disease, chronic mucocutaneous candidiasis, alopecia totalis, keratopathy and asplenia treated as an isolated endocrinopathy for 25 years. In the adulthood, the diagnosis of APECED was made by genetic analysis which demonstrated homozygous nonsense p.R257* (c.769C>T) mutation of AIRE. APECED has been shown to be frequent in some ethnicities including Iranian Jews. Therefore, we reviewed 39 Iranian APECED patients published in the literature. We found that most of the Iranian patients were of Jewish ethnic background and presented hypoparathyroidism, adrenal insufficiency, and candidiasis as the main clinical manifestation.

Three Markers in Cancerous and Healthy Cells of Patients with Non-Small-Cell Lung Carcinoma (NSCLC).

Introduction: Lung cancer is the most common cause of cancer-related death among males and females. The diagnosis of lung cancer is of great importance for clinical considerations and follow-up treatment. This study aimed to examine the expression of CEA, LUNX, and CK19 biomarkers in the cancerous and healthy tissues of patients suffering from NSCLC. Methods: In this study, 30 patients with NSCLCs referring to Masih Daneshvari Hospital in Tehran were voluntarily selected prior to taking any treatment. A tissue sample from the center and a sample of healthy tissues close to the cancerous masses were prepared by a specialist in the bronchoscopy sector and tested using real-time RT-PCR. Results: Positive CEA mRNA was observed in cancerous tissues in the center of tumors of 25 out of 30 cases. In the healthy tissue group, the same was found in 10 out of 30 cases (P<0.001). The markers CK19 and LUNX mRNAs showed to be positive in cancerous samples in the center of tumors of 15 and 22 out of 30 cases, and in the healthy tissue group, the expression was observed in 5 and 4 out of 30 cases, respectively(P<0.001). Conclusion: This study confirms that the aformentioed markers are the ones with a relatively appropriate sensitivity and specificity for the diagnosis of lung cancer.

Immunologic Role of Extracellular Vesicles and Exosomes in the Pathogenesis of Cystic Fibrosis.

Cystic Fibrosis (CF) is the most common lethal autosomal recessive disease that affects many organs including, lung, pancreas and liver. Cystic fibrosis is a monogenic disease and occurs in the white Caucasians. Massive neutrophil granulocyte influx in the airways is one of the characteristics of CF. Extracellular Vesicles (EVs), microvesicles, and exosomes are vesicles released from cells into extracellular space of the body and are able to influence other cells by different methods. They have an important role in the intracellular communication by transferring information between donor and recipients cells. Granulocytes are known as the main source of microparticles in the CF patients. Microparticles derived from neutrophils are associated with the extensive neutrophil influx into airways and aggregation at the epithelial surface of the CF patient's respiratory tract. Exosomes are found in almost all body fluids, such as urine, sputum, Bronchoalveolar Lavage (BAL), milk, Cerebrospinal Fluid (CSF), plasma and sputum. Examination of exosomes derived from CF patients may be helpful in the characterization of pathogenesis of disease in detail. In this mini review, we have summarized the role of microparticles and exosomes in pathogenesis of CF and finally discussed the feasibility of this particle in treatment approaches.

Susceptibility to mycobacterial disease due to mutations in IL-12Rß1 in three Iranian patients.

In the last decade, autosomal recessive interleukin-12 receptor ß1 (IL-12Rß1) deficiency, the most common cause of Mendelian susceptibility to mycobacterial disease (MSMD), has been diagnosed in a few children and adults with severe tuberculosis in Iran. Here, we report three cases referred to the Immunology, Asthma and Allergy ward at the National Research Institute of Tuberculosis and Lung Diseases (NRITLD) at Masih Daneshvari Hospital from 2012 to 2017 with Mycobacterium tuberculosis and non-tuberculous mycobacteria infections due to defects in IL-12Rß1 but with different clinical manifestations. All three were homozygous for either an IL-12Rß1 missense or nonsense mutation that caused the IL-12Rß1 protein not to be expressed on the cell membrane and completely abolished the cellular response to recombinant IL-12. Our findings suggest that the presence of IL-12Rß1 deficiency should be determined in children with mycobacterial infections at least in countries with a high prevalence of parental consanguinity and in areas endemic for TB like Iran.

