Evaluation of Laboratory Findings of Patients with Coronavirus Disease 2019 in Kerman, Iran.

Background & Objective: Since December 2019 in Wuhan, China there is a new form of pneumonia and after expansion in other countries, World Health Organization (WHO) called it Coronavirus Disease 2019 (COVID-19). Since the clinical laboratory findings have played an important role in the progression of the disease, this study aimed to evaluate the laboratory findings in COVID-19 patients (before vaccination). Methods: In this case-control study that was conducted from February to August 2020; the laboratory test status in 101 positive COVID-19 patients was evaluated and compared with 101 healthy individuals. Results: The results of our study showed that 21% of patients had low WBC, 24.75% low RBC, 37.62%, low Hb, 18.81% with low HCT, 29.7%, low Plt, 41.58% had High PT, 71.29% high CRP, 17.82% high urea, 11.88% high CR, 15.84% high LDH, 10.89% low sodium, 14.75% low potassium (K). The quantitative examination of blood factors showed that lymph%, mixed%, PLT, HCT, Hb, and RBC were higher in the control group than in the case group. While Neu%, WBC, PTT, CRP, UREA, LDH, K in the patient group were higher than in the control group. Conclusion: According to the results of the study, it can be concluded that in the clinical treatment of COVID-19 patients, much attention should be paid to the laboratory indicators to identify and intervene early in critically ill patients.

Ellagic acid ameliorates aging-induced renal oxidative damage through upregulating SIRT1 and NRF2.

BACKGROUND: Aging is associated with impaired renal function and structural alterations. Oxidative stress plays a vital role in renal senescence and damage. Sirtuin 1 (SIRT1) is thought to protect cells from oxidative stress through nuclear factor erythroid 2-related factor 2 (NRF2). Ellagic acid (EA), a natural antioxidant, has been demonstrated to have renoprotective roles in vitro and in vivo. This study investigated if SIRT1 and NRF2 mediate the protective effects of EA in aged kidneys. METHODS: Male Wistar rats were divided into three groups including young (4 months), old, and old + EA (25 months). Young and old groups received EA solvent, while the old + EA group was treated with EA (30 mg/kg) by gavage for 30 days. Then, the level of renal oxidative stress, SIRT1 and NRF2 expression, kidney function parameters, and histopathological indices were measured. RESULTS: Treatment with EA significantly increased the level of antioxidant enzymes and reduced malondialdehyde concentration (P < 0.01). Moreover, EA administration remarkably upregulated mRNA and protein levels of SIRT1 and NRF2 as well as deacetylated NRF2 protein (P < 0.05). Additionally, EA treated rats improved kidney function and histopathological scores (P < 0.05). CONCLUSIONS: These findings suggest that ellagic acid exerts protective effects on aged kidneys by activating SIRT1 and NRF2 signaling.

Prediction of hamstring tendon autograft diameter using preoperative measurements with different cut-offs between genders.

PURPOSE: Studies have suggested some predictors for hamstring tendon (HT) autograft diameter based on anthropometric factors and preoperative magnetic resonance imaging (MRI) with variable results. Some authors have attributed the variability to gender differences. This prospective cohort reports the sensitivity and specificity of anthropometric and MRI predictors in males and females separately to determine the difference. METHODS: Forty-two eligible patients who underwent anterior cruciate ligament reconstruction (ACLR) and MRI in our center were included. ACLR was performed by the senior surgeon using a 4-stranded HT autograft for all patients. A blinded musculoskeletal radiologist measured the cross-sectional area (CSA) of gracilis and semitendinosus tendons using the free-hand region of interest tool for all patients. An orthopaedic resident (PGY4) collected anthropometric factors and measured intraoperative autograft diameter. RESULTS: Mean intraoperative autograft diameter was 8.0 mm. Females had a significantly lower autograft diameter (7.4 vs. 8.2, P < 0.001), smaller gracilis (6.9 vs. 7.9, P = 0.003) and semitendinosus CSA (11.5 vs. 12.8, P = 0.014) compared to males. ROC curve analysis resulted different cut-off values with high sensitivity and specificity for semitendinosus and combined CSA regarding gender. CONCLUSION: Based on the results of this study, CSA of either isolated or combined HTs on preoperative axial MRI, height, and weight are the strongest predictors of intraoperative autograft diameter. It is suggested to consider different cut-offs for males and females to have a better clinical guide for surgeons. LEVEL OF EVIDENCE: Level II.

Gemfibrozil, a lipid-lowering drug, reduces anxiety, enhances memory, and improves brain oxidative stress in d-galactose-induced aging mice.

