Screening for drugs potentially interfering with MCT8-mediated T3 transport in vitro identifies dexamethasone and some commonly used drugs as inhibitors of MCT8 activity.

BACKGROUND: Monocarboxylate transporter 8 (MCT8) is the first thyroid hormone transporter that has been linked to a human disease. Besides genetic alterations other factors might impair MCT8 activity. AIM: This study aimed at investigating whether some common drugs having a structural similarity with TH and/or whose treatment is associated with thyroid function test abnormalities, or which behave as antagonists of TH action can inhibit MCT8-mediated T3 transport. METHODS: [125I]T3 uptake and efflux were measured in COS-7 cells transiently transfected with hMCT8 before and after exposure to increasing concentrations of hydrocortisone, dexamethasone, prednisone, prednisolone, amiodarone, desethylamiodarone, dronedarone, buspirone, carbamazepine, valproic acid, and L-carnitine. The mode of inhibition was also determined. RESULTS: Dexamethasone significantly inhibited T3 uptake at 10 µM; hydrocortisone reduced T3 uptake only at high concentrations, i.e. at 500 and 1000 µM; prednisone and prednisolone were devoid of inhibitory potential. Amiodarone caused a reduction of T3 uptake by MCT8 only at the highest concentrations used (44% at 50 µM and 68% at 100 µM), and this effect was weaker than that produced by desethylamiodarone and dronedarone; buspirone resulted a potent inhibitor, reducing T3 uptake at 0.1-10 µM. L-Carnitine inhibited T3 uptake only at 500 mM and 1 M. Kinetic experiments revealed a noncompetitive mode of inhibition for all compounds. All drugs inhibiting T3 uptake did not affect T3 release. CONCLUSION: This study shows a novel effect of some common drugs, which is inhibition of T3 transport mediated by MCT8. Specifically, dexamethasone, buspirone, desethylamiodarone, and dronedarone behave as potent inhibitors of MCT8.

Effects of three treatment modalities (diet, myoinositol or myoinositol associated with D-chiro-inositol) on clinical and body composition outcomes in women with polycystic ovary syndrome.

OBJECTIVE: To evaluate, in overweight/obese PCOS women, which of three distinct treatment modalities achieved the greatest clinical benefits in terms of clinical and body composition outcomes. PATIENTS AND METHODS: Forty-three polycystic ovary syndrome (PCOS) overweight/obese patients were randomly treated for 6 months with: only diet (Group 1, n = 21); diet and myo-inositol (MI) 4 g + folic acid 400 µg daily (group 2, n = 10); diet in association with MI 1.1 g + D-chiroinositol (DCI) 27.6 mg + folic acid 400 µg daily (group 3, n = 13). Menstrual cycle, Ferriman-Gallwey score, body mass index (BMI), waist circumference, hip circumference, waist-hip ratio (WHR), and body composition by bioimpedentiometry were measured at baseline, 3 and 6 months. RESULTS: Body weight, BMI, waist and hip circumferences decreased significantly in all groups. There was a significant difference between the 3 groups regarding the restoration of menstrual regularity (p = 0.02) that was obtained in all patients only in-group 3. CONCLUSIONS: MI+DCI in association with diet seems to accelerate the weight loss and the fat mass reduction with a slight increase of percent lean mass, and this treatment contributes significantly in restoring the regularity of the menstrual cycle.

Incidence of hypocalcemia and hypercalcemia in hospitalized patients: Is it changing?

