Selenium supplementation in the management of thyroid autoimmunity during pregnancy: results of the "SERENA study", a randomized, double-blind, placebo-controlled trial.

PURPOSE: Selenium is frequently in nutraceuticals for pregnancy, given its role on fertility and thyroid metabolism. However, most evidence rise from non-controlled studies. We aimed to evaluate the protective effect of selenium against thyroid autoimmunity during and after pregnancy. METHODS: A multicenter, randomized, double-blind, placebo-controlled trial was performed and promoted by the Young Italian Endocrinologists Group (EnGioI)-Italian Society of Endocrinology. Forty-five women with thyroiditis in pregnancy were enrolled and randomly assigned to L-selenomethionine (L-Se-Met) 83 mcg/day or placebo (PLB) and evaluated at 10 ± 2 (T1), 36 ± 2 weeks of gestation (T2) and 6 months after delivery (postpartum, PP). RESULTS: We measured a significant reduction of autoantibodies after pregnancy in L-Se-Met group [at PP: TgAb 19.86 (11.59-52.60), p < 0.01; TPOAb 255.00 (79.00-292.00), p < 0.01], and an antibodies titer's rebound in PLB group (TgAb 151.03 ± 182.9, p < 0.01; TPOAb 441.28 ± 512.18, p < 0.01). A significant increase in selenemia was measured in L-Se-Met group at T2 (91.33 ± 25.49; p < 0.01) and PP (93.55 ± 23.53; p = 0.02). Two miscarriage occurred in PLB. No differences were found in thyroid volume, echogenicity, quality of life, maternal/fetal complications. CONCLUSIONS: SERENA study demonstrated a beneficial effect of L-Se-Met supplementation on autoantibody titer during pregnancy and on postpartum thyroiditis recurrence.

The relationship between attention deficit hyperactivity disorder, bipolarity and mixed features in major depressive patients: Evidence from the BRIDGE-II-Mix Study.

OBJECTIVE: This study primarily focused on the relationship between comorbid attention deficit-hyperactivity disorder (ADHD), mixed features and bipolarity in major depressive patients. METHODS: The sample comprised 2777 patients with Major Depressive Episode (MDE) enrolled in a multicentre, multinational study originally designed to assess different definitions of mixed depression. Socio-demographic, familial and clinical characteristics were compared in patients with (ADHD + ) and without (ADHD-) comorbid ADHD. RESULTS: Sixty-one patients (2.2%) met criteria for ADHD. ADHD was associated with a higher number of (hypo)manic symptoms during depression. Mixed depression was more represented in ADHD + patients than in ADHD- using both DSM-5 and experimental criteria. Differences were maintained after removing overlapping symptoms between (hypo)mania and ADHD. ADHD in MDE was also associated with a variety of clinical and course features such as onset before the age of 20, first-degree family history of (hypo)mania, past history of antidepressant-induced (hypo)manic switches, higher number of depressive and affective episodes, atypical depressive features, higher rates of bipolarity specifier, psychiatric comorbidities with eating, anxiety and borderline personality disorders. LIMITATIONS: The study was primarily designed to address mixed features in ADHD, with slightly reduced sensitivity to the diagnosis of ADHD. Other possible diagnostic biases due to heterogeneity of participating clinicians. CONCLUSIONS: In a sample of major depressive patients, the comorbid diagnosis of current ADHD is associated with bipolar diathesis, mixed features, multiple psychiatric comorbidity and a more unstable course. Further prospective studies are necessary to confirm the possible mediating role of temperamental mood instability and emotional dysregulation in such a complex clinical presentation.

The impact of affective temperaments on clinical and functional outcome of Bipolar I patients that initiated or changed pharmacological treatment for mania.

BACKGROUND: Affective temperaments have been shown to impact on the clinical manifestations and the course of bipolar disorder. We investigated their influence on clinical features and functional outcome of manic episode. METHOD: In a naturalistic, multicenter, national study, a sample of 194 BD I patients that initated or changed pharmacological treatment for DSM-IV-TR manic episode underwent a comprehensive evaluation including briefTEMPS-M, CTQ, YMRS, MADRS, FAST, and CGI-BP. Factorial, correlation and comparative analyses were conducted on different temperamental subtypes. RESULTS: Depressive, cyclothymic, irritable and anxious temperaments resulted significantly correlated with each other. On the contrary, hyperthymic temperament scores were not correlated with the other temperamental dimensions. The factorial analysis of the briefTEMPS-M sub-scales total scores allowed the extraction of two factors: the Cyclothymic-Depressive-Anxious (Cyclo-Dep-Anx) and the Hyperthymic. At final evaluation Dominant Cyclo-Dep-Anx patients reported higer scores in MADRS and in CTQ emotional neglect and abuse subscale scores than Dominant Hyperthymic patients. The latter showed a greater functional outcome than Cyclo-Dep-Anx patients. CONCLUSIONS: Affective temperaments seem to influence the course of mania. Childhood emotional abuse and neglect were related to the cyclothymic disposition. Cyclothymic subjects showed more residual depressive symptoms and Hyperthymic temperament is associated with a better short-term functional outcome.