Gemfibrozil (GFZ) is a lipid-lowering drug with several other effects, such as antioxidant and anti-inflammatory activities. In the current study, chronic d-galactose treatment (d-gal, 150 mg/kg/day; i.p., 6 weeks) induced a model of accelerated aging in male mice and was used to study the behavioral, anti-oxidative, and neuroprotective effects of GFZ (100 mg/kg/day; p.o.). Anxiety-like behaviors were assessed using the elevated plus-maze while working memory was measured by spontaneous alternation in a Y-maze. Brain oxidative stress was determined by measuring malondialdehyde (MDA) levels, superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities. Neuropathological evaluation of the brain with hematoxylin-eosin and Masson's trichrome staining was also performed. The results demonstrated that the anxious-like phenotype and the cognitive impairments observed in d-gal-treated mice could be prevented in those animals coadministered with GFZ. Besides, the decrease in SOD and GPx antioxidant enzymatic activities and increase of MDA levels were also prevented in the brains of d-gal plus GFZ treated mice. Preliminary hematoxylin-eosin staining also suggested neuroprotective effects of GFZ. The results of Masson's trichrome staining showed no evidence of fibrosis in brain sections of different experimental groups. The current data provide novel insights into GFZ in the d-galactose-induced aging mouse model that open promising future research lines to determine inflammatory mediators and cell signaling underlying these effects.

Improving SIRT1 by trehalose supplementation reduces oxidative stress, inflammation, and histopathological scores in the kidney of aged rats.

The aging process leads to progressive loss of kidney function. Sirtuin1 (SIRT1) exerts renoprotective effects by conferring resistance to cellular stresses. Trehalose potentially displayed various beneficial effects to promote health span. In this study, we investigated the effects of trehalose on renal SIRT1 and kidney function in senescent rats. Trehalose (2% w/v) was administrated in drinking water for 1 month to male aged rats (24 months). Then, the level of SIRT1 mRNA and protein, malondialdehyde, total antioxidant capacity, tumor necrosis factor α as well as parameters related to the function and histology of the kidneys were evaluated. Trehalose supplementation increased the level of SIRT1, whereas alleviated the level of oxidative stress, inflammation, and histopathology scores in senescent tissues. However, trehalose administration did not alter kidney function indices in old rats. Collectively, these findings suggested that trehalose was an effective intervention to ameliorate some aspects of age-associated injury in the old kidneys. PRACTICAL APPLICATIONS: Aging is associated with impairment in renal structure and function. Trehalose is a natural disaccharide, which is widely distributed in many organisms. The consumption of trehalose as a dietary supplement is increasing worldwide. This study showed that trehalose administration to aged rats had renoprotective effects through reducing oxidative stress and inflammation, which was mediated by SIRT1. Our results provide useful information for individuals using this sugar as a supplement.

Pathogenesis of COVID-19; Acute Auto-inflammatory Disease (Endotheliopathica & Leukocytoclastica COVIDicus).

BACKGROUND: The pathogenesis of the COVID19 pandemic, that has killed one million nine hundred people and infected more the 90 million until end of 2020, has been studied by many researchers. Here, we try to explain its biological behavior based on our recent autopsy information and review of literature. METHODS: In this study, patients with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) result were considered eligible for enrollment. Histopathological examinations were done on 13 people who were hospitalized in Afzalipour hospital, Kerman, Iran. Clinical and laboratory data were reviewed. Tissue examination was done by light microscopy, immunohistochemistry and electron microscopy. RESULTS: The most frequent co-morbidity in the patients was cardiovascular disease. The common initial symptoms of COVID-19 infection were dyspnea and cough. In all cases, the number of white blood cells was higher than the normal range. Common histopathological findings were variable degrees of vasculitis as degenerative to necrotic changes of endothelium and trafficking of inflammatory cells in the vessel wall with fibrinoid necrosis. Tissue damage included interstitial acute inflammatory cells reaction with degenerative to necrotic changes of the parenchymal cells. CD34 and Factor VIII immunohistochemistry staining showed endothelial cell degeneration to necrosis at the vessel wall and infiltration by inflammatory cells. Electron microscopic features confirmed the degenerative damages in the endothelial cells. CONCLUSION: Our histopathological studies suggest that the main focus of the viral damage is the endothelial cells (endotheliopathica) in involved organs. Also, our findings suggest that degeneration of leukocytes occurs at the site of inflammation and release of cytokines (leukocytoclastica) resulting in a cytokine storm.

