D-chiro-inositol in clinical practice: A perspective from The Experts Group on Inositol in Basic and Clinical Research (EGOI).

BACKGROUND: D-chiro-inositol is a natural molecule that, in association with its well-studied isomer myo-inositol, may play a role in treating various metabolic and gynecological disorders. OBJECTIVES: This perspective seeks to explore the mechanisms and functions of D-chiro-inositol, laying the foundations to discuss its use in clinical practice, across dysmetabolism, obesity, and hormonal dysregulation. METHODS: A narrative review of all the relevant papers known to the authors was conducted. OUTCOME: D-chiro-inositol acts through a variety of mechanisms, acting as an insulin sensitizer, inhibiting the transcription of aromatase, in addition to modulating white adipose tissue/brown adipose tissue trans differentiation. These different modes of action have potential applications in a variety of therapeutic fields including: PCOS, dysmetabolism, obesity, hypoestrogenic/hyperandrogenic disorders, and bone health. CONCLUSIONS: D-chiro-inositol mode of action has been studied in detail in recent years, resulting in a clear differentiation between D-chiro-inositol and its isomer myo-inositol. The insulin sensitizing activities of D-chiro-inositol are well understood; however, its potential applications in other fields, in particular obesity and hyperestrogenic/hypoandrogenic disorders in men and women, represent promising avenues of research that require further clinical study.

Molecular targets of tyrosine kinase inhibitors in thyroid cancer.

Thyroid cancer (TC) is the eighth most frequently diagnosed cancer worldwide with a rising incidence in the past 20 years. Surgery is the primary strategy of therapy for patients with medullary TC (MTC) and differentiated TC (DTC). In DTC patients, radioactive iodine (RAI) is administered after thyroidectomy. Neck ultrasound, basal and thyroid-stimulating hormone-stimulated thyroglobulin are generally performed every three to six months for the first year, with subsequent intervals depending on initial risk assessment, for the detection of possible persistent/recurrent disease during the follow up. Distant metastases are present at the diagnosis in ∼5 % of DTC patients; up to 15 % of patients have recurrences during the follow up, with a survival reduction (70 %-50 %) at 10-year. During tumor progression, the iodide uptake capability of DTC cancer cells can be lost, making them refractory to RAI, with a negative impact on the prognosis. Significant advances have been done recently in our understanding of the molecular pathways implicated in the progression of TCs. Several drugs have been developed, which inhibit signaling kinases or oncogenic kinases (BRAFV600E, RET/PTC), such as those associated with Platelet-Derived Growth Factor Receptor and Vascular Endothelial Growth Factor Receptor. Tyrosine kinase receptors are involved in cancer cell proliferation, angiogenesis, and lymphangiogenesis. Several tyrosine kinase inhibitors (TKIs) are emerging as new treatments for DTC, MTC and anaplastic TC (ATC), and can induce a clinical response and stabilize the disease. Lenvatinib and sorafenib reached the approval for RAI-refractory DTC, whereas cabozantinib and vandetanib for MTC. These TKIs extend median progression-free survival, but do not increase the overall survival. Severe side effects and drug resistance can develop in TC patients treated with TKIs. Additional studies are needed to identify a potential effective targeted therapy for aggressive TCs, according to their molecular characterization.

Biochemical features of eugonadal patients with idiopathic gynaecomastia: A retrospective cross-sectional study.

Patients with idiopathic gynaecomastia have greater BMI and an unfavourable lipid profile compared with age-matched controls. Twenty-five adult eugonadal patients with idiopathic gynaecomastia and 50 age- and BMI-matched controls were selected. Clinical and biochemical parameters and ultrasound testis volume were reviewed retrospectively. Patients and controls differed for no biochemical parameter, except for LH levels, which were 31% higher in patients (p = 0.019), although within the normal range. Compared with controls, patients had a threefold greater rate of elevated LDL-c (p = 0.025). Patients ≥ 25 years had higher levels of serum LDL-c compared with either patients < 25 years (p = 0.006) or controls ≥ 25 years (p = 0.012). In patients, both at bivariate analysis and at linear regression, age correlated positively with total cholesterol and LDL-c, the latter correlated inversely with total testosterone. Negative interactions were found for age and total testosterone with LDL-c, for LH and estradiol to testosterone ratio (E2:T) with LDL-c, and for age and E2:T with total cholesterol. Our data suggest inadequate local androgen action in patients with idiopathic gynaecomastia. This partial androgen resistance might blunt the beneficial effects of testosterone on lipid metabolism. Further studies are needed to verify whether this metabolic derangement impacts the cardiovascular health of these patients.

