Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 21, Issue 11, 2021

COVID-19 (Virus named as severe acute respiratory syndrome coronavirus 2 (SARS-- CoV-2)) is a pandemic disease characterized by respiratory infection caused by a coronavirus. It has spread worldwide after an outbreak began in Wuhan, China, in December 2019. SARS-CoV-2 has infected more than 15 million people globally. The disease severity and mortality increased in patients with heart-related comorbidities. Cardiovascular disease patients are more susceptible and infected with SARS-CoV-2. Early screening and management of these patients prevent or ameliorate adverse outcomes. Several treatments have been used to combat these effects, as previously seen in MERS and SARS. This review will cover the association of cardiovascular diseases with COVID 19. It showed that cardiovascular diseases are common in patients with COVID- 19. Increased attention to highlight the gaps should be paid to the care of this unique group of patients.

Background: Thyroid disease and obesity are widespread clinical conditions in the population. They can occur together in the same subject, but their relationship does not seem exclusively stochastic. Aim: Literature was critically reviewed to explain the association between thyroid disease and obesity and to understand the possible benefits of levothyroxine therapy in euthyroid obese patients. Results: A low energy expenditure rate can lead to obesity. Maintaining Basal Metabolic Rate (BMR) is the leading cause of energy expenditure in the body, which is regulated by thermogenesis. Thyroid hormone receptors (TR) play different roles in the induction of thermogenetic mechanisms; TRα is fundamental to induce thermogenesis, and TRβ triggers the expression of uncoupling protein 1(UCP1). Despite such mechanisms, there is no current evidence related to the treatment of subjects suffering from obesity with thyroid hormones. Conclusion: Replacement therapy should be reserved only for patients with clear signs of subclinical or clinical hypothyroidism. Definitions: Basal metabolic rate (BMR) or basal energy expenditure (BEE): measurement obtained under total inactivity and controlled research conditions; resting energy expenditure (REE): measurement obtained when an individual is sitting quietly (is mildly higher than BMR/BEE)

Background: Plants have been regarded as essential source of food for human beings, as confirmed by archeological studies that have revealed the presence of proteins from cereals and legumes on old pottery. Specific Aims: In this review, major health effects derived from the consumption of plant fibers, polyunsaturated fatty acids (PUFAs) and polyphenols, respectively, will be described with special emphasis on their mechanisms of action, both at cellular and molecular levels. Dietary Compounds: Fibers exhibit a prevalent prebiotic effect, acting on the intestinal microbiota with the production of protective metabolites, such as short chain fatty acids. Plant PUFAs include α-linolenic and stearidonic acids, which are the precursors of other two major PUFAs, namely, eicosapentaenoic and docosahexaenoic acids. Some clinical trials demonstrated the ability of PUFAs to lower the risk of coronary disease, while other trials did not confirm such a finding. Polyphenols are endowed with anti-oxidant and anti-inflammatory activity in view of their property to inhibit NF-ΚB activation, to induce the anti-inflammatory T regulatory cells and to normalize the intestinal microbiota. The beneficial effects of polyphenols on obesity/diabetes, allergic/autoimmune and inflammatory disease are elucidated. Conclusion: Plants are one of the major sources of healthy dietary products, whose exploitation may promote prevention of chronic disease.

