Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 20, Issue 3, 2020

Objective: To provide an overview of the hormone actions and receptors expressed in the female pelvic floor muscles, relevant for understanding the pelvic floor disorders. Methods: We performed a literature review focused on the expression of hormone receptors mainly in the pelvic floor muscles of women and female rats and rabbits. Results: The impairment of the pelvic floor muscles can lead to the onset of pelvic floor dysfunctions, including stress urinary incontinence in women. Hormone milieu is associated with the structure and function alterations of pelvic floor muscles, a notion supported by the fact that these muscles express different hormone receptors. Nuclear receptors, such as steroid receptors, are up till now the most investigated. The present review accounts for the limited studies conducted to elucidate the expression of hormone receptors in pelvic floor muscles in females. Conclusion: Hormone receptor expression is the cornerstone in some hormone-based therapies, which require further detailed studies on the distribution of receptors in particular pelvic floor muscles, as well as their association with muscle effectors, involved in the alterations relevant for understanding pelvic floor disorders.

Objective: Asthma is correlated with a higher risk of manifesting other diseases, including hypertension, diabetes, obesity, psychiatric and neurological diseases, and cancer. Therefore, revealing this interplay between asthma and these illnesses may provide novel insights into their pathogenesis. Results: It is highly debated that dysregulation of Ca2+ homeostasis is involved in the pathogenesis of these maladies. Not surprisingly, calcium (Ca2+) channel blockers (CCBs), classically used as antihypertensive medicines, have been demonstrating off-label effects such as alleviating asthma symptoms, in addition to antidiabetic, antiobesity, anticancer and antineurodegenerative effects. Our studies about Ca2+/cAMP signalling may shed some new light on this field. Conclusion: Thus, considering that asthma and associated illnesses such as hypertension, diabetes, obesity, cancer and neurodegenerative diseases have become highly prevalent medical problems in the world, the comprehension of this interplay between asthma and other disorders could improve drug therapy.

Background: Cardiovascular complications account for the majority of deaths caused by diabetes mellitus. Platelet hyperactivity has been shown to increase the risk of thrombotic events and is a therapeutic target for their prevention in diabetes. Modulation of platelet function by diabetes agents in addition to their hypoglycemic effects would contribute to cardiovascular protection. Newly introduced antidiabetic drugs of sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors may have anti-platelet effects, and in the case of SGLT2i and GLP-1RA may contribute to their proven cardiovascular benefit that has been shown clinically. Objective: Here, we reviewed the potential effects of these agents on platelet function in diabetes. Results and Conclusion: GLP-1RA and DPP-4i drugs have antiplatelet properties beyond their primary hypoglycemic effects. Whilst we have little direct evidence for the antiplatelet effects of SGLT2 inhibitors, some studies have shown that these agents may inhibit platelet aggregation and reduce the risk of thrombotic events in diabetes.

Background: There is not a time in the history when epidemics did not loom large: infectious diseases have always had civilisation and evolution-altering consequences. Throughout history, there have been a number of pandemics: cholera, bubonic plague, influenza, smallpox are some of the most brutal killers in human history. Historical accounts of pandemics clearly demonstrate that war, unhygienic conditions, social and health inequality create conditions for the transmission of infectious diseases, and existing health disparities can contribute to unequal morbidity and mortality. The Renaissance was a period of European cultural, artistic, political and economic “rebirth” following the Middle Ages, but it was also the time when new infectious disease appeared, such as Syphilis. The epidemic spread of Syphilis began between the late 15th century and early 16th century due to the increased migration of peoples across Europe. The rapid spread of venereal syphilis throughout Europe suggests the introduction of a disease into a population that had not previously been exposed. Syphilis is a type of treponematosis, which includes syphilis, bejel, yaws, and pinta, but, while syphilis is venereal disease, the others are nonvenereal. Syphilis was, at the beginning, a disease of great severity due to its novelty, as the population had no time to gain any immunity against this venereal disease. Methods: The purpose of this study is to investigate the origin of syphilis and the evolution of the treatments from the empiric means to the discovery of penicillin, but also to understand how this venereal disease has largely influenced human lifestyle and evolution. Conclusion: The first of the three hypotheses about its origins is the Columbian hypothesis, which states that Columbus's crew acquired syphilis from Native Americans and carried it back to Europe in 1493 A. D. On the contrary, the second hypothesis (pre-Columbian) asserts that syphilis was present in Europe long before Columbus's voyage and was transferred to the New World by Columbus's men. The Unitarian theory argues that syphilis, bejel, yaws, and pinta are not separate diseases but they represent syndromes caused by slightly different strains of one organism. Nowadays, Syphilis’ origin is still uncertain and remains controversial. However, the large impact on the social behavior and international public health is an important reason to investigate about its origins and how to prevent the transmission.

