The nongenomic neuroprotective effects of estrogen, E2-BSA, and G1 following traumatic brain injury: PI3K/Akt and histopathological study.

OBJECTIVES: Studies suggest that both genomic and nongenomic pathways are involved in mediating the salutary effects of steroids following traumatic brain injury (TBI). This study investigated the nongenomic effects of 17ß-estradiol (E2) mediated by the PI3K/p-Akt pathway after TBI. METHODS: Ovariectomized rats were apportioned to E2, E2-BSA (E2 conjugated to bovine serum albumin), G1 [G-protein-coupled estrogen receptor agonist (GPER)] or their vehicle was injected following TBI, whereas ICI (classical estrogen receptor antagonist), G15 (GPER antagonist), ICI + G15, and their vehicles were injected before the induction of TBI and injection of drugs. Diffuse TBI was induced by the Marmarou model. Evans blue (EBC, 5 h), brain water contents (BWC), histopathological changes, and brain PI3K and p-Akt protein expressions were measured 24 h after TBI. The veterinary comma scale (VCS) was assessed before and at different times after TBI. RESULTS: The results showed a reduction in BWC and EBC and increased VCS in the E2, E2-BSA, and G1 groups. Also, E2, E2-BSA, and G1 reduced brain edema, inflammation, and apoptosis. The ICI and G15 inhibited the beneficial effects of E2, E2-BSA, and G1 on these parameters. All drugs, following TBI, prevented the reduction of brain PI3K/p-Akt expression. The individual or combined use of ICI and G15 eliminated the beneficial effects of E2, E2-BSA, and G1 on PI3K/p-Akt expressions. CONCLUSIONS: These findings indicated that PI3K/p-Akt pathway plays a critical role in mediating the salutary effects of estradiol on histopathological changes and neurological outcomes following TBI, suggesting that GPER and classic ERs are involved in regulating the expression of PI3K/p-Akt.

The effect of positive thyroglobulin antibodies on the prognosis and treatment response in patients with papillary thyroid carcinoma.

Almost 15-30% of patients with papillary thyroid carcinoma (PTC) experience some degree of recurrence after treatment. Long-term follow-up and examination after thyroidectomy are very important in dealing with this issue. Serum thyroglobulin (Tg) level and neck ultrasound are the main part of follow-up for this purpose. The presence of thyroglobulin antibodies (TgAbs) leads to unreliable thyroglobulin (Tg) levels. The present study aims to evaluate the relationship between the simultaneous measurement of Tg and TgAb with long-term survival and response to treatment in these patients. This study was conducted by surveying available data from the medical records of 204 out of 600 patients over a 20-year period. In this research, 104 patients with positive TgAb were considered as the case group, and 100 patients with negative TgAb were selected as the control group. The relationship of TgAb titer was investigated with the staging, response to treatment (including the surgery number, number of radiotherapies, and dose of radioactive iodine), and recurrence in these patients. Also, the trend of TgAb changes was examined in the presence of high or low thyroglobulin levels during the follow-up period. Patients with high TgAb levels had more lymph node involvement, higher cumulative dose, a higher number of times received iodine, more surgical number, higher recurrence rate, and less excellent response (ER) to treatment during follow-ups. This effect of TgAb worsened in the presence of high Tg titer and remained up to 36 months. Overall, the baseline level of TgAb and its changes can be a suitable factor for predicting subsequent response to treatment and recurrence in patients with PTC. Accordingly, in cases with high TgAb and Tg levels, close follow-up should be considered up to Tg and TgAb normalization.

Evaluating the neuroprotective effects of progesterone receptors on experimental traumatic brain injury: The PI3K/Akt pathway.

BACKGROUND: Studies have confirmed the salutary effects of progesterone (P4) on traumatic brain injury (TBI). This study investigated the beneficial effects of P4 via its receptors on TBI, and also whether progesterone receptors (PRs) can modulate TBI through PI3K/Akt pathway. MATERIAL AND METHODS: Marmarou method was utilized to induce diffuse TBI in ovariectomized rats. P4 (1.7 mg/kg) or the vehicle (oil) was administered 30 min after TBI induction. Moreover, RU486 (PR antagonist) and its vehicle (DMSO) were injected before TBI induction and P4 injection. Brain Evans blue content, brain water content (WC), various oxidative stress parameters, IL-1ß levels, tumor necrosis factor-α (TNF-α), histopathological alterations, and also phosphorylated Akt (p-Akt) and PI3K expressions in the brain were assessed 24 h after TBI. The veterinary comma scale (VCS) was measured before and after TBI at different times. RESULTS: The findings revealed that P4 caused an increase in VCS and a decrease in brain WC, oxidative stress, TNF-α and IL-1ß levels. RU486 inhibited the beneficial effects of P4 on these indices. Moreover, RU486 prevented the reduction of brain edema, inflammation, and apoptosis caused by P4. Moreover, P4 following TBI increased the expression of PI3K/p-Akt protein in the brain. RU486 eliminated the effects of P4 on PI3K/p-Akt expression. CONCLUSION: According to these findings, PRs are acting as critical mediators for the neuroprotective properties of P4 on oxidative stress, pro-inflammatory cytokine levels, and neurological outcomes. PRs also play an important role in regulating the PI3K/p-Akt expression and nongenomic function of P4.

