COVID-19 induced liver injury from a new perspective: Mitochondria.

Liver damage is a common sequela of COVID-19 (coronavirus disease 2019), worsening the clinical outcomes. However, the underlying mechanism of COVID-induced liver injury (CiLI) is still not determined. Given the crucial role of mitochondria in hepatocyte metabolism and the emerging evidence denoting SARS-CoV-2 can damage human cell mitochondria, in this mini-review, we hypothesized that CiLI happens following hepatocytes' mitochondrial dysfunction. To this end, we evaluated the histologic, pathophysiologic, transcriptomic, and clinical features of CiLI from the mitochondria' eye view. Severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2), the causative agent of COVID-19, can damage hepatocytes through direct cytopathic effects or indirectly after the profound inflammatory response. Upon entering the hepatocytes, the RNA and RNA transcripts of SARS-CoV-2 engages the mitochondria. This interaction can disrupt the mitochondrial electron transport chain. In other words, SARS-CoV-2 hijacks the hepatocytes' mitochondria to support its replication. In addition, this process can lead to an improper immune response against SARS-CoV-2. Besides, this review outlines how mitochondrial dysfunction can serve as a prelude to the COVID-associated cytokine storm. Thereafter, we indicate how the nexus between COVID-19 and mitochondria can fill the gap linking CiLI and its risk factors, including old age, male sex, and comorbidities. In conclusion, this concept stresses the importance of mitochondrial metabolism in hepatocyte damage in the context of COVID-19. It notes that boosting mitochondria biogenesis can possibly serve as a prophylactic and therapeutic approach for CiLI. Further studies can reveal this notion.

Investigating the role of body force or strength (Quwa) in causing diseases in Iranian traditional medicine and the role of cellular energy in causing diseases in conventional medicine.

Although much of conventional medicine has its roots in traditional medicine, from the point of view of Iranian medicine, health means when organs function naturally, and disease occurs when organs cannot performproperly. Doing actions naturally requires force, some actions require one force and some require two or more. The forces of the human body include the natural forces, the spiritual forces, and the vital forces, with the help of which human actions are performed. Therefore, in order to perform actions normally, a person must have all the forces of his body in a proper situation. According to the principles of modern medicine, the function of the body and cells depends on the energy content of cells, and most of the chemical reactions in the cells are related to the availability of energy in foods for various cell physiological systems. Any event that leads to a drop in energy production or energy loss or a reduction in cells' access to energy can lead to a range of related diseases. On the other hand, if the body cells have enough access to energy and perform all functions well, the disease will not occur and the ability to fight possible diseases will be higher. The aim of this study was to investigate the role of potency in causing diseases in Iranian medicine and the role of cellular energy in causing diseases in conventional medicine. It was concluded that all principles of health refer to the optimization of energy production and consumption in the cells. Accordingly, more energy available to the cell leads to the normal function of cells and the higher ability of the body cells to fight disease.

Targeted Anti-Mitochondrial Therapy: The Future of Oncology.

Like living organisms, cancer cells require energy to survive and interact with their environment. Mitochondria are the main organelles for energy production and cellular metabolism. Recently, investigators demonstrated that cancer cells can hijack mitochondria from immune cells. This behavior sheds light on a pivotal piece in the cancer puzzle, the dependence on the normal cells. This article illustrates the benefits of new functional mitochondria for cancer cells that urge them to hijack mitochondria. It describes how functional mitochondria help cancer cells' survival in the harsh tumor microenvironment, immune evasion, progression, and treatment resistance. Recent evidence has put forward the pivotal role of mitochondria in the metabolism of cancer stem cells (CSCs), the tumor components responsible for cancer recurrence and metastasis. This theory highlights the mitochondria in cancer biology and explains how targeting mitochondria may improve oncological outcomes.

Mitochondria determine response to anti-programmed cell death protein-1 (anti-PD-1) immunotherapy: An evidence-based hypothesis.

Immunotherapy based on programmed cell death protein-1 (PD-1) is a promising approach in oncology. However, a significant fraction of patients remain unresponsive. Therefore, it is imperative to clarify the relevant predictive factors. A decrease in cellular adenosine triphosphate (c-ATP) level can predispose to cellular dysfunction. ATP is a prerequisite for proper T cell migration and activation. Therefore, a decrease in the c-ATP level impairs T cell function and promotes cancer progression. This article gives an overview of the potential predictive factors of PD-1 blockade. Besides, it highlights the pivotal role of mitochondria in response to anti-PD-1 therapies.