Evidence for M2 macrophages in granulomas from pulmonary sarcoidosis: A new aspect of macrophage heterogeneity.

BACKGROUND: Sarcoidosis is a granulomatous disease of unknown etiology. Macrophages play a key role in granuloma formation with the T cells, having a significant impact on macrophage polarization (M1 and M2) and the cellular composition of the granuloma. This study evaluates macrophage polarization in granulomas in pulmonary sarcoidosis. MATERIALS AND METHODS: Tissue specimens from the Department of Pathology biobank at the Masih Daneshvari Hospital were obtained. Paraffin sections from 10 sarcoidosis patients were compared with those from 12 cases of tuberculosis using immunohistochemical staining. These sections consisted of mediastinal lymph nodes and transbronchial lung biopsy (TBLB) for sarcoidosis patients versus pleural tissue, neck, axillary lymph nodes and TBLB for tuberculosis patients. The sections were stained for T-cells (CD4+, CD8+) and mature B lymphocytes (CD22+). CD14+ and CD68+ staining was used as a marker of M1 macrophages and CD163+ as a marker for M2 macrophages. RESULTS: Immunohistochemical staining revealed a 4/1 ratio of CD4+/CD8+ T-cells in sarcoidosis granuloma sections and a 3/1 ratio in tuberculosis sections. There was no significance difference in single CD4+, CD8+, CD22+, CD14+ and CD68+ staining between sarcoidosis and tuberculosis sections. CD163 expression was significantly increased in sarcoidosis sections compared with those from tuberculosis subjects. CONCLUSION: Enhanced CD163+ staining indicates a shift towards M2 macrophage subsets in granulomas from sarcoidosis patients. Further research is required to determine the functional role of M2 macrophages in the immunopathogenesis of sarcoidosis.

Pattern recognitions receptors in immunodeficiency disorders.

Pattern recognition receptors (PRRs) recognize common microbial or host-derived macromolecules and have important roles in early activation and response of the immune system. Initiation of the innate immune response starts with the recognition of microbial structures called pathogen associated molecular patterns (PAMPs). Recognition of PAMPs is performed by germline-encoded receptors expressed mainly on immune cells termed pattern recognition receptors (PRRs). Several classes of pattern recognition receptors (PRRs) are involved in the pathogenesis of diseases, including Toll-like receptors (TLRs), C-type lectin receptors (CLRs), and Nod-like receptors (NLRs). Patients with primary immune deficiencies (PIDs) affecting TLR signaling can elucidate the importance of these proteins in the human immune system. Defects in interleukin-1 receptor-associated kinase-4 and myeloid differentiation factor 88 (MyD88) lead to susceptibility to infections with bacteria, while mutations in nuclear factor-κB essential modulator (NEMO) and other downstream mediators generally induce broader susceptibility to bacteria, viruses, and fungi. In contrast, TLR3 signaling defects are associated with susceptibility to herpes simplex virus type 1 encephalitis. Other PIDs induce functional alterations of TLR signaling pathways, such as common variable immunodeficiency in which plasmacytoid dendritic cell defects enhance defective responses of B cells to shared TLR agonists. Altered TLR responses to TLR2 and 4 agonists are seen in chronic granulomatous disease (CGD) and X-linked agammaglobulinemia (XLA). Enhanced TLR responses, meanwhile, are seen for TLRs 5 and 9 in CGD, TLRs 4, 7/8, and 9 in XLA, TLRs 2 and 4 in hyper IgE syndrome (HIES), and for most TLRs in adenosine deaminase deficiency. In this review we provide the reader with an update on the role of TLRs and downstream signaling pathways in PID disorders.

A fuzzy rule-based expert system for diagnosing cystic fibrosis.