Medicinal plants have been used in the indigenous system of medicine for the treatment of numerous human health complications. Medicinal plants were used for the separation and isolation of pure phytochemical and some of the best examples are tubocurarine, aspirin, morphine, digoxin, atropine, quinine and reserpine. Phytoconstituents are pure, plant-derived, natural chemicals found to be present in medicinal plants and examples are flavonoids, alkaloids and phenolic compounds, etc. In modern medicine, there has been a global growth of herbal medicines due to their nutrition, physical effectiveness and pharmacological activities. Plants have been used in the traditional medicines and modern drug discoveries program. In order to investigate the biological potential of poncirin in modern medicine, here, different scientific data have been analyzed in the present investigation through various literature sources. Detailed pharmacological activities of poncirin were also investigated in the present investigation to reveal the medicinal properties of poncirin in medicine and other allied health sectors. Analytical techniques used for the isolation of poncirin from various medicinal plants have been also presented in this study. Poncirin is a flavanone glycoside found to be present in the Poncirus trifoliata and Citrus reticulate having a bitter taste. The biological importance of poncirin for their anti-inflammatory activity through inhibition of PGE2 and IL-6 production has been investigated in the scientific field. The biological importance of poncirin against bacterial, viral infections, gastric disease and human gastric cancer has been investigated in medicine. Pharmacological data analysis revealed the biological application of poncirin against bone loss, inflammation, colitis, human gastric cancer, gastritis, liver injury and Alzheimer's disease. From the analysis of the presented scientific information of poncirin, it was found that poncirin has significant biological activities and health benefits in the modern health sectors for the treatment of human health complications and could be used as a drug in the future.

Background: Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) (COVID-19) infection provokes serious clinical consequences, which in many situations need hospitalization of the patient in Intensive Care Unit. Additionally, SARS-COV-2 infection can indirectly cause deaths in aged individuals as well as in patients with co-morbidities. Objective: To evaluate the effects of nutrition during the COVID-19 pandemic in both hospitalized patients and the general population. Methods: Authors searched Medline (PubMed), Web of Science, EMBASE, Cochrane Library, Google, and Institutional websites for medical subheadings terms and free full text referred to “SARS-CoV-2”, COVID-19”, “nutrition”, “immune system”, before 31st July 2020. Results: A total of 20 articles describing different nutritional interventions for patients with SARS-- CoV-2 infection focusing on the general population have been included. Of these, 6 studies are dealing with nutritional interventions for patients with SARS-CoV2 infection. The others are focalized on a potential beneficial effect exerted by a Mediterranean diet (MD), related to the supplementation of micronutrients and vitamins. Conclusion: A correct lifestyle, including the consumption of nutrients largely present in MD, may be beneficial for preventing or improving prognosis in the SARS-CoV-2 infection.

Background: Antinuclear antibody (ANA) and Antineutrophil autoantibodies (ANCA) are often used as markers for the diagnosis of autoimmune diseases. In clinical practice, we have found that ANA and ANCA often occur in sera of patients with hyperthyroidism. Objective: The study aimed to discover the positive features of anti-nuclear antibodies (ANA) and anti-neutrophil cytoplasmic antibodies (ANCA) in hyperthyroidism. Materials and Methods: In sera samples from 171 patients with hyperthyroidism and 50 healthy controls, ANA and ANCA were detected with indirect immunofluorescence (IIF) method. Results: ANA and ANCA positive rates were higher in hyperthyroidism (33.9% and 29.2%, respectively) than those in control (4.0% and 2.0%, respectively); the low titer (≤1:320)of ANA was dominated (86.2%) in 58 hyperthyroidism patients with positive ANA, the major pattern involved homogeneous (48.3%) and speckled patterns (48.3%). The low titer (≤1:32) of ANCA was dominated( 64.6%) in 50ANCA positive samples and the major pattern was perinuclear (p) ANCA (96%). Conclusion: The positive rates of ANA and ANCA were increased and mainly appeared of low titer in hyperthyroidism, which supplement the laboratory characteristics of hyperthyroidism.