Estimating and interpreting nonlinear receptive field of sensory neural responses with deep neural network models.

Our understanding of nonlinear stimulus transformations by neural circuits is hindered by the lack of comprehensive yet interpretable computational modeling frameworks. Here, we propose a data-driven approach based on deep neural networks to directly model arbitrarily nonlinear stimulus-response mappings. Reformulating the exact function of a trained neural network as a collection of stimulus-dependent linear functions enables a locally linear receptive field interpretation of the neural network. Predicting the neural responses recorded invasively from the auditory cortex of neurosurgical patients as they listened to speech, this approach significantly improves the prediction accuracy of auditory cortical responses, particularly in nonprimary areas. Moreover, interpreting the functions learned by neural networks uncovered three distinct types of nonlinear transformations of speech that varied considerably from primary to nonprimary auditory regions. The ability of this framework to capture arbitrary stimulus-response mappings while maintaining model interpretability leads to a better understanding of cortical processing of sensory signals.

The powerful immune system against powerful COVID-19: A hypothesis.

On March 11, 2020, the World Health Organization declared the coronavirus outbreak a pandemic. Since December 2019, the world has experienced an outbreak of coronavirus disease 2019 (COVID-19). Epidemiology, risk factors, and clinical characteristics of patients with COVID-19 have been reported but the factors affecting the immune system against COVID-19 have not been well described. In this article, we provide a novel hypothesis to describe how an increase in cellular adenosine triphosphate (c-ATP) can potentially improve the efficiency of innate and adaptive immune systems to either prevent or fight off COVID-19.

SP-A and TLR4 localization in lung tissue of SM-exposed patients.

INTRODUCTION: Long-term pulmonary complications are one of the major long-term consequences of sulfur mustard (SM) exposure. Toll-like receptor 4 (TLR4) involves in the pathogenesis of several pulmonary disorders. Surfactant protein-A (SP-A) regulates LPS-induced TLR4 localization and activation responses. However, the intensity and significance of TLR4 and SP-A expression by lung cells in SM-exposed patients is not clear. METHODS: The gene expression of TLR4 (through real-time PCR) and TLR4 and SP-A positive cells and alveolar type II cells, as SP-A producers, (using IHC) were assessed in formalin fixed paraffin embedded (FFPE) specimens from SM-exposed (n = 17), and non-SM exposed individuals (n = 12). RESULTS: TLR4 gene expression did not change between study groups. However, its cell surface presentation was significantly reduced in SM-exposed patients and particularly in which with constrictive bronchiolitis compared with the control group (P < 0.001 and P = 0.002, respectively). Frequency of alveolar type II cells was lower in the case group rather than the control group while the number of SP-A positive cells did not alter. CONCLUSIONS: These findings suggest that reduced TLR4 cell surface presentation may have anti-inflammatory function and SP-A may have a critical role in regulation of inflammatory responses in SM-exposed patients. Further investigation on other possible mechanisms involved in TLR4 internalization maybe help to illustrate the modulatory or inflammatory activity of TLR4 in these patients.

Cell Energy: A New Hypothesis in Decoding Cancer Evolution.

The present study deviates from previous approaches as it focuses on the concept of energy to illuminate cancer-related issues. Energy is a prerequisite for any function; cellular function is no exception, and thus, reduced energy in human cells can impair their performance. This hypothesis provides a novel view of cancer formation. It shows that a normal cell transforms into its cancerous counterpart in response to cellular adenosine triphosphate (ATP) depletion. Moreover, it presents a new definition for the origin of cancer stem cells and how they can regenerate cancer. This article regards a distinct aspect of cancer that helps to differentiate various phases of its progression and shed light on some of the uncharted zones of its pathway for the first time that needs further confirmation by empirical studies.

Towards reconstructing intelligible speech from the human auditory cortex.