Inositols: From Established Knowledge to Novel Approaches.

Myo-inositol (myo-Ins) and D-chiro-inositol (D-chiro-Ins) are natural compounds involved in many biological pathways. Since the discovery of their involvement in endocrine signal transduction, myo-Ins and D-chiro-Ins supplementation has contributed to clinical approaches in ameliorating many gynecological and endocrinological diseases. Currently both myo-Ins and D-chiro-Ins are well-tolerated, effective alternative candidates to the classical insulin sensitizers, and are useful treatments in preventing and treating metabolic and reproductive disorders such as polycystic ovary syndrome (PCOS), gestational diabetes mellitus (GDM), and male fertility disturbances, like sperm abnormalities. Moreover, besides metabolic activity, myo-Ins and D-chiro-Ins deeply influence steroidogenesis, regulating the pools of androgens and estrogens, likely in opposite ways. Given the complexity of inositol-related mechanisms of action, many of their beneficial effects are still under scrutiny. Therefore, continuing research aims to discover new emerging roles and mechanisms that can allow clinicians to tailor inositol therapy and to use it in other medical areas, hitherto unexplored. The present paper outlines the established evidence on inositols and updates on recent research, namely concerning D-chiro-Ins involvement into steroidogenesis. In particular, D-chiro-Ins mediates insulin-induced testosterone biosynthesis from ovarian thecal cells and directly affects synthesis of estrogens by modulating the expression of the aromatase enzyme. Ovaries, as well as other organs and tissues, are characterized by a specific ratio of myo-Ins to D-chiro-Ins, which ensures their healthy state and proper functionality. Altered inositol ratios may account for pathological conditions, causing an imbalance in sex hormones. Such situations usually occur in association with medical conditions, such as PCOS, or as a consequence of some pharmacological treatments. Based on the physiological role of inositols and the pathological implications of altered myo-Ins to D-chiro-Ins ratios, inositol therapy may be designed with two different aims: (1) restoring the inositol physiological ratio; (2) altering the ratio in a controlled way to achieve specific effects.

Intraoperative sonography for nonpalpable breast lesions: Additional indications for a consolidate technique.

This prospective study evaluated the intraoperative ultrasound scan (IUSS) for nonpalpable breast lesions' detection. A total of 108 consecutive female patients underwent surgery using IUSS: Frozen sections demonstrated clear margins in 95.5% of neoplastic patients. Only four (4.5%) patients underwent local re-excision in the same operation. IUSS demonstrated to be quick, accurate, useful, effective, and safe for the intraoperative management of neoplastic nonpalpable breast lesions when performed by a surgeon who has undergone US training, particularly for people in whom alternative approaches can show some limitations due to contraindications or because of scheduling constraints, costs, and patient discomfort.

The Risk For Malignancy of the Thyroid Nodule is Modulated by Gender, Echotexture, and Intranodular Lymphocytic Thyroiditis.

Based on the American (Bethesda, 2017) or Italian (SIAPEC 2014) cytological categories of thyroid nodules, the risk of malignancy and management vary. This risk is 5-10% or<3% (benign or TIR2), 6-18% or<10% (AUS/FLUS or TIR3A), 10-40% or 15-30% (FN/SFN or TIR3B), 45-60% or 60-80% (suspicious or TIR4), 94-96% or 95% (malignant or TIR5). In 408 thyroid nodules evaluated cytologically, we computed the malignancy rate in each category considering gender (325 females, 83 males), echotexture (268 isoechoic, 140 hypoechoic), intranodular chronic lymphocytic thyroiditis (ICLT: 113 with and 295 without); histology (263 benign, 145 malignant). It was 0-1.7% for the benign categories, except hypoechoic/ICLT+ve nodules of females (25%); 0-2.3% for the AUS/FLUS category, except isoechoic/ICLT-ve nodules of males (11.1%) and hypoechoic/ICLT-ve nodules of females (22.2%). For the FN/SFN category, rate was the most variable (from 0% in isoechoic/ICLT+ve nodules of males to 100% in hypoechoic/ICLT-ve nodules of males). The 30% threshold for risk was passed in four subgroups, and the 40% threshold in two subgroups (45% in isoechoic/ICLT-ve nodules of males, 80% in hypoechoic/ICLT+ve nodules of females). For the suspicious category, rate was 100% in males, except those with isoechoic/ICLT-ve nodules (75%), and>80% in females with hypoechoic nodules. For the malignant category, rate was always 100%. In conclusion, particular groups of nodules (based on gender, echotexture, and ICLT) within the cytologically benign through the suspiciously malignant category are at risk of malignancy substantially greater (even 100%) than the standard one. Accordingly, the suggested management cannot be standardized.