Background: Polycystic ovary syndrome (PCOS) is the most frequent endocrine disorder affecting 6–7% of premenopausal women. Recent studies revealed that the immune system, especially CD4+ T helper cells are important in the context PCOS. Proteome analysis of CD4+ T lymphocytes can provide valuable information regarding the biology of these cells in the context of PCOS. Objective: To investigate immune dysregulation in CD4+ T lymphocytes at the protein level in the context of PCOS using two-dimensional gel electrophoresis (2DE) and mass spectrometry (MS). Methods: In the present study, we applied two-dimensional gel electrophoresis / mass spectrometry to identify proteins differentially expressed by peripheral blood CD4+ T cells in ten PCOS women compared with ten healthy women. Western blot technique was used to confirm the identified proteins. Results: Despite the overall proteome similarities, there were significant differences in the expression of seven spots between the two groups (P <0.05). Three proteins, namely phosphatidylethanolaminebinding protein 1, proteasome activator complex subunit 1 and triosephosphate isomerase 1 were successfully identified by Mass technique and confirmed by western blot. All characterized proteins were over-expressed in CD4+ T cells from patients compared to CD4+ T cells from controls (P <0.05). Insilico analysis suggested that the over-expressed proteins interact with other proteins involved in cellular metabolism, especially glycolysis and ferroptosis pathway. Conclusion: These findings suggest that metabolic adjustments in CD4+ T lymphocytes, which is in favor of increased glycolysis and Th2 differentiation are important in the context of PCOS.

Background: Type 1-diabetes (T1D) is characterized by autoimmune destruction of β-cells and loss of endogenous insulin. A lifelong dependency on exogenous supply of insulin presents a great challenge in the pharmacotherapy of T1D that elicits a quest for alternative therapies, which can protect β-cells and revive their insulinogenic functions. GABA (γ-aminobutyric acid) has immunoprotective and β-cell regenerative capabilities. Co-administration of an insulin secretagogue, such as glibenclamide (Glib), along with GABA may enhance the pancreatic insulin output in T1D. Objective: The present study evaluated the possible mechanism of GABA in the improvement of glucose tolerance and its effects in streptozotocin (STZ) induced T1D along with Glib. Methods: Wistar rats (180-220 g) were administered a single dose of STZ (55 mg/kg, i.p.). GABA (100 mg/kg, i.p.) and Glib (5 or 10 mg/kg, i.p.) alone or in combination were administered for 28 days. Body weight (b.w.), water consumption, fasting blood glucose (FBG), oral glucose tolerance, plasma lipids, insulin, and muscle GLUT-4 (glucose transporters) protein level were assessed. Results: T1D significantly decreased b.w. and increased water-intake in rats. An increase in FBG and a decrease in plasma insulin and muscle GLUT-4 indicated STZ-triggered destruction of β-cells in diabetic rats accompanied with dyslipidemia. GABA or Glib (10 mg/kg) significantly improved b.w., plasma insulin and GLUT-4 levels, and ameliorated FBG and blood lipid profile in diabetic rats. GABA and Glib (5 mg/kg) combination therapy achieved far better control over hyperglycemia and related pathogenic conditions (b.w., water-intake, insulin, GLUT-4, lipids). The anti-diabetic effect of combination therapy was significantly more pronounced in comparison to individual drug treatments. Histopathological analysis revealed an increase in the number of functional pancreatic-islets by combination therapy. Conclusion: GABA revitalized β-cells against STZ-toxicity. GABA and Glib synergistically augmented insulin secretion that can be used to manage T1D and its complications. GABA has the potential to remarkably enhance the therapeutic outcome in diabetic patients and reduce the dose of existing anti-diabetic drugs such as Glib.

