Endocrine, Metabolic & Immune Disorders-Drug Targets - Volume 20, Issue 2, 2020

Background and Objective: Primary immunodeficiency diseases (PIDs) are a group of more than 350 disorders affecting distinct components of the innate and adaptive immune systems. In this review, the classic and advanced stepwise approach towards the diagnosis of PIDs are simplified and explained in detail. Results: Susceptibility to recurrent infections is the main hallmark of almost all PIDs. However, noninfectious complications attributable to immune dysregulation presenting with lymphoproliferative and/or autoimmune disorders are not uncommon. Moreover, PIDs could be associated with misleading presentations including allergic manifestations, enteropathies, and malignancies. Conclusion: Timely diagnosis is the most essential element in improving outcome and reducing the morbidity and mortality in PIDs. This wouldn’t be possible unless the physicians keep the diagnosis of PID in mind and be sufficiently aware of the approach to these patients.

Background: Metformin is an oral hypoglycemic agent extensively used as first-line therapy for type 2 diabetes. It improves hyperglycemia by suppressing hepatic glucose production and increasing glucose uptake in muscles. Metformin improves insulin sensitivity and shows a beneficial effect on weight control. Besides its metabolic positive effects, Metformin has direct effects on inflammation and can have immunomodulatory and antineoplastic properties. Aim: The aim of this narrative review was to summarize the up-to-date evidence from the current literature about the metabolic and non-metabolic effects of Metformin. Methods: We reviewed the current literature dealing with different effects and properties of Metformin and current recommendations about the use of this drug. We identified keywords and MeSH terms in Pubmed and the terms Metformin and type 2 diabetes, type 1 diabetes, pregnancy, heart failure, PCOS, etc, were searched, selecting only significant original articles and review in English, in particular of the last five years. Conclusion: Even if many new effective hypoglycemic agents have been launched in the market in the last few years, Metformin would always keep a place in the treatment of type 2 diabetes and its comorbidities because of its multiple positive effects and low cost.

Background and Objectives: Regarding the development of diagnostic tests based on saliva and the prevalence of metabolic syndrome (MetS), the aim of this study is to review Persian Medicine manuscripts in the field of saliva manifestations, its relation to metabolic syndrome, and treatment recommendations. Methods: This study is a mini-review. We investigated the canon of medicine and some important Persian medical or pharmaceutical manuscripts from the 9th to the 19th centuries. PubMed and Google Scholar databases were explored for finding relevant information about the relationship between saliva and metabolic syndrome and its treatment. Results: Studies have suggested that maldigestion is one of the important causes of MetS. Sialorrhea may be an early symptom of maldigestion. Attention to sialorrhea and its treatment may be useful in the prevention and treatment of metabolic syndrome based on PM sources. In PM, sialorrhea is treated with 3 major approaches: lifestyle modification along with simple or compound medicines. Conclusion: Saliva manifestations could be considered as early symptoms of metabolic syndrome. As mentioned in WHO strategies, traditional medicine can be used along with modern medicine due to its effectiveness in the management of various ailments.

Background: The prevalence of allergic rhinitis in the world is 10-15%, and it is currently the most common chronic disease among children. There is no comprehensive statistics about the prevalence of allergic rhinitis among Iranian children, therefore, this systematic review and metaanalysis was conducted to evaluate the prevalence of allergic rhinitis among the Iranian children. Methods: The present study was conducted based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. The data was collected using key words including allergic rhinitis, prevalence, epidemiology, child OR children, pediatrics and Iran, in international databases including PubMed, Scopus, Web of Science, Cochrane, Embase, and three national databases including Magiran, Iran Medex, and Scientific Information Databank (SID) till December 2018. The STROBE checklist was used for quality assessment. The data were analyzed using STATA software version 12.1. Results: The prevalence of allergic rhinitis in children and adolescents were 18% (99.7% CI: 10-28% with publication bias of 0.174) and 25% (99.8% CI: 17-33 with publication bias of 0.617) respectively. The prevalence of allergic rhinitis in males was estimated to be 27% (99.4% CI: 17-36) with publication bias of 0.538 and in females was 23% (99.4% CI: 14-31) with publication bias of 0.926. Conclusion: The prevalence of allergic rhinitis is approximately high among Iranian children and adolescents; thus, educational strategies should be considered to decrease the prevalence of this disease in Iran.