Thyroid volume and serum calcitonin changes during pregnancy.

BACKGROUND: Pregnancy has a profound impact on thyroid homeostasis which results in change of thyroid function and thyroid volume (TV). Moreover, calcitonin (CT), and its gene-related peptide have been demonstrated to play an important role in the implantation process. PURPOSE: To evaluate changes in TV and serum CT levels during pregnancy. METHODS: One hundred and fifty-five pregnant women were consecutively enrolled at the first trimester of gestation and underwent clinical, biochemical and sonographic assessment at enrollment, at the second and third trimesters and at 6 months after delivery. RESULTS: Throughout gestation serum TSH exceeded the upper specific first trimester cut-off in 5% of patients. TV significantly increased at the third trimester of gestation and returned to baseline levels at 6 months after delivery, while serum CT levels did not show significant changes. TV directly correlated with BMI or gestational weight gain at each trimester of pregnancy, while no significant association between serum CT levels and either weight or TV were found. Finally, in none of the patients with nodular goiter an increase in the volume of the nodules was noted. The appearance of a nodule was recorded during the second trimester in one patient. CONCLUSION: This study confirms a prevalence of thyroid autoimmunity/hypertropinemia in 3-5% of pregnant women and shows that serum CT does not change in relation to the transient increase in TV occurring during gestation. An adequate daily iodine supplementation might be particularly useful during pregnancy to limit the TSH increase and the resulting thyroid gland and nodule enlargement.

Attention deficit/hyperactivity disorder symptoms in Italian bipolar adult patients: a preliminary report.

BACKGROUND: It has been recently suggested that bipolar disorder (BD) with comorbid ADHD represents a distinct clinical phenotype of BD. With the aim to assess the impact of ADHD symptoms, we investigated the prevalence, epidemiological and clinical features associated with such a comorbidity in a sample of adult BD patients. METHODS: A total of 96 outpatients (aged 18-65 years) with BD were included. All patients were screened using the Adult ADHD Self-report Scale (ASRS) and the Diagnostic, Clinical and Therapeutic Checklist (DCTC), a semi-structured interview developed for systematic collection of familial, demographic, anamnestic and clinical informations and exploration of DSM-IV-TR diagnostic criteria for mood, anxiety, eating, impulse control and alcohol and substance use disorders. The DCTC also includes the Clinical Global Impression Bipolar scale (CGI-BP), the Global Assessment of Functioning scale (GAF) and the Sheehan Disability Scale (SDS). RESULTS: In our sample, 19 (19.8%) out of 96 BD patients fulfilled ASRS criteria for current and lifetime (onset before 7 years of age) ADHD symptoms (ADHD+). Compared to BD probands without ADHD symptoms (ADHD-), ADHD+ patients showed higher rates of current mixed episode, and lower rates of mania. ADHD+ resulted in more severe mean scores on the CGI-BP mixed, depressive and global subscales. None of the ADHD+ patients were in remission of BD at the time of the evaluation, versus 24 (31.2%) of the ADHD- group. ADHD+ patients also reported higher rate of lifetime comorbidity with Substance Use Disorder (SUD) and Alcohol Abuse in comparison to ADHD- patients. In particular the different rate in substance abuse was related to cocaine and poly-drug abuse. The two groups did not report significant differences in functioning and social adjustment with the exception of familial adjustment that was more compromised in ADHD+ than in ADHD- patients. LIMITATIONS: Retrospective design and limited sample size. CONCLUSIONS: In ADHD+ patients, BD is associated with higher rate of mixed states, more severe psychopathology and more impaired familial functioning as well as higher rates of comorbid substance, alcohol and poly-drug abuse compared to BD patients without adult ADHD. Our findings suggest that ADHD symptoms in adults may influence clinical presentation, course and prognosis of BD. Further prospective research is needed to confirm our findings and to explore treatment implications for the management of BD.