Objective: Diabetic cardiomyopathy (DCM) is an important complication of diabetes. This study was attempted to discover the effects of long noncoding RNA OIP5-AS1 (OIP5-AS1) on the viability and oxidative stress of cardiomyocyte in DCM. Methods: The expression of OIP5-AS1 and microRNA-34a (miR-34a) in DCM was detected by qRT-PCR. In vitro, DCM was simulated by high glucose (HG, 30 mM) treatment in H9c2 cells. The viability of HG (30 mM)-treated H9c2 cells was examined by MTT assay. The reactive oxygen species (ROS), superoxide dismutase (SOD) and malondialdehyde (MDA) levels were used to evaluate the oxidative stress of HG (30 mM)-treated H9c2 cells. Dual-luciferase reporter assay was used to confirm the interactions among OIP5-AS1, miR-34a and SIRT1. Western blot was applied to analyze the protein expression of SIRT1. Results: The expression of OIP5-AS1 was down-regulated in DCM, but miR-34a was up-regulated. The functional experiment stated that OIP5-AS1 overexpression increased the viability and SOD level while decreased the ROS and MDA levels in HG (30 mM)-treated H9c2 cells. The mechanical experiment confirmed that OIP5-AS1 and SIRT1 were both targeted by miR-34a with the complementary binding sites at 3′UTR. MiR-34a overexpression inhibited the protein expression of SIRT1. In the feedback experiments, miR-34a overexpression or SIRT1 inhibition weakened the promoting effect on viability and mitigated the reduction effect on oxidative stress caused by OIP5-AS1 overexpression in HG (30 mM)-treated H9c2 cells. Conclusion: OIP5-AS1 overexpression enhanced viability and attenuated oxidative stress of cardiomyocyte via regulating miR-34a/SIRT1 axis in DCM, providing a new therapeutic target for DCM.

Background: The existence of a link between Graves’ Disease (GD) and Thyroid Cancer (TC) has long been investigated, however a clear pathogenic correlation is yet to be found. Objective: We verified the presence of TC in patients submitted to surgery for GD, both with and without thyroid nodules (TN). Methods: In this study we analyzed retrospectively a cohort of 151 patients treated at our clinic with total thyroidectomy between 2013 and 2018. All the patients were symptomatic at the time of surgery, preoperatively ultrasonographic (US) study was performed to evaluate the presence of nodules and their distribution. All patients reached euthyroid state before surgery. Results: Nodules were detected in 53% of cases, above 60 years of age, at least one nodule was found; however, younger patients were mostly nodules free. Bilateral diffusion of nodules appeared with increasing age. Cancer was found in 19 of 151 subjects (12.5%), all were papillary carcinomas, and among them 93% were microcarcinomas. Among cancer-proven patients, 14 had thyroid nodules while 5 were nodule-free. During the follow up period, no cancer recurrence was recorded. The most common complication after surgery was transient hypocalcemia (36%). Conclusions: Graves’ patients are burdened by major incidence of TC in the context of their TN. Pre-operative assessment in GD patients should consider the risk of cancer, US scan can help in rapid evaluation of nodules and new rising frontiers in molecular biomarkers analysis may help defining pathogenic basis of Graves’ neoplastic development.

Objective: Achillea fragrantissima L. (Asteraceae) is a traditionally used medicinal herb in the rural communities of Jordan. Methods: The present study evaluated the efficacy of the ethanol extract of this species on angiogenesis in both, ex vivo using a rat aortic ring assay and in vivo using a rat excision wound model. Results: In concentrations of 50 and 100 μg/ml, the ethanol extract showed angiogenic stimulatory effect and significantly increased length of capillary protrusions around aorta rings of about 60% in comparison to those of untreated aorta rings. In MCF-7 cells, the ethanol extract of A. fragrantissima stimulated the production of VEGF in a dose-dependent manner. 1% and 5% of ethanol extract of A. fragrantissima containing vaseline based ointment was applied on rat excision wounds for six days and found to be effective in wound healing and maturation of the scar. Both preparations resulted in better wound healing when compared to the untreated control group and vaseline- treated group. This effect was comparable to that induced by MEBO, the positive control. Conclusion: The results indicate that A. fragrantissima has a pro-angiogenic effect, which may act through the VEGF signaling pathway.