Background and Aim: Recent data have shown that olfactory dysfunction is strongly related to Alzheimer’s Disease (AD) that is often preceded by olfactory deficits suggesting that olfactory dysfunction might represent an early indicator of future cognitive in prediabetes. Methods: We have applied to a group of normal (n=15), prediabetic (n=16) and type 2 diabetic outpatients (n=15) olfactory testing, 1.5-T MRI scanner and detailed cognitive evaluation including the standard Mini-Mental State Examination (MMSE) form, Short Blessed Test (SBT), Letter Fluency Test (LFT) and the category fluency test with animal, Fruit and Vegetable Naming (CFT). Results: We have shown that Odour Threshold (OT), Discrimination (OD), and Identification (OI) scores and most cognitive test results were significantly different in the prediabetes and diabetes group compared to those in the control group. OD and OT were significantly different between the prediabetes and diabetes group, although the cognitive test results were only significantly different in the prediabetes and diabetes group compared to those in the control group. In evaluating the association between OI, OT, OD scores and specific cognitive tests, we have found, that impaired olfactory identification was the only parameter that correlated significantly with the SBT both in the pre-diabetes and diabetes group. Although spot glucose values were only correlated with OT, HbA1c levels were correlated with OT, OD, and OI, as well as results of the letter fluency test suggesting that HbA1c levels rather than the spot glucose values play a critical role in specific cognitive dysfunction. Conclusion: To the best of our knowledge, this is the first prospective study to demonstrate a strong association between olfactory dysfunction and specific memory impairment in a population with prediabetes and diabetes suggesting that impaired olfactory identification might play an important role as a specific predictor of memory decline.

Background: Hypoxic ischemic encephalopathy (HIE) is a serious condition which results in neonatal morbidity and mortality. Early prediction of HIE especially in the first six hours of birth leads to early treatment with better prognosis. Aim: The aim of this study was to compare the concentrations of leptin, adiponectin, and erythropoietin between normal neonates and those with HIE for the possible use of these markers for assessment of the degree of HIE and as markers for early prediction of HIE. Patients and Methods: This study was carried out on 50 appropriate for gestational age (AGA) neonates with HIE born in Tanta University Hospital during the period from June 2016 to March 2018 (Group I). This study also included 50 appropriate for gestational age (AGA) normal neonates not suffering from any complications and matched with group I in age and sex as a control group (Group II). For all neonates in both groups, the following were done: Complete prenatal, natal, and postnatal history, assessment of APGAR score at 5 and 10 minutes, complete clinical examination with special account on clinical evidence of encephalopathy including hypotonia, abnormal oculomotor or pupillary movements, weak or absent suckling, apnea, hyperpnea, or seizures, measurement of cord blood gases and measurement of serum erythropoietin, leptin and adiponectin levels by ELISA immediately after birth. Results: There were no significant differences between Group I and Group II regarding gestational age, male to female ratio, mode of delivery, and weight while there were significant differences regarding Apgar score at 1 and 5 minutes with significantly lower Apgar score at 1 and 5 minutes in group I compared with Group II. There were significantly lower cord blood PH and adiponectin level and significantly higher cord blood Leptin and erythropoietin in group I compared with group II. There were significant differences between cord blood adiponectin, leptin, erythropoietin, and PH in different degrees of HIE with significantly lower cord blood adiponectin and PH and significantly higher cord blood leptin and erythropoietin in severe degree of hypoxia compared with moderate degree and in moderate degree compared with mild degree of hypoxia. There was a significant positive correlation between cord blood erythropoietin and leptin and a significant negative correlation between cord blood erythropoietin and both adiponectin and PH in studied neonates with hypoxia. ROC curve showed that EPO had the best sensitivity and specificity followed by leptin then adiponectin while the PH had the least sensitivity and specificity as early predictors of hypoxic neonates. Conclusion and Recommendations: Neonates with HIE had lower cord blood PH and adiponectin levels and higher leptin and erythropoietin levels than normal healthy neonates at birth and during the early postnatal period. The significant differences between cord blood erythropoietin, leptin, and adiponectin between neonates with hypoxia compared with normal neonates may arouse our attention about the use of these markers in the cord blood as early predictors of neonatal HIE which can lead early treatment and subsequently better prognosis.