Background: The thyroid gland influences the metabolic processes in our body by producing thyroid hormones, and thyroid disorders can range from a harmless goiter to life-threatening cancer. A growing number of evidence support the link between gut microbiota composition and thyroid homeostasis. Gut dysbiosis can disrupt the normal gut barrier function, leading to immunologic and metabolic disorders. Objective: The aim of this review was to discuss the main features of gut dysbiosis associated with different thyroid disorders. Results: Gut microbiota contributes to thyroid hormone synthesis and hydrolysis of thyroid hormones conjugates. It has been shown that microbial metabolites may play a role in autoimmune thyroid diseases via modulating the immune system. Intestinal microbiota can contribute to the thyroid malignancies via controlling DNA damage and apoptosis and influencing inflammatory reactions by the microbiota- derived metabolites. However, the pathogenic role of altered gut microbiota in different thyroid disorders has not yet fully elucidated. Conclusion: Further research is needed to assess the role of alterations of the gut microbiota in disease onset and development in order to achieve novel strategies for the prevention and treatment of these diseases.

Background: Immune thrombocytopenia (ITP) is an acquired immune mediated disorder characterized by isolated thrombocytopenia. Pediatric ITP patients can develop autoantibodies such as anti-thyroglobulin (TG) and anti-thyroperoxidase (TPO), even in the absence of clinical signs of autoimmune disease. Objective: The purpose of this article is to provide a review about: 1) the prevalence of positivity of anti-thyroid antibodies (TPO and TG) in pediatric patients with chronic ITP; 2) the role of autoimmune thyroiditis on the outcome of chronic ITP. Methods: The authors individually completed a review of the literature for this article. Retrospective and prospective clinical studies with pediatric cohorts were considered. Results: From the analysis of data, we found 4 papers which included studies only on pediatric population, and which corresponded to selected criteria. Pediatric ITP patients have been shown to have a statistically significant prevalence of anti-thyroid antibodies over healthy controls (11.6-36% versus 1.2-1.3%). No correlation has been found between the platelet count and the prevalence of positive anti-thyroid antibodies at any time of the follow up. Conclusion: The results of our bibliographic research demonstrated that: a) pediatric patients with chronic ITP tend to have a statistically significant prevalence of anti-thyroid antibodies positivity respect to general pediatric population; b) there are no clear data about the role of autoimmune thyroiditis as prognostic factor for chronic course of ITP in pediatric age.

Introduction: Impacted third molars (ITMs) surgery, is one of the most common methods in the field of oral and maxillofacial surgical operations. Administration of corticosteroid such as dexamethasone diminishes the postoperative sequelae. The study aimed to compare the impact of dexamethasone administration on pre-operative and post-operative complications in third molar surgery. Methods: We collected all randomized controlled trial data on the influences of pre-operative and postoperative dexamethasone administration between 2006-2019 on third molar surgery sequelae by searching the keywords: dexamethasone, third molar surgery, wisdom teeth, corticosteroids, oral surgery, maxillofacial surgery, preoperative, postoperative, pain, swelling, and trismus in international databases such as: Web of Science (ISI), PubMed, Scopus, Embase and Cochrane Library. Results: Twenty-three articles were included in this narrative review. Among them, 22 studies used dexamethasone in particular and 1 study used dexamethasone with amoxicillin. Twenty studies evaluated the prescription of dexamethasone in pre-operative and post-operative routes on pain, trismus and edema following third molars operation. Five studies administered dexamethasone postoperatively and 15 studies administered the drug preoperatively. Two studies evaluated the preoperative and postoperative administration method. Fourteen studies used a 4 mg dexamethasone dose and drug administration was variable. The treatment period in postoperative studies varied between 1 to 7 days. Conclusion: Dexamethasone appears to be a promising agent in in reduction of post-operative complications following third molar surgery. As a potent anti-inflammatory agent, it has an effective role in pain, trismus and edema reduction distinguished from the routes of administration, dosage and timing, pre or postoperative prescription.