Disorders of calcium metabolism are frequently encountered in routine clinical practice. However limited data are available on the epidemiology of hypocalcemia and hypercalcemia in hospitalized patients. Our aim was to evaluate the frequency of hypocalcemia and hypercalcemia in hospitalized patients. This is a retrospective study based on the laboratory results of all hospitalized subjects (n = 12,334) whose calcemia was determined between January 1st, 2011 and December 31st, 2014. Measurements of serum calcium were carried out by a single centralized laboratory. Hypocalcemia was defined as serum calcium levels <8.2 mg/dl and hypercalcemia as serum calcium levels >10.4 mg/dl. Albumin correction was applied to adjust serum calcium values. Overall, hypocalcemia accounted for 27.72% (n = 3420) and hypercalcemia for 4.74% (n = 585) of the 12,334 inpatients. The highest prevalence of hypocalcemia was found in patients over 65 yr. (n = 2097, 61.31%) vs. younger subjects, while the highest prevalence of hypercalcemia was observed in patients aged 0-18 yr. (n = 380, 64.95%). Hypocalcemia was more often encountered in males (n = 1952, 57.07%) while no gender differences were found regarding hypercalcemia. Incidence of hypocalcemia changed over time varying from 35.42% (n = 1061) in 2011 to 21.93% (n = 672) in 2014 (r = -0.98; p = 0.01). Differently, incidence of hypercalcemia did not significantly increase significantly from 3.47% (n = 104) in 2011 to 6.92% (n = 211) in 2014 (r = 0.94; p = 0.052). Despite increased awareness about electrolytes disturbance, physicians should consider calcium levels because of life-threatening consequences associated to hypo- and hypercalcemia. Patient's gender and age could be associated to a different risk of calcium disturbance in hospitalized patients.

CXCL8 and CXCL11 chemokine secretion in dermal fibroblasts is differentially modulated by vanadium pentoxide.

An increase in skin rashes or atopic dermatitis has been observed in individuals working with vanadium. However, to the best of our knowledge no in vivo or in vitro studies have evaluated the effect of exposure to vanadium in dermal fibroblasts. Cells viability and proliferation were assessed by WST­1 assay, cells were treated with increasing concentrations of V2O5 (1, 10 and 100 nM). CXCL8 and CXCL11 concentrations were measured in the supernatants using an ELISA assay. V2O5 was not observed as having a significant effect on dermal fibroblast's viability and proliferation. However, it was revealed that V2O5 was able to induce the secretion of CXCL8 and CXCL11 chemokines into dermal fibroblasts. V2O5 synergistically increased the effect of interferon (IFN)γ on CXCL11 secretion. In addition, V2O5 synergistically increased the effect of the tumor necrosis factor α on CXCL8 secretion and abolished the inhibitory effect of IFNγ. V2O5 induction of CXCL8 and CXCL11 chemokines may lead to the appearance and perpetuation of an inflammatory reaction into the dermal tissue. Further studies are required to evaluate dermal integrity and manifestations in subjects occupationally exposed, or living in polluted areas.

Induction of Th1 chemokine secretion in dermal fibroblasts by vanadium pentoxide.

Vanadium is a soft, silvery­grey metal with a number of different oxidation states. The most common commercial form of vanadium is vanadium pentoxide (V2O5). All vanadium compounds are considered toxic. An increase in skin rashes has been observed in certain vanadium workers, including the development of atopic dermatitis. However, to the best of our knowledge, no prior in vivo or in vitro studies have evaluated the effect of vanadium exposure in human dermal fibroblasts. The present study evaluated the effect of V2O5 on proliferation and chemokine secretion in dermal fibroblasts. The results revealed that V2O5 had no significant effect on the viability or proliferation of fibroblasts, however it was able to induce the secretion of T­helper (Th)1 chemokines from dermal fibroblasts, synergistically increasing the effect of important Th1 cytokines, including interferon­Î³ and tumor necrosis factor­α. Through these processes, V2O5 may lead to the induction and perpetuation of an inflammatory reaction in dermal tissue. The induction and perpetuation of inflammation in the dermis and the variety of involved candidate genes may be at the base of V2O5­induced effects following occupational and environmental exposures. Further studies are necessary to evaluate dermal integrity and manifestations in subjects who are occupationally exposed, or living in polluted areas.

Vanadium pentoxide induces the secretion of CXCL9 and CXCL10 chemokines in thyroid cells.