Immunomodulatory effects of vitamin D3 on gene expression of MDGF, EGF and PDGFB in endometriosis.

RESEARCH QUESTION: Endometriosis, an inflammatory disease, is assumed to be associated with an increased production of growth-related cytokines. Based on the emerging immunomodulatory role of vitamin D3 in different inflammatory conditions, this study aimed to examine its modulatory effect on the expression levels of the genes for platelet-derived growth factor-B (PDGFB), monocyte/macrophage-derived growth factor (MDGF, also known as PPBP) and epidermal growth factor (EGF) in peritoneal fluid mononuclear cells (PFMC) in women with and without endometriosis. DESIGN: PFMC from 10 women with endometriosis and 10 control participants were treated with vitamin D3.The gene expression levels of PDGFB, MDGF and EGF were measured 6, 24 and 48 h following vitamin D3 administration using real-time PCR. RESULTS: Gene expression levels of EGF and PDGFB were higher in the PFMC of women with endometriosis than the control group (P = 0.006, P < 0.001, respectively). Although MDGF expression showed an increase in the endometriosis group compared with non-endometriotic controls, no significant difference was found. Vitamin D3 significantly decreased EGF expression at 6, 24 and 48 h (P < 0.001, P < 0.001 and P = 0.007, respectively), MDGF at 24 and 48 h (P < 0.001 and P = 0.009, respectively) and PDGFB at 6 h (P = 0.047) in the endometriosis group. Vitamin D3 treatment had no significant effect on expression of the genes in the PFMC of non-endometriotic women. CONCLUSIONS: The study concluded that PDGFB and EGF gene expression increases in endometriosis, and vitamin D3 could markedly decrease this expression, suggesting its therapeutic potential in endometriosis.

Immune Checkpoint Molecules in Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System.

INTRODUCTION: Primary Diffuse Large B Cell Lymphoma of CNS (PCNSL) is a rare variant of Diffuse Large B Cell Lymphoma (DLBCL) and presents with an aggressive clinical course and usually resistant to commonly used therapy regimens. Recently, role of immune checkpoint molecules including PD-1 and PD-L1 confirmed in some solid tumors and lymphoma resulting tumor cells escape the immune system and help to survive and to spread. Inhibitors of PD-1 and PD-L1 have shown lasting responses in several solid and some hematological tumors, while limited studies evaluate checkpoint molecules on PCNSL. METHOD: In this study, we investigated PD-1 and PD-L1 expression by immunostaining on 71 patients with PCNSL and correlation with demographic data, location of the tumor, proliferation rate, cell of origin, and CD8 positive T cell infiltration in tumor microenvironment. RESULTS: 16 from71 showed PD-1 expression, while PD-L1 expression were 42/71. No association was determined between PD-1/PD-L1 expression and gender, cell of origin, and proliferation rate, but a highly significant difference was determined between the infiltration of CD8 positive T cells in two groups of PD-1/PD-L1 positive and negative. CONCLUSION: This study revealed expression of check point molecules in remarkable number of PCNSL which may open new therapeutic recommendations in this aggressive lymphoma type.

Secondary Malignant Transformation of Giant Cell Tumor of Bone: Is It a Fate?

The malignant transformation of conventional giant cell tumor of bone (GCTOB) is rare and usually occurs with irradiation. Here we report two neglected cases of conventional GCTOB with spontaneous malignant transformation at 11 and 16 years after initial diagnosis. In the former case, the patient refused to receive any treatment following the incisional biopsy, and in the latter, the first recurrence that occurred 5 years after initial treatment, was neglected. Although rare, the occurrence of sarcomatous changes in these cases indicates that secondary malignant transformation may be part of the natural course of this tumor. In addition, in both cases, immunohistochemistry showed diffuse and strong p53 expression in the malignant tumor but not in the primary lesion. It suggests that p53 overexpression may play a key role in the malignant transformation of GCTOB and that investigating for p53 expression in recurred lesions may help in predicting cases of giant cell tumor, prone to malignant transformation.

MYC, BCL2, and BCL6 rearrangements in primary central nervous system lymphoma of large B cell type.