BACKGROUND: Finding a valid diagnosis is mostly a prolonged process. Current advances in the sector of artificial intelligence have led to the appearance of expert systems that enrich the experiences and capabilities of doctors for making decisions for their patients. OBJECTIVE: The objective of this research was developing a fuzzy expert system for diagnosing Cystic Fibrosis (CF). METHODS: Defining the risk factors and then, designing the fuzzy expert system for diagnosis of CF were carried out in this cross-sectional study. To evaluate the performance of the proposed system, a dataset that corresponded to 70 patients with respiratory disease who were serially admitted to the CF Clinic in the Pediatric Respiratory Diseases Center, Masih Daneshvari Hospital in Tehran, Iran during August 2016 to January 2017 was considered. Whole procedures of system construction were implemented in a MATLAB environment. RESULTS: Results showed that the suggested system can be used as a strong diagnostic tool with 93.02% precision, 89.29% specificity, 95.24% sensitivity and 92.86% accuracy for diagnosing CF. There was also a good relationship between the user and the system through the appealing user interface. CONCLUSION: The system is equipped with information, knowledge, and expertise from certified specialists; hence, as a training tool it can be useful for new physicians. It is worth mentioning that the accomplishment of this project depends on advocacy of decision making in CF diagnosis. Nevertheless, it is expected that the system will reduce the number of false positives and false negatives in unusual cases.

The Roles of T Helper 1, T Helper 17 and Regulatory T Cells in the Pathogenesis of Sarcoidosis.

Sarcoidosis is a systemic granulomatous disorder of unidentified etiology, with a heterogeneous clinical presentation. It is characterized by a reduced delayed-type hypersensitivity to tuberculin and common antigens. The balance between Th1, Th17 and Regulatory T(Treg) cells controls T-cell proliferation and activation.The Th17/Treg ratio in the peripheral blood and bronchoalveolar lavage fluidis increased in patients with active sarcoidosis. Amplified IL-17A expression in granulomas and the presence of IL-17A+, IL-17A+IL-4+ and IL-17A+IFN-γ+ memory T helper cells in the circulation and BAL indicate Th17 cell involvement in granuloma induction and/or maintenance in sarcoidosis. Sarcoidosis should therefore be considered as a Th1/Th17 multisystem disorder and anti-IL-17/Th17 approaches that control and reduce IL-17Amay be an option, therefore, for the treatment of sarcoidosis.Here we provide a short overview as to the role of Th17 cells as critical cells in the pathogenesis of sarcoidosis.

Determining the lymphadenopathy characteristics of the mediastinum in lung CT scan of children with tuberculosis.

OBJECTIVE/BACKGROUND: Most tuberculosis cases in children are primary infection, with difficult and imprecise diagnosis mainly based on the existence of mediastinal lymphadenopathy. Here, we investigated the characteristics of mediastinal lymphadenopathy in lung computed tomography (CT) scans of children with tuberculosis. METHODS: This cross-sectional study was performed on 75 children with tuberculosis referred to Masih Daneshvari Hospital in Tehran, Iran, from 2009 to 2013. Their medical records were investigated, and CT-scan characteristics were extracted by a radiologist. RESULTS: Mean±standard deviation age of cases was 11.2±4.6years. CT-scan results indicated 94.7% of cases had lymphadenopathy, with lower paratracheal, upper paratracheal, hilar, and subcarinal forms observed in 81.7%, 69.1%, 53.5%, and 47.9% of cases as the most involved stations in lymph nodes, respectively. In 74.6% of patients with mediastinal lymphadenopathy, perilymph node fat inflammation (matting) was observed, with 52.11% exhibiting conglomeration. Bronchial pressure was observed in 4.23% of children with tuberculosis, and bilateral-, right-, and left-parenchymal involvement was observed in 42.7%, 25.3%, and 8% of these cases, respectively. Left- and right-pleural effusion and calcification was reported in 6.7%, 12%, and 5.6% of patients, respectively. Additionally, nearly 80% of patients exhibited mediastinal lymphadenopathy and lung-parenchyma involvement simultaneously. Lung-parenchyma involvement was significantly correlated with subcarinal (p<.001), hilar (p<.001), subaortic (p=.030), lower paratracheal (p=.037), and axillary (p=.006) stations. CONCLUSION: Situation of mediastinal lymphadenopathy and its synchronicity with lung-parenchyma involvement can help in differential diagnosis of pulmonary tuberculosis from other lung diseases.

Cancers Related to Immunodeficiencies: Update and Perspectives.

