Epigenetic Dysregulation of Dopaminergic System by Maternal Cafeteria Diet During Early Postnatal Development.

Dopamine is a neurotransmitter crucial for motor, motivational, and reward-related functions. Our aim was to determine the effect of a palatable maternal diet on the transcriptional regulation of dopaminergic-related genes during perinatal development of rat offspring. For that, female offspring from dams fed with a control (CON) or a cafeteria (CAF) diet were sacrificed on embryonic day 21 (E21) and postnatal day 10 (PND10). Using micropunch techniques, ventral tegmental area (VTA) and nucleus accumbens (NAc) were isolated from brain's offspring. Bioinformatic analysis of the promoter regions, mRNA quantification and methylation studies were done. The increase in tyroxine hidroxylase (TH), dopamine receptor (DRD) 1 and ghrelin receptor (GHSR) expression in VTA and NAc from E21 to PND10 was correlated with changes in DNA methylation of their promoter regions. Maternal diet did not affect the expressionpatternsin E21. At PND10, maternal CAF diet decreased the transcription of TH, GHSR, DRD2 and dopamine transporter (DAT) in VTA. Interestingly, the changes in TH, DRD2 and DAT expression were related to the methylation status of their promoters. In NAc, maternal CAF diet reduced DRD1, DRD2 and DAT expression in the offspring at PND10, although alternations in the methylation patterns were only detected in DAT promoter. These results show the importance of maternal nutrition and provide novel insights into the mechanisms through which maternal junk-food feeding can affect reward system during development and early postnatal life. Particularly important is the expression decline of DRD2 given its physiological implication in obesity and addiction.

Perinatal exposure to bisphenol A (BPA) impairs neuroendocrine mechanisms regulating food intake and kisspetin system in adult male rats. Evidences of metabolic disruptor hypothesis.

Bisphenol A (BPA) is a compound used in the polymerization of plastic polycarbonates. It is an endocrine disruptor and it has been postulated to be an obesogen. Our objective was to determine the influence of perinatal exposure to BPA on body weight, hormone levels, metabolic parameters and hypothalamic signals that regulate food intake and kisspeptin system in adult male rats. Male rats were exposed to 50 µg/kg/day of BPA or vehicle from day 9 of gestation to weaning in the drinking water. Since weaning, they were fed with control or high fat diet for 20 weeks. Perinatal exposure to BPA impaired glucose homeostasis, induced obesity and increased food intake in adult male rats altering hypothalamic signals, partially mimicking and/or producing an exacerbation of the effects of feeding fat diet. We also observed an increase in kisspeptin expression by BPA exposure. Evidences shown in this work support the metabolic disruptor hypothesis for BPA.

Metaphyseal debonding of the Corail collarless cementless stem: report of 18 cases and case-control study.

AIMS: The Corail stem has good long-term results. After four years of using this stem, we have detected a small group of patients who have presented with symptomatic metaphyseal debonding. The aim of this study was to quantify the incidence of this complication, to delineate the characteristics of patients presenting with this complication and to compare these patients with asymptomatic controls to determine any important predisposing factors. PATIENTS AND METHODS: Of 855 Corail collarless cementless stems implanted for osteoarthritis, 18 presented with symptomatic metaphyseal debonding. A control group of 74 randomly selected patients was assembled. Clinical and radiological parameters were measured and a logistic regression model was created to evaluate factors associated with metaphyseal debonding. RESULTS: The prevalence of this complication was 2.1% in our series. In the multivariable model, the presence of a Dorr B-type proximal femur was associated with metaphyseal debonding (odds ratio (OR) 10.73, 95% confidence interval (CI) 2.31 to 49.97, p = 0.002), as was a body mass index > 25 kg/m2 (OR 6.85, 95% CI 1.06 to 44.28, p = 0.04). Smaller stems and the use of a polyethylene acetabular liner appeared to be protective when compared with metal and ceramic setting hard-on-hard bearings. CONCLUSION: We have described an uncommon but important mode of failure of the Corail stem. Surgeons should be aware of this phenomenon; overweight patients with Dorr B-type femurs and in whom hard bearings are used appear to be particularly at risk. Cite this article: Bone Joint J 2017;99-B:1435-41.

B-scan ultrasonography following open globe repair.