Primary central nervous system lymphoma (PCNSL) is a rare specific subtype of non-Hodgkin lymphoma limited to the brain, leptomeninges, spinal cord, or eyes without any systemic presentation and relapse which mostly takes place in CNS. In more than 95% of patients, it is of diffuse large B cell lymphoma (DLBCL) type. Categorizing PCNSL to germinal center cell like or activated B cell like, as we usually do for DLBCL NOS, may not be applicable for predicting outcome. Possible prognostic significance of MYC, BCL2, and/or BCL6 rearrangements may be important given what we know about their impact in systemic DLBCL, but we have limited knowledge about the status of double or triple hit molecular changes in PCNSL. Here, we have investigated prevalence of these molecular alterations in PCNSL. Two independent tissue microarrays constructed from 78 formalin-fixed paraffin-embedded blocks of confirmed PCNSL were tested for rearrangement of MYC, BCL2, and BCL6 by interphase fluorescent in situ hybridization (FISH) using break apart dual color probes. BCL6 translocation was detected in 15 (12%) cases. Translocation involving MYC and BCL2 was identified in 3 cases (3.8%) and 1 case (1.3%) respectively. One double hit lymphoma was discovered with both MYC/BCL2 translocation (1.3%). To the best of our knowledge, few organized studies have been conducted for MYC, BCL2, and/or BCL6 rearrangement in PCNSL. This study is evaluating large number of PCNSL. Double or triple hit events which are rarely seen in PCNSL.

P63 expression as a biomarker discriminating giant cell tumor of bone from other giant cell-rich bone lesions.

INTRODUCTION: Giant cell tumor of bone (GCTOB) is a locally aggressive neoplasm that accounts for 5% of all primary bone tumors. This tumor overlaps in histopathologic and radiographic presentations with different malignant, benign, and metabolic giant cell-rich lesions. The purpose of this study is to evaluate p63 expression status in giant cell tumor of bone in comparison with other giant cell-rich lesions. MATERIALS AND METHODS: In a cross-sectional study we examined immunohistochemical expression of p63 in a series of 100 giant cell-rich bone lesions, including 31 giant cell tumors of bone, 14 osteosarcomas (including 3 giant cell-rich variants), 18 aneurysmal bone cysts (including one solid variant), 8 non-ossifying fibromas, 17 chondroblastomas, 8 tenosynovial giant cell tumors, and 4 brown tumors. RESULTS: Immunohistochemical analysis showed p63 nuclear expression in 96.8% of giant cell tumors of bone, 14.3% of osteosarcomas, 50% of non-ossifiying fibromas, 22.2% of aneurysmal bone cysts, 68.7% of chondroblastomas, 75.0% of brown tumors and none of the tenosynovial giant cell tumors. Taking into account the intensity of staining, we identified strong staining in 48.4% of giant cell tumors of bone, 35.3% of chondroblastomas and 7.1% of osteosarcomas (in 2 cases which were both giant cell-rich variants). Considering extent of staining, extensive staining was only observed in 58.0% of giant cell tumors of bone, 23.5% of chondroblastomas and 14.3% of osteosarcomas. CONCLUSION: A large number of giant cell tumors of bone (96.8%) are positive for p63, which is considerably more than any other giant cell-rich lesion. However, positive staining for p63 is not specific for GCTOB and may be seen in other lesions such as chondroblastoma, non-ossifying fibroma, brown tumor, and giant cell-rich osteosarcoma. P63 is a sensitive (96.8%) and relatively specific marker for discriminating GCTOB from other types of giant cell-rich lesions. We suggest a combined scoring method for p63 IHC staining interpretation in GC-rich lesions, considering both intensity and extent of reaction, with a 2+ cut off as a more accurate marker for the diagnosis of GCTOB within the appropriate clinical context.

Aneurysmal Bone Cyst: An Analysis of 38 Cases and Report of Four Unusual Surface Ones.

Aneurysmal bone cyst (ABC) is a benign expansile bone tumor, most commonly involving the medulla of long bones. ABC rarely arises within the cortex or in the subperiosteal region, radiographically mimicking other conditions, in particular surface osteosarcomathat is low-grade in nature and may go secondary ABC changes, and telangiectatic osteosarcoma. Both of these are sometimes mistaken microscopically for primary ABC. We review the characteristics of ABC cases in our center and report four unusualsurface ABCs arising in the subperiosteal or cortical region of long bones, identified among 38 histologically proven ABCs during a four-year period in our center. The surface ABCs occurred at an older agewith a predilection for diaphysis of femur, tibia, and humerus.

Distribution of breast density in Iranian women and its association with breast cancer risk factors.

