Hypothalamic AMPKα2 regulates liver energy metabolism in rainbow trout through vagal innervation.

Hypothalamic AMPK plays a major role in the regulation of whole body metabolism and energy balance. Present evidence has demonstrated that this canonical mechanism is evolutionarily conserved. Thus, recent data demonstrated that inhibition of AMPKα2 in fish hypothalamus led to decreased food intake and liver capacity to use and synthesize glucose, lipids, and amino acids. We hypothesize that a signal of abundance of nutrients from the hypothalamus controls hepatic metabolism. The vagus nerve is the most important link between the brain and the liver. We therefore examined in the present study whether surgical transection of the vagus nerve in rainbow trout is sufficient to alter the effect in liver of central inhibition of AMPKα2. Thus, we vagotomized (VGX) or not (Sham) rainbow trout and then intracerebroventricularly administered adenoviral vectors tagged with green fluorescent protein alone or linked to a dominant negative isoform of AMPKα2. The inhibition of AMPKα2 led to reduced food intake in parallel with changes in the mRNA abundance of hypothalamic neuropeptides [neuropeptide Y (npy), agouti-related protein 1 (agrp1), and cocaine- and amphetamine-related transcript (cartpt)] involved in food intake regulation. Central inhibition of AMPKα2 resulted in the liver having decreased capacity to use and synthesize glucose, lipids, and amino acids. Notably, these effects mostly disappeared in VGX fish. These results support the idea that autonomic nervous system actions mediate the actions of hypothalamic AMPKα2 on liver metabolism. Importantly, this evidence indicates that the well-established role of hypothalamic AMPK in energy balance is a canonical evolutionarily preserved mechanism that is also present in the fish lineage.

Knowledge and attitude of health staff towards breastfeeding in NICU setting: are we there yet? An Italian survey.

The benefits of human milk in preterm infants, a population at high risk for developing adverse outcomes for which breast milk is a protective factor, are widely acknowledged. However, preterms' admission in a neonatal intensive care unit (NICU) and newborn's clinical conditions have been described as significant barriers, leading to lower rates of breastfeeding initiation and duration. Healthcare workers play a crucial role in encouraging breastfeeding. We conducted a cross-sectional survey among nurses working in six Italian NICUs, exploring their knowledge and attitude towards breastfeeding. Although the majority of nurses had a specific breastfeeding education, our results show still some variations among answers regarding aspects of breastfeeding support in this setting. Specifically, family-centered care, transition feeding to the breast, and skin-to-skin practice, despite being extensively addressed by the Neo Baby-Friendly Hospital Initiative, are the items that highlighted a range of answers that could result in conflicting information to mothers.Conclusion: By underlining the gaps of knowledge and attitude towards breastfeeding of nurses working in NICUs, this study provides an insight into what needs to be improved, with the aim of promoting higher rates of breastfeeding in the preterm population. What is Known: • Breastfeeding is particularly challenging in the preterm population, despite its universally recognized health benefits. • Improving healthcare professionals' knowledge and attitude towards breastfeeding has been shown to be crucial for promoting breastfeeding in NICUs. What is New: • Our results provide useful insight into nurses' knowledge and attitude towards breastfeeding in NICU settings. • By acknowledging strengths and weaknesses highlighted by this study, tailored strategies could be developed to improve health staff breastfeeding education and support to parents in NICU settings.

Cognition and dementia in older patients with epilepsy.

With advances in healthcare and an ageing population, the number of older adults with epilepsy is set to rise substantially across the world. In developed countries the highest incidence of epilepsy is already in people over 65 and, as life expectancy increases, individuals who developed epilepsy at a young age are also living longer. Recent findings show that older persons with epilepsy are more likely to suffer from cognitive dysfunction and that there might be an important bidirectional relationship between epilepsy and dementia. Thus some people with epilepsy may be at a higher risk of developing dementia, while individuals with some forms of dementia, particularly Alzheimer's disease and vascular dementia, are at significantly higher risk of developing epilepsy. Consistent with this emerging view, epidemiological findings reveal that people with epilepsy and individuals with Alzheimer's disease share common risk factors. Recent studies in Alzheimer's disease and late-onset epilepsy also suggest common pathological links mediated by underlying vascular changes and/or tau pathology. Meanwhile electrophysiological and neuroimaging investigations in epilepsy, Alzheimer's disease, and vascular dementia have focused interest on network level dysfunction, which might be important in mediating cognitive dysfunction across all three of these conditions. In this review we consider whether seizures promote dementia, whether dementia causes seizures, or if common underlying pathophysiological mechanisms cause both. We examine the evidence that cognitive impairment is associated with epilepsy in older people (aged over 65) and the prognosis for patients with epilepsy developing dementia, with a specific emphasis on common mechanisms that might underlie the cognitive deficits observed in epilepsy and Alzheimer's disease. Our analyses suggest that there is considerable intersection between epilepsy, Alzheimer's disease and cerebrovascular disease raising the possibility that better understanding of shared mechanisms in these conditions might help to ameliorate not just seizures, but also epileptogenesis and cognitive dysfunction.