The life span of patients with primary and secondary immunodeficiency is increasing due to recent improvements in therapeutic strategies. While the incidence of primary immunodeficiencies (PIDs) is 1:10,000 births, that of secondary immunodeficiencies are more common and are associated with posttransplantation immune dysfunction, with immunosuppressive medication for human immunodeficiency virus or with human T-cell lymphotropic virus infection. After infection, malignancy is the most prevalent cause of death in both children and adults with (PIDs). PIDs more often associated with cancer include common variable immunodeficiency (CVID), Wiskott-Aldrich syndrome, ataxia-telangiectasia, and severe combined immunodeficiency. This suggests that a protective immune response against both infectious non-self-(pathogens) and malignant self-challenges (cancer) exists. The increased incidence of cancer has been attributed to defective elimination of altered or "transformed" cells and/or defective immunity towards cancer cells. The concept of aberrant immune surveillance occurring in PIDs is supported by evidence in mice and from patients undergoing immunosuppression after transplantation. Here, we discuss the importance of PID defects in the development of malignancies and the current limitations associated with molecular pathogenesis of these diseases and emphasize the need for further knowledge of how specific mutations can modulate the immune system to alter immunosurveillance and thereby play a key role in the etiology of malignancies in PID patients.

The roles of miRNAs as potential biomarkers in lung diseases.

MicroRNAs (miRNAs) are small non-coding RNAs which can act as master regulators of gene expression, modulate almost all biological process and are essential for maintaining cellular homeostasis. Dysregulation of miRNA expression has been associated with aberrant gene expression and may lead to pathological conditions. Evidence suggests that miRNA expression profiles are altered between health and disease and as such may be considered as biomarkers of disease. Evidence is increasing that miRNAs are particularly important in lung homeostasis and development and have been demonstrated to be the involved in many pulmonary diseases such as asthma, COPD, sarcoidosis, lung cancer and other smoking related diseases. Better understanding of the function of miRNA and the mechanisms underlying their action in the lung, would help to improve current diagnosis and therapeutics strategies in pulmonary diseases. Recently, some miRNA-based drugs have been introduced as possible therapeutic agents. In this review we aim to summarize the recent findings regarding the role of miRNAs in the airways and lung and emphasise their potential therapeutic roles in pulmonary diseases.

Features of Adolescents Tuberculosis at a Referral TB's Hospital in Tehran, Iran.

OBJECTIVE: To identify the pattern of the clinical, radiological, diagnostic procedures and loss to follow-up of the diagnosed cases of active tuberculosis (TB) adolescents. METHODS: This study was a retrospective analysis of the medical records of 143 adolescents aged 10 to 18 years with tuberculosis who were admitted TB wards of National Research Institute of Tuberculosis and Lung Disease (NRITLD) in Tehran, Iran, between March 2006 and March 2011. RESULTS: Of the 143 patients identified, 62.9% were females. Median age of the patients was 16 years. The contact source was identified in 47.5%. The most common presenting symptom was cough (86%). Isolated pulmonary TB (PTB) was detected in 113 patients (79%), 21 patients (14.7%) had extrapulmonary TB(EPTB), and 9 patients (6.3%) had PTB and EPTB. The most common site of EPTB was pleural (14%). The most common radiographic finding was infiltration (61%). Positive acid fast smears were seen in 67.6%. Positive cultures for Mycobacterium tuberculosis (M. TB) were seen in 44.7%. Positive Polymerase chain reaction (PCR) results were seen in 60%. The adolescents aged 15 to 18 years were more likely to lose weight (p=0.001), smear positive (p=0.001), culture positive (p<0.001) and have positive PCR results (p=0.009). The type of TB (p=0.017) was a significant factor influencing loss to follow-up. CONCLUSIONS: The study has revealed that the clinical and radiological findings of TB in adolescents are combination as identified in children and adults. The TB control programs should pay more attention to prevention and treatment of TB in adolescents.

Assessment of the EuroSCORE risk scoring system for patients undergoing coronary artery bypass graft surgery in a group of Iranian patients.