Organochlorine pesticides and epigenetic alterations in thyroid tumors.

Purpose: Cancer incidence depends on various factors e.g., pesticide exposures which cause epigenetic alterations. The present research aimed to investigate the organochlorine pesticides (OCPs) impacts on promoter methylation of three tumor-suppressor genes and four histone modifications in thyroid nodules in 61 Papillary thyroid carcinoma (PTC) and 70 benign thyroid nodules (BTN) patients. Methods: OCPs were measured by Gas chromatography. To identify promoter methylation of TSHR, ATM, and P16 genes, the nested-methylation-specific PCR (MSP) was utilized, and histone lysine acetylation (H3K9, H4K16, and H3K18) and lysine methylation (H4K20) were detected by performing western blot analysis. Results: Further TSHR methylation and less P16 methylation were observed in PTC than in BTN. No substantial difference was detected for ATM methylation between PTC and BTN groups. Also, OCP dramatically increased the odds ratio of TSHR (OR=3.98, P=0.001) and P16 (OR=5.65, P<0.001) methylation while confounding variables reduced the chances of ATM methylation arising from 2,4-DDE and 4,4-DDT influence. Hypomethylation of H4K20 and hypo-acetylation of H3K9, H4K16, and H3K18 (P<0.001) were observed in PTC samples than BTN. Furthermore, OCPs substantially decreased the odds ratio of H3K9 (OR=3.68, P<0.001) and H4K16 (OR=6.03, P<0.001) acetylation. Conclusion: The current research indicated that OCPs could contribute to PTC progression by TSHR promoter hypermethylation and decreased acetylation of H3K9 and H4K16. In addition, in PTC patients, assessing TSHR promoter methylation and acetylation of H3K9 and H4K16 could have predictive values.

Organochlorine pesticides induce thyroid tumors through oxidative stress; an in vivo and in silico study.

Thyroid disease is one of the most common endocrine problems around the world. Among the numerous factors, exposure to environmental elements such as pesticides is associated with an increase in the incidence of thyroid disorders. The aim of the present study was to investigate the role of organochlorine pesticides (OCPs) in induction of oxidative stress (OS) and development of thyroid tumors. This case-control study was conducted on 61 patients with papillary thyroid carcinoma (PTC), 70 patients with benign thyroid nodules (BTN), and 73 healthy individuals as control. Seven derived OCPs residues measured by gas chromatography (GC), and enzyme activities of acetylcholinesterase (AChE), superoxide dismutase3 (SOD3), catalase (CAT), glutathione peroxidase3 (GPx3) and paraoxonase1 (PON1) and also, non-enzymatic antioxidant including; malondialdehyde (MDA), total antioxidant capacity (TAC), protein carbonyl (PC), and nitric oxide (NO) biomarkers in all participants were investigated. Furthermore, all of the above enzymes were docked against measured OCPs. The results revealed that ß-HCH, γ-HCH, 2,4 DDE, 4,4 DDE, 2,4-DDT, and 4,4-DDT levels along with MDA, NO, and PC levels were elevated, while AChE, SOD3, GPx3, CAT, and PON1 activities and TAC levels were decreased in the PTC and BTN groups compared with the control group. Therefore, OCPs might play a role in the development of thyroid tumors through several mechanisms including generation of OS. Importantly, in silico analysis confirmed the in vivo findings.

Thyroid Cancer-Specific Health-Related Quality of Life Questionnaire: Psychometric Properties of the Persian Version.