Rituximab treatment in patients with active Graves' orbitopathy: effects on proinflammatory and humoral immune reactions.

In active Graves' orbitopathy (GO), proinflammatory cytokines predominate. Circulating thyroid stimulating hormone (TSH)-receptor antibodies (TRAb) have been correlated with GO clinical activity and severity. In preliminary studies rituximab (RTX), an anti-CD 20 monoclonal antibody, has induced clinical improvement of active GO without a change in serum anti-thyroid antibodies. We have studied whether RTX in GO acts by affecting proinflammatory cytokines and thyroid and orbital-directed antibodies. Ten patients with GO were treated with RTX, administered twice intravenously (i.v.) (1000 mg) at days 1 and 15, and 20 with methylprednisolone, administered weekly i.v. (500 mg), for 16 weeks. Patients were studied before treatment, at B cell depletion and at 4, 8, 16, 20, 30 and 50 weeks. Peripheral lymphocytes, serum interleukin (sIL)-6, sIL-6r, chemokine (C-X-C motif) ligand 10 (CXCL10), TRAb and stimulating antibodies (TSAb) and autoantibodies against orbital calsequestrin, collagen XIII and flavoprotein subunit of succinate dehydrogenase (FP-SDH) were measured at baseline and after treatment. Serum IL-6 and sIL-6R concentrations did not change after RTX [P = not significant (n.s.)]. Serum CXCL10 increased after RTX at B cell depletion and at 30 weeks (P < 0·003). Serum TSAb did not change in relation to TRAb, nor did antibodies against orbital antigens (P = n.s.). In conclusion, this study shows that RTX in GO does not affect humoral reactions. The observed increase of serum CXCL10 concentrations at B cell depletion may result from cell lysis. We suggest that RTX may exert its effect in GO by inhibiting B cell antigen presentation.

Graves' orbitopathy activation after radioactive iodine therapy with and without steroid prophylaxis.

CONTEXT: The reactivation of Graves' orbitopathy (GO) after radioiodine (RAI) for Graves' disease (GD) is a known effect, and its clinical relevance is controversial. Prevention of RAI-induced GO activation is possible in at-risk patients with oral glucocorticoids (OGC). OBJECTIVES: The aim of the study was to analyze the effects of RAI on GO with or without prophylactic steroids based on known risk factors and to compare the effectiveness of prophylaxis with iv glucocorticoids (IVGC) and OGC. DESIGN: We conducted a retrospective study in which patients were assessed before and 1-12 months after RAI. PATIENTS AND SETTING: A total of 113 patients were included in the study; 83 underwent RAI without prophylactic steroids for the absence of risk of activation, and 30 were treated with either OGC (n = 21) or IVGC (n = 9). MAIN OUTCOME MEASURES: We analyzed the prevalence of GO activation with or without steroid prophylaxis and the difference in the prevalence of GO activation after OGC or IVGC. RESULTS: GO activation was observed in 7.2% of patients without and 33.3% of patients with steroid prophylaxis (P < 0.0001), for an overall prevalence of 14.6%. GO activation occurred in 47.6% of patients treated with OGC but in none of the nine patients treated with IVGC (P = 0.0001). Disease activation was more prevalent in males (P < 0.02) and in older patients (P = 0.04) with a shorter duration of GD (P < 0.01) and time from GO onset (P < 0.01). CONCLUSIONS: GO may occur after RAI in approximately 15% of patients also in the absence of signs of active GO. Prophylactic OGC did not prevent GO activation in a large proportion of patients, compared to IVGC.

New immunomodulators in the treatment of Graves' ophthalmopathy.