Vanadium is a grey metal, existing in different states of oxidation, whose most common form in commercial products is vanadium pentoxide (V2O5). All vanadium compounds have been considered toxic. A carcinogenic role of vanadium on the thyroid has recently been proposed. However no in vivo or in vitro studies have evaluated thyroid disruption in humans and/or animals after exposure to vanadium. In the present study we evaluate the effect of V2O5 on proliferation, and chemokine secretion in normal thyrocytes. Our study demonstrated that V2O5 has no effect on thyroid follicular cell viability or proliferation, but it is able to induce the secretion of T-helper (Th)1 chemokines into the thyroid, synergistically increasing the effect of important Th1 cytokines such as interferon (IFN)γ and tumor necrosis factor (TNF)α. Through this process, V2O5 promotes the induction and perpetuation of an inflammatory reaction in the thyroid. Further studies are necessary to evaluate thyroid function, and nodules, in subjects occupationally exposed, or living in polluted areas.

Diagnosis and management of treatment-refractory hypothyroidism: an expert consensus report.

There is a frequently encountered subset of hypothyroid patients who are refractory to standard thyroid hormone replacement treatment and require unexpectedly high doses of levothyroxine. In addition to clinical situations where hypothyroid patients are non-compliant, or where there is the possibility of excipient-induced disease exacerbation (gluten/celiac disease), therapeutic failure may be due to impaired absorption of the administered drug. The common approach to managing patients with unusual thyroxine needs is to escalate the dose of levothyroxine until targeted TSH levels are achieved. This approach can increase the risk for prolonged exposure to supratherapeutic doses of levothyroxine, which increase the chances of adverse outcomes. Repeated adjustments of levothyroxine can also escalate the costs of treatment, as frequent office visits and laboratory tests are required to determine and maintain the desired dose. Clinicians should take a systematic approach to managing patients whom they suspect of having treatment-refractory hypothyroidism. This may include searching for, and adjusting, occult medical conditions and/or other factors that may affect the absorption of levothyroxine, before up-titrating the dose of traditional levothyroxine therapy. Depending on the underlying pathology, another approach that may be considered is to try alternative formulations of levothyroxine that are less susceptible to intolerance issues related to excipients, or, in some cases, to malabsorption. The early discovery of these factors via a thoughtful patient work-up may avoid unnecessary thyroid medication adjustments and their consequences for both patients and clinicians.

Favorable effects of myo-inositol, selenomethionine or their combination on the hydrogen peroxide-induced oxidative stress of peripheral mononuclear cells from patients with Hashimoto's thyroiditis: preliminary in vitro studies.

OBJECTIVE: The aim of this study was to assess whether blood mononuclear cells (PBMC) from Hashimoto's thyroiditis (HT) and control women, were protected from in vitro H2O2-induced oxidative stress after addition of antioxidants. PATIENTS AND METHODS: PBMC, from 8 HT women and 3 healthy women (controls), were cultured in the presence of 200 µM H2O2 alone, with subsequent addition of myo-inositol (Myo) (0.25, 0.5, 1.0 µM), selenomethionine (SelMet) (0.25, 0.5, 1.0 µM), or their combination (0.25+0.25, 0.5+0.5, 1.0+1.0 µM). PBMC proliferation, vitality, genotoxicity (Comet score) and secretion in the medium of the chemokines CXCL10 [IP10], CCL2 e CXCL9 [MIG] were the indices measured. RESULTS: PBMC proliferation was decreased by H2O2 alone, and it decreased further and dose-dependently in either group (greatest decrease with Myo+SelMet in HT). H2O2 alone decreased vitality by 5% in controls and 10% in the HT group, but vitality was rescued by the three additions. The addition of H2O2 alone increased the Comet score at +505% above baseline in controls and +707% in HT women. In either group, each addition dose-dependently contrasted genotoxicity. Concentrations of chemokines in the medium were increased by H2O2 alone, and in HT women more than in controls. Each addition dose-dependently decreased these concentrations in either group, and often below baseline levels, with Myo+SelMet being the most potent addition (up to approximately -80% of baseline). CONCLUSIONS: The tested antioxidants exert beneficial effects on PBMC exposed in vitro to H2O2-induced oxidative stress in both control and HT women. Particularly, the association Myo+SelMet is the most effective. After the demonstration of a favorable in vitro outcomes in a large cohort of HT patients, we could predict favorable in vivo outcomes given by the same supplement. Thus, one can select HT patients with a high chance of benefit from supplementation.