An evaluation of the psychosocial impact of epilepsy on marriage in the United Kingdom.

OBJECTIVES: The primary objective of this study was to measure the psychosocial burden for persons with epilepsy (PWEs) and for their spouses and to compare and correlate this with the clinical burden of seizures. A secondary objective was to examine the presence of gender-specific differences in the perception of psychosocial burdens by both PWE and their spouses, as well as in the factors that may influence this perception. We also sought to delineate differences in perceived stigmatization if the onset of epilepsy was within matrimony or if seizure onset was prior to marriage. METHODS: A questionnaire was constructed from previously validated instruments to measure stigma and was administered to 50 PWE-spouse pairs. A copy was applied to the PWE, and another was administered separately to the spouse. The medical notes were scrutinized by a Consultant Neurologist to enable an assessment of seizure severity for each type of seizure that the PWE experienced. Pearson correlation significance was examined at 95% level of significance. RESULTS: Higher seizure severity over the month prior to data collection correlated with smaller reporting differences in psychosocial outcome between spouses and the PWE (p = 0.005), an effect that maintained significance when the period over which seizure severity was evaluated was extended to one year (p = 0.021). Regarding gender-specific differences, low mood over the month prior to administration of the questionnaire was associated with worse psychosocial scores in females only (p = 0.001). Significant impairment in driving was correlated with worse outcomes in males only (p = 0.008). Male spouses' judgment on the 'overall health' of their wife correlated to seizure severity (p = 0.003). However, the psychosocial scores reported by male spouses were inversely correlated to those of the PWE (p = 0.042). Finally, in PWE with seizure onset within marriage, a high degree of perceived stigmatization (p = 0.025) and low mood (p = 0.004) was correlated to worse psychosocial functioning. This group also tended to be more anxious when the PWE was experiencing severe seizures (p = 0.013). CONCLUSION: Although severe seizures in this sample of couples were correlated with a smaller discrepancy in perceived seizure burden, gender-specific differences in perception of epilepsy-related psychosocial burden exist. This is true for both PWE and their spouses. Irrespective of gender, onset of epilepsy within matrimony was correlated with higher levels of anxiety and stigma. These factors need to be considered during efforts to reduce epilepsy-related stigmatization, as well as in tailoring therapies that aim to support the spouse as well as the PWE.

2017 ATA guidelines on the management of thyroid dysfunctions in pregnancy: what do OB/GYNs need to know?

In the past two decades, the issue of thyroid dysfunctions during pregnancy and the postpartum period received increasing attention by both endocrinologists and obstetrics/gynecologists (OB/GYNs), the latter often became the first to diagnose an impaired thyroid function in pregnant women. In this setting, a series of different clinical guidelines have been published and reviewed, the latest ones being represented by the 2017 ATA guidelines, which extensively address a wide variety of topics, including iodine supplementation, thyroid autoimmunity, hyper- and hypo-thyroidism, thyroid nodules and cancer, post-partum management, as well as the need for pre-conception screening. Aim of this editorial is to offer a practical guidance to the OB/GYN reader by focusing upon evidence-based changes introduced by the latest guidelines, with particular regard to: (a) prescribing further endocrine testing before referral; (b) providing evidence-based answers to some of the frequently asked questions.

GENDER INFLUENCES THE CLINICAL PRESENTATION AND LONG-TERM OUTCOME OF GRAVES DISEASE.