Background: Obesity is characterized by increased body fat and involves an imbalance between the synthesis and degradation of lipids. Objective: The study aimed to investigate the effect of African walnuts (Tetracarpidium conophorum) on lipids storage and the regulatory enzymes of hepatic lipid metabolism in obese rats. Methods: Nuts were extracted in ethanol (WE) and further separated to obtain the ethyl-acetate fraction (ET) and the residue (RES). These were administered orally to 3 groups of monosodium glutamate- obese rats (n = 6), respectively, for 6 weeks. Other groups in the study were: normal (NC), obese control (OC) and standard control (SC) which received orlistat. Hepatic total lipids, total phospholipids, triacylglycerol (TG), total cholesterol (TCHOL), 3-hydroxyl-3-methylglutaryl-CoA (HMG-CoA) reductase and paraoxonase were studied. Results: Total lipids, TG and TCHOL which increased in OC compared to NC group, decreased. HMG-CoA reductase activity decreased in the 3 study groups relative to OC. Paraoxonase activity which decreased in OC was up-regulated, while the magnitude of hepatic cholesterol decreased from 94.32 % in OC to 52.19, 65.43 and 47.04 % with WE, ET and RES, respectively. Flavonoids, alkaloids, glycosides, tannins and saponins were detected in the nut. GC-MS analysis revealed 16, 18 and 10 volatile components in WE, ET and RES, respectively. Unsaturated fatty acids (linolenic acids: 33.33, 47.95 and 50.93 %, and α-linolenic acids: 25, 19.66 and 26.63 %) in WE, ET and RES, respectively, are the most abundant, and likely to be responsible for the observed activity. Conclusion: African walnuts can prevent hepatic lipid accumulation through reciprocal actions on HMG-CoA reductase and paraoxonase in obesity.

Objective: The ability of an aqueous extract of the sclerotia of Pleurotus tuberregium to modulate hematological parameters was investigated in normal and alloxan treated rabbits. Methods: The extract was subjected to atomic absorption spectrophotometric and flame ionization detector-coupled-gas chromatographic (GC-FID) analysis. Diabetes mellitus was induced by a 120 mg/kg body weight intravenous injection of alloxan. Metformin was orally administered at 50 mg/kg, while the extract was administered (both to normal and diabetic rabbits) at 100, 200 and 300 mg/kg. Results: Analysis of the extract showed that it had high contents of calcium, magnesium, manganese and potassium. Eleven known glycosides were detected, comprising mainly of amygdalin (37.7%), digoxin (14.4%), dhurrin (14.0%), linamarin (13.6%), prunasin (10.8%) and digitoxin (8.4%). Also detected were twelve known saponins, consisting mainly of sapogenin (40.3%) and neochlorogenin (21.8%); and twelve known lignans, consisting mainly of matairesinol (59.7%), secoisolariciresinol (20.9%) and lariciresinol (14.9%). Compared to the Diabetic control, the hematocrit, hemoglobin concentration, mean cell hemoglobin, mean cell hemoglobin concentration, mean corpuscular volume, red cell distribution width; and red cell, total white cell, lymphocytes, granulocytes and platelet counts of the treated groups were significantly (p<0.05) higher. Conclusion: The above result showed that the extract had a positive effect on the hemopoietic system of the treated animals, at least at the doses at which it was administered in this study.