The history of pituitary dysfunction after traumatic brain injury.

PURPOSE: To estimate the total number of articles on traumatic brain injury (TBI)-related hypopituitarism and patients (including children and adolescents) with such disorder that were published until now, particularly after the author's review published on April 2000. METHODS: Review of the literature retrievable on PubMed. RESULTS: TBI-related hypopituitarism accounts for 7.2% of the whole literature on hypopituitarism published during the 18 years and half between May 2000 and October 2018. As a result, the total number of patients with TBI-related hypopituitarism now approximates 2200. A number of patients, both adults and children, continue to be published as case reports. Articles, including reviews and guidelines, have been published in national languages in order to maximize locally the information on TBI-related hypopituitarism. TBI-related hypopituitarism has been also studied in animals (rodents, cats and dogs). CONCLUSIONS: The interest for the damage suffered by anterior pituitary as a result of TBI continues to remain high both in the adulthood and childhood.

The increasing prevalence of chronic lymphocytic thyroiditis in papillary microcarcinoma.

Although the incidence of some malignancy has decreased over the recent years, this is not the case of papillary thyroid microcarcinoma (PTMC), whose incidence has increased worldwide. Most PTMC are found incidentally after histological examination of specimens from surgery for benign thyroid disease. Hashimoto's thyroiditis, whose incidence has also increased, coexists in about one in three PTMC patients. Three different mechanisms have been proposed to clarify the association between chronic lymphocytic thyroiditis and PTMC, namely tumor development/growth by: (i) TSH stimulation, (ii) expression of certain proto-oncogenes, (iii) chemokines and other molecules produced by the lymphocytic infiltrate. Whether Hashimoto's thyroiditis protects against lymph node metastasis is debated. Overall, autommune thyroiditis seems to contribute to the favorable prognosis of PTMC. Major limitations of the studies so far performed include: (i) retrospective design, (ii) limited statistical power, (iii) high risk of selection bias, (iv) and predominant Asian ethnicity of patients. Full genetic profiling of both diseases and identification of environmental factors capable to trigger them, as well as well-powered prospective studies on different ethnical groups, may help understand their causal association and why their frequencies are continuing raising.

Gut microbiota and Hashimoto's thyroiditis.

About two third of the human microbial commensal community, namely the gut microbiota, is hosted by the gastrointestinal tract which represents the largest interface of the organism to the external environment. This microbial community co-evolved in a symbiotic relationship with the human beings. Growing evidence support the notion that the microbiota plays a significant role in maintaining nutritional, metabolic and immunologic homeostasis in the host. Microbiota, beside the expected role in maintaining gastrointestinal homeostasis also exerts metabolic functions in nutrients digestion and absorption, detoxification and vitamins' synthesis. Intestinal microbiota is also key in the correct development of the lymphoid system, 70% of which resides at the intestinal level. Available studies, both in murine models and humans, have shown an altered ratio between the different phyla, which characterize a" normal" gut microbiota, in a number of different disorders including obesity, to which a significant part of the studies on intestinal microbiota has been addressed so far. These variations in gut microbiota composition, known as dysbiosis, has been also described in patients bearing intestinal autoimmune diseases as well as type 1 diabetes mellitus, systemic sclerosis and systemic lupus erythematosus. Being Hashimoto's thyroiditis the most frequent autoimmune disorder worldwide, the analysis of the reciprocal influence with intestinal microbiota gained interest. The whole thyroid peripheral homeostasis may be sensitive to microbiota changes but there is also evidence that the genesis and progression of autoimmune thyroid disorders may be significantly affected from a changing intestinal microbial composition or even from overt dysbiosis. In this brief review, we focused on the main features which characterize the reciprocal influence between microbiota and thyroid autoimmunity described in the most recent literature.