OBJECTIVE: The outcome of antithyroid drug (ATD) treatment for Graves disease (GD) is difficult to predict. In this study, we investigated whether male gender, besides other factors usually associated with a poor outcome of ATD treatment, may affect disease presentation and predict the response to medical treatment in subjects with GD. METHODS: We studied 294 patients with a first diagnosis of GD. In all patients, ATD treatment was started. Clinical features, thyroid volume, and eye involvement were recorded at baseline. Serum levels of free thyroxine (FT4), free triiodothyronine (FT3), thyroid-stimulating hormone (TSH), and TSH-receptor antibodies (TRAb) were measured at baseline and during the follow-up. Treatment outcome (FT4, FT3, and TSH serum levels and further treatments for GD after ATD withdrawal) was evaluated. RESULTS: When compared to women, men showed a significantly larger thyroid volume and a higher family positivity for autoimmune diseases. During ATD, the mean serum levels of TSH, FT4, FT3, and TRAb did not differ between groups. Within 1 year after ATD discontinuation, relapse of hyperthyroidism was significantly more frequent in men than in women. Within the 5-year follow-up period, the prevalence of men suffering a late relapse was higher compared with that of women. The outcome at the end of the 5-year follow-up period was significantly associated with gender and TRAb levels at disease onset. CONCLUSION: Male patients with GD have a poorer prognosis when submitted to medical treatment with ATDs. A larger goiter at presentation and a stronger genetic autoimmune background might explain this gender difference in patients with GD. ABBREVIATIONS: ATD = antithyroid drug FT3 = free triiodothyronine FT4 = free thyroxine GD = Graves disease GO = Graves orbitopathy RAI = radioiodine TRAb = thyroid-stimulating hormone-receptor antibody TSH = thyroid-stimulating hormone.

Anti-Mullerian hormone as a predictor of ovarian reserve in ART protocols: the hidden role of thyroid autoimmunity.

BACKGROUND: Protocols of controlled ovarian hyper-stimulation (COH) require, as a crucial step, the identification of reliable predictors of ovarian reserve. Anti-Mullerian hormone (AMH) is one of the most reliable predictors of ovarian reserve but other factors including autoimmune thyroid diseases (ATD) have been associated with reduced fertility and poor COH outcome. Aim of the present study was to evaluate the relationship between ATD and AMH, and their role on the outcome of COH. METHODS: The study group included 288 sub-fertile euthyroid women aged less than 40 years attending a single center for Reproductive Medicine. Among them, 55 were ATD-positive and 233 ATD-negative. The serum levels of AMH, FSH, LH, estradiol (E2), and TSH were measured before COH. The ratio between serum E2 concentration on the day of oocytes pick-up and the total dose of administered recombinant FSH (r-FSH) (E2/r-FSH ratio) was calculated. RESULTS: The serum levels of AMH were significantly related to E2/r-FSH ratio, total dose of r-FSH and number of M II oocytes, both in ATD-positive and ATD-negative women. Within the low stratum of AMH levels, the presence of ATD did not further affect the outcome of COH. When the serum levels of AMH were in the high stratum, the presence of ATD significantly affected the E2/rFSH ratio, the total dose of r-FSH and the number of M II oocytes. CONCLUSIONS: The probability of a poor response to COH is high, and independent from ATD, in women with low AMH serum levels. In women with a good ovarian reserve, as assessed by high AMH serum levels, the presence of ATD impairs the outcome of COH.

Maximal stiffness evaluation by real-time ultrasound elastography, an improved tool for the differential diagnosis of thyroid nodules.

OBJECTIVE: The aim of the study was to evaluate the diagnostic performance of a new ultrasound elastography (USE) parameter based on the measurement of the percentage of maximal stiffness within a nodule as compared with the already established elastographic strain index (SI) and to investigate their diagnostic performance according to nodule size. METHODS: The study included 218 nodules. Each nodule underwent conventional ultrasound (US), USE evaluation, and fine-needle aspiration cytology (FNAC). Thyroid nodules were further stratified into 4 subgroups (G) according to their size (G1, <1 cm; G2, 1-2 cm; G3, >3 cm). USE evaluation comprised the measurement of the percentage of the areas included in the region of interest corresponding to the maximal stiffness (% Index) and of the SI. RESULTS: The % Index and of the SI were significantly higher in malignant than in benign thyroid nodules, and both measurements displayed a good diagnostic performance (SI sensitivity and specificity, 0.66 and 0.90, respectively; % Index sensitivity and specificity, 0.76 and 0.89, respectively). Compared with SI, the % Index was more informative, both in the whole group of thyroid nodules (odds ratio [OR], 18.68; 95% confidence interval [CI], 6.06 to 63.49; P<.0001 versus OR, 26.15; 95% CI, 8.01 to 102.87; P<.0001, respectively) and in the G1 and G2 subgroups. CONCLUSION: The % Index is a stronger predictor of nodule malignancy than both the SI and the conventional US signs. This is particularly true in nodules smaller than 1 cm, which are more difficult to explore both by conventional US and FNAC.

