Ipotiroidismo ed ipertiroidismo nel neonato pretermine

Le cause di ipotiroidismo in età neonatale sono numerose e per la maggior parte sono responsabili di ipotiroidismo permanente; altre, invece, provocano un ipotiroidismo transitorio. L’ipotiroidismo congenito (IC) è una delle più comuni endocrinopatie dell’età infantile. Colpisce con la medesima incidenza neonati a termine e pretermine, ed è la causa più frequente di ritardo mentale prevenibile mediante tempestiva diagnosi e terapia. Nel neonato pretermine la funzionalità tiroidea è influenzata da diversi fattori, come l’improvvisa interruzione del trasporto materno-fetale di T4, l’immaturità dell’asse ipotalamo-ipofisi-tiroide, l’eccesso di iodio (contenuto negli antisettici o negli agenti radio-opachi), l’insufficiente riserva di iodio e gli effetti di patologie neonatali (malattie non tiroidee) e di farmaci usati. I neonati pretermine (prima della 30°settimana di età gestazionale) e i neonati con molto basso peso alla nascita (<1500gr) hanno un rischio 8 volte superiore di sviluppare ipotiroidismo transitorio primitivo. Per questi neonati è quindi necessario un re-screening a 2 e a 6 settimane di età. L’eziologia dell’ipotiroxinemia nel pretermine è multifattoriale e il suo andamento è altamente variabile. Studi incrociati suggeriscono che l’ipotiroxinemia severa neonatale può essere associata con una morbilità perinatale e con difficoltà di sviluppo a lungo termine. Nel nostro studio abbiamo preso in considerazione 85 neonati nati tra la 24° e la 33° settimana di età gestazionale con l’obiettivo di analizzare quanti neonati pretermine presentano una severa ipotiroxinemia durante le prime 4-6 settimane di vita. Sei neonati (7%) presentavano una ipotiroxinemia severa con livelli di FT4<5 pg/ml e presenza di segni clinici sfumati e sono stati trattati con L-T4. Le manifestazioni cliniche di ipotiroidismo non sempre sono chiaramente evidenti alla nascita, potendo rendersi manifeste anche dopo alcune settimane. La Malattia di Graves complica circa lo 0,2% delle gravidanze ed è associata con un aumentato rischio di aborto, parti pretermine o ritardo di crescita intrauterina. L’ipertiroidismo fetale-neonatale si manifesta più frequentemente in neonati di madri con morbo di Basedow o con tiroidite di Hashimoto che sono state rese eutiroidee in periodi precedenti alla gravidanza con la tiroidectomia subtotale o il radioiodio, ma che continuano ad avere Trab (anticorpi antirecettore del TSH stimolanti) in circolo. La tachicardia fetale (> 160 bpm) e il ritardo di crescita intrauterina sono le manifestazioni più comuni della tireotossicosi in utero. In alcuni casi l’ecografia fetale dimostra la presenza di un gozzo. In rari casi è stato descritto un inizio tardivo dell’ipertiroidismo nel 1°-2° mese di vita. Questo fenomeno è stato attribuito alla contemporanea presenza nel siero del neonato di anticorpi tireostimolanti (TSAb) e bloccanti (TSHBAb) materni. Nel nostro studio abbiamo valutato gli aspetti diagnostici e terapeutici della tireotossicosi congenita nei neonati pretermine considerando i neonati pretermine con tireotossicosi congenita nati presso la nostra Unità Operativa o a noi inviati da altri punti nascita. In conclusione, dal primo studio possiamo affermare che: la nascita pretermine interrompe il processo di maturazione dell’asse ipotalamo-ipofisi tiroide fetale in un ambiente protetto e priva il neonato dell’apporto degli ormoni tiroidei materni; in presenza di ipotiroidismo primitivo transitorio con elevati livelli di TSH è sempre indicato il trattamento con L-Tiroxina; la ipotiroxinemia del neonato pretermine con livelli normali/bassi di TSH è la forma più comune, ma deve essere esclusa la presenza di un ipotiroidismo centrale, secondario o terziario, da altre cause; bassi livelli di FT4 nelle prime settimane di vita sono associati ad un peggior outcome neurologico a distanza; non c’è evidenza che la supplementazione con ormoni tiroidei migliori l’outcome neurologico del neonato pretermine, ma allo stesso modo non c’è evidenza che la supplementazione con ormoni tiroidei non sia necessaria in neonati pretermine con bassi livelli di FT4; infine, i neonati di età gestazionale <28 settimane potrebbero avere i migliori benefici dal trattamento con L-tiroxina, ma sono necessari studi randomizzati controllati che includano l’uso di test standardizzati di sviluppo mentale, psicomotorio e cognitivo. Dall’analisi diagnostica e terapeutica della tireotossicosi congenita è emerso che nei neonati molto pretermine con IUGR la diagnosi può essere sottostimata e la tireotossicosi può peggiorare la morbilità associata con la nascita pretermine. Inoltre, in particolare nei neonati di molto basso peso alla nascita, non è prevedibile una risposta alla terapia con tionamidi. E’ poi da considerare che la necessità di ridurre i prelievi di sangue rende il monitoraggio del trattamento difficile. L’allattamento al seno non è controindicato