Auditory stimulus reconstruction is a technique that finds the best approximation of the acoustic stimulus from the population of evoked neural activity. Reconstructing speech from the human auditory cortex creates the possibility of a speech neuroprosthetic to establish a direct communication with the brain and has been shown to be possible in both overt and covert conditions. However, the low quality of the reconstructed speech has severely limited the utility of this method for brain-computer interface (BCI) applications. To advance the state-of-the-art in speech neuroprosthesis, we combined the recent advances in deep learning with the latest innovations in speech synthesis technologies to reconstruct closed-set intelligible speech from the human auditory cortex. We investigated the dependence of reconstruction accuracy on linear and nonlinear (deep neural network) regression methods and the acoustic representation that is used as the target of reconstruction, including auditory spectrogram and speech synthesis parameters. In addition, we compared the reconstruction accuracy from low and high neural frequency ranges. Our results show that a deep neural network model that directly estimates the parameters of a speech synthesizer from all neural frequencies achieves the highest subjective and objective scores on a digit recognition task, improving the intelligibility by 65% over the baseline method which used linear regression to reconstruct the auditory spectrogram. These results demonstrate the efficacy of deep learning and speech synthesis algorithms for designing the next generation of speech BCI systems, which not only can restore communications for paralyzed patients but also have the potential to transform human-computer interaction technologies.

Management of Penetrating Cerebrovascular Injuries in Pediatric Trauma: A Retrospective Multicenter Study.

BACKGROUND: Blunt cerebrovascular injury is uncommon in the pediatric population; penetrating cerebrovascular injuries are even rarer and are thus poorly understood. OBJECTIVE: To describe the diagnosis and management of penetrating cerebrovascular injuries and describe outcomes of available treatment modalities. METHODS: Clinical and radiographic data were collected retrospectively from a multicenter trauma registry for children screened for cerebrovascular injury during 2003 to 2013 at 4 academic pediatric trauma centers. RESULTS: Among 645 pediatric patients evaluated with computed tomography angiography with blunt cerebrovascular injury, 130 also had a penetrating trauma indication. Seven penetrating cerebrovascular injuries were diagnosed in 7 male patients (mean age 12.4 years, range 12-18 years). Focal neurological deficit and concomitant intracranial injury were each seen in 2 patients. There were 2 intracranial carotid artery injuries, 4 extracranial carotid artery injuries, and 1 vertebral artery injury. The majority of injuries were higher than grade I (5/7; 71%): 2 were grade I, 1 grade II, 2 grade III, and 2 grade IV. The 2 patients with grade III injuries required open surgery, and 1 patient with a grade IV injury underwent endovascular treatment. Two patients suffered immediate stroke secondary to the penetrating cerebrovascular injury. There were no delayed neurological deficits from the penetrating injuries, and no patients died as a result of the injuries. CONCLUSION: This is the largest series of penetrating cerebrovascular trauma in the pediatric literature. Although rare, penetrating cerebrovascular injuries can be high-grade injuries that require urgent recognition and may require aggressive endovascular and/or open surgery for treatment.

Predicting Blunt Cerebrovascular Injury in Pediatric Trauma: Validation of the "Utah Score".

Risk factors for blunt cerebrovascular injury (BCVI) may differ between children and adults, suggesting that children at low risk for BCVI after trauma receive unnecessary computed tomography angiography (CTA) and high-dose radiation. We previously developed a score for predicting pediatric BCVI based on retrospective cohort analysis. Our objective is to externally validate this prediction score with a retrospective multi-institutional cohort. We included patients who underwent CTA for traumatic cranial injury at four pediatric Level I trauma centers. Each patient in the validation cohort was scored using the "Utah Score" and classified as high or low risk. Before analysis, we defined a misclassification rate <25% as validating the Utah Score. Six hundred forty-five patients (mean age 8.6 ± 5.4 years; 63.4% males) underwent screening for BCVI via CTA. The validation cohort was 411 patients from three sites compared with the training cohort of 234 patients. Twenty-two BCVIs (5.4%) were identified in the validation cohort. The Utah Score was significantly associated with BCVIs in the validation cohort (odds ratio 8.1 [3.3, 19.8], p < 0.001) and discriminated well in the validation cohort (area under the curve 72%). When the Utah Score was applied to the validation cohort, the sensitivity was 59%, specificity was 85%, positive predictive value was 18%, and negative predictive value was 97%. The Utah Score misclassified 16.6% of patients in the validation cohort. The Utah Score for predicting BCVI in pediatric trauma patients was validated with a low misclassification rate using a large, independent, multicenter cohort. Its implementation in the clinical setting may reduce the use of CTA in low-risk patients.

Evaluation of Apoptosis in the Lung Tissue of Sulfur Mustard-exposed Individuals.