Hypothalamic free fatty acid receptor-1 regulates whole-body energy balance.

OBJECTIVE: Free fatty acid receptor-1 (FFAR1) is a medium- and long-chain fatty acid sensing G protein-coupled receptor that is highly expressed in the hypothalamus. Here, we investigated the central role of FFAR1 on energy balance. METHODS: Central FFAR1 agonism and virogenic knockdown were performed in mice. Energy balance studies, infrared thermographic analysis of brown adipose tissue (BAT) and molecular analysis of the hypothalamus, BAT, white adipose tissue (WAT) and liver were carried out. RESULTS: Pharmacological stimulation of FFAR1, using central administration of its agonist TUG-905 in diet-induced obese mice, decreases body weight and is associated with increased energy expenditure, BAT thermogenesis and browning of subcutaneous WAT (sWAT), as well as reduced AMP-activated protein kinase (AMPK) levels, reduced inflammation, and decreased endoplasmic reticulum (ER) stress in the hypothalamus. As FFAR1 is expressed in distinct hypothalamic neuronal subpopulations, we used an AAV vector expressing a shRNA to specifically knockdown Ffar1 in proopiomelanocortin (POMC) neurons of the arcuate nucleus of the hypothalamus (ARC) of obese mice. Our data showed that knockdown of Ffar1 in POMC neurons promoted hyperphagia and body weight gain. In parallel, these mice developed hepatic insulin resistance and steatosis. CONCLUSIONS: FFAR1 emerges as a new hypothalamic nutrient sensor regulating whole body energy balance. Moreover, pharmacological activation of FFAR1 could provide a therapeutic advance in the management of obesity and its associated metabolic disorders.

Shear wave elastography in the diagnosis of thyroid nodules: feasibility in the case of coexistent chronic autoimmune Hashimoto's thyroiditis.

OBJECTIVE: ShearWave™ Elastography (SWE) is real-time, quantitative and user-independent technique, recently introduced in the diagnostic work-up of thyroid nodules. Hashimoto's thyroiditis (HT), characterized by variable degrees of lymphocytic infiltration and fibrosis, might affect shear wave propagation. The aim of this study was to assess the feasibility of SWE in cytologically benign thyroid nodules within both Hashimoto's and nonautoimmune thyroid glands. The effect of autoimmunity on the gland stiffness was also evaluated. DESIGN: longitudinal study in a single centre. PATIENTS: SWE was performed in 75 patients with a benign thyroid nodule at cytology: 33 with Hashimoto's thyroiditis (HT group) and 42 with uni- or multi-nodular goitre, negative for thyroid autoimmunity (non-HT group). RESULTS: The elasticity index (EI) of the extra-nodular tissue was greater, though not statistically significant, in the HT than in the non-HT group (24·0 ± 10·5 kPa vs 20·8 ± 10·4 kPa; P = 0·206). However, the EI of extra-nodular tissue was related to the TPOAb titre in the HT group (P = 0·02) and was significantly higher in patients with HT receiving L-thyroxine than in the euthyroid subjects (P = 0·02). The EI of thyroid nodules was similar in HT and non-HT groups. In both groups, the stiffness of nodules was significantly higher than that of the embedding tissue. CONCLUSIONS: Our data indicate that SWE correctly defines the elasticity of thyroid nodules independently from the coexistence of autoimmune thyroiditis, always being able to differentiate nodular tissue from the surrounding parenchyma. In HT, the stiffness of extra-nodular tissue increases in relation to both the thyroid antibody titre and the degree of impairment of thyroid function.

Temperature modulates systemic and central actions of thyroid hormones on BAT thermogenesis.