Thyroid disorders induced by checkpoint inhibitors.

Immune checkpoint inhibitors are drugs that inhibit the "checkpoint molecules". Different types of cancer immune checkpoint inhibitors have been approved recently: CTLA-4 monoclonal antibodies (as ipilimumab); anti-PD-1 monoclonal antibodies (as pembrolizumab and nivolumab); and anti-PD-L1 monoclonal antibodies (as atezolizumab, avelumab, and durmalumab). The increased immune response induced by these agents leads to immune-related adverse events (irAEs), that can vary from mild to fatal, according to the organ system and severity. Immune-related endocrine toxicities are thyroid dysfunctions, hypophysitis, adrenal insufficiency, and type 1 diabetes mellitus, and are usually irreversible in 50%. In particular, hypophysitis is the most frequent anti-CTLA-4-antibodies-related irAE, while thyroid abnormalities (as hypothyroidism, thyrotoxicosis, painless thyroiditis, or even "thyroid storm") are more frequently associated with anti-PD-1-antibodies. The combination of anti-CTLA-4-antibodies, with anti-PD-1-antibodies, is associated with about 30% of irAEs. Clinical signs and symptoms vary according to the influenced target organ. Endocrinopathies can often be managed by the treating oncologist. However in more severe cases (i.e. in the presence of insulin-dependent diabetes, adrenal insufficiency, or disorders of gonadal hormones, or severe hyperthyroidism, or hypothyroidism, or long-lasting management of hypophysitis) an endocrinological evaluation, and a prompt therapy, are needed.

The protective effect of myo-inositol on human thyrocytes.

Patients affected by autoimmune thyroiditis reached positive effects on indices of thyroid autoimmunity and/or thyroidal function, after following a treatment with selenomethionine (Se) alone, or Se in combination with Myo-inositol (Myo-Ins). Our purpose was to investigate if Myo-Ins alone, or a combination of Se + Myo-Ins, is effective in protecting thyroid cells from the effects given by cytokines, or hydrogen peroxide (H2O2). We assessed the interferon (IFN)-γ-inducible protein 10 (IP-10/CXCL10) secretion by stimulating primary thyrocytes (obtained from Hashimoto's thyroiditis or from control patients) with cytokines in presence/absence of H2O2. Our results confirm: 1) the toxic effect of H2O2 in primary thyrocytes that leads to an increase of the apoptosis, to a decrease of the proliferation, and to a slight reduction of cytokines-induced CXCL10 secretion; 2) the secretion of CXCL10 chemokine induced by IFN-γ + tumor necrosis factor alpha (TNF)-α has been decreased by Myo + Ins, both in presence or absence of H2O2; 3) no effect has been shown by the treatment with Se. Therefore, a protective effect of Myo-Ins on thyroid cells has been suggested by our data, which exact mechanisms are at the basis of this effect need to be furtherly investigated.

HypoparaNet: A Database of Chronic Hypoparathyroidism Based on Expert Medical-Surgical Centers in Italy.

Hypoparathyroidism is a rare disease characterized by low serum calcium levels and absent or deficient parathyroid hormone level. Regarding the epidemiology of chronic hypoparathyroidism, there are limited data in Italy and worldwide. Therefore, the purpose of this study was to build a unique database of patients with chronic hypoparathyroidism, derived from the databases of 16 referral centers for endocrinological diseases, affiliated with the Italian Society of Endocrinology, and four centers for endocrine surgery with expertise in hypoparathyroidism, to conduct an epidemiological analysis of chronic hypoparathyroidism in Italy. The study was approved by the Institutional Review Board. A total of 537 patients with chronic hypoparathyroidism were identified. The leading etiology was represented by postsurgical hypoparathyroidism (67.6%), followed by idiopathic hypoparathyroidism (14.6%), syndromic forms of genetic hypoparathyroidism (11%), forms of defective PTH action (5.2%), non-syndromic forms of genetic hypoparathyroidism (0.9%), and, finally, other forms of acquired hypoparathyroidism, due to infiltrative diseases, copper or iron overload, or ionizing radiation exposure (0.7%). This study represents one of the first large-scale epidemiological assessments of chronic hypoparathyroidism based on data collected at medical and/or surgical centers with expertise in hypoparathyroidism in Italy. Although the study presents some limitations, it introduces the possibility of a large-scale national survey, with the final aim of defining not only the prevalence of chronic hypoparathyroidism in Italy, but also standards for clinical and therapeutic approaches.