Background: Atorvastatin (ATOR) is widely used for the treatment and prevention of hypercholesterolemia and various diseases, such as cardiovascular complications, with little data about the histopathological and ultrastructural renal alterations that might be induced by this drug. Objectives: The present study was undertaken to investigate the potential toxicity of therapeutic doses of atorvastatin on the microanatomy and ultrastructure of renal tissues from Wistar albino rats. Methods: Adult male Wistar albino rats received an oral daily dose of 5 mg/kg bodyweight for 90 consecutive days. Biopsies from both kidneys of each study rat were taken for histopathological and ultrastructural examination. Results: ATOR-treated rats exhibited glomerular, tubular, and interstitial histological alterations, including degeneration, necrosis, hyaline droplets, edema, cortical hemorrhages, mesangial hypercellularity, and blood capillary dilation and congestion. In addition, ATOR exposure increased the activity of glucose-6-phosphate dehydrogenase and alkaline phosphatase with a concurrent reduction in proteins and neutral mucosubstances content of the glomeruli and renal cells. Moreover, ATOR-treated animals demonstrated glomerular ultrastructural alterations, consisting mainly of capillary tuft dilatation, glomerular basement membrane thickening, and mesangial cell proliferation. The renal cells of the proximal tubules demonstrated damaged mitochondria, degenerative cellular changes, endoplasmic reticulum dilatation, lysosomal and autophagosome activation, nuclear alteration, myelin figure formation, and microvilli disorganization. Conclusion: The findings of the present work may indicate that ATOR can induce renal histological, histochemical, and ultrastructural alterations that may affect kidney and other vital organ functions.

Background: Interleukin (IL)-6, total antioxidant capacity (TAC) and uric acid (UA) increase after exercise in able-bodied individuals. Wheelchair Basketball Athletes (WBA), having low muscle mass, could be at risk of post-exercise ketosis. Objective: This study aimed to evaluate the post-exercise ketosis, IL-6, and antioxidant response, in WBA of the Italian National team, after a simulated match. Methods: Dietary intakes, Starvation Symptoms Inventory (SSI), percentage of fat mass (FM%) and basal Respiratory Exchange Ratio (RER) and Basal Energy Expenditure (BEE), were evaluated. Salivary TAC, UA and IL-6 were measured: before (PreM), at the end (EM) and 20 minutes after (PostM) the match. Capillary glucose and β-hydroxybutyrate (βHB) were monitored. Percentage of Heart Rate Reserve (%HRR) was measured to evaluate exercise intensity. Results: WBA had low carbohydrates (43.5% of daily energy intake (En)) and high fat (36.3% En) intakes. The increase in UA at PostM correlated with En (0.810, p<0.01) and was inversely related to βHB at EM (-0.719, p<0.05). Furthermore, at PostM growing IL-6 levels correlated with BEE (0.778, p<0.05) and inversely related to FM% (-0.762, p<0.5) were found, which in turn was correlated to SSI (0.781, p<0.05). Also βHB PostM correlated with SSI (0.761, p<0.05) but was inversely related to RER (-0.745, p<0.05) and En (-0.826, p<0.01). Conclusion : Our study suggests that some WBA should improve their dietary habit in order to prevent post-exercise ketosis and ameliorate the endogenous antioxidant response after exercise.

Background: Diabetic retinopathy (DR) is one of the diabetic microvascular complications, which is also one of the important causes of blindness in adults. Objective: To investigate the association between proliferative retinopathy and serum bile acid level in patients with type 2 diabetes mellitus (T2DM). Methods: Three hundred and thirty-six patients with T2DM were included, of which, 229 had a history of more than 10 years without diabetic retinopathy (no diabetic retinopathy, NDR) and 107 had proliferative diabetic retinopathy (PDR). The baseline characteristics of the two groups were compared. According to the level of bile acid, the patients were divided into low, medium and high bile acid groups. The ratio of proliferative retinopathy in each group was compared. The presence of retinopathy was taken as the dependent variable, and the significant variables were analyzed by logistic regression. Results: The level of total bilirubin and bile acid in the NDR group was significantly higher than that in the PDR group, while the levels of triglyceride, cholesterol and LDL-C were significantly lower than that in the PDR group (P<0.05). With the increase of bile acid level, the proportion of proliferative retinopathy decreased. Logistic regression analysis showed that bilirubin and bile acid were protective factors of diabetic retinopathy, while SBP, LDL-C and UAER were risk factors of diabetic retinopathy. Conclusion: Bile acid might be a protective factor for diabetic retinopathy in T2DM, which might be a potential therapeutic role in retinal disorders.