Thyroid hormones (THs) play a major role regulating energy balance and brown adipose tissue (BAT) thermogenesis, as well as body temperature, as shown in hyperthyroid patients. However, the current landscape of preclinical thyroid hormone models is complex. For example, while rats become catabolic after TH administration, mice gain weight; so, these differences in species need to be analyzed in detail and specially whether temperature could be a factor. Here, we aimed to investigate the effect of environmental temperature on those actions. Rats were subcutaneously treated with L-thyroxine (T4) or stereotaxically within the ventromedial nucleus of the hypothalamus (VMH) with triiodothyronine (T3) and housed at 23°C, 4°C or 30°C; energy balance, BAT thermogenesis and AMP-activated protein kinase (AMPK) in the VMH were analyzed. Our data showed that the effect of both systemic T4 of central T3 on energy balance and BAT thermogenesis was dependent upon environmental temperature. This evidence is of interest in the design of experimental settings highlighting the species-specific metabolic actions of THs, and in understanding its physiological role in the adaptation to temperature.

Thyroid wars: the rise of central actions.

In the field of thyroid hormone (TH) action on energy balance, huge advances have been achieved in the past decade, from human, animal, and in vitro studies. A key achievement was the demonstration of the TH 'central' metabolic action, which was recently discovered in rodent models and challenged the previous 'peripheral' paradigm. In this opinion, we dissect and try to unify the two paradigms, from analyzing the respective bench models to extrapolating the possible translational bedside implications.

Orally Induced Hyperthyroidism Regulates Hypothalamic AMP-Activated Protein Kinase.

Besides their direct effects on peripheral metabolic tissues, thyroid hormones (TH) act on the hypothalamus to modulate energy homeostasis. However, since most of the hypothalamic actions of TH have been addressed in studies with direct central administration, the estimation of the relative contribution of the central vs. peripheral effects in physiologic conditions of peripheral release (or administration) of TH remains unclear. In this study we used two different models of peripherally induced hyperthyroidism (i.e., T4 and T3 oral administration) to assess and compare the serum and hypothalamic TH status and relate them to the metabolic effects of the treatment. Peripheral TH treatment affected feeding behavior, overall growth, core body temperature, body composition, brown adipose tissue (BAT) morphology and uncoupling protein 1 (UCP1) levels and metabolic activity, white adipose tissue (WAT) browning and liver metabolism. This resulted in an increased overall uncoupling capacity and a shift of the lipid metabolism from WAT accumulation to BAT fueling. Both peripheral treatment protocols induced significant changes in TH concentrations within the hypothalamus, with T3 eliciting a downregulation of hypothalamic AMP-activated protein kinase (AMPK), supporting the existence of a central action of peripheral TH. Altogether, these data suggest that peripherally administered TH modulate energy balance by various mechanisms; they also provide a unifying vision of the centrally mediated and the direct local metabolic effect of TH in the context of hyperthyroidism.

Accumulation of overoxidized Peroxiredoxin III in aged rat liver mitochondria.

Overoxidation and subsequent inactivation of Peroxiredoxin III (PrxIII), a mitochondrial H(2)O(2) scavenging enzyme, have been reported in oxidative stress conditions. No data are available in the literature about the presence of overoxidized forms of PrxIII in aged tissues. Liver mitochondria from 12-month-old rats and 28-month-old rats were here analyzed by two-dimensional gel electrophoresis. A spot corresponding to the native form of PrxIII was present in adult and old rats with the same volume, whereas an additional, more acidic spot, of the same molecular weight of the native form, accumulated only in old rats. The acidic spot was identified, by MALDI-MS analysis, as a form of PrxIII bearing the cysteine of the catalytic site overoxidized to sulphonic acid. This modified PrxIII form corresponds to the irreversibly inactivated enzyme, here reported, for the first time, in aging. Three groups of 28-month-old rats treated with acetyl-l-carnitine were also examined. Reduced accumulation of the overoxidized PrxIII form was found in all ALCAR-treated groups.

Differential Role of Hypothalamic AMPKα Isoforms in Fish: an Evolutive Perspective.