A patient-specific treatment model for Graves' hyperthyroidism.

BACKGROUND: Graves' is disease an autoimmune disorder of the thyroid gland caused by circulating anti-thyroid receptor antibodies (TRAb) in the serum. TRAb mimics the action of thyroid stimulating hormone (TSH) and stimulates the thyroid hormone receptor (TSHR), which results in hyperthyroidism (overactive thyroid gland) and goiter. Methimazole (MMI) is used for hyperthyroidism treatment for patients with Graves' disease. METHODS: We have developed a model using a system of ordinary differential equations for hyperthyroidism treatment with MMI. The model has four state variables, namely concentration of MMI (in mg/L), concentration of free thyroxine - FT4 (in pg/mL), and concentration of TRAb (in U/mL) and the functional size of the thyroid gland (in mL) with thirteen parameters. With a treatment parameter, we simulate the time-course of patients' progression from hyperthyroidism to euthyroidism (normal condition). We validated the model predictions with data from four patients. RESULTS: When there is no MMI treatment, there is a unique asymptotically stable hyperthyroid state. After the initiation of MMI treatment, the hyperthyroid state moves towards subclinical hyperthyroidism and then euthyroidism. CONCLUSION: We can use the model to describe or test and predict patient treatment schedules. More specifically, we can fit the model to individual patients' data including loading and maintenance doses and describe the mechanism, hyperthyroidism→euthyroidism. The model can be used to predict when to discontinue the treatment based on FT4 levels within the physiological range, which in turn help maintain the remittance of euthyroidism and avoid relapses of hyperthyroidism. Basically, the model can guide with decision-making on oral intake of MMI based on FT4 levels.

Autoimmunity to heterogeneous nuclear ribonucleoprotein A1 in psoriatic patients and correlation with disease severity.

BACKGROUND AND OBJECTIVES: The heterogeneous nuclear ribonucleoprotein A1 (hnRNP-A1) has been postulated as an autoantigen of psoriasis, but correlation between serum levels of anti-hnRNP-A1 autoantibodies and the severity of disease has not been investigated. We aimed to assess the frequency of anti-hnRNP-A1 autoimmunity in patients with moderate to severe psoriasis and in healthy controls, and to determine the correlation between serum levels of anti-hnRNP-A1 autoantibodies and disease severity. PATIENTS AND METHODS: We performed a case-control study on 40 adult psoriatic patients with a PASI (Psoriasis Area and Severity Index) of > 10 and 40 healthy controls matched for age and gender. Immunoblotting was used to assess serum levels of anti-hnRNP-A1 autoantibodies. RESULTS: Anti-hnRNP-A1 autoantibodies were found in 9/40 psoriatic patients (22.5 %) but in no healthy controls. The PASI was significantly higher in anti-hnRNP-A1-positive patients than in anti-hnRNP-A1-negative patients (40.33 ± 3.24 vs 26.06 ± 9.28, p = 0.0001). In patients positive for anti-hnRNP-A1, serum levels of such autoanti-bodies were correlated with the PASI (R = 0.89, p = 0.001). CONCLUSIONS: Consistent with reports in the literature, our results suggest a role of anti-hnRNP-A1 autoimmunity in psoriasis, although probably not as the primary cause or initial/fundamental event. Unlike previously published reports, our results also suggest that anti-hnRNP-A1 autoimmunity is particularly frequent among psoriatic patients with more severe disease. Further studies are necessary with a larger number of patients.

Autoimmunität gegen heterogenes nukleäres Ribonukleoprotein A1 bei Psoriasispatienten und Korrelation mit dem Schweregrad der Erkrankung.