Steroids have been used in the therapy of the moderate to severe forms of Graves' ophthalmopathy (GO) and other autoimmune diseases as they act only as general immunosuppressants. Previous work has shown that blocking the CD-20 receptor on B lymphocytes has significantly affected the clinical course of GO, by rapidly reducing inflammation and the degree of proptosis. We have studied nine patients with Graves' disease, of whom seven had active GO and two, with newly diagnosed hyperthyroidism, only mild lid signs. We also studied a group of 20 consecutive patients, treated with intravenous glucocorticoids (IVGC) according to a standard protocol. Patients treated with RTX (1000mg i.v. twice at two-week interval) and those treated with IVGC (500mg i.v. for 16 weeks) were studied monthly up to 12 months after the first drug infusion. By ophthalmological examination, GO was assessed by the clinical activity score (CAS) and by the NOSPECS score. Thyroid function and lymphocyte count were measured by standardized methods. RTX was well-tolerated and only minor side-effects were reported in 30% of patients during the first infusion. All patients attained peripheral B-cell depletion with the first RTX infusion. All but one patients showed both CD20+ cells and CD19+ cells depletion, while one had persistent 3-5% CD19+ cells in the periphery, mostly CD19+5+. Thyroid function was not affected by RTX therapy. Titers of antithyroglobulin (TgAb), antithyroperoxidase and anti-TSH receptor antibodies (TRAb) did not change significantly (P=NS) and did not correlate to CD20+ depletion (P=NS). CAS values decreased significantly (P<0.0001). Proptosis decreased significantly after RTX in both patients with active GO (ANOVA; P<0.0001) and in those with Graves' hyperthyroidism and lid signs (ANOVA; P<0.003). The degree of inflammation (NOSPECS class 2) decreased significantly in response to RTX (ANOVA; P<0.001). In patients treated with IVGC, mean CAS value decreased significantly less than in those treated with RTX (P<0.05). Adverse effects were more frequent after IVGC (45% of patients). Seventy-five percent of patients responded to IVGC and 10% showed relapse of active GO six to eight weeks after withdrawal. The results of this study on RTX in GO suggest that the drug is effective in modifying the disease course and that the improvement of the clinical activity of GO after RTX was more significant than after IVGC. We did not observe relapse of active GO, even after B-cell return in peripheral blood. This might be related to the persistence of a significant degree of B-cell depletion after RTX observed in the peripheral blood as late as two years of follow-up. RTX therapy was also effective in improving proptosis and soft tissue inflammation. The mechanism by which RTX affects GO is unknown. It may act as a true immunosuppressor by switching off reactions inducing the active phase of TAO, perhaps by influencing the cytokine production in the orbit or by inducing depletion of antigen presenting B-cells.

Rituximab induces distinct intraorbital and intrathyroidal effects in one patient satisfactorily treated for Graves' ophthalmopathy.

Hyperthyroid Graves' disease (GD) is a B-cell-mediated disease caused by antibodies stimulating the thyroid stimulating hormone (TSH) receptor (TRAb). A proportion of patients (40-60%) present with an associated ophthalmopathy (TAO), a progressive inflammatory autoimmune disease of the retroorbital tissue. We thought that the anti-CD20 monoclonal antibody rituximab (RTX), by inducing transient B-cell depletion, may potentially modify the active inflammatory phase of TAO. One patient with GD and TAO in its active phase and unresponsive to steroid, was treated with RTX. Whereas the ophthalmopathy responded to RTX therapy and a decrease in the clinical activity score from 5 to 2 was observed during the B-cell depletion, serum antithyroid antibodies, and in particular serum TRAb, were not affected by therapy. When the patient underwent total thyroidectomy, we found B-cells in the thyroid tissue specimens. The eye disease remained stable (clinical activity score=2) and the patient subsequently underwent orbital decompression to correct proptosis of the eye. At that time we did not find lymphocytes in any of the orbital tissue specimens. We believe that RTX therapy in GD may cause amelioration of ophthalmopathy by depleting total lymphocyte population in the orbit, but not lymphocyte depletion in thyroid tissue with consequent unchanged serum TRAb levels.

[The protection of drinking water in a public health department]. / La tutela delle acque potabili: un momento di valorizzazione dell'attività di prevenzione.

The protection of drinking water is a key issue in a Public Health Department's activity. A substantial amount of planning and monitoring work is involved in the development and implementation of a water safety plan, aimed not only at the enforcement of public health regulations, but also at the improvement of the quality water. We provide an overview of the quality monitoring program of the municipality of Prato, a highly populated and industrialized area, where ground water is contaminated by anthropogenic pollutants such as trichloroethylene, tetrachloroethylene and nitrate. We show how, in spite of the intrinsically poor quality of the basic water resource, the careful application of an appropriate prevention plan, with the cooperation of the local water authority, allows the delivery of drinking water of increasing safety and quality.

Monoallelic expression of mutant thyroid peroxidase allele causing total iodide organification defect.