Myo-inositol and selenium reduce the risk of developing overt hypothyroidism in patients with autoimmune thyroiditis.

OBJECTIVE: The beneficial effects obtained by myo-inositol in association with seleno-methionine in patients affected by subclinical hypothyroidism have been recently demonstrated. Here, we evaluate the immune-modulating effect of myo-inositol in association with seleno-methionine in patients with euthyroid autoimmune thyroiditis (AT). PATIENTS AND METHODS: Twenty-one consecutive Caucasian patients with newly diagnosed euthyroid chronic AT were evaluated. All subjects were treated with myo-inositol in association with selenium (600 mg/83 mg) tablets, twice per day, for six months. A complete thyroid assessment was done before the treatment, and after six months. RESULTS: After the treatment thyroid-stimulating hormone (TSH) levels significantly declined with respect to basal values, overall in patients with an initial TSH value in the high normal range (2.1

Gly972Arg of IRS-1 and Lys121Gln of PC-1 polymorphisms act in opposite way in polycystic ovary syndrome.

PURPOSE: Polycystic ovary syndrome (PCOS) was associated with a number of polymorphisms of genes involved in insulin signaling. So far, they have been studied separately. The aim of this study was to verify the impact of the coexistence of two polymorphisms of insulin signaling. METHODS: One hundred consecutive PCOS women (diagnosed by Rotterdam criteria) and 45 age-matched healthy women were genotyped for two polymorphisms: Gly972Arg of IRS-1 and Lys121Gln of PC-1. Also, they underwent clinical evaluation, blood sampling for measurement of metabolic and hormonal indices, and a 75-g oral glucose tolerance test (OGTT). RESULTS: Comparing PCOS women with controls, the rate of homo-/heterozygosity was significantly greater (50 vs. 24.5%, P = 0.004) for IRS-1 polymorphism, but insignificantly greater (20 vs. 13.3%, P = 0.33) for PC-1 polymorphism. In PCOS women, compared with controls, the genotypes IRS-1 hetero/PC-1 wild type (WT) (36 vs. 17.8%, P = 0.03) and IRS-1 hetero/PC-1 hetero (14 vs. 6.7%, P = 0.20) were overrepresented at the expense of IRS-1 WT/PC-1 WT (44 vs. 68.8%, P = 0.005), while IRS-1 WT/PC-1 hetero was similarly represented (6 vs. 6.7%). Based on genotype, metabolic and hormonal indices changed significantly. For instance, six indices (HOMA-IR, fasting insulin, insulin area under the curve at OGTT, triglycerides, total and calculated free testosterone) were the highest in IRS-1 hetero/PC-1 WT women. CONCLUSIONS: Genetic variations in insulin signaling contribute to the extent and the variability of metabolic and hormonal derangement.

Cortical excitability in patients with resistance to thyroid hormone compared to patients with hypothyroidism and euthyroid controls: a transcranial magnetic stimulation study.

Resistance to thyroid hormone (RTH) describes a rare syndrome in which serum levels of thyroid hormones are elevated but serum levels of thyroid stimulating hormone (TSH) are unsuppressed. The importance of thyroid hormones for the normal function of the adult brain is corroborated by the frequent association of thyroid dysfunctions with neurological and psychiatric symptoms. In this study we investigated whether adult thyroid hormone resistance affects cortical excitability and modulates inhibitory and excitatory intracortical circuitries by using transcranial magnetic stimulation. Cortical excitability was probed with transcranial magnetic stimulation in 4 patients with thyroid hormone resistance, 10 patients affected by overt hypothyroidism (OH) and 10 age-matched healthy controls. We tested motor thresholds, motor evoked potential recruitment curve, cortical silent period (CSP), short interval intracortical inhibition (SICI) and intracortical facilitation. In both OH and RTH patients, the inhibitory cortical circuits were affected compared with euthyroid controls, but in opposite ways. In OH patients, CSP was prolonged and SICI was decreased. On the contrary, in RTH patients CSP was shortened and SICI was increased. Thyroid hormones may influence cortical excitability and cortical inhibitory circuits.