Lung exposure to sulfur mustard (SM) results in pulmonary complications, which is the main cause of long-term disability and morbidity. Up to now, the precise mechanisms of SM-induced lung complications has not been identified. The aim of this study was to evaluate apoptosis in the lung tissue of SM-exposed individuals. The study was performed on archived lung paraffin-embedded tissue specimens of21 patients suffering from pulmonary complications due to previous SM exposure and 9 unexposed patients who had undergone lung resections for another lung disease. Evaluation of apoptosis in paraffin-embedded lung tissue sections was performed using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay and the cleaved caspase-3 immunohistochemistry assays. TUNEL-positive apoptotic features and caspase-3 expression of specimens were significantly higher in the SM-exposed group compared with the control group. This result demonstrates higher apoptosis rate in the SM-exposed group. Furthermore, the majority of positive cells consisted of alveolar epithelial cells in both methods. In conclusion,it seems that exposure to SM may result in increased apoptosis in respiratory epithelium. More studies are needed to evaluate the role of apoptosis in SM-induced lung complications in order to design new and effective therapeutic protocols.

Hyperoxia-induced preconditioning against renal ischemic injury is mediated by reactive oxygen species but not related to heat shock proteins 70 and 32.

OBJECTIVE: Pre-exposure of rats to normobaric hyperoxia (O2 ≥ 95%) may induce late preconditioning against renal ischemia-reperfusion (IR) injury. In this study we investigated probable mechanisms of IR injury such as the role of reactive oxygen species (ROS), renal antioxidant agents, and heat shock proteins (HSP) 32 and 70 during delayed hyperoxia-preconditioning (HO). METHODS: Fifty-two rats were divided into 7 groups: (A) IR, (B) HO + IR, (C) mercaptopropionyl glycine (MPG) + HO + IR, (D) MPG + IR, (E) HO + sham, (F) MPG + sham, and (G) sham. Rats in the following study groups (group B, C and E) were kept in a normobaric hyperoxic environment for 4 h/day for 6 consecutive days, after which they were subjected to 40 minutes of ischemia; animals in the control group (group A, D, F, and G) were kept in a normoxic cage. At the end of the preconditioning period, 24 hours of reperfusion was performed. Renal function was assessed by measuring serum creatinine (Cr), blood urea nitrogen (BUN), and creatinine clearance (CLCr). Induction of the antioxidant system was evaluated by measuring renal catalase (CAT) and superoxide dismutase (SOD) activities and glutathione (GSH) and malondialdehyde (MDA) content. The role of ROS was investigated by use of MPG (a ROS scavenger). HSP32 & 70 mRNA and protein also were determined. RESULTS: The hyperoxia-preconditioned IR group (B) had a lower plasma Cr and BUN and greater CLCr compared with the IR group (A) (P ≤ .016). Administration of MPG led to an increase in plasma Cr and BUN and a decrease in CLCr in group C compared with the hyperoxia-preconditioned group B (P ≤ .004). The hyperoxia-preconditioned IR group had a greater CAT activity and GSH level compared with the IR group A (P ≤ .007), whereas the administration of MPG did not change the GSH level but led to a decrease in CAT activity in group D compared with group B (P < .001). SOD activity did not change in hyperoxia-preconditioned ischemic rats compared with ischemic rats. Hyperoxia preconditioning and MPG administration in ischemic animals did not result in any considerable change in MDA level compared with the IR group A. Also, there were no clinically relevant differences in HSP32 & 70 mRNA and protein between all groups. CONCLUSION: The present study demonstrates that repeated pre-exposure to hyperoxia can decrease subsequent renal IR damage in this rat model of renal ischemia. Free radical production after hyperoxia appears to play a pivotal role in the hyperoxia-induced renal protection independent of HSP level. Antioxidant enzyme activities and especially catalase seem to be implicated in this renal protective mechanism.

Functionalized nanoscale ß-1,3-glucan to improve Her2+ breast cancer therapy: In vitro and in vivo study.

We fabricated a targeted delivery system for doxorubicin (Dox) using ß-1,3-glucan (Glu) as a carrier and decorated by trastuzumab antibody having the status of targeting agent against Her2+ breast tumors. Glu-Dox conjugates were also functionalized with polyethylenimine (PEI) intended for increasing specific cellular uptake of prepared nanoparticles. The self-assembled nanoparticles were prepared through conjugation of Dox- [Glu-Dox-] using succinic anhydride (Sa) in place of a linker. Nanoparticles had spherical morphology with positive zeta potential. In-vitro cell viability assay on two breast cancer cell lines demonstrated acceptable toxicity against tested cell lines. Confocal microscopic images demonstrated the remarkable cytoplasmic uptake of the nanoparticles in Her2-overexpressing 4T1 cells. A controlled release of Dox from Glu-Dox nanoparticles was investigated. In-vivo studies were performed on female Balb/C mice. The volume of the induced tumors was calculated following intravenous administration of nanoparticles. The tumor volume diminished efficiently and more rapidly after administration of nanoparticles containing Dox. Based on survival results, the formulation of Dox targeted nanoparticles appeared very promising for the treatment of tumors. It could be concluded that Glu-Dox targeted nanoparticles have potential advantages for delivering anticancer drugs to the target tissue.