Objective: Coronary artery disease (CAD) is one of the most common causes of death worldwide. Risk factors of CAD include high LDL-C, low high-density lipoprotein (HDL), hypertension, lack of exercise, genetic factors, etc. Polymorphisms of the LDLR gene have been associated with CAD in previous studies. Methods: The LDLR-rs72658855 C>T genotyping was detected by using allele-specific PCR (ASPCR). The association of rs2228671 and rs72658855 with CAD in a south Indian cohort (200 CAD patients and 200 matched healthy controls was studied. Results: Our findings showed that rs2228671 gene variability is associated with increased susceptibility to coronary artery disease in the codominant inheritance model for variant CC vs. CT OR 3.42(1.09-10.7), with P<0.034. A non-significant association was reported in the recessive inheritance model for the variant (CC+CT) vs. TT OR 0.56(0.16-1.95), at P<0.36. and in the dominant inheritance model for variant CC vs. (CT+TT) OR 2.8(1.07-7.34), at P<0.032 .In case of allelic comparison, it was indicated that the LDLR rs2228671-T allele was associated with an increased risk of developing CAD compared to C allele OR=2.4, with 95% CI (1.05-5.64) and P< 0.036 . Our findings showed that LDLR rs72658855 C>T gene variability was associated with an increased susceptibility to coronary artery disease in the codominant inheritance model for variant CC vs. CT OR 1.7(1.1-2.6), at P<0.015 and in the dominant inheritance model for variant CC vs. (CT+TT) OR 1.66(1.07-2.58), at P<0.0.02.. In case of allelic comparison, a non-significant association was reported in LDLR rs72658855-T and C allele. Conclusion: We concluded that the heterozygosity in LDLR-rs72658855 and rs2228671 and T allele in LDLR rs2228671 are strongly associated with increased susceptibility to coronary artery disease. These results must be validated by future well-designed studies with larger sample sizes and different populations.

Background: Cardiopulmonary bypass (CPB) has been demonstrated to provoke a systemic inflammatory response believed to be responsible for some of the serious postoperative complications such as renal dysfunction. Therefore, we tested the hypothesis suggesting that the serum levels of IL- 17A (IL-17), as an inflammatory cytokine, and its gene variants are associated with acute kidney injury after CPB (AKI-CPB). Methods: A total of 135 Iranian patients undergoing cardiopulmonary bypass were included in this study, of whom 65 (48.1%) developed AKI. Blood specimens were collected preoperatively and at 12 hours postoperatively. The IL-17 gene polymorphisms (rs2275913 and rs3819024) were determined using sequence-specific primers (PCR-SSP) technique.Pre- and postoperative IL-17 levels were measured and analyzed in relation to polymorphisms. Results: IL-17 concentrations in CBP subjects, were increased after cardiopulmonary bypass (P<0.00001)but there were no statistically significant differences in IL-17 serum level between AKI and non-AKI groups. Different genotypes of IL-17 rs2275913 SNP (G→A) were associated with different circulating IL-17 levels before bypass and also after AKI development. There were no associations between gene polymorphisms (rs2275913and rs3819024) and incidence of AKI- CPB. There was an association between thers2275913 SNP and the severity of AKI. Conclusion: This study clarified that the rs2275913 SNP to some extent determines plasma IL-17 concentrations in CPB patients. No significant association was found between IL-17 levels or gene polymorphisms (rs2275913and rs3819024) and incidence of AKI-CPB. Our results suggest that there is an association between rs2275913 and the severity of AKI- CPB.

Background: Nowadays, the potential therapeutic role of various bioflavonoids including Curcumin, Luteolin and Resveratrol has currently been well-documented in a vast range of fatal complications including synaptic failure and cancers. These bioflavonoids are widely being implemented for the treatment of various cancers as they possess anti-cancerous, anti-oxidant and anti-inflammatory properties. Moreover, they are also used as a better alternative to conventional therapies since; these are non-toxic to cells and having no or least side effects. Notably, the pertinent therapeutic role of Rutin in cervical cancer is still unsettled however, its anti-cancerous role has already been reported in other cancers including prostate and colon cancer. Rutin (Vitamin P or Rutoside) is a polyphenolics flavonoid exhibiting multi-beneficial roles against several carcinomas. Objective: Despite the evidence for its several biological activities, the anticancer effects of Rutin on human cervical cancer (C33A) cells remain to be explored. In this study, the anticancer potential of Rutin was investigated by employing the key biomarkers such as nuclear condensation reactive oxygen species (ROS), apoptosis, and changes in mitochondrial membrane potential (MMP). Results: Our findings showed that Rutin treatment reduced the cell viability, induced significant increase in ROS production and nuclear condensation in dose-dependent manner. Moreover, Rutin provoked apoptosis by inducing decrease in MMP and activation of caspase-3. Cell cycle analysis further confirmed the efficacy of Rutin by showing cell cycle arrest at G0/G1 phase. Conclusion: Thus, our study is envisaged to open up interests for elucidating Rutin as an anticancerous agent against cervical cancer.