Objective: Immune thrombocytopenia (ITP) is an acquired immuno-mediated disorder characterized by thrombocytopenia with an increased risk of bleeding. In recent years 1,25[OH]2D3 has been rediscovered as an immune modulator. We decided to evaluate serum Vitamin D levels in a cohort of children with immune thrombocytopenia in order to discover if Vitamin D concentrations may predict ITP duration. Methods: Thirty children were enrolled in this study (sixteen with chronic ITP and fourteen with newly diagnosed ITP) to assess serum Vitamin D levels. Results: The results showed that 80% of the enrolled children presented a D hypovitaminosis status. Children with newly diagnosis ITP showed no statistically significantly higher median values of Vitamin D compared to chronic ITP. Conclusion: This study may suggest that Vitamin D deficiency does not represent a chronicity factor for ITP. However, further studies are needed to understand the role of Vitamin D in ITP pathogenesis.

Background: Dyslipidemia is recognized as an important factor in the incidence of Preterm Birth (PTB). The early diagnosis of factors affecting PTB is important in the reduction of maternalneonatal complications; therefore, we aimed to evaluate the association between dyslipidemia and PTB in women from the Guilan province of Iran. Methods: The current investigation was a prospective cohort study on 378 pregnant women in Rasht city (Guilan province), during 2018-2019. Samples were randomly selected among pregnant women who referred to Al-Zahra hospital. Association of the lipid profiles: Total Cholesterol (TC), High- Density Lipoprotein (HDLC), Low-Density Lipoprotein (LDLC), and Triglycerides (TG) with PTB was assessed using the Chi-square, Fisher tests and logistic regression analysis. Results: Our findings showed that of the evaluated lipid profiles, TG and TC had the highest predictive power with AUC =0.833 (95, CI: 0.736-0.930) and 0.772 (95%, CI: 0.676-0.867), respectively; also, their sensitivity and specificity were 83.3%, 70.2% and 83.3%, 66.1%, respectively. Moreover, abnormal LDL concentrations increase the risk of PTB by two folds (P < 0.05). Conclusion: It seems that by controlling the lipid profiles of pregnant women, the risk of PTB could be reduced.

Objective: The aim of this study was to investigate the association of Sex Hormone Binding Globulin (SHBG) with leptin, Triidothyronine (T3), and Uncoupling Protein 2 (UCP2) in obese women with low and normal Resting Energy Expenditure (REE) and to determine the role of these factors in the regulation of REE in obese women. Method: A total 49 subjects (25-50 years old) were selected. Anthropometric and body composition parameters and resting energy expenditure were measured. Fasting circulating leptin, T3, SHBG and UCP2 levels were measured. Subjects were divided into three groups: Group I (BMI>30 and low resting energy expenditure, 16 subjects), group II (BMI>30 and normal resting energy expenditure, 17 subjects), and group III (control group, 16 non-obese subjects). Result: It was found that obese subjects who had higher SHBG and leptin levels were at risk for high levels of UCP2. A significant association was found between T3 and REE. Obese subjects with higher concentrations of UCP2 and SHBG had decreased resting energy expenditure. A significant association was observed between SHBG and leptin in group I (r=0.90, p<0.0001) and group II (r=0.83, p<0.0001). Moreover, a significant association was found between T3 and SHBG in group I (r=-0.69, P=0.003). Conclusion: Changes of the UCP2, leptin, and thyroid hormone (T3) levels may be related to SHBG levels. Thus, lower leptin and T3 levels may decrease SHBG in obese women. Therefore, lower SHBG, leptin, T3 and UCP2 levels may decrease the REE level in obese women.

Background: Obesity is a global epidemic which is associated with several cardiometabolic comorbidities and is characterized by chronic, low grade systemic inflammation. Numerous biomarkers have been implicated in the pathophysiology of the disease, including transcription factors and coregulators. Steroid Receptor Coactivator (SRC)-family represent the master regulators of metabolic pathways and their dysregulation is strongly associated with numerous metabolic disorders. Methods: 50 morbidly obese patients participated in the present study. Biopsies were collected from visceral adipose tissue, subcutaneous adipose tissue, skeletal muscle, extra-myocellular adipose tissue and liver. We evaluated the differential protein expression of NFATc1, SRC-2/TIF-2, SRC-3/AIB-1 and inflammatory biomarkers CD68 and CD3 by immunohistochemistry. The current study was designed to determine any correlations between the transcription factor NFATc1 and the SRC coregulators, as well as any associations with the inflammatory biomarkers. Results: We identified SRC-3 as a hepatic NFATc1 coactivator and we demonstrated its possible role in energy homeostasis and lipid metabolism. Moreover, we revealed a complex and extensive intraand inter-tissue network among the three main investigated proteins and the inflammatory biomarkers, suggesting their potential participation in the obesity-induced inflammatory cascade. Conclusion: Steroid receptor coactivators are critical regulators of human metabolism with pleiotropic and tissue-specific actions. We believe that our study will contribute to the better understanding of the complex multi-tissue interactions that are disrupted in obesity and can therefore lead to numerous cardiometabolic diseases. Further on, our present findings suggest that SRC-3/AIB-1 could constitute possible future drug targets.