Mutations in the thyroid peroxidase (TPO) gene lead to severe congenital hypothyroidism due to total iodide organification defect (TIOD). According to the recessive mode of inheritance, patients are homozygous or compound heterozygous for gene mutations. However, about 17% of cases with typical phenotype harbor a single TPO-mutated allele. We present a TIOD family in which the three affected siblings had a single genomic TPO mutation (R693W) inherited from the unaffected father. Other mutations were not found, although all TPO coding exons and exon/intron boundaries were sequenced. Eleven different polymorphisms were found in hetero- or homozygosity in all family members. On the contrary, using retrotranscribed thyroid tissue RNA, all heterozygous polymorphisms and the mutation were homozygous. The distribution of the polymorphisms indicated that only the mutant paternal allele is transcribed at the thyroid tissue level. We excluded the presence of major deletions involving the maternal chromosome at 2p25 and of maternal imprinting or mutations in part of the regulatory regions of the gene. In summary, we report one family with TIOD due to monoallelic expression of a mutant TPO allele in the thyroid. This mechanism might be generally involved in TIOD cases with a single TPO-mutated allele.

Genetic analyses and evaluation of peripheral parameters of thyroid hormone action for the differential diagnosis of RTH. A novel heterozygous missense mutation (M334T) discovered.

Resistance to thyroid hormone (RTH) is a rare disease characterized by goiter and elevated free thyroid hormone (TH) levels in the presence of detectable concentrations of TSH. Most RTH patients harbor mutations in the ligand binding domain (LBD) of thyroid hormone receptor beta (TRbeta) gene, without a clear correlation between genotype and phenotype. Clinical, biochemical and genetic analyses were performed in several members of one family, because the index case presented with elevated free TH, measurable TSH and no hyperthyroid manifestations, but with a pituitary lesion at MRI. High free TH levels and TSH concentrations in the normal range were found also in 4 relatives. The presence of euthyroidism in all patients together with peripheral parameters of TH action in the normal range led to the diagnosis of generalized RTH (GRTH). In the five affected members, the genetic analysis revealed a novel heterozygous missense mutation at codon 334 (M334T). A different mutation at codon 334 was previously described in association with selective pituitary resistance to thyroid hormone (PRTH). Therefore, we confirm that substitutions at Methionine 334 are critical for the structural integrity of TRbeta LBD. The association of different phenotypes with substitutions affecting the same codon is another contribution confirming that RTH phenotype does not generally depend upon the site of the mutation in the LBD of TRbeta1.

The role of pendrin in iodide regulation.

Recent advances in human genetics have catalyzed the attention on Pendred's syndrome and its disease-gene, PDS. Studies on the expression of the PDS gene and on the function of its encoded protein, which has been named pendrin, are currently in progress. Consistent with the Pendred's syndrome phenotype, which is characterized by thyroid dysfunction associated to deafness, PDS expression has been demonstrated in the thyroid and in the inner ear. Despite its high homology to known sulfate transporters, pendrin has been shown to transport iodide and chloride, but not sulfate. Thus, it is probably devoted to regulate, at the apical membrane where it has been immunolocalized, the flux of iodide from the thyroid cell to the colloid space. The function of pendrin in the inner ear is not well understood, but it seems to function also at this level as an anion transporter. Indeed, a pronounced PDS expression has been detected in structures of the inner ear, such as the membranous labyrinth and the endolymphatic duct and sac. At this level, the possible role of pendrin could be the maintenance of the appropriate ionic composition of the endolymph. Although many questions remain to be answered, these recent achievements concerning the putative role of pendrin aid to better understand the genetic basis of the peculiar phenotype of Pendred's syndrome, which associate the dysfunction of two so different organs such as the thyroid and the inner ear.

An asbestos hazard in the reprocessed textile industry.

Epidemiologic studies have identified an excess risk of lung cancer and mesothelioma among workers in the reprocessed textile industry in Prato, Italy. These studies suggested that there may have been asbestos hazard in this industry although exposure was not known to exist. An industrial hygiene investigation was conducted to determine whether there was previous or current asbestos exposure in the industry. Walk-through surveys, environmental sampling, process documentation, and management and worker interviews were conducted in 13 textile reprocessing establishments. Polypropylene bags that once contained asbestos were found in 2 of the 13. Asbestos bags were cut open and used to cover bales of rags which were then distributed throughout the world. Workers were exposed to asbestos while handling the bags which were contaminated with chrysotile, amosite, and crocidolite. Additional sources of asbestos exposure that may have existed in the past in the industry are also discussed.