Background: Neuregulin 4 (Nrg4) is a novel adipocytokine that has been proposed to play a role in modulating energy metabolism and pathogeneses of atherosclerosis. However, no published research is available about the mechanisms underlying the anti-atherosclerotic effect of Nrg4. Regarding the close link between adipocytokines and the immune system, we wonder whether there is a relation between Nrg4 and athero-protective cytokines. The aim of this study was to investigate the relationship between serum Nrg4 levels and type 2 cytokines in Iranian patients with coronary artery disease (CAD). Methods: In this case-control study, 125 CAD patients were compared to 55 healthy controls. The serum concentrations of Nrg4, IL-5, IL-9, and IL-13 were measured using ELISA. The associations of circulating Nrg4 and IL-5, IL-9, IL-13 were assessed using linear regression analyses. Results: Serum concentration of IL-9 was significantly higher in patients compared to the healthy controls (317.9±139 versus 228.3±99.1, P= <0.0001). IL-13 and Nrg4 were significantly lower in patients compared to the healthy controls (4.3±3.7 versus 6.1±3.9, P=0.01 and 0.5 versus 1.3, P=0.001 respectively). Multiple linear regression analyses revealed that IL-9 was negatively correlated with Nrg4 (β= -0.3, P=0.009). Conclusion: Our study, for the first time, provides the clinical evidence revealing that circulating Nrg4 concentrations are inversely correlated with IL-9 in Iranian patients with CAD, suggesting that the protective role of Nrg4 on atherosclerosis may be, in part, mediated by the proatherogenic cytokine, IL-9.

Background: With the increasing prevalence of diabetes in recent years, diabetic nephropathy (DN) has also become a dangerous disease that greatly endangers human health. The study was designed to determine the mechanism and effect of Electro-acupuncture (EA) in alleviating DN-induced inflammation. Methods: Mice were intraperitoneally injected with STZ (streptozotocin, 50 mg/kg, S0130, Sigma, St. Louis, MO, USA) for five consecutive days. After 12 weeks of induction, blood glucose levels were measured (>300 mg/dL). Results: The serum levels of IL-1β and IL-6 were decreased in EA-treated DN mice, and EA protected renal injury. EA could suppress HMGB1/NLRP3/NF-ΚB pathway. HMGB1 inhibition increased the anti-inflammatory effects of EA on DN by suppressing NLRP3/NF-ΚB pathway. The activation of HMGB1 attenuated the anti-inflammatory effects of EA on DN by inducing NLRP3/ NF-ΚB pathway. Conclusion: These results suggested that EA protected DN-induced inflammation through the suppression of NLRP3 inflammasome.

Objective: Schizophrenia (Sch) is a complex, multifactorial psychiatric disorder. Growing evidence shows that oxidative damage and immunological dysfunction exist in the Sch physiopathology. In the present study, we aimed to evaluate whether the Uncoupling protein 2 and Complement factor H gene variants play any role in susceptibility to Sch. Methods: This study was carried out on 200 individuals (100 Sch patients and 100 healthy controls). Genomic DNA was extracted from blood samples. UCP2-866G /A (rs659366) and CFHY402H variants were analyzed by PCR-RFLP analysis. Results: The UCP2 -866G/A variant G/G genotype and G allele were associated significantly with increased risk of Sch (p=0.001, p=0.001, respectively). The subjects were carrying UCP2 -866G/A variant G/G genotype had 4.377-fold increased risk for Sch. There was no significant difference between the groups for the genotype and allele frequencies of the CFH Y402H variant (p>0.05). The observed genotype counts deviated significantly from those expected in Sch patients according to the HWE for UCP2 -866G/A variant (p=0.001). Conclusion: We present the first results investigating UCP2 -866G/A/ and CFH Y402H variants for susceptibility to Sch in a Turkish population. These results indicate that the UCP2 -866G/A, but not CFH Y402H variant, might play an important role in the development of Sch.