Background: CYP2C19 a metabolizing enzyme and Heat Shock Proteins (HSP) are induced in stress conditions, such as hypoxia and ischemia. Recently, polymorphism in the CYP2C19 and HSP genes has been established in Aspirin-Exacerbated Respiratory Disease (AERD). Objective: We investigated the polymorphism of these two genes in Kurdish patients with AERD. Methods: This study involved 306 subjects, referred to the Be’sat hospital in Kurdistan Province, which were divided into three groups, (i) Aspirin Induced Asthma (AIA), (ii) Aspirin Tolerant Asthma (ATA), and (iii) healthy subjects as control. The subjects as control and ATA\AIA groups were verified by the physician. The demographic data of each subject with respect to age, sex, parental education, and residence was collected. Spirometry was performed on subjects and blood samples were collected for serum Immunoglobulin E (IgE) estimation and molecular tests. Genotyping was done for CYP2C19 681G>A#140; CYP2C19 636G>A, and HSPA1B1267A>G by using PCR- Restriction Fragment Length Polymorphism (RFLP) and for HSPA1B-179C>T by High Resolution Melting (HRM). Results: Demographic statistics were not significantly different between the three groups (p>0.05). Further, genotypes were also not observed to be significantly different in the genes of CYP2C19 681G>A, CYP2C19 636G>A and HSPA1B1267A>G (p>0.05). However, the heterozygote genotype in HSPA1B-179 C>T in AIA group was higher than the control group (p<0.05). Notably, 92.8 % of the subjects showed heterozygote genotype in HSPA1B1267 A>G. In clinical tests, FEV-1, FVC, and asthma severity in the AIA group were higher than control and additionally IgE levels were lower in this group (p<0.05). Conclusion: The results confirm the association of polymorphism in the HSPA1B-179C>T and HSPA1B1267A>G with AERD in the Kurdish population.

Background: The knowledge of the pathophysiology of Lysosomal Storage Disorders has gradually increased, but information on their incidence is still scarce. The objective of this study was to evaluate the status and use of resources of these disorders in Spain from 1997 to 2015. Methods: Records from 4,999 patients diagnosed with a Lysosomal Storage Disorder were extracted from a Spanish database containing data from public and private hospitals from 1997 to 2015. Results: The database registered 2,441 patients with an LSD in Spain during the study period. Leukodystrophy, Krabbe disease, Pelizaeus-Merzbacher disease and sulfatide lipidosis represented, as a group, the most common combination of diseases in Spain, affecting 26% of total patients. The average age of diagnosis of these disorders was 16.7 years. A sex bias was observed in most of the groups, with a proportion of male/female of 60 to 40%. The direct medical cost of Lysosomal Storage Diseases was 5,686 per patient with an average cost per hospital admission of 4,923. Global costs displayed a growing tendency. Conclusion: Contrary to worldwide disease incidence estimations, the group with Krabbe disease registered the highest number of patients in the study period, which makes evident the need for accurate regional disease incidence and patient demographic studies. Altogether, data suggest the need to improve LSDs diagnostic protocols, and support the inclusion of these disorders in standard newborn screening programs.