Background: Serum electrolytes, Creatinine, and thyroid profile play an important role in 131I treated patients of thyroid disorders. Objectives: To determine the effect of radioactive iodine (131I) on renal parameters, serum electrolytes and the correlation among TFT’S, creatinine, and chloride levels before and after I131 treatment in thyroid disorders. Methods: The study was performed on 55 patients of thyrotoxicosis with age ranging from 16-65 years (mean age= 41±14years and BMI=24.8±4.46). The significance of the differences between the results of 1st, 2nd, and 3rd-time serum analysis was assessed by paired Student's t-test. Association between parameters was assessed by Spearman correlation analysis. Results: 40 patients were taking Carbimazole, and 15 were directly recommended for I131 therapy. Strongly significant variations were observed for TFT’S (T3=0.012, T4 =0.017, and TSH=0. 001) during the follow-up treatment. Before taking I131 (Serum analyzed at 1st time), there observed negative correlation of T3(r=-.46, p=0. 002) and TSH (r=-0.31, p=0.02) with creatinine, and positive correlation of TSH(r=0.29,p=0.02) with chloride. BMI was negatively correlated with potassium(r=-0.30, p=0.02). At the 2nd time (after stopping the Carbimazole), no correlation results were observed. Two months after oral administration of ¹³¹I, creatinine, and chloride level was significantly increased (p=0.000), (P=0. 03) respectively, but had no correlation with TFT’S. Conclusion: Our findings suggest that patients with goiter (diffused or toxic) have association of TFT’S and BMI with serum electrolytes and creatinine, ¹³¹I therapy is also associated with the increase in creatinine and chloride levels of patients leading to kidney problems.

Background: Obesity, dyslipidemia and vitamin D deficiency are growing health problems in the Arabian Gulf region. Their association with each other is yet to be clarified. Methods: Three-hundred and fourteen Bahraini adults, 164 males and 150 females comparable in median age (34.5 vs. 31.0 yrs), body mass index (BMI), and ethnicity were recruited. The plasma level of 25-hydroxyvitamin D3 (25OHD3) was measured by chemiluminescent immunoassay and lipid profile parameters were measured by an automated clinical chemistry analyzer. Based on BMI, study subjects were grouped into underweight, normal, overweight, moderate obesity, and severe obesity subjects. Results: The results revealed an extremely high prevalence of vitamin D deficiency (79.9%) and insufficiency (18.8%). The predictors of low 25OHD3 levels were female gender, small age, conservative dressing, least exposure to sunlight, and less fish intake. In all subjects, the lowest 25OHD3 level was seen in underweight and severe obesity groups. Furthermore, the 25OHD3 level was significantly higher in males as compared to females and it was positively correlated with the age. However, detailed analysis showed that overweight males unlike females had the highest 25OHD3 levels which were significantly higher than in the severely obese males. While the lipid profile parameters were positively correlated with BMI, the total and LDL cholesterols were negatively correlated with the levels of 25OHD3 in males. Conclusion: Vitamin D deficiency was associated with both severely obese and underweight subjects, in the former it was likely to be institutional while in the latter it was likely to be nutritional. Furthermore, hypercholesterolemia (LDL-C) was associated with 25OHD3 sub-normality. Further analysis revealed that the significant associations were gender-dependent.