BACKGROUND AND AIMS: Previous studies around the world indicated validity and accuracy of European System for Cardiac Operative Risk Evaluation (EuroSCORE) risk scoring system we evaluated the EuroSCORE risk scoring system for patients undergoing coronary artery bypass graft (CABG) surgery in a group of Iranian patients. MATERIALS AND METHODS: In this cohort 2220 patients more than 18 years, who were performed CABG surgery in Massih Daneshvari Hospital, from January 2004 to March 2010 were recruited. Predicted mortality risk scores were calculated using logistic EuroSCORE and Acute Physiology and Chronic Health Evaluation II (APACHE II) and compared with observed mortality. Calibration was measured by the Hosmer-Lemeshow (HL) test and discrimination by using the receiver operating characteristic (ROC) curve area. RESULTS: Of the 2220 patients, in hospital deaths occurred in 270 patients (mortality rate of 12.2%). The accuracy of mortality prediction in the logistic EuroSCORE and APACHE II model was 89.1%; in the local EuroSCORE (logistic) was 91.89%; and in the local EuroSCORE support vector machines (SVM) was 98.6%. The area under curve for ROC curve, was 0.724 (95% confidence interval [CI]: 0.57-0.88) for logistic EuroSCORE; 0.836 (95% CI: 0.731-0.942) for local EuroSCORE (logistic); 0.978 (95% CI: 0.937-1) for Local EuroSCORE (SVM); and 0.832 (95% CI: 0.723-0.941) for APACHE II model. The HL test showed good calibration for the local EuroSCORE (SVM), APACHE II model and local EuroSCORE (logistic) (P = 0.823, P = 0.748 and P = 0.06 respectively); but there was a significant difference between expected and observed mortality according to EuroSCORE model (P = 0.033). CONCLUSION: We detected logistic EuroSCORE risk model is not applicable on Iranian patients undergoing CABG surgery.

Association of serum TNF-α, IL-8 and free light chain with HLA-DR B alleles expression in pulmonary and extra-pulmonary sarcoidosis.

BACKGROUND: Sarcoidosis is a systemic disease of unknown etiology characterized histologically by the observation of non-caseating granulomas and several immunological abnormalities. Sarcoidosis is a multi-organ disorder which involves formation of granulomas in many tissues including the lungs (pulmonary) and others such as skin, bone, heart (extra pulmonary). Associations between human leukocyte antigens (HLA), the encoded cell surface receptor (HLA-DR) and sarcoidosis have been reported in several studies. Several HLA-DR alleles have been described as potential risk factors for sarcoidosis in distinct ethnic groups however evidence for a relationship between HLA-DR alleles and pulmonary and extra-pulmonary sarcoidosis (EPS) is still scarce. Although the etiology of the disease remains unclear, infectious and environmental factors have been postulated. Inflammatory cytokines and chemokines may play important roles in the pathogenesis of sarcoidosis and serum free light chain (FLC) numbers have been implicated in several immunologic disorders. PURPOSE OF THE STUDY: The aim of the present study was to investigate HLA associations with serum cytokines and FLC in Iranian patients with pulmonary (n = 86) and EPS (n = 46). RESULTS: We found that among the 16 HLA DRB alleles only *7 and *12 were different in sarcoidosis patients. The levels of TNF-α and IL-8 in pulmonary sarcoidosis patients were higher than in EPS (P < 0.05) whereas the levels of FLC subunits in EPS were higher than in pulmonary sarcoidosis. CONCLUSION: This data may suggests a link between HLA-DRB *12 and sarcoidosis in Iranian population.

Mycobacterial infection and the impact of rifabutin treatment in organ transplant recipients: a single-center study.

Tuberculosis (TB) is a frequently encountered infection among organ transplant recipients in developing countries, and the incidence of infection after the first year of transplantation is considerably high. In this study, the impact of rifabutin treatment on organ transplant recipients with TB infection was evaluated with respect to the trend of infection, management and outcome. The medical records of 26 post-transplant patients who received an organ transplant between 2004 and 2012 and later diagnosed with TB of different organs were reviewed retrospectively. We retrieved data regarding clinical features as well as treatment and outcomes. The median time interval between transplantation and TB was 36 months (IQR 12-101 months). The most common form of infection was pulmonary/pleural TB. All our subjects received rifabutin instead of rifampin in the anti-TB treatment regime as rifabutin is a less-potent inducer of cytochrome P-450. All patients responded satisfactorily to the treatment and maintained excellent allograft function. Moreover, we did not have any mortality among our recipients. Drug-induced hepatitis was observed in nine (35%) patients. Rifabutin is an excellent alternative medication to rifampin in the setting of TB management. Hepatotoxicity is a potential risk for treatment because of the potential additive toxicity of immunosuppressive drugs.