In mammals, hypothalamic AMP-activated protein kinase (AMPK) α1 and α2 isoforms mainly relate to regulation of thermogenesis/liver metabolism and food intake, respectively. Since both isoforms are present in fish, which do not thermoregulate, we assessed their role(s) in hypothalamus regarding control of food intake and energy homeostasis. Since many fish species are carnivorous and mostly mammals are omnivorous, assessing if the role of hypothalamic AMPK is different is also an open question. Using the rainbow trout as a fish model, we first observed that food deprivation for 5 days did not significantly increase phosphorylation status of AMPKα in hypothalamus. Then, we administered adenoviral vectors that express dominant negative (DN) AMPKα1 or AMPKα2 isoforms. The inhibition of AMPKα2 (but not AMPKα1) led to decreased food intake. The central inhibition of AMPKα2 resulted in liver with decreased capacity of use and synthesis of glucose, lipids, and amino acids suggesting that a signal of nutrient abundance flows from hypothalamus to the liver, thus suggesting a role for central AMPKα2 in the regulation of peripheral metabolism in fishes. The central inhibition of AMPKα1 induced comparable changes in liver metabolism though at a lower extent. From an evolutionary point of view, it is of interest that the function of central AMPKα2 remained similar throughout the vertebrate lineage. In contrast, the function of central AMPKα1 in fish relates to modulation of liver metabolism whereas in mammals modulates not only liver metabolism but also brown adipose tissue and thermogenesis.

The BRAF-inhibitor PLX4720 inhibits CXCL8 secretion in BRAFV600E mutated and normal thyroid cells: a further anti-cancer effect of BRAF-inhibitors.

CXCL8 is a chemokine secreted by normal and thyroid cancer cells with proven tumor-promoting effects. The presence of BRAFV600E mutation is associated with a more aggressive clinical behavior and increased ability to secrete CXCL8 by papillary-thyroid-cancer cells. Aim of this study was to test the effect of the BRAF-inhibitor (PLX4720) on the basal and TNF-α-induced CXCL8 secretions in BRAFV600E mutated (BCPAP, 8305C, 8505C), in RET/PTC rearranged (TPC-1) thyroid-cancer-cell-lines and in normal-human-thyrocytes (NHT). Cells were incubated with increasing concentrations of PLX4720 alone or in combination with TNF-α for 24-hours. CXCL8 concentrations were measured in the cell supernatants. PLX4720 dose-dependently inhibited the basal and the TNF-α-induced CXCL8 secretions in BCPAP (F: 14.3, p < 0.0001 for basal and F: 12.29 p < 0.0001 for TNF-α), 8305C (F: 407.9 p < 0.0001 for basal and F: 5.76 p < 0.0001 for TNF-α) and 8505C (F:55.24 p < 0.0001 for basal and F: 42.85 p < 0.0001 for TNF-α). No effect was found in TPC-1 (F: 1.8, p = 0.134 for basal; F: 1.6, p = 0.178 for TNF-α). In NHT an inhibitory effect was found only at the highest concentration of PLX4720 (F: 13.13 p < 0.001 for basal and F: 2.5 p < 0.01 for TNF-α). Cell migration assays showed that PLX4720 reduced both basal and CXCL8-induced cell migration in BCPAP, 8305C, 8505C and NHT but not in TPC-1 cells. These results constitutes the first demonstration that PLX4720 is able to inhibit the secretion of CXCL8 in BRAFV600E mutated thyroid cancer cells indicating that, at least some, of the anti-tumor activities of PLX4720 could be exerted through a lowering of CXCL8 in the thyroid-cancer-microenvironment.

Post-partum and non-post-partum relapsing Graves' hyperthyroidism display different response to anti-thyroid drugs.

DESIGN: Graves' disease (GD) patients in remission after a full course of methimazole (MMI) therapy are at risk for a relapse of hyperthyroidism during the post-partum (PP) period, but whether this relapse may display any peculiarity is still unknown. Aim of this study was to compare GD patients undergoing a relapse of hyperthyroidism either in the PP period or not. METHODS: We retrospectively evaluated forty-three GD female patients in their childbearing age who experienced a relapse of hyperthyroidism. Eighteen of them relapsed in the PP period (i.e. within 12 months after delivery, PP group); the remaining 25 relapsed elsewhere during life (NPP group). RESULTS: Age at relapse, thyroid volume, thyroid function tests, TRAb titers, smoking habit, presence and degree of orbitopathy and duration of methimazole (MMI) treatment did not differ in the two groups. However, the remission rate was much greater (79%) in the PP as compared with the NPP (32%) group (P = 0.002). A significant reduction in TRAb levels occurred at 12-month MMI treatment in the PP (F = 9.016; P = 0.001), but not in the NPP group (F = 2.433; NS). At 12 months, the PP group had significantly lower mean TRAb levels (0.6 ± 1.1 U/L and 4.5 ± 4.7 U/L in the PP and the NPP group, respectively; P = 0.029). CONCLUSIONS: Relapsing Graves' hyperthyroidism in the PP period is more prone to undergo a remission after a second course of MMI treatment. In these patients, a conservative therapeutic approach is more appropriate.