Background: Adverse effects related to treatment negatively affect the quality of life of patients with thyroid cancer. The current study aimed to evaluate the psychometric properties of the Persian version of the thyroid-cancer-specific health-related quality of life (TC-specific HRQoL) questionnaire among patients with thyroid cancer in Kerman province, Iran. Methods: This research was a cross-sectional study conducted on 240 patients with thyroid cancer in Kerman province from 2000 to 2015. The patients were selected through the census method and were asked to complete the thyroid-cancer-specific quality of life questionnaire. Data were analyzed by SPSS version 19.0 and LISREL version 8.80. The reliability of the Persian version was determined by Cronbach's α coefficient and the intraclass correlation coefficient (ICC). Exploratory and confirmatory factor analysis (CFA) was also conducted. Results: The Cronbach's α and ICCs were determined as 0.92 and 0.88, respectively. Five factors were extracted in the exploratory factor analysis with a total of 55.76% explained variance. Acceptable goodness of fit indices were found in CFA. Conclusions: The Persian version of the TC-specific HRQoL has sufficient psychometric properties and can be used to assess HRQoL among patients with thyroid cancer.

Substitution of calorie restriction for protective effects of estrogen on cardiometabolic risk factors and oxidative stress in obese postmenopausal rat model.

Estrogen has an anti-obesity effect and plays an important role in improving cardiometabolic disorders. Weight loss and reduction in calorie intake impede the development of obesity-related cardiometabolic risk factors. Therefore, we investigated the substitution of calorie restriction for effects of estrogen on cardiometabolic risk factors and oxidative stress in obese postmenopausal rat model. In this study, adult female Wistar rats were allocated into Sham and ovariectomized (OVX) groups and were given standard diet (SD) or 60% high-fat diet (HFD) or 30% calorie restriction (CR) for 16 weeks, following this, animals received E2 (17-ß estradiol; 1 mg/kg; i.p.) every four days for 4 weeks. Results showed that HFD elevated the body weight, BMI, food intake, and blood glucose (BG) level in both sham and OVX groups. In addition, HFD had negative effects on lipid profile and oxidative stress in these groups. Whereas CR decreased these indices in both Sham and OVX groups fed an HFD, it could not diminish the BG level in the OVX-HFD group. E2 treatment in OVX animals with or without CR reduced body weight, BMI, food intake, and BG level, and also had positive effects on lipid profile alterations and oxidative stress reduction. In comparison, no significant differences were observed regarding the effects of E2 with CR between two groups for body weight, lipid profile, BG, and oxidative stress in the OVX-HFD rats. Overall, CR prevents and ameliorates cardiometabolic risk factors induced by obesity in postmenopausal conditions and is also a good candidate for E2 substitution.

Asymptomatic COVID-19 as a Risk Factor of Diabetic Ketoacidosis and Mucormycosis: A Case Report and Review of the Literature.

Mucormycosis is a lethal and life-threatening fungal infection. Several cases describing the association of COVID-19 and mucormycosis have been reported. In this article, we report a 58-year-old female with a history of diabetes mellitus type 2 who presented by diabetic ketoacidosis, rhino-orbital mucormycosis, and COVID-19. The patient was treated with liposomal amphotericin B and debridement of necrotic tissue of the rhino-orbital area and paranasal sinuses. Unfortunately, she passed away a few days after orbital surgery. We also conducted a review of the literature and reported 3 other similar cases that suffered from mucormycosis in association with COVID-19 and diabetic ketoacidosis and discussed the importance of this association.

Henoch-Schönlein Purpura (IgA Vasculitis) in Association with Thyrotoxicosis.

Graves' disease is the most common cause of hyperthyroidism, which is characterized by thyroid antibodies and the following clinical manifestations: goiter, ophthalmopathy, and pretibial myxedema. On the other hand, Henoch-Schönlein purpura is an IgA-mediated small-vessel vasculitis. Review of the literature showed a relationship between propylthiouracil overdose and the following Henoch-Schönlein purpura (IgA vasculitis) as a side effect. The patient was a 31-year-old woman with a chief complaint of tremor and significant weight loss who contracted pruritic palpable purpura during her disease course. Then, she underwent the treatment of hyperthyroidism by methimazole which intensified her cutaneous lesions. The diagnosis of Henoch-Schönlein purpura (IgA vasculitis) was confirmed after skin biopsy. Finally, she was treated with colchicine, prednisolone, and radioiodine ablation, which caused her lesions to disappear. The temporal priority of pruritic palpable skin lesions to hyperthyroidism treatment with methimazole suggested that Henoch-Schönlein purpura (IgA vasculitis) was related to hyperthyroidism and was intensified by antithyroid agents in this patient.

The effect of IFN-ß 1a on expression of MDA5 and RIG-1 in multiple sclerosis patients.