Background: Numerous investigations demonstrate efflux as a worldwide bacterial mode of action which contributes to the resistance of drugs. The activity of antibiotics, which subjects to efflux, can be improved by the combined usage of efflux inhibitors. However, the efflux role to the overall levels of antibiotic resistance of clinical M. tuberculosis isolates is inadequately comprehended and is still disregarded by many. Methods: Here, we assessed the contribution of resistant genes associated with isoniazid (INH) and rifampin (R) resistance to the levels of drug resistance in the (27) clinical isolates of MDR-TB. Additionally, the role of the resistance for six putative drug efflux pump genes to the antibiotics was investigated. The level of katG expression was down-regulated in 24/27 (88.88%) of MDR-TB isolates. Of the 27 MDR-TB isolates, inhA, oxyR-ahpC, and rpoB showed either overexpression or up-regulation in 8 (29.62%), 4 (14.81 %), and 24 (88.88%), respectively. Moreover, the efflux pump genes drrA, drrB, efpA, Rv2459, Rv1634, and Rv1250 were overexpressed under INH/RIF plus fresh pomegranate juice (FPJ) stress signifying the efflux pumps contribution to the overall levels of the resistance of MDR-TB isolates. Conclusion: These results displayed that the levels of drug resistance of MDR-TB clinical isolates are due to combination among drug efflux pump and the presence of mutations in target genes, a truth which is often ignored by the specialists of tuberculosis in favour of the almost undoubted significance of drug target- gene mutations for the resistance in M. tuberculosis.

Background: Thyroid gland is a probable goal tissue for radiation-related injury. Occupational exposure to ionizing radiation leads to thyroid dysfunction and exposure to high dose may lead to thyroid carcinoma. Objective: Evaluation of the role of Thyroid peroxidase antibody as a predictor for thyroid dysfunction among nurses and technicians in the radiology department in Mansoura Specialized Medical hospital (MSMH). Subjects and Methods: Subjects were Nurses and technicians who are working in (MSMH) with persistent daily duty in the last 3 years and fulfilling the inclusion and exclusion criteria. All subjects included in the study were recruited in one month and divided into two groups; Group 1: 50 subjects who were working in radiology, coronary angiography and ERCP unit, Radiation -exposed group. Group 2: 33 subjects who were working in In-patient departments and in out- patient clinics and not exposed to any type of radiation. Non fasting blood sample was taken from all enrolled subjects for measurement of TSH and Anti-TPO. Results: TPO was positively and significantly correlated to age, TSH, duration of radiology/ y (r=0.388, 0.364, 0.342respectively) p value <0.05. Roc curve was done to detect the sensitivity and specificity of TSH in relation to TPO that revealed the cutoff value of TSH > 1.69 with Sensitivity and Specificity. PPV, NPV and accuracy at cutoff >1.69 were 70.6%, 51.5%, 42.8%, 77.3% and 58%. Conclusion: Working personnel with positive anti TPO and their TSH levels are more than 1.69 associated with symptoms of hypothyroidism, a trial of treatment is mandatory to relieve symptoms.

Introduction: Medullary thyroid carcinoma (MTC) is an infrequent thyroid malignancy rarely observed and managed during pregnancy. An accurate diagnostic workup is extremely important in this clinical setting to correctly diagnose and treat the disease, avoiding both maternal and fetal complications. Objective: We report our experience in managing an MTC incidentally diagnosed during pregnancy in a 28-year female, highlighting critical aspects through the diagnostic workup. Additionally, we provide a literature revision searching on PubMed terms related to “medullary thyroid carcinoma”, “primary thyroid paraganglioma”, “paraganglioma-like medullary thyroid cancer” in relationship with a nodular appearance at neck US, serum CT measurement, cytological and histological findings. Methods: Specimens for cytological evaluation were stained with the Papanicolaou method while tissue sections were stained with hematoxylin and eosin and Congo red stain. Immunohistochemical evaluation was also performed for thyroid transcription factor-1, enolase, thyroglobulin, cytokeratin, chromogranin A, S-100 protein, glial fibrillary acidic protein, calcitonin and Ki-67. Results: Serum CT was incidentally found to be elevated in two consecutive venous samples. However, the cytological assessment of the fine needle aspiration (FNAc) showed “cells with round-shaped nuclei and granular chromatin, organized to form nests or syncytial flaps, scattered among histocytes, and immunocytochemical positivity for CT, thyroid transcriptional factor-1, cytokeratin, S-100 protein”, highlighting a suspicion of both MTC and intrathyroidal paraganglioma. MTC was finally supposed after the evidence of a really elevated CT (3,726 pg/ml) measurement in the FNA washout fluid. After a careful discussion about both risks and benefits, the patient decided to postpone the surgery after the delivery. Conclusion: The histological diagnosis finally confirmed a rare case of paraganglioma-like MTC (T1 N0 Mx), emphasizing the complexity of our differential diagnosis, between an MTC and a thyroidal paraganglioma. In similar cases, due to a relevant impact on surgical timing, patients should be adequately informed about both risk and benefits of the surgery during pregnancy, and a careful management of the disease is required until and after surgery.