Background: Thyroid disorders may have a negative impact on the prognosis of patients affected by chronic heart failure (CHF). Objective: The aim of the current study was to evaluate the prognostic role of all thyroid disorders over a long term follow-up in a single centre large sample of CHF outpatients. Methods: In all patients, the function of the thyroid was evaluated at the enrolment and during the follow- up. On the basis of free triiodothyronine (T3), free thyroxine (fT4) and thyroid-stimulating hormone (TSH) serum levels, patients were classified into one of the following four categories: euthyroid subjects, patients affected by hypothyroidism, low T3 (LT3) syndrome and hyperthyroidism. During the follow-up, death for all causes was assessed as primary end-point, whereas time to the first hospitalization for heart failure worsening was the secondary end-point analyzed. Results: Among 762 patients, 190 patients were affected by hypothyroidism (Hypo). LT3 syndrome was diagnosed in 15 patients and 59 patients were affected by hyperthyroidism (Hyper). During a long term follow-up (5.1±3.7 years), 303 patients died. Patients with Hypo showed an increased risk of death as well as of hospitalization due to heart failure worsening at univariate regression analysis. At multivariate regression analysis, Hypo remained associated with hospitalization after correction for age >75 years, ischemic aetiology, diabetes, therapy with ACE-inhibitors or ARBs, therapy with betablockers and with aldosterone antagonists, NYHA class 3, systolic arterial pressure <95 mmHg, left ventricular ejection fraction <30%, estimated glomerular filtration rate <60 ml/min, hyponatremia and NTproBNP> 1000 pg/ml. At multivariate analysis, the independent association with death was significant only for the subgroup of patients with TSH >10 mIU/L. LT3 was independently associated with both heart failure hospitalization and death, whereas Hyper was not associated with any of the two considered end-points. Conclusion: Hypo is associated with a worse prognosis over a long-term follow-up. The association with heart failure hospitalization is not dependent on the baseline TSH levels, whereas the association with death is significant only when TSH >10 mIU/L. Finally, Hyper does not have any association with a worse prognosis.

Background: This study aimed to investigate the effects of guluronic acid (G2013) on blood sugar, insulin, and gene expression profile of oxLDL receptors (SR-A, CD36, LOX-1, and CD68) in the experimental model of diabetes. Methods: 18 Sprague Dawley rats were randomly assigned to three groups of healthy control, diabetic control, and G2013 group. Diabetes was induced through intraperitoneal (IP) injection of 60 mg/kg streptozotocin. The subjects were IP treated with 25 mg/kg of G2013 per day for 28 days. The body weight, food intake, fasting blood glucose and insulin were measured. In addition, the expression of mentioned genes was investigated through quantitative real-time PCR. Results: The data showed that the final weight increased significantly in the G2013-treated subjects compared to the diabetic control (p < 0.05). The results indicated that final food intake significantly reduced in the G2013-treated subjects compared to the diabetic control (p < 0.05). The study findings also suggested that the final fasting blood glucose significantly reduced in the G2013-treated group, whereas the final fasting serum insulin level significantly increased in this group compared to the diabetic control (p < 0.05). Moreover, the gene expression levels of SR-A, CD36, LOX-1, and CD68 in the G2013 group significantly reduced compared to the diabetic control (p < 0.05). Conclusion: This study showed that G2013, could reduce blood glucose and increase insulin levels and reduce the gene expression level of oxLDL receptors. In addition, it may probably play an important role in reducing the severity of diabetes-induced inflammatory symptoms.

Background: NGF deficiency is one of the reasons for reduced β-cells survival in diabetes. Our previous experiments revealed the ability of low-weight NGF mimetic, GK-2, to reduce hyperglycaemia in a model of advanced diabetes. The increase in DNA damage in advanced diabetes was repeatedly reported, while there were no data about DNA damage in the initial diabetes. Aim: The study aimed to establish whether DNA damage occurs in initial diabetes and whether GK-2 is able to overcome the damage. Methods: The early-stage diabetes was modelled in Balb/c mice by streptozotocin (STZ) (130 mg/kg, i.p.). GK-2 was administered at a dose of 0.5 mg/kg, i.p., subchronically. The evaluation of DNA damage was performed using the alkaline comet assay; the percentage of DNA in the tail (%TDNA) and the percentage of the atypical DNA comets (“ghost cells”) were determined. Results: STZ at this subthreshold dose produced a slight increase in glycemia and MDA. Meanwhile, pronounced DNA damage was observed, concerning mostly the percentage of “ghost cells” in the pancreas, the liver and kidneys. GK-2 attenuated the degree of hyperglycaemia and reduced the % of “ghost cells” and %TDNA in all the organs examined; this effect continued after discontinuation of the therapy. Conclusion: Early-stage diabetes is accompanied by DNA damage, manifested by the increase of “ghost cells” percentage. The severity of these changes significantly exceeds the degree of hyperglycaemia and MDA accumulation. GK-2 exerts an antihyperglycaemic effect and attenuates the degree of DNA damage. Our results indicate that the comet assay is a highly informative method for search of antidiabetic medicines.