The aims of this study were to compare mRNA levels of melanoma differentiation-associated protein 5 (MDA5) and retinoic acid-inducible gene 1 (RIG-1) in multiple sclerosis (MS) patients in comparison to the healthy controls as well as investigating the effects of IFN-ß 1a on the expression of these molecules. In this study, mRNA levels of MDA5 and RIG-1 in peripheral leukocytes of 30 new cases of MS patients and 35 healthy controls were evaluated using the real-time-PCR method. mRNA levels of MDA5 and RIG-1 were determined in the MS patients 6 months after treatment with standard doses of IFN-ß 1a. mRNA levels of MDA5 and RIG-1 were significantly decreased in the MS patients in comparison to the healthy controls. The analysis also revealed that IFN-ß 1a therapy leads to the upregulation of RIG-1, but not MDA5, in the total MS patients and the female group. MS patients suffer from insufficient expression of MDA5 and RIG-1, and IFN-ß 1a therapy results in the upregulation of RIG-1 in the patients, especially in the female patients. Thus, it seems that IFN-ß 1a not only decreased pathogenic inflammatory responses but also modulated the expression of RIG-1 to protect the patients from infectious diseases and upregulation of IFN-I in a positive feedback.

Enhanced expression of Cyclin D1 and C-myc, a prognostic factor and possible mechanism for recurrence of papillary thyroid carcinoma.

A direct association has been shown between Cyclin D1 and C-myc gene expressions and the proliferation of human thyroid tumor cells. Our previous study showed that increased ß catenin led to a reduction in disease-free probability in patients with papillary thyroid cancer. This study was designed to investigate Cyclin D1 and C-myc genes as targets for ß catenin function in PTC and to determine the association between genes expression and staging, recurrence, metastasis, and disease-free survival of PTC. This study was conducted via a thorough investigation of available data from medical records as well as paraffin blocks of 77 out of 400 patients over a 10-year period. Cyclin D1 and C-myc gene expression levels were measured using real-time polymerase chain reaction (RT-PCR) and the Kaplan-Meier method was used to evaluate disease-free survival. Higher levels of Cyclin D1 and C-myc gene expressions were observed in patients with recurrence by 8.5 (P = 0.004) and 19.5 (p = 0.0001) folds, respectively. A significant positive correlation was found between Cyclin D1 expression and the cumulative dose of radioactive iodine received by patients (r = -0.2, p value = 0.03). The ten-year survival rate in the patients included in this study was 98.25% while disease-free survival was 48.1%. Higher Cyclin D1 and C-myc gene expression levels were observed in patients with recurrence/distant metastasis. Inversely, lower expression of Cyclin D1 and C-myc genes were associated with better survival of patients (SD, 0.142-0.052) (Mantel-Cox test, P = 0.002). The enhancement of Cyclin D1 and C-myc gene expression may be a potential mechanism for recurrence and aggressiveness of PTC.

Downregulation of IL-22 can be considered as a risk factor for onset of type 2 diabetes.

There is some controversy as for the roles played by tumor growth factor-ß (TGF-ß), interleukin-1ß (IL-1ß), and IL-22 in the onset process of type 2 diabetes (T2D). The main aim of this project was to examine serum levels of TGF-ß, IL-1ß, and IL-22 in the new cases and long period T2D patients as well as healthy controls. In this study, 115 new T2D patient cases (group 1), 434 T2D patients who have suffered from the disease more than 2 years (group 2), and 104 healthy controls have been selected from 6240 (3619 females) patients who were under study population from Kerman Coronary Artery Disease Risk Factor Study. Serum levels of TGF-ß, IL-1ß, and IL-22 have been evaluated using commercial kits. Serum levels of TGF-ß and IL-1ß significantly increased, while IL-22 decreased in 2 groups in comparison to healthy controls. Serum levels of IL-22, but not TGF-ß and IL-1ß, were significantly decreased in group 1 in comparison to healthy controls. There were no significant differences between groups 1 and 2 as for the cytokine levels. Serum levels of IL-22 increased in the females in group 2 when compared to females in group 1. It appears that TGF-ß and IL-1ß participate in the induction of inflammation after establishment of T2D, while decrease in IL-22 may be considered as a key factor for onset of the disease. Gender can also be considered as the main risk factor for variation in cytokine levels.

ENHANCED BETA-CATENIN EXPRESSION IS ASSOCIATED WITH RECURRENCE OF PAPILLARY THYROID CARCINOMA.