Solving Equations Using Khovanskii Bases

We develop a new eigenvalue method for solving structured polynomial equations over any field. The equations are defined on a projective algebraic variety which admits a rational parameterization by a Khovanskii basis, e.g., a Grassmannian in its Pl\"ucker embedding. This generalizes established algorithms for toric varieties, and introduces the effective use of Khovanskii bases in computer algebra. We investigate regularity questions and discuss several applications.Comment: 25 pages, 1 figure, 2 table

Using a calibration experiment to assess gene-specific information: full Bayesian and empirical Bayesian models for two-channel microarray data.

MOTIVATION: Microarray studies permit to quantify expression levels on a global scale by measuring transcript abundance of thousands of genes simultaneously. A difficulty when analysing expression measures is how to model variability for the whole set of genes. It is usually unrealistic to assume a common variance for each gene. Several approaches to model gene-specific variances are proposed. We take advantage of calibration experiments, in which the probes hybridized on the two channels come from the same population (self-self experiment). In this case it is possible to estimate the gene-specific variance, to be incorporated in comparative experiments on the same tissue, cellular line or species. RESULTS: We present two approaches to introduce prior information on gene-specific variability from a calibration experiment: an empirical Bayes model and a full Bayesian hierarchical model. We apply the methods in the analysis of human lipopolysaccharide-stimulated leukocyte experiments. AVAILABILITY: The calculations are implemented in WinBugs. The codes are available on request from the authors

Melanoma-prone families: new evidence of distinctive clinical and histological features of melanomas in CDKN2A mutation carriers.

Germline mutations on the CDKN2A gene, the most important known genetic factors associated with cutaneous melanomas (CMs), predispose carriers to multiple primary CMs (MPMs) with higher frequency and younger onset compared to non-carriers. Most of the largest published studies concerning clinical and histological characteristics of CMs with CDKN2A mutation carriers did not specify if the described CMs are first or subsequent to the first, and they used sporadic CMs from non-genotyped patients as controls. We conducted a single-centre observational study to compare clinical and histological CM features of 32 unrelated carriers (MUT) of 5 germline CDKN2A mutations (one of which was never previously described) compared to 100 genotyped wild-type (WT) patients. We stratified the data based on time of diagnosis, anatomical site and histological subtype of CMs, demonstrating several significant unreported differences between the two groups. MUT developed a higher number of dysplastic nevi and MPMs. We proved for the first time that anatomical distribution of CMs in MUT was independent of gender, unlike WTs. MUTs developed in situ and superficial spreading melanomas (SSMs) more frequently, with significantly higher number of SSMs on the head/neck. In MUTs, Breslow thickness was significantly lower for all invasive CMs. When CMs were stratified on the basis of the time of occurrence, statistical significance was maintained only for SSMs subsequent to the first. In WTs, Clark level was significantly higher, and ulceration was more prevalent than in MUTs. Significant differences in ulceration were observed only in SSMs. In nodular CMs, we did not find differences in terms of Breslow thickness or ulceration between WTs and MUTs. In situ CMs developed 10 years earlier in MUTs with respect to WTs, whereas no significant differences were observed in invasive CMs. In contrast to those reported previously by other authors, we did not find a difference in skin phototype

A functional assay for the clinical annotation of genetic variants of uncertain significance in Diamond\u2013Blackfan anemia

Diamond-Blackfan anemia (DBA) is a rare genetic hypoplasia of erythroid progenitors characterized by mild to severe anemia and associated with congenital malformations. Clinical manifestations in DBA patients are quite variable and genetic testing has become a critical factor in establishing a diagnosis of DBA. The majority of DBA cases are due to heterozygous loss-of-function mutations in ribosomal protein (RP) genes. Causative mutations are fairly straightforward to identify in the case of large deletions and frameshift and nonsense mutations found early in a protein coding sequence, but diagnosis becomes more challenging in the case of missense mutations and small in-frame indels. Our group recently characterized the phenotype of lymphoblastoid cell lines established from DBA patients with pathogenic lesions in RPS19 and observed that defective pre-rRNA processing, a hallmark of the disease, was rescued by lentiviral vectors expressing wild-type RPS19. Here, we use this complementation assay to determine whether RPS19 variants of unknown significance are capable of rescuing pre-rRNA processing defects in these lymphoblastoid cells as a means of assessing the effects of these sequence changes on the function of the RPS19 protein. This approach will be useful in differentiating pathogenic mutations from benign polymorphisms in identifying causative genes in DBA patients

Lymphoblastoid cell lines from Diamond Blackfan anaemia patients exhibit a full ribosomal stress phenotype that is rescued by gene therapy