Objective: The present study was designed to investigate the effects of renin angiotensin system (RAS) blockade on cardiac arrhythmias and sympathetic nerve remodelling in heart tissues of type 2 diabetic rats. Methods: Thirty-two male Sprague Dawley rats were randomly allocated into 4 equal groups; a) normal control group: normal rats, b) DM group; after type 2 diabetes induction, rats received 2ml oral saline daily for 4 weeks, c) DM+ ACEi: after type 2 diabetes induction, rats were treated with enalapril (10 mg/kg, orally for 4 weeks) and d) DM+ ARBs: after type 2 diabetes induction, rats were treated with losartan (30 mg/kg, orally for 4 weeks). Results: In type 2 diabetic rats, the results demonstrated significant prolongation in Q-T interval and elevation of blood sugar, HOMA-IR index, TC, TGs, LDL, serum CK-MB, myocardial damage, myocardial MDA, myocardial norepinephrine and tyrosine hydroxylase (TH) density with significant reduction in serum HDL, serum insulin and myocardial GSH and CAT. On the other hand, blockade of RAS at the level of either ACE by enalapril or angiotensin (Ag) receptors by losartan resulted in significant improvement in ECG parameters (Q-T), cardiac enzymes (CK-MB), cardiac morphology, myocardial oxidative stress (low MDA, high CAT and GSH) and myocardial TH density. Conclusion: RAS plays a role in the cardiac sympathetic nerve sprouting and cardiac arrhythmias induced by type 2 DM and its blockade might have a cardioprotective effect via attenuation of sympathetic nerve fibres remodelling, myocardial norepinephrine contents and oxidative stress.

Background/Objective: LPS-responsive beige-like anchor protein (LRBA) deficiency is a combined immunodeficiency and immune dysregulation. The authors present a case report of LPSresponsive beige-like anchor protein (LRBA) deficiency with the history of autoimmunity, enteropathy and visceral leishmaniasis. Sirolimus therapy was started for autoimmunity and enteropathy but was discontinued due to recurrent leishmaniasis. Therefore, a common side-effect of many immunosuppressive drugs in patients with LRBA deficiency is increased susceptibility to infections. Methods: Whole exome sequencing was performed to detect the underlying genetic mutation and Leishmania DNA was detected by the PCR technique in this patient. Results: Whole exome sequencing of the patient reported a homozygous frameshift deletion mutation in the LRBA gene (NM_006726: exon29: c.4638delC, p. S1546fs). Leishmania DNA PCR was positive in this case. Conclusion: Parasite infections manifestations report in LRBA deficiency. Leishmania infections in patients with chronic diarrhea and autoimmunity should be considered for immunodeficiency.

Introduction: Adrenocortical carcinoma (ACC) is a rare neoplasm characterized by a high risk of recurrence after radical resection. The role of adjuvant systemic therapy in radically resected patients is unclear. Mitotane, a steroidogenesis inhibitor, is the only drug approved for the systemic treatment of advanced ACC. In 2007, a retrospective case-control study provided the evidence that mitotane, administered for two years after successful surgery, could prolong recurrence-free survival. Adrenal insufficiency (AI), which occurs in almost all patients during the first 12 months of treatment, is an expected side effect of mitotane and requires steroid replacement therapy. Due to its long halflife, mitotane-induced AI persists several months after treatment discontinuation and is managed by cautious tapering of glucocorticoid replacement therapy. Results: We report a case of symptomatic AI diagnosed after a severe allergic reaction occurring three years after the discontinuation of adjuvant mitotane therapy. Conclusion: The case suggests that mitotane-induced AI should be monitored for a long time to asses full recovery of adrenal function, in order to prevent adrenal crises.