BACKGROUND: Breast cancer is one of the most common cancers and the first-leading cause of cancer deaths among women in the world. Indeed, breast cancer is ranked as the first malignancy among Iranian women. Breast density, defined as the percentage of fibro glandular breast tissue in mammographic images, is one of the known risk factors for breast cancer. According to American college of radiology-Breast Imaging Reporting and Data System (ACR-BIRADS), mammographic density is divided into four categories. Studies have shown that increased breast density is associated with significant increase in breast cancer risk. Therefore, it is assumed that breast density should be associated with other breast cancer risk factors. OBJECTIVES: The aim of this study was to assess the epidemiologic distribution of breast density of the patients in a referral center in Iran, and to evaluate the association of high breast density and breast cancer risk factors and other factors that may possibly affect the mammographic density according to previous studies. PATIENTS AND METHODS: In an analytical cross-sectional study, 728 of those who had referred to Imam Khomeini Imaging Center either for diagnostic or screening purposes, participated in the study, after filling out the informed consent form, the survey questionnaire based survey assessing breast cancer risk factors affecting the breast density and related demographic features, was conducted. SPSS 11.5 software and chi-square, t-test and logistic regression tests were used to analyze the data. RESULTS: Most of patients (75%) in categories 2 and 3 of mammographic density had a breast density of 51.9%, however, this amount was less (49.2%) in screening mammograms, while in diagnosing group it was more (51.6%). The Findings showed an increase in age, body mass index (BMI), duration of breast feeding, and also to be menopause e, unemployed and married, younger than 29 years old at first delivery, having children up to 8 and smoking are associated with less breast density. Diagnostic mammograms and symptomatic patients showed denser breasts. But density had no association with oral contraceptives pill (OCP) consumption or hormone replacement therapy or calcium and/or vitamin D consumption, age at menarche and menopause, menstruation cycle phase and family history of breast cancer. Age at the first delivery, menopausal status and parity were independently associated with breast density. CONCLUSIONS: Density distribution and risk factors prevalence is different among symptomatic patients and the diagnostic mammograms of the screened persons, hence such information should be considered in the patient managements. In order to consider the effect of marriage and parity on decreasing the breast density, basic consultations should be performed. Smokers and obese women may falsely show low breast density while they may be in high-risk group. In this study no specific phase of menstrual cycle is suggested for mammographic examinations.

Association of mammographic density with pathologic findings.

BACKGROUND: Breast cancer is one of the most common cancers in the world and is the first cause of death due to cancer among women. Mammography is the best screening method and mammographic density, which determines the percentage of fibro glandular tissue of breast, is one of the strongest risk factors of breast cancer. Because benign and malignant lesions may present as dense lesions in mammography so it is necessary to take a core biopsy of any suspicious lesions to evaluate pathologic findings. OBJECTIVES: The aim of this study was to assess the association between mammographic density and histopathological findings in Iranian population. Moreover, we assessed the correlation between mammographic density and protein expression profile. We indeed, determined the accuracy and positive predictive value and negative predictive value of mammographic reports in our center. PATIENTS AND METHOD: This study is a cross-sectional study carried out among 131 eligible women who had referred to imaging center for mammographic examination and had been advised to take biopsy of breast tissue. All participants of the study had filled out the informed consent. Pathologic review was performed blinded to the density status. Patients were divided into low density breast tissue group (ACR density group 1-2) and high density breast tissue group (ACR 3, 4) and data was compared between these two groups. Statistical analysis performed using SPSS for windows, version 11.5. We used chi-square, t-test, and logistic regression test for analysis and Odds Ratio calculated where indicated. RESULTS: In patients with high breast densities, malignant cases (61.2%) were significantly more in comparison to patients with low breast densities (37.3%) (P= 0.007, OR=2.66 95% CI=1.29-5.49). After adjusting for age, density was associated with malignancy in age groups <46 years (P=0.007), and 46-60 years (P=0.024) but not in age group >60yrs (P=0.559). Adjusting for menopausal status, density showed association with malignancy in both pre-menopause (P=0.041) and menopause (P=0.010) patients. Using logistic regression test, only age and density showed independent association with risk of breast cancer. No association was found between density and protein profile expression. Mammographic method has a false negative percent of 10.3% for negative BI-RADS group and a Positive Predictive Value (PPV) of 69.6% for positive BI-RADS group. PPVs for BI-RADS 4a, 4b, 4c and 5 were 16%, 87.5%, 84.6%, and 91.5% respectively. NPVs for BI-RADS 1, 2 and 3 were 66.7%, 95.8% and 90.0% respectively. CONCLUSIONS: In this study we found that increasing in mammographic density is associated with an increase in malignant pathology reports. Expression of ER, PR and HER-2 receptors didn't show association with density. Our mammographic reports had a sensitivity of 94.1% and a specificity of 55.6%, which shows that our mammography is an acceptable method for screening breast cancer in this center.