OBJECTIVE: A direct role of ß-catenin 1 (ß-cat) in the proliferation of human thyroid tumor cells has been identified. This study aimed to determine if there is an association between ß-cat gene expression and the staging, recurrence, metastasis, and disease-free survival of papillary thyroid cancer. METHODS: A retrospective cohort study was conducted using data from available information in the medical records and paraffin blocks of 81 of 400 patients referred to the endocrine clinic over a 10-year period. Real-time polymerase chain reaction was used to evaluate ß-cat gene expression. Disease-free survival was assessed using the Kaplan-Meier method. RESULTS: The 10-year survival rate in these patients was 98.25%, and disease-free survival was 48.1%. Cumulative dose of radioactive iodine that patients received was significantly and positively correlated with ß-cat gene expression ( r = -0.2; P = .03). Also, in patients with recurrence, ß-cat gene expression was higher and statistically significant (5-fold increase; P = .002). Patients in more advanced stage and those with recurrence/distant metastasis had higher ß-cat gene expression. We found that the patients had a better survival (lower recurrence) if they had a lower ß-cat gene expression (SD, 0.142 to 0.052) (Mantel-Cox test, P = .002). CONCLUSION: We conclude that ß-cat gene expression is positively correlated with recurrence, distant metastasis, and tumor-node-metastasis stage. ABBREVIATIONS: ß-cat = ß-catenin 1; CI = confidence interval; PTC = papillary thyroid carcinoma; ROC = receiver operating characteristic.

Immunohistochemical Evaluation of ß-Catenin Marker in Papillary Thyroid Cancer: Clinicopathologic Significance.

BACKGROUND & OBJECTIVE: papillary thyroid cancer is the most common cancer of thyroid accounting for 75%-85% of all thyroid malignancies. Recently, ß-catenin has been determined to play a role in clinical course of human epithelial cancers. This study was designed to reveal the association of ß-catenin marker and papillary thyroid carcinoma behavior. METHODS: 63 paraffin blocks of papillary thyroid carcinoma were stained with ready to use monoclonal ß-catenin antibody according to manufacturer's instructions. Memberanous, cytoplasmic and nuclear staining was scored according to intensityof immunoreactivity. ß-catenin immunostaining association with clinical parameters like number of recurrences and cumulative dose of radioiodine therapy were analyzed using SPSS version 15. Histopathologic parameters like tumor stage, grade, capsular invasion, lymphovascular invasion, lymph node involvement, distant metastasis andother variables were also evaluated for association with ß-catenin immunoreactivity. RESULTS: 77.8% of papillay thyroid carcinoma were well differentiated and the remaining were poorly differentiated. Loss of ß-catenin membrane immunostaining depicted correlation with number of recurrences (P=0.023% , Pearson correlation=-0.285). Its loss of memberanous staining correlated similarly with cumulative dose of radioiodine (P= 0.046, Pearson correlation = -0.253). Loss of membranous ß-catenin was significantly associated with some histopathologic findings like nodal involvement (P<0.001), distant metastasis (P=0.003) and tumor dedifferentiation (P< 0.001). CONCLUSION: Loss of ß -catenin membranous staining and its cytoplasmic accumulation were associated with aggressive clinicopathologic behavior. The exact effect of radioiodine exposure on ß-catenin pathway remained to be determined in future.

Evaluation of effect of acarbose consumption on weight losing in non-diabetic overweight or obese patients in Kerman.

BACKGROUND: High prevalence of obesity and the importance of this issue as a risk factor for chronic diseases such as severe cardiovascular diseases, diabetes, and cancer necessitate the need for treatment. The aim of this study was the evaluation of acarbose effect on the weight loss in non diabetic overweight or obese patients in Kerman. MATERIALS AND METHODS: A double blind randomized controlled clinical trial was performed on 66 patients with the body mass index (BMI) between 25 and 35 kg/m(2). Patients were divided in treatment and control groups using the randomization. The treatment group took 100 mg acarbose 3 times a day for 20 weeks in combination with the low calorie diet and exercise. Control group was given placebo, low calorie diet, and exercise. BMI was measured after 20 weeks. The analyses were carried out using t-test and repeated measured ANOVA. RESULTS: Patients in acarbose and placebo group had a non significant difference in BMI at baseline. Reducing in weight was considered in every month in both groups, but this reduction was higher in the treatment group. At the 5(th) month, the difference of BMI in the treatment group was significantly lower than the placebo group (2.31 ± 0.6 vs. 0.76 ± 0.6 kg/m(2), P < 0.001). CONCLUSION: Acarbose, especially in combination with the low calorie diet and exercise, seems to lose weight effectively in obese and overweight patients in communities that have a high carbohydrate intake (like Persian diet).