Thyroid hormone autoantibodies: are they a better marker to detect early thyroid damage in patients with hematologic cancers receiving tyrosine kinase inhibitor or immunoregulatory drug treatments?

BACKGROUND: Unlike cytotoxic agents, novel antineoplastic drugs can variably affect thyroid function and so impair patient outcomes. However, the widely used standard thyroid tests have demonstrated low sensitivity for detecting early thyroid damage that leads to dysfunction of the gland. To find a more reliable thyroid marker, we assessed the presence of antibodies binding thyroid hormones (thAbs) in a cancer population undergoing potentially thyrotoxic treatment. METHODS: From April 2010 to September 2013, 82 patients with hematologic malignancies treated with tyrosine kinase inhibitors or immunoregulatory drugs were recruited. Healthy volunteers (n = 104) served as control subjects. Thyroid function, autoimmunity tests, thAbs, and thyroid sonography were assessed once during treatment. RESULTS: Overall, thAb positivity was recorded in 13% of the entire cohort. In most cases, the thAbs were of a single type, with a predominance of T3 immunoglobulin G. More specifically, thAbs were detected in 11 cancer patients; and abnormal levels of thyroid-stimulating hormone, thyroglobulin antibody, and thyroperoxidase antibody were detected in 6 (p = 0.05), 0 (p = 0.0006), and 2 cancer patients (p = 0.001) respectively. Ultrasonographic alterations of the thyroid were observed in 12 cancer patients. In contrast, of the 104 healthy control subjects, only 1 was positive for thAbs (1%). CONCLUSIONS: We have demonstrated for the first time that thAbs are a reliable marker of early thyroid dysfunction when compared with the widely used standard thyroid tests. A confirmatory prospective trial aiming at evaluating thAbs at various time points during treatment could clarify the incidence and timing of antibody appearance.

Growth Hormone and Cerebral Amyloidosis.

Great interest has recently been focused on a paper reporting characteristic deposits of amyloid-ß protein associated with Alzheimer's disease in brains of adults who died of Creutzfeldt-Jakob disease. As they had contracted such disease after treatment with prion-contaminated human growth hormone extracted from cadaver-derived pituitaries, the authors have suggested that interhuman transmission of Alzheimer's disease had occurred. Our previous research led us to find that amyloid-forming peptides share amino acid sequence homology, summarized by a motif. Here, we probed the amino acid sequence of human growth hormone for such a motif, and found that 2 segments fit the motif and are potentially amyloid-forming. This finding was confirmed by Aggrescan, another well-known software for the prediction of amyloidogenic peptides. Our results, taken together with data from the literature that are missing in the aforementioned paper and associated commentaries, minimize the contagious nature of the iatrogenically-acquired coexistence of Creutzfeldt-Jakob disease and Alzheimer's disease. In particular, the above mentioned paper misses literature data on intratumoral amyloidosis in growth hormone- and prolactin-secreting adenomas, tumors relatively frequent in adults, which are often silent. It cannot be excluded that some pituitaries used to extract growth hormone contained clinically silent microadenomas, a fraction of which containing amyloid deposits, and patients might had received a fraction of growth hormone (with or without prolactin) that already was an amyloid seed. The intrinsic amyloidogenicity of growth hormone, in the presence of contaminating prion protein (and perhaps prolactin as well) and amyloid-ß contained in some cadavers' pituitaries, may have led to the observed co-occurring of Creutzfeldt-Jakob disease and Alzheimer's disease.

TP53 polymorphism may contribute to genetic susceptibility to develop Hashimoto's thyroiditis.