Prevalence and characteristics of Epstein-Barr virus-associated gastric cancer in Iran.

BACKGROUND/AIMS: Gastric cancer (GC) is the second leading cause of cancer-related deaths worldwide and is the most frequent cancer in Iran. Epstein-Barr virus (EBV) has been shown to be associated with gastric cancer. The present study was carried out to investigate the prevalence of Epstein-Barr virus (EBV) associated gastric cancer among Iranian patients. METHODS: Ninety formalin fixed paraffin-embedded cases of gastric cancer were studied. The specimens were investigated for the presence of the EBV genome by quantitative real-time polymerase chain reaction. RESULTS: Of ninety specimens, EBV was detected in six cases (6.66%). The mean age for patients EBV-positive gastric carcinomas was 72.1 years, whereas the mean age for the entire group was 65.7 years. Four out of 64 (6.25%) male patients and 2 out of 26 (7.69%) female cases were positive for EBV. According to anatomic location, EBV was detected in 4 out of 39 (10.25% ) gastric cancer were located in cardia and 2 out of 26 (7.69%) gastric cancer were located in middle/corpus. CONCLUSIONS: The present study shows that the frequency of EBV-associated gastric carcinoma in Iran is  low. Differences of EBV-associated gastric carcinoma incidence in different countries may reflect the epidemiologic factors and dietary habits. Further analysis of clinical pathology features of EBV-associated gastric carcinoma using a larger number of cases would give invaluable insights into its etiology.

Evaluation of the cytotoxicity of Satureja spicigera and its main compounds.

Satureja spicigera (Lamiaceae) grows wildly in Northwest of Iran. In this study, bioassay-guided isolation and identification of the main compounds has been reported using various chromatographic methods and comparison of their spectral data with those reported in the literature. Brine shrimp lethality and four cancerous cell lines HT29/219, Caco(2), NIH-3T3, and T47D were used for cytotoxicity evaluations. From the aerial parts of S. spicigera, nine known compounds including two flavanones, 5,7,3',5'-tetrahydroxy flavanone (8) and 5,4'-dihydroxy-3'-methoxyflavanone-7-(6''-O-α-L-rhamnopyranosyl)-ß-D-glucopyranoside (9), one dihydrochalcone, nubigenol (7), together with thymoquinone (1), thymol (2), carvacrol (3), ß-sitosterol (4), ursolic acid (5) and oleanolic acid (6) were identified. Among the isolated chalcone and flavanones, compound 8 was effective against Artemia salina larva (LC(50)= 2 µg/mL) and only the compound 9 demonstrated IC(50) value of 98.7 µg/mL on the T47D (human, breast, ductal carcinoma). Other compounds did not show significant inhibition of the cell growth.

Use of immunohistochemistry techniques in patients exposed to sulphur mustard gas.

We performed a pathologic study with further using an immunohistochemical technique (using anti-p63 and anti-CK5) on tissues obtained by open lung biopsy from 18 patients with previous exposure to sulphur mustard (SM) as case group and 8 unexposed patients (control group). The most frequent pathologic diagnosis was constrictive bronchiolitis (44.4%), followed by respiratory (22.2%) and chronic cellular bronchiolitis (16.7%) in the case group, and hypersensitivity bronchiolitis (50%) in the control group. The pathologic diagnoses were significantly different in the case and control groups (P = 0.042). In slides stained by anti-p63 and anti-CK5, the percent of stained cells and the mean number of epithelial cells were lower in the case group in comparison to the control group. This difference was significant for the mean number of cells stained by anti-CK5 (P = 0.042). Furthermore, there was a significant correlation between pathologic diagnosis and total number of cells and mean number of cells stained with anti-p63 and anti-CK5 (P value = 0.002, <0.001, 0.044). These results suggest that constrictive bronchiolitis may be the major pathologic consequence of exposure to SM. Moreover, decrease of p63 in respiratory tissues affected by SM may suggest the lack of regenerative capacity in these patients.

Hepatitis B virus genotype in Iranian patients with hepatocellular carcinoma.