Background: Curcumin has demonstrated many pharmacological effects including antioxidants, anti-inflammation, eliminating free radicals, anti-tumor, lipid regulation, and anti-coagulation. Objective: This study aimed to assess and compare the effects of curcumin and nano-curcumin on lipid profile, oxidative stress, and inflammatory factors related to patient’s heart. Methods: This randomized, double-blind, placebo-controlled clinical trial was conducted on 90 patients undergoing coronary elective angioplasty who were randomly divided into 3 groups. The doses administered for 8 weeks were a 500 mg capsule of curcumin daily for the first group and an 80 mg capsule of nano-curcumin for the second group. However, the placebo group received capsules like curcumin. Lipid profile, oxidative stress factors, and inflammatory markers were measured at the baseline and end of the experiment. Results: Statistically significant changes were observed in the total cholesterol (TC), triacylglycerol (TG) and low-density lipoprotein cholesterol (LDL-C) in the intervention groups to the control group (p<0.05). Curcumin and nano-curcumin supplementation also exhibited significant changes in plasma levels of total antioxidant capacity (TAC), malondialdehyde (MDA), Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), high-sensitivity C-reactive protein (hs- CRP), Interleukin 1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) in comparison to the placebo (p<0.05). Furthermore, the nano-curcumin group compared to the curcumin group demonstrated significant changes (p<0.05) in TC, TG, SOD, MDA and TNF-α levels. Conclusion: The effects of curcumin on nano formula may be better for cardiac patients due to its high bioavailability.

Kabuki syndrome is a rare congenital anomaly/mental retardation syndrome characterized by intellectual disability, developmental delay, short stature, facial dysmorphic features including ectropion of the lateral third of the lower eyelids, long palpebral fissures, and prominent finger pads. Pathogenic variants of KMT2D (MLL2) and KDM6A are found to be the major causes of Kabuki syndrome. Here, we report the first Iranian case with Kabuki syndrome with an IQ of 79, two episodes of viral pneumonia and distinctive facial features, prominent ears, and persistent fetal fingertip pads. These characteristics raised our suspicion of performing whole-exome sequencing (WES), which revealed 2 heterozygous pathogenic missense variants in the KMT2D gene: c.C10024T in exon 34, leading to p.R3342C and c.G15005A in exon 48, leading to p.R5002Q. Hence, the definitive diagnosis of Kabuki syndrome was made based on molecular findings along with the intellectual disability and characteristic facial features.

Objective: The first edition of the American Association of Clinical Endocrinology/American College of Endocrinology/Associazione Medici Endocrinologi Guidelines for the Diagnosis and Management of Thyroid Nodules was published in 2006 and updated in 2010 and 2016. The American Association of Clinical Endocrinology/American College of Endocrinology/Associazione Medici Endocrinologi multidisciplinary thyroid nodules task force was charged with developing a novel interactive electronic algorithmic tool to evaluate thyroid nodules. Methods: The Thyroid Nodule App (termed TNAPP) was based on the updated 2016 clinical practice guideline recommendations while incorporating recent scientific evidence and avoiding unnecessary diagnostic procedures and surgical overtreatment. This manuscript describes the algorithmic tool development, its data requirements, and its basis for decision making. It provides links to the web-based algorithmic tool and a tutorial. Results: TNAPP and TI-RADS were cross-checked on 95 thyroid nodules with histology-proven diagnoses. Conclusion: TNAPP is a novel interactive web-based tool that uses clinical, imaging, cytologic, and molecular marker data to guide clinical decision making to evaluate and manage thyroid nodules. It may be used as a heuristic tool for evaluating and managing patients with thyroid nodules. It can be adapted to create registries for solo practices, large multispecialty delivery systems, regional and national databases, and research consortiums. Prospective studies are underway to validate TNAPP to determine how it compares with other ultrasound-based classification systems and whether it can improve the care of patients with clinically significant thyroid nodules while reducing the substantial burden incurred by those who do not benefit from further evaluation and treatment.