PURPOSE: p53, which is encoded by the tumor suppressor gene TP53, plays a crucial role in the regulation of mechanisms of cell cycle arrest and apoptosis. Some SNPs of TP53, involving a different apoptotic ability of p53, have been associated with increased susceptibility to develop autoimmune diseases as well as cancer. We investigated the genotypic distribution of TP53 exon 4 SNPs in a cohort of Caucasian patients affected by Hashimoto's thyroiditis (HT). METHODS: Peripheral blood for DNA extraction was collected from 109 Caucasian unrelated subjects, 79 HT patients and 30 healthy controls. SNPs analysis was carried out by amplification and sequencing of exon 4 TP53. RESULTS: For the Pro72Arg (rs 1042522) SNP we found these rates in HT patients: 11.4% wild-type C/C (Pro72Pro), 24.0% heterozygous G/C (Pro72Arg), 64.6% homozygous G/G (Arg72Arg). The corresponding rates in healthy controls were 10, 46.7 and 43.3%, respectively. Thus, significantly different were G/C heterozygosity (24.0 vs 46.7 %, p = 0.039) and G/G homozygosity (64.6 vs 43.3%, p = 0.042). These differences were also confirmed when comparing our study population to published Caucasian control groups. The other described SNPs (Pro34Pro rs 11575998, Pro36Pro rs1800370, Pro47Ser rs1800371, and Arg110Leu rs 11540654) were absent or very rare in our study population. CONCLUSIONS: Our preliminary data, the first on a Caucasian population, indicate an increased prevalence of the homozygous genotype Arg/Arg and a decreased prevalence of heterozygous genotype Arg/Pro of rs 1042522 in HT patients compared to controls, suggesting that such SNP may contribute to confer susceptibility to HT.

Pregnancy outcome in women treated with methimazole or propylthiouracil during pregnancy.

PURPOSE: Control of thyroid function in hyperthyroid women during pregnancy is based on antithyroid drugs (ATD) [propylthiouracil (PTU) and methimazole (MMI)]. While a teratogenic effect has been suggested for MMI and, more recently, for PTU, a clear demonstration is still lacking. Aim of this study was to assess the safety of ATD during pregnancy. METHODS: A total of 379 pregnancies were retrospectively recruited in eight Italian Departments of Endocrinology and divided in five groups: (1) MMI-treated and euthyroid throughout pregnancy (n = 89); (2) MMI-treated and hyperthyroid on at least two occasions (n = 35); (3) PTU-treated women and euthyroid throughout pregnancy (n = 32); (4) PTU-treated women and hyperthyroid on at least two occasions (n = 20); and (5) non-ATD-treated (n = 203). Data on maternal thyroid function, miscarriages, type of delivery, neonatal weight, length and TSH, perinatal complications and congenital malformation were analyzed. RESULTS: The gestational age at delivery, the rate of vaginal delivery, neonatal weight, length and neonatal TSH did not significantly differ among groups. In all groups, the rates of spontaneous miscarriage and of major congenital malformations were not higher than in the general population. No newborns were born with a phenotype similar to those described in the "MMI embryopathy". CONCLUSIONS: While a clear demonstration of a teratogenic effect of MMI is currently lacking, it seems reasonable to follow the current guidelines and advice for PTU treatment in hyperthyroid women during the first trimester of pregnancy. Further, large and prospective worldwide studies will be needed to fully clarify the issue of ATD safety during pregnancy.

High prevalence of circulating autoantibodies against thyroid hormones in vitiligo and correlation with clinical and historical parameters of patients.