HINTERGRUND UND ZIELE: Das heterogene nukleäre Ribonukleoprotein A1 (hnRNP-A1) wurde als Autoantigen bei Psoriasis vorgeschlagen; eine mögliche Korrelation zwischen dem Serumspiegel von Anti-hnRNP-A1-Antikörpern und dem Schweregrad der Erkrankung wurde bislang nicht untersucht. Unser Ziel war es, die Häufigkeit der Anti-hnRNP-A1-Autoimmunität bei Patienten mit mäßig schwerer bis schwerer Psoriasis und gesunden Kontrollpersonen zu bestimmen und festzustellen, ob eine Korrelation zwischen dem Anti-hnRNP-A1-Autoantikörper-Serumspiegel und dem Schweregrad der Erkrankung besteht. PATIENTEN UND METHODEN: Wir führten eine Fallkontrollstudie an 40 erwachsenen Psoriasispatienten mit einem Psoriasis Area and Severity Index (PASI) von > 10 und 40 gesunden Kontrollpersonen mit ähnlicher Alters- und Geschlechtsverteilung durch. Die Bestimmung des Serumspiegels von hnRNP-A1-Autoantikörpern erfolgte mit Immunoblots. ERGEBNISSE: Anti-hnRNP-A1-Autoantikörper wurden bei 9 von 40 Psoriasispatienten (22,5 %) nachgewiesen, jedoch bei keiner der gesunden Kontrollpersonen gefunden. Der PASI-Wert war bei Anti-hnRNP-A1-positiven Patienten signifikant höher als bei Anti-hnRNP-A1-negativen Patienten (40,33 ± 3,24 vs. 26,06 ± 9,28, p  =  0,0001). Bei Anti-hnRNP-A1-positiven Patienten korrelierte der Serumspiegel der Autoantikörper mit dem PASI-Wert (R = 0,89, p = 0,001). SCHLUSSFOLGERUNGEN: Übereinstimmend mit Berichten aus der Literatur legen unsere Ergebnisse nahe, dass Anti-hnRNP-A1-Autoimmunität bei Psoriasis eine Rolle spielt, wenn auch möglicherweise nicht als primäre Ursache oder als initiales oder grundlegendes Ereignis. Anders als bei früheren Publikationen weisen unsere Daten auch darauf hin, dass Autoimmunität gegen Anti-hnRNP-A1 unter Patienten mit schwererer Erkrankung besonders häufig ist. Weitere Studien mit einer größeren Anzahl von Patienten sind erforderlich.

Myo-inositol and melatonin in the menopausal transition.

INTRODUCTION: The aim of the study was to evaluate the effects on serum insulin and serum thyroid profile of a dietary supplement, myo-inositol, given alone or in combination with melatonin to women during menopausal transition. METHODS: Forty women aged 45-55 years and at least 6 months of amenorrhea were enrolled in this study. They were randomly assigned to two groups of 20 each. One group took myo-inositol (myo-Ins) (2 g twice a day) and the other group took 2 g/d myo-Ins plus 3 g/d melatonin before sleeping. At the beginning of the study and after 6 months, all women were evaluated for the following indices: waist circumference, body mass index, blood pressure, endometrial thickness, as well as serum concentrations of TSH, FT3, FT4 and insulin. RESULTS: Both at baseline and at 6 months, the two groups were statistically similar for each of the considered indices. If percent changes (Δ%, 6 months over baseline) are contrasted in the two groups, serum TSH decreased in the myo-Ins group but increased in the latter, while serum insulin decreased in both groups. CONCLUSIONS: The combination of myo-Ins plus melatonin seems to affect positively glucose metabolism, while myo-Ins only seems to improve thyroid function.

Inositol(s) in thyroid function, growth and autoimmunity.

Myo-inositol and phosphatidylinositol(s) play a pivotal function in many metabolic pathways that, if impaired, impact unfavorably on human health. This review analyzes several experimental and clinical investigations regarding the involvement of this class of molecules in physiological and pathological situations, with a major focus on thyroid. Central issues are the relationship between phosphatidylinositol and thyrotropin (TSH) signaling on one hand, and phosphatydylinositol and autoimmunity on the other hand. Other issues are the consequences of malfunction of some receptors, such as those ones for TSH (TSHR), insulin (IR) and insulin-like growth factor-1 (IGF-1R), or the connection between serum TSH concentrations and insulin resistance. Also covered are insulin resistance, metabolic syndrome and their allied disorders (diabetes, polycystic ovary syndrome [PCOS]), autoimmunity and certain malignancies, with their reciprocal links. Myoinositol has promising therapeutic potential. Appreciation of the inositol pathways involved in certain disorders, as mentioned in this review, may stimulate researchers to envisage additional therapeutic applications.

Molecular mimicry and autoimmune thyroid disease.