Diamond Blackfan anaemia (DBA) is a congenital bone marrow failure syndrome characterised by selective red cell hypoplasia. DBA is most often due to heterozygous mutations in ribosomal protein (RP) genes that lead to defects in ribosome biogenesis and function and result in ribosomal stress and p53 activation. The molecular mechanisms underlying this pathology are still poorly understood and studies on patient erythroid cells are hampered by their paucity. Here we report that RP-mutated lymphoblastoid cell lines (LCLs) established from DBA patients show defective rRNA processing and ribosomal stress features such as reduced proliferation, decreased protein synthesis, and activation of p53 and its target p21. These phenotypic alterations were corrected by gene complementation. Our data indicate that DBA LCLs could be a useful model for molecular and pharmacological investigations

Benefit-risk profile of cytoreductive drugs along with antiplatelet and antithrombotic therapy after transient ischemic attack or ischemic stroke in myeloproliferative neoplasms

We analyzed 597 patients with myeloproliferative neoplasms (MPN) who presented transient ischemic attacks (TIA, n = 270) or ischemic stroke (IS, n = 327). Treatment included aspirin, oral anticoagulants, and cytoreductive drugs. The composite incidence of recurrent TIA and IS, acute myocardial infarction (AMI), and cardiovascular (CV) death was 4.21 and 19.2%, respectively at one and five years after the index event, an estimate unexpectedly lower than reported in the general population. Patients tended to replicate the first clinical manifestation (hazard ratio, HR: 2.41 and 4.41 for recurrent TIA and IS, respectively); additional factors for recurrent TIA were previous TIA (HR: 3.40) and microvascular disturbances (HR: 2.30); for recurrent IS arterial hypertension (HR: 4.24) and IS occurrence after MPN diagnosis (HR: 4.47). CV mortality was predicted by age over 60 years (HR: 3.98), an index IS (HR: 3.61), and the occurrence of index events after MPN diagnosis (HR: 2.62). Cytoreductive therapy was a strong protective factor (HR: 0.24). The rate of major bleeding was similar to the general population (0.90 per 100 patient-years). In conclusion, the long-term clinical outcome after TIA and IS in MPN appears even more favorable than in the general population, suggesting an advantageous benefit-risk profile of antithrombotic and cytoreductive treatment

Marine sustainability in an age of changing oceans and seas

The report is the result of fruitful collaboration between EASAC and the JRC. It has been prepared by a working group of experts drawn from the European National Science Academies, which was supported by the JRC. It is hoped that the report will prove useful in the further development and implementation of European Union marine and maritime policy as well as the organisation of supporting science needed to inform and guide these policies. The last ten years have seen a growth in marine and maritime policymaking within the European Union with a key feature being the concept of the ecosystem approach to guide sustainable use of the seas. In view of this increasing focus on coherent marine and maritime policy and governance within the EU, as well as globally, the EASAC Council decided in December 2013 to conduct a study on the issue of marine sustainability. This decision particularly acknowledged the need to provide advice from the point of view of the European science academies on this new direction of marine policy and to highlight the particular challenges that this poses to the organisation of science. The report has the aim of contributing to the governance challenge of how to integrate the various aspects of marine policy (fisheries management, biodiversity conservation and marine environmental protection) as part of a coherent ecosystem approach. It considers how current science knowledge on marine ecosystems and the organisation of science can support an integrated approach to management of the seas. The report looks at a number of key aspects for sustainable development in changing oceans and seas, and particularly highlights the key scientific challenges in addressing these issues. The report presents both recommendations from science for policy development, and recommendations on policy for science. The health of the oceans and coastal seas is vital for the future well-being of all of Europe, indeed of entire mankind, and sustainable management of this sensitive and fast changing component of the global ecosystem is essential.JRC.A.3-Inter-institutional, International Relations and Outreac

Germline mutations in DNA repair genes predispose asbestos-exposed patients to malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer caused by asbestos exposure. An inherited predisposition has been suggested to explain multiple cases in the same family and the observation that not all individuals highly exposed to asbestos develop the tumor. Germline mutations in BAP1 are responsible for a rare cancer predisposition syndrome that includes predisposition to mesothelioma. We hypothesized that other genes involved in hereditary cancer syndromes could be responsible for the inherited mesothelioma predisposition. We investigated the prevalence of germline variants in 94 cancer-predisposing genes in 93 MPM patients with a quantified asbestos exposure. Ten pathogenic truncating variants (PTVs) were identified in PALB2, BRCA1, FANCI, ATM, SLX4, BRCA2, FANCC, FANCF, PMS1 and XPC. All these genes are involved in DNA repair pathways, mostly in homologous recombination repair. Patients carrying PTVs represented 9.7% of the panel and showed lower asbestos exposure than did all the other patients (p=0.0015). This suggests that they did not efficiently repair the DNA damage induced by asbestos and leading to carcinogenesis. This study shows that germline variants in several genes may increase MPM susceptibility in the presence of asbestos exposure and may be important for specific treatment