BACKGROUND: Autoantibodies against thyroid hormones (THAbs) directed towards triiodothyronine (T3-Ab) and/or thyroxine (T4-Ab) are very rare in the general population. They are increased in some nonthyroidal autoimmune diseases, where they seem to predict autoimmune thyroid disorders (ATDs). So far, their presence in patients with vitiligo has not been evaluated, but it might have a possible predictive role. OBJECTIVES: To assess the prevalence of THAbs in a group of vitiligo patients and to correlate their presence with clinical and historical parameters. METHODS: In total 79 patients with nonsegmental vitiligo and 100 controls were examined. Clinical characteristics of vitiligo and family and personal medical history were evaluated. Antinuclear autoantibodies, thyroid hormones and thyroid autoantibodies were measured. IgM T3-Ab, IgG T3-Ab, IgM T4-Ab and IgG T4-Ab were assayed by a radioimmunoprecipitation technique. Fisher's test, Student's t-test and χ(2)-test were used for statistical analysis. RESULTS: Overall 77 of 79 patients (97%) had at least one type of THAb (11 T3-Ab, 10 T4-Ab, 56 both). In the control group, only one person (1%) had THAbs. In patients with vitiligo, T3-Abs were significantly associated with leucotrichia (IgM+IgG, P = 0.033; IgG, P = 0.039; IgM, P = 0.005) and thyroglobulin autoantibodies (IgM+IgG, P = 0.031; IgG, P = 0.058), while the absence of T3-Ab was related to personal history of cancer (IgM+IgG, P = 0.021; IgG, P = 0.039). T4-Abs were significantly associated with vitiligo activity (IgM+IgG, P < 0.001; IgM, P = 0.037) and duration (IgG, P = 0.013). CONCLUSIONS: The surprisingly high prevalence of THAb in patients with vitiligo and their associations suggest a possible pathogenetic role in the disease and stress the tight link between vitiligo and ATDs. Further evaluation in a larger group of patients and an adequate follow-up are needed to define their potential predictive role.

Influence of high-normal serum TSH levels on major cardiovascular risk factors and Visceral Adiposity Index in euthyroid type 2 diabetic subjects.

Although several observations indicate that serum TSH levels in the high normal range are related to cardiovascular (CVD) risk factors in the general population, similar data are limited in diabetic subjects. The aim of this study was to investigate the potential associations between TSH serum levels within the normal range and major metabolic and non-metabolic CVD risk factors in a cohort of euthyroid type 2 diabetic subjects. Thyroid hormones, TSH levels, anthropometric parameters, lipid profile, glucose control, and blood pressure were measured in 490 euthyroid type 2 diabetic subjects, consecutively attending two outpatient diabetic units in Southern Italy. In all subjects, we also calculated the Visceral Adiposity Index (VAI), an obesity-related index associated with CVD risk. Diabetic women showed higher mean serum TSH levels and lower FT4 concentration than diabetic men, while FT3 levels were comparable in the two genders. Stratifying the study population according to quartiles of TSH levels, subjects in the highest TSH quartile were more likely to be female and younger, with higher values of BMI and waist circumference (P = 0.05 both), higher triglycerides (P = 0.002) and non-HDL cholesterol concentrations (P = 0.01), higher VAI values (P = 0.02), and lower FT4 levels (P = 0.05), when compared to those in the lowest quartile. At multivariate analysis, a younger age, female gender, triglycerides levels, and waist circumference were independently associated with higher TSH levels. In conclusion, in type 2 diabetic subjects with no evidence of thyroid disease, higher TSH concentrations within the normal range were more frequent in women and in younger subjects, and they were associated with visceral obesity and higher triglycerides concentrations, two well-known CVD risk factors.

Ação de inseticidas sobre os ovos e lagartas da broca-pequena-dofruto do tomate, em bioensaio de laboratório / Action of insecticides on the eggs and larvae of the borer small-fruit tomato in laboratory bioassay