OBJECTIVE: Chronic hepatitis B virus (HBV) infection is a major risk factor for the development of hepatocellular carcinoma (HCC). HBV appears to be the most common cause of HCC in Iran. To date, no study has been carried out on the HBV genotype in Iranian HCC patients. This study was undertaken to determine the HBV genotype in Iranian patients with HCC. METHODS: Paraffin-embedded tissue samples from 40 patients (31 males and nine females) with HBV-associated HCC were collected from different pathology centers during 2000-2007. Genotyping of HBV was performed by nested PCR-mediated amplification of the target sequence. PCR products were sequenced, and the genotype of each HBV sequence was determined by comparison with sequences of known genotypes in the GenBank. A phylogenetic tree was constructed. RESULTS: Phylogenetic analysis revealed that all of the HBV isolates were clustered in genotype D. CONCLUSIONS: Our results concur with other reports from Iran, all showing that genotype D is the only detectable genotype in the different clinical forms of HBV infection in this country.

An international collaborative pathologic study of surgical lung biopsies from mustard gas-exposed patients.

BACKGROUND: Recent studies have shown strong evidence that bronchiolitis obliterans is the major long-term sequelae of exposure to sulfur mustard (SM). This study is the first to examine the histopathologic spectrum of changes in a large number of surgical lung biopsies from patients exposed to SM. METHOD: Fifteen patients with chronic respiratory disease from mustard gas exposure were divided into severe (6 cases) and mild exposure (9 cases). All had surgical (open or thoracoscopic) lung biopsy, pulmonary function tests (PFTs) and chest high-resolution computed tomography scan (HRCT). RESULT: The mean age of the cases was 43.8+/-9.6 (range 33-65). All patients had dyspnea and cough as the two main complaints. Only one patient was a smoker. Thirteen patients had normal PFTs, while one had obstruction and one had mild restriction. Six (66.6%) patients in the mild exposure and 3 (50%) in the severe exposure group showed evidence of more than 25% air trapping on chest HRCT. Among the mild group, 3 had features of constrictive bronchiolitis and another had features suggestive of this (bronchiolectasis and mucus stasis). The next most common finding was a mild-to-moderate chronic cellular bronchiolitis (3 patients). Two among the 6 in the severe group showed constrictive bronchiolitis and one showed features suggestive of constrictive bronchiolitis. CONCLUSION: We conclude that about half of patients had diagnostic constrictive bronchiolitis, or bronchiolectasis and mucus stasis consistent with more proximal luminal compromise. The fact that there were no differences between the low- and high-dose groups suggests that effects of SM are not solely dependent on the severity of exposure. The results also indicate that the diagnosis of chronic lung disease due to SM may be difficult. Surgical lung biopsy may be helpful in difficult cases, as constrictive (obliterative) bronchiolitis can be present in symptomatic patients with normal PFTs and chest HRCT.

Clinical differentiation between resistant asthma and chronic bronchiolitis: testing a practical approach.

Intractable asthma is a challenging clinical problem. This study was conducted to determine whether a subset of patients with Intractable asthma may be misdiagnosed and have a form of bronchiolitis instead and also to determine the effectiveness of macrolide therapy in these patients. Seventy six patients with Intractable asthma were re-treated with recommended maximal doses of oral prednisolone for 5 days, beclomethasone, cromolyn sodium, salbutamol and ipratropium bromide for 30 days. Thirty five patients were considered as unresponsive and constituted the study group. They underwent high-resolution CT (HRCT) scan following which they were offered with video-assisted thoracoscopic surgical biopsy. Group 1 (n= 27) refused biopsy and each was treated with macrolide therapy, while Group 2 (n=8) underwent biopsy, and then received macrolide therapy. The patients were treated and followed for three months. The study group consisted of 27 patients, with a mean age of 46.9 +/- 11.1 years. The mean duration of time between the onset of symptoms and the start of this study was 8.1 years. In group 2, no patient had pathologic findings of asthma, and 7/8 had a form of bronchiolitis. There was significant improvement in dyspnea, cough and pulmonary function indices at the end of the 3-month in both groups (p< 0.001). Our results suggest that patients with Intractable asthma could be misdiagnosed and some of them have some forms of chronic bronchiolitis. We believe that any patient who does not respond to standard treatments for Intractable asthma should be evaluated with expiratory HRCT; those with significant air trapping should be considered for a course of macrolide therapy or biopsy for better identification of the underlying disease.