PURPOSE: To examine the accuracy and predictive ability of B-scan ultrasonography in the post-repair assessment of an open globe injury. METHODS: In all, 965 open globe injuries treated at the Massachusetts Eye and Ear Infirmary between 1 January 2000 and 1 June 2010 were retrospectively reviewed. A total of 427 ultrasound reports on 210 patients were analyzed. Ultrasound reports were examined for the following characteristics: vitreous hemorrhage, vitreous tag, retinal tear, RD (including subcategories total RD, partial RD, closed funnel RD, open funnel RD, and chronic RD), vitreous traction, vitreous debris, serous choroidal detachment, hemorrhagic choroidal detachment, kissing choroidal detachment, dislocated crystalline lens, dislocated intraocular lens (IOL), disrupted crystalline lens, intraocular foreign body (IOFB), intraocular air, irregular posterior globe contour, disorganized posterior intraocular contents, posterior vitreous detachment, choroidal vs retinal detachment, vitreal membranes, and choroidal thickening. The main outcome measure was visual outcome at final follow-up. RESULTS: Among 427 B-scan reports, there were a total of 57 retinal detachments, 19 retinal tears, 18 vitreous traction, 59 serous choroidal detachments, 47 hemorrhagic choroidal detachments, and 10 kissing choroidal detachments. Of patients with multiple studies, 26% developed retinal detachments or retinal tears on subsequent scans. Ultrasound had 100% positive predictive value for diagnosing retinal detachment and IOFB. The diagnoses of retinal detachment, disorganized posterior contents, hemorrhagic choroidal detachment, kissing choroidal detachment, and irregular posterior contour were associated with worse visual acuity at final follow-up. Disorganized posterior contents correlated with particularly poor outcomes. CONCLUSIONS: B-scan ultrasonography is a proven, cost-effective imaging modality in the management of an open globe injury. This tool can offer both diagnostic and prognostic information, useful for both surgical planning and further medical management.

Persistence and clearance of HPV from the penis of men infected and non-infected with HIV.

Due to high rates of human papillomavirus (HPV) infection, the incidence of intraepithelial neoplasia and anal cancer, most studies concerning HPV in men seropositive for HIV have focused on the anal canal. Few studies have targeted the penile region in HIV-infected men. A total of 72 men seropositive for HIV and 72 men seronegative for HIV were followed-up for 6 months, and their penile exfoliated cells were tested for HPV DNA. There were no significant differences between the HIV-positive and HIV-negative men in persistence (respectively, 69.5% vs. 66.9%), clearance (respectively, 15.3% vs. 23.1%), and those men never infected with HPV during the four follow-up visits (15.2% for HIV-positive vs. 20% for HIV-negative). High-risk HPV types were detected more frequently in penile smears from men infected with HIV, while, in HIV-seronegative men, the low-risk HPV types were more abundant (P = 0.001). Multiple infections with both high- and low-risk HPV types were significantly more frequent in HIV-seropositive compared to those who were HIV-seronegative (P = 0.0004). The attendance rates at follow-up visits were 86%, 78%, and 58% in months 1, 2, and 6, respectively, for men infected with HIV and 93%, 72%, and 60% for the HIV-negative group. It is concluded that HIV infection can be considered a risk factor for clearance and persistence of HPV. Multiple infections with different types of HPV including high-risk HPVs are frequent in men who are infected with HIV.

Functional role of Calcium-stimulated adenylyl cyclase 8 in adaptations to psychological stressors in the mouse: implications for mood disorders.

The Ca(2+)/calmodulin stimulated adenylyl cylcase 8 (AC8) is a pure Ca(2+) sensor, catalyzing the conversion of ATP to cAMP, with a critical role in neuronal plasticity. A role for AC8 in modulating complex behavioral outcomes has been demonstrated in AC8 knock out (KO) mouse models in which anxiety-like responses were differentially modulated following repeated stress experiences, suggesting an involvement of AC8 in stress adaptation and mood disorders. To further investigate the role of this enzyme in phenotypes relevant for psychiatric conditions, AC8 KO mice were assessed for baseline behavioral and hormonal parameters, responses to repeated restraint stress experience, and long-term effects of chronic social defeat stress. The lack of AC8 conferred a hyperactive-phenotype both in home-cage behaviors and the forced swim test response as well as lower leptin plasma levels and adrenal hypertrophy. AC8 KO mice showed baseline "anxiety" levels similar to wild type littermates in a variety of procedures, but displayed decreased anxiety-like responses following repeated restraint stress. This increased stress resilience was not seen during the chronic social defeat procedure. AC8 KO did not differ from wild type mice in response to social stress; similar alterations in body weight, food intake and increased social avoidance were found in all defeated subjects. Altogether these results support a complex role of cAMP signaling pathways confirming the involvement of AC8 in the modulation of stress responses. Furthermore, the hyperactivity and the increased risk taking behavior observed in AC8 KO mice could be related to a manic-like behavioral phenotype that warrants further investigation.

[Prevention and therapy of critical ischemia in hemodialyzed patients]. / Prevenzione e terapