Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 19, Issue 1, 2019

Background and Objective: The thienopyridine family includes ticlopidine, clopidogrel and prasugrel which are antiplatelet drugs largely used, mainly associated to aspirin, for treatment of acute coronary syndromes and after percutaneous coronary interventions, to avoid thrombosis. In some patients, thienpyridines may cause hypersensitivity reactions which jeopardize the optimal therapeutic and preventive approach to vascular diseases. The management of thienopyridine hypersensitivity seems to be best done as an interdisciplinary collaboration between the allergist and cardiologist. Method: The present study investigates the management of thienopyridines hypersensitivity on the basis of published case reports and studies, comparing the pro and contro of pharmacological treatments, different desensitization protocols to thienopyridines and substitution of antiplatelet agents eaches others, according to the point of view of cardiologist and allergist. For the cardiologist, the important issues are the necessity of continuing therapy, the desired duration of therapy based on the clinical indication of the individual patient and appropriateness of using one of the alternative P2Y12 inhibitors. For the allergist, the important issues are weighing the risk and benefits of the various therapeutic options: treating “through” desensitization, or switching to an alternative agent. Results and Conclusion: All the data seem to suggest that only working together, a cardio-allergy team of specialists may evaluate and offer the best approach to clinical decision-making for the individual patient.

Background: Multiple cross sectional and longitudinal studies reported the benefits of vitamin K intake for management of cardiometabolic risk factors so as to minimize the risk of cardiovascular diseases. Objective: In present systematic review and meta-analysis, we aimed to evaluate the effect of vitamin K supplementation on cardiometabolic risk factors. Methodology: A systematic literature search of PubMed, Cochrane central, Clinicaltrials.gov, Google Scholar, Web of Science, EBSCO and Scopus databases was done from inception to November, 2017. A total of 13 trials were selected for inclusion into the present systematic review to evaluate the effect of vitamin K supplementation on cardiometabolic risk factors in healthy or in population at high risk of cardiovascular diseases. Results: Significant beneficial effects of vitamin K supplementation were found only in case of Creactive protein (p = 0.01) and insulin sensitivity index (p <0.001), while no significant effects of vitamin K supplementation were found in case of total cholesterol (p=0.857), low density lipoprotein – cholesterol (p=0.964), high density lipoprotein – cholesterol (p=0.998), interleukin – 6 (p=0.766), systolic blood pressure (p=0.660), diastolic blood pressure (p=0.818), fasting plasma glucose (p=0.362), fasting plasma insulin (p=0.928) and homeostasis model assessment for insulin resistance (p=0.672). Conclusion: Presently available evidence are insufficient to ascertain the beneficial effects of vitamin K supplementation for the management of cardiometabolic risk factors. In order to explore the true potential of vitamin K supplementation for management of cardiometabolic diseases, large randomized placebo controlled trials are required in population with disturbed cardiometabolic profile. Present systematic review and meta-analysis is registered with PROSPERO (Registration number: CRD42018084608).

Background and Objective: The sleep-wake cycle is characterized by a circadian rhythm involving neurotransmitters and neurohormones that are released from brainstem nuclei and hypothalamus. The aim of this review is to analyze the role played by central neural pathways, neurotransmitters and neurohormones in the regulation of vigilance states. Method: We analyzed the literature identifying relevant articles dealing with central neural pathways, neurotransmitters and neurohormones involved in the control of wakefulness and sleep. Results: The reticular activating system is the key center in the control of the states of wakefulness and sleep via alertness and hypnogenic centers. Neurotransmitters and neurohormones interplay during the dark-light cycle in order to maintain a normal plasmatic concentration of ions, proteins and peripheral hormones, and behavioral state control. Conclusion: An updated description of pathways, neurotransmitters and neurohormones involved in the regulation of vigilance states has been depicted.

Background: Due to the sensitizing constituents of eye cosmetics, allergic contact dermatitis is considered a frequent cause of eyelid dermatitis. An association between eyelid dermatitis and nickel contained in make-ups remains controversial. Objective: The study aimed to assess the association between nickel allergy, the use of pigmented makeup products and self-reported eyelid dermatitis. Method: This multi-centric, cross-sectional study enrolled 165 women sensitized to nickel (patients) and 103 women without intolerance to metals (controls). We recorded: demographics, atopy, use of pigmented eye cosmetics (mascara, eyeshadow, eyeliner, eyebrow pencil), and previous eyelid dermatitis. Among the patients, any co-sensitization to cosmetics or metals was recorded. Results: 87.3% of the patients and 91.3% of the controls reported their use of eye make-up; 44.9% and 52.4%, respectively, reported previous episodes of eyelid dermatitis, without significant differences. The occurrence of eyelid dermatitis was significantly associated with the use of eye make-up products, both in general and considering each product separately. Age, atopy, or co-sensitization to other metals or cosmetics did not affect the occurrence of eyelid dermatitis. Conclusion: Nickel allergy should not be considered the main risk factor for eyelid dermatitis. The use of pigmented eye make-up may be a triggering factor for eyelid dermatitis, probably due to an irritant action.

Background: Sickle Cell Disease (SCD) is characterized by defective hemoglobin synthesis, hemolytic anemia, frequent thrombosis and chronic organ damage including endocrine organs. Aim: To assess thyroid function in children with SCD in correlation and iron load. Patients and Method: This study was conducted on 40 children with SCD with iron overload (serum ferritin more than 1000 ng/ml) including 22 males and 18 females with their ages ranging from 11-14 years and mean age value of 11.63±1.36 years and 40 healthy children of matched age and sex as a control group. For all patients; complete blood count, hemoglobin electrophoresis, serum ferritin, serum iron, iron binding capacity and thyroid function including Free Thyroxine (FT4), Free Triiodothyronine (FT3), Thyroid Stimulating Hormone (TSH), Thyroid Peroxidase Antibody (TPOAb) and Thyroglobulin Antibody (TgAb) were done. Results: Significantly higher serum ferritin and iron and significantly lower Total Iron Binding Capacity (TIBC) were found in patients compared with controls (mean serum ferritin was 1665.2±1387.65ng/ml in patients versus 192.55±107.2ng/ml in controls with p-value of 0. 007, mean serum iron was 164±83.9 ug/dl in patients versus 89.5±4.5ug/dl in controls with p-value of 0.039, mean TIBC was 238±44.5ug/dl in patients versus 308±11ug/dl in controls with p-value of 0.001). Significantly higher serum TSH and significantly lower Free T3 and Free T4 were found in patients compared with controls with no significant correlation between thyroid hormones and serum ferritin (mean serum TSH was 4.61±1.2 μIU/mL in patients versus 2.11 ± 0.54 μIU /mL in controls with p-value of 0. 045, mean serum FT3 was 2.61 ±1.3 pg/mL versus 3.93±0.47pg/mL in controls with p-value of 0.027, mean serum FT4 was 0.91±0.174 ng/dL versus 1.44± 0.164 ng/dLin controls with p-value of 0.047, r = - 0. 008 and p-value was 0. 973 for correlation between free T4 and serum ferritin, r = -0. 028 and p-value was 0. 9 for correlation between TSH and serum ferritin and r= - 0.259 and p-value was 0.27 for correlation betweenT3 and serum ferritin). There were no significant differences between patients and controls regarding thyroid peroxidase antibody and thyroglobulin antibody (mean serum thyroid peroxidase antibody was 22.45± 4.32 in patients versus 22.45 ± 3.21 in controls with p-value of 0.98 while mean serum thyroglobulin antibody was 12.32 ± 2.65 in patients versus 12.99 ± 2.34 in controls with p-value of 0.76. Conclusion: Thyroid hormones deficiency may occur in some patients with SCD. Recommendations: Regular assessment of thyroid function in children with SCD may be recommended as they are more vulnerable to develop hypothyroidism and may require replacement therapy.

Background: IL-10 is an important pleiotropic, immunoregulatory and anti-inflammatory cytokine which plays a significant role in the pathogenesis of psoriasis. Objective: The aim of the present study was to determine whether the three polymorphic sites of the IL-10 gene, haplotype and serum level confer susceptibility to psoriasis. Method: 200 psoriatic patients and 200 controls were genotyped for three IL-10 polymorphic sites by ARMS polymerase chain reaction. Serum levels of IL -10 were measured by ELISA. Results: Our results demonstrated that polymorphism of IL-10 -592 C/A (adjusted* OR = 9.25; 95% CI =3.16- 27.06) and IL-10 1082 A/G (adjusted* OR = 4.28; (95% CI =1.46- 12.56) was found to be in association with increased risk of psoriasis while as IL- 10 819 C/T (adjusted* OR= 1.60; (95% CI = 0.65-3.95) polymorphism does not show any significant association with the risk of psoriasis. HT7 GTC haplotype is associated with increased risk of psoriasis. Serum levels of IL-10 were found to be significantly low in patients, as compared to controls with a non-significant correlation between serum IL-10 level and psoriasis severity. Conclusion: IL-10 polymorphism imparted significant risk towards the development of psoriasis in North Indian population. Highlighting the role of IL-10 cytokine in the pathogenesis of psoriasis will help in the development of psoriasis management.

Background: The sesquiterpene lactone cynaropicrin, a major constituent of the artichoke leaves extracts, has shown several biologic activities in many preclinical experimental models, including anti-proliferative effects. Objective: Herein we evaluated the effects of cynaropicrin on the growth of three human anaplastic thyroid carcinoma cell lines, investigating the molecular mechanism underlying its action. Method: MTT assay was used to evaluate the viability of CAL-62, 8505C and SW1736 cells, and flow cytometry to analyse cell cycle distribution. Western blot was performed to detect the levels of STAT3 phosphorylation and NFkB activation. Antioxidant effects were analyzed by measuring the reactive oxygen species and malonyldialdehyde dosage was used to check the presence of lipid peroxidation. Results: Viability of CAL-62, 8505C and SW1736 cells was significantly reduced by cynaropicrin in a dose- and time-dependent way, with an EC50 of about 5 μM observed after 48 h of treatment with the compound. Cellular growth inhibition was accompanied both by an arrest of the cell cycle, mainly in the G2/M phase, and the presence of a significant percentage of necrotic cells. After 48 h of treatment with 10 μM of cynaropicrin, a reduced nuclear expression of NFkB and STAT3 phosphorylation were also revealed. Moreover, we observed an increase in lipid peroxidation, without any significant effect on the reactive oxygen species production. Conclusion: These results demonstrate that cynaropicrin reduces the viability and promotes cytotoxic effects in anaplastic thyroid cancer cells associated with reduced NFkB expression, STAT3 phosphorylation and increased lipid peroxidation. Further characterization of the properties of this natural compound may open the way for using cynaropicrin as an adjuvant in the treatment of thyroid cancer.

Aim: Studies have evaluated the association of miRNA-423 C>A genotyping with the susceptibility to various diseases such cancers, atherosclerosis and inflammatory bowel disease but the results were contradictory. However, no studies have reported the association between miRNA-423 rs6505162 C>A polymorphism and susceptibility of coronary artery disease. MicroRNAs regulate expression of multiple genes involved in atherogenesis. Therefore, we investigated the association of microRNA-423C>T gene variations with susceptibility to coronary artery disease. Methodology: This study was conducted on 100 coronary artery disease patients and 117 matched healthy controls. The genotyping of the microRNA-423 rs6505162C>A was performed by using Amplification refractory mutation system PCR method (ARMS-PCR). Results: A significant difference was observed in the genotype distribution among the coronary artery disease cases and sex-matched healthy controls (P=0.048). The frequencies of all three genotypes CC, CA, AA reported in the patient’s samples were 55%, 41% and 4% and in the healthy controls samples were 55%, 41% and 4% respectively. Our findings showed that the microRNA-423 C>A variant was associated with an increased risk of coronary artery disease in codominant model (OR = 1.96, 95 % CI, 1.12-3.42; RR 1.35(1.05-1.75, p=0.017) of microRNA-423CA genotype and significant association in dominant model (OR 1.97, 95% CI (1.14-3.39), (CA+AA vs CC) and non-significant association for recessive model (OR=1.42, 95%CI=0.42-4.83, P=0.56, AA vs CC+CA).While, the A allele significantly increased the risk of coronary artery disease (OR =1.56, 95 % CI, 1.03-2.37; p=0.035) compared to C allele. Therefore, it was observed that more than 1.96, 1.97 and 1.56 fold increased risk of developing coronary artery disease. Conclusion: Our findings indicated that microRNA-423 CA genotype and A allele are associated with an increased susceptibility to Coronary artery disease.

Background: The prevalence of thyroid dysfunction and autoimmunity in the Portuguese population has not yet been estimated. However, the national prevalence of the metabolic syndrome remains high. The association of thyroid pathology with cardiovascular risk has been addressed but is still unclear. Our study aimed to evaluate the prevalence of thyroid dysfunction and autoimmunity and to assess the associations of thyroid-stimulating hormone and thyroid hormones and antibodies with metabolic syndrome, its components, and other possible determinants in a national sample. Material and Methods: The present study included a subsample of 486 randomly selected participants from a nationwide cross-sectional study sample of 4095 adults. A structured questionnaire was administered on past medical history and socio-demographic and behavioural characteristics. Blood pressure and anthropometric measurements were collected, and the serum lipid profile, glucose, insulin, hs- CRP, TSH, FT4, FT3 and thyroid antibodies were measured. Results: In our sample, the prevalence of hypothyroidism, hyperthyroidism and undiagnosed dysfunction was 4.9%, 2.5% and 72.2%, respectively. Overall, the prevalence of positivity for the thyroid peroxidase and thyroglobulin antibodies was 11.9% and 15.0%, respectively. A positive association was found between free triiodothyronine and metabolic syndrome (OR: 2.019; 95% CI: 1.196, 3.410). Additionally, thyroid peroxidase antibodies had a negative association with metabolic syndrome (OR: 0.465; 95% CI: 0.236, 0.917) and its triglyceride component (OR: 0.321; 95% CI: 0.124, 0.836). Conclusion: The prevalence of undiagnosed thyroid dysfunction and autoimmunity was high. Thyroid peroxidase antibodies were negatively associated with metabolic syndrome and its triglyceride component, whereas the free triiodothyronine level was positively associated with metabolic syndrome.