Autoimmune Thyroid Diseases in Patients Treated with Alemtuzumab for Multiple Sclerosis: An Example of Selective Anti-TSH-Receptor Immune Response.

Alemtuzumab, a humanized anti-CD52 monoclonal antibody, is approved for the treatment of active relapsing-remitting multiple sclerosis (MS). Alemtuzumab induces a rapid and prolonged depletion of lymphocytes from the circulation, which results in a profound immuno-suppression status followed by an immune reconstitution phase. Secondary to reconstitution autoimmune diseases represent the most common side effect of Alemtuzumab treatment. Among them, Graves' disease (GD) is the most frequent one with an estimated prevalence ranging from 16.7 to 41.0% of MS patients receiving Alemtuzumab. Thyrotropin (TSH) receptor (R)-reactive B cells are typically observed in GD and eventually present this autoantigen to T-cells, which, in turn, secrete several pro-inflammatory cytokines and chemokines. Given that reconstitution autoimmunity is more frequently characterized by autoantibody-mediated diseases rather than by destructive Th1-mediated disorders, it is not surprising that GD is the most commonly reported side effect of Alemtuzumab treatment in patients with MS. On the other hand, immune reconstitution GD was not observed in a large series of patients with rheumatoid arthritis treated with Alemtuzumab. This negative finding supports the view that patients with MS are intrinsically more at risk for developing Alemtuzumab-related thyroid dysfunctions and in particular of GD. From a clinical point of view, Alemtuzumab-induced GD is characterized by a surprisingly high rate of remission, both spontaneous and after antithyroid drugs, as well as by a spontaneous shift to hypothyroidism, which is supposed to result from a change from stimulating to blocking TSH-receptor antibodies. These immune and clinical peculiarities support the concept that antithyroid drugs should be the first-line treatment in Alemtuzumab-induced Graves' hyperthyroidism.

ER-alpha and ER-beta expression in differentiated thyroid cancer: relation with tumor phenotype across the TNM staging and peri-tumor inflammation.

Thyroid cancer may express estrogen receptors (ERs) and various grades of peri-tumor inflammation. The aim of the study was to evaluate the expression of ERs in relation to the TNM stage and peri-tumor inflammatory infiltrate in differentiated thyroid cancers. 127 patients (109 females, 18 males) with differentiated thyroid cancer (T1 = 91, T2 = 18, T3 = 11, T4 = 7) were evaluated. In tumors and in the correspondent extra-tumor parenchyma, ERs expression was evaluated by immunohistochemistry. In 114 tumors and correspondent peri-tumor tissues, the presence of inflammatory infiltration was also recorded. ER-alpha expression was higher in clinical than in incidental tumors of the T1 subgroup (p = 0.037), and was associated with capsular invasion in T2 tumors (p < 0.0001). ER-beta expression was negatively associated with vascular invasion in T1 (p = 0.005) and T2 tumors (p = 0.015). No significant relationship between ERs expression and tumor phenotype emerged in T3 and T4 subgroups. Tumors without inflammatory cell infiltrate showed a higher expression of both ER-alpha (p = 0.035) and ER-beta (p = 0.026) than the ones with inflammatory infiltrate. The relationship between tumor phenotype and ERs expression did not vary in the presence or absence of peri-tumor inflammatory infiltration. ER-alpha positivity and ER-beta negativity are associated with a more aggressive phenotype in both T1 and T2 thyroid cancers, suggesting that tumor biology may be more relevant than tumor size for cancer risk assessment. Inflammatory status is also associated with ERs expression, but not with tumor growth or phenotype.