A broca-pequena-do-fruto é praga-chave na cultura do tomate por causar danos significativos às partes reprodutivas. Devido a isto, foi objetivo deste trabalho avaliar a eficiência de inseticidas sobre ovos e lagartas recém-emergidas, com e sem a adição de óleo vegetal (0,25%), em bioensaios de laboratório. Frutos com ovos foram coletados em cultivo de tomate estaqueado na quinzena posterior à última aplicação de agrotóxicos, sendo selecionados os frutos com ovos de coloração variável de branco a marrom claro, com 1 e 4 dias de incubação, e imersos em 1 L da calda inseticida por 5 segundos. O delineamento estatístico utilizado foi o inteiramente casualizado, com média de 18 frutos nos tratamentos e de, aproximadamente, 4 ovos/fruto. A avaliação da ação inseticida de 24 produtos foi realizada após a imersão na calda inseticida, observando-se, sob microscópio estereoscópico, os ovos quanto à integridade do córion, textura e coloração, lagartas emergidas, bem como os orifícios de entrada e de saída das larvas (aos 7 e 21 dias). Os produtos testados diferiram da testemunha quanto à densidade de lagartas eclodidas, bem como quanto à redução populacional de lagartas, podendo-se destacar Trebon 100 SC (etofenprox; 200 mL do produto comercial/100 L), Lannate BR (methomil; 100 mL), Thiobel 500 (cartap; 250 g) e Vertimec 18 CE (abamectin; 100 mL). A adição de óleo vegetal resultou em incremento na eficiência dos produtos.

Action of insecticides on tomato fruit borer eggs and larvae using laboratory bioassay. The tomato fruit borer is a key tomato pest in light of its damages to the plants’ reproductive parts. Therefore, the present study was aimed to evaluate the effectiveness of insecticides on the eggs and newly hatched larvae, when applied alone or associated with vegetable oil (0.25%), in laboratory bioassays. Fruits with eggs were collected in staked tomato crops fifteen days after the last application of agro-chemicals, selecting the fruits with eggs colored from white to light brown, which had between 1 and 4 days of incubation, followed by immersion of the fruit for 5 seconds in 1 L of the insecticide solutions. The experimental design was completely randomized, with an average of 18 fruits per treatment (24 insecticides and a control) and about 4 eggs per fruit. The evaluations were performed 7 and 21 days after immersion, using a stereomicroscope to observe the corion integrity, egg color, number of larvae emerged, and larvae fruit holes (entry and exit). The insecticides differed significantly from the control, most notably Trebon SC 100 (etofenprox; 200 mL of the commercial product/100 L), Lannate BR (methomil; 100 mL), Thiobel 500 (cartap; 250 g) and Vertimec 18 CE (abamectin; 100 mL). The addition of vegetable oil increased the insecticides’ effectiveness.

HGF/C-MET system pathways in benign and malignant histotypes of thyroid nodules: an immunohistochemical characterization.

OBJECTIVE: Upon binding with HGF, the thyrosine-kinase receptor c-met induces cell growth, scattering and morphogenic effects via the trasducers STAT3 and phosphorylated-STAT3, PI3K/Akt, Rho. HGF, c-met and STAT3 are expressed with very high frequency in papillary thyroid carcinomas (PTC), suggesting a role in PTC. Herein we first investigate the simultaneous expression of HGF, c-met, STAT3, phosphor-STAT3, PI3K, Akt and Rho in thyroid nodules. DESIGN AND METHODS: Using immunohistochemistry, we studied: 30 colloid nodules (CN), 18 hyperplastic nodules (HN), 20 follicular adenomas (FA), 15 oncocytic adenomas (OA), 20 PTC, 16 follicular carcinomas (FTC) and 6 anaplastic carcinomas (ATC). RESULTS: All 7 proteins were expressed in 15% of FA (with HGF, PI3K and Rho stromal reactivity) and 25% of PTC, and the combination HGF/c-met/STAT3/ pSTAT3/PI3K was expressed by all PTC, each protein being expressed by tumor cells. In contrast, 13/16 FTC (81%) exhibited immunoreactivity for PI3K (both epithelial and stromal), and 100% of ATC was PI3K+ (both epithelial and stromal) and Rho+ (epithelial). Epithelial expression of PI3K correlated with the clinical behavior of histotypes and, within FTC, the proportion of PI3K+ cells correlated with both the clinical and pathological stage (r=0.95; p<0.001). As for the shared epithelial expression of PI3K, this concerned approximately one-fourth of tumor cells in FTC and ATC vs one-thirtieth in PTC. CONCLUSIONS: Our data may have practical implications for the targeted medical therapy of thyroid cancer arising from the follicular epithelium.