Hypothesized 40 years ago, molecular mimicry has been thereafter demonstrated as an extremely common mechanism by which microbes elude immune response and modulate biosynthetic/metabolic pathways of the host. In genetically predisposed persons and under particular conditions, molecular mimicry between microbial and human antigens can turn a defensive immune response into autoimmunity. Such triggering role and its pathogenetic importance have been investigated and demonstrated for many autoimmune diseases. However, this is not the case for autoimmune thyroid disease, which appears relatively neglected by this field of research. Here we review the available literature on the possible role of molecular mimicry as a trigger of autoimmune thyroid disease. Additionally, we present the results of in silico search for amino acid sequence homologies between some microbial proteins and thyroid autoantigens, and the potential pathogenetic relevance of such homologies. Relevance stems from the overlap with known autoepitopes and the occurrence of specific HLA-DR binding motifs. Bioinformatics data published by our group support and explain the triggering role of Borrelia, Yersinia, Clostridium botulinum, Rickettsia prowazekii and Helicobacter pylori. Our new data suggest the potential pathogenic importance of Toxoplasma gondii, some Bifidobacteria and Lactobacilli, Candida albicans, Treponema pallidum and hepatitis C virus in autoimmune thyroid disease, indicating specific molecular targets for future research. Additionally, the consistency between in silico prediction of cross-reactivity and experimental results shows the reliability and usefulness of bioinformatics tools to precisely identify candidate molecules for in vitro and/or in vivo experiments, or at least narrow down their number.

Conservation in the phylum of the local homology of apolipoproteins with the thyroid hormone plasma carriers.

Thyroxine-binding globulin (TBG), transthyretin (TTR), albumin (HSA), plus other plasmatic proteins, which include apolipoproteins, can bind and transport thyroid hormones (TH). In 1994, a 5-residue motif (Y, L/I/M, X, X, V/L/I) conserved in human TBG, TTR, HSA, and human and animal apolipoproteins was identified. Recently, we noticed that a number of residues upstream and downstream that motif are also conserved.We tested in silico the conservation of this larger motif in the many additional animal sequences of TH plasma carriers discovered after 1994. To this aim, we searched for the occurrence of the "new" motif in human and animal apolipoprotein and non-apolipoprotein TH-binding plasmatic proteins, and in a group of randomly selected proteins (2918 sequences from 56 species) not known as TH binders.Our results confirm the conservation of the "new" motif, associated with TH binding, in a total of 426 sequences analyzed (220 belonging to 169 apolipoproteins from 69 species, 206 belonging to 123 nonapolipoproteins from 54 species). Additionally, we found that within such conserved segments some differences between groups of TH plasma carriers exist. Interestingly, number and type of differences appear related to the affinity of each carrier for thyroid hormones. No occurrence of the motif was found in control proteins (alpha- and beta-tubulin, eosinophil cationic protein, endothelin-1, -2 and -3, IgG receptor, tropomyosin, Wnt inhibitory factor 1, erythropoietin, insulin and haptoglobin).Maintenance of a TH-binding domain in apolipoproteins throughout the phylum should be not less important that maintenance of the lipid binding domain.

Hypothyroid myopathy: A peculiar clinical presentation of thyroid failure. Review of the literature.

Abnormalities in thyroid function are common endocrine disorders that affect 5-10 % of the general population, with hypothyroidism occurring more frequently than hyperthyroidism. Clinical symptoms and signs are often nonspecific, particularly in hypothyroidism. Muscular symptoms (stiffness, myalgias, cramps, easy fatigability) are mentioned by the majority of patients with frank hypothyroidism. Often underestimated is the fact that muscle symptoms may represent the predominant or the only clinical manifestation of hypothyroidism, raising the issue of a differential diagnosis with other causes of myopathy, which sometimes can be difficult. Elevated serum creatine kinase, which not necessarily correlates with the severity of the myopathic symptoms, is certainly suggestive of muscle impairment, though it does not explain the cause. Rare muscular manifestations, associated with hypothyroidism, are rhabdomyolysis, acute compartment syndrome, Hoffman's syndrome and Kocher-Debré-Sémélaigne syndrome. Though the pathogenesis of hypothyroid myopathy is not entirely known, proposed mechanisms include altered glycogenolytic and oxidative metabolism, altered expression of contractile proteins, and neuro-mediated damage. Correlation studies of haplotype, muscle gene expression and protein characterization, could help understanding the pathophysiological mechanisms of this myopathic presentation of hypothyroidism.