Background and Objective: Charles Bonnet Syndrome (CBS) has been defined as complex visual hallucinations (CVH) due to visual loss. The underlying mechanism of CBS is not clear and the underlying pathophysiology of the visual hallucinations in CBS patients and pure visually impaired patients is still not clear. Methods: In our study, we have scanned three patients with eye disease and CBS (VH+) and three patients with eye disease without CBS (VH-) using FDG-PET. Results: Our results showed underactivity in the pons and overactivity in primary right left visual cortex and inferior parietal cortex in VH- patients and underactivity in left Broca, left inf frontal primary visual cortex and anterior and posterior cingulate cortex in VH+ patients relative to the normative 18FFDG PET data that was taken from the database consisting of 50 age-matched healthy adults without neuropsychiatric disorders. Conclusion: From this distributed pattern of activity changes, we conclude that the generation of visual hallucination in CBS is associated with bottom-up and top-down mechanism rather than the generally accepted visual deafferentation-related hyperexcitability theory.

Backgraund and Objective: Anti-Saccharomyces Cerevisiae Antibodies (ASCA) that are considered to reflect immune response against increased intestinal permeability due to mucosal damage are among the serological markers of Crohn' Disease. Methods: This microbial seromarker was recently shown to be elevated in several autoimmune disorders such as celiac disease, autoimmune liver diseases, type 1 diabetes, and Graves' disease. Despite that fact, ASCA seropositivity in Autoimmune Polyglandular Syndrome (APS) has never been reported before. Results: Herein, we present a 46-year-old woman who has uveitis, autoimmune thyroiditis, and primary ovarian failure. Conclusion: Based on the coexistence of these diseases, the patient was diagnosed with APS type III. Moreover, ASCA seropositivity was detected although she has no overt intestinal disease.

Background and Objective: Zenker Diverticulum (ZD) can sometimes be misinterpreted as a thyroid nodule both at clinical evaluation and at Ultrasound (US). Case Presentation: We reported the case of a 46-years-old woman complaining of a lump in the anterior left aspect of the neck. Following clinical examination and US evaluation, a thyroid nodule was initially diagnosed and the patient was referred to our institution to be submitted to a fine-needle aspiration cytology. Management and Outcome: A ZD was suspected by US and diagnosed by gastrografin esophagram, thus an endoscopic diverticulotomy was requested. Conclusion: A correct US evaluation can be crucial for the appropriate management of a neck mass.

Background: Experimental studies have reported beneficial effects of Capparis spinosa L., a perennial shrub from the Capparidaceae family, on the glycemic status and serum lipids in diabetic animals. Objective: The aim of the present randomized triple-blind placebo-controlled clinical trial was to investigate the safety and efficacy of C. spinosa oxymel on blood glucose, lipid profile, and other diagnostic indexes of metabolic syndrome in patients with poorly controlled type 2 diabetes. Method: The C. spinosa oxymel was prepared by adding hydroalcoholic extract of C. spinosa fruit to simple oxymel (a mixture of grape vinegar and lactulose). Thirty diabetic patients with metabolic syndrome whose glycemic status was not controlled despite receiving full doses of oral hypoglycemic agents did not want to start insulin therapy and were randomly allocated to three groups to receive placebo, simple oxymel, or C. spinosa oxymel (10 mL/thrice daily for 3 months). All patients continued conventional therapy with hypolipidemic, antihyperlipidemic, and antihypertensive drugs during the study. Results: C. spinosa oxymel significantly decreased the body weight and body mass index at the end of the study compared to the baseline. While the patients in the placebo and simple oxymel groups displayed further increase in the level of FBG or PPBG, administration of C. spinosa oxymel inhibited the progression of hyperglycemia. Nevertheless, there was not a significant difference between placebo and intervention groups regarding HbA1c at the end of the study. C. spinosa oxymel had no significant effect on the serum cholesterol but inhibited the progression of hypertriglyceridemia during the study. There were no significant changes in creatinine, microalbuminuria, AST, ALT, and ALP values following C. spinosa treatment, suggesting that it had no unwanted effects on kidney and liver function. Conclusion: The results suggest that although C. spinosa oxymel cannot enhance the effects of hypoglycemic and hypolipidemic drugs, it can prevent further increase of blood glucose and triglycerides in patients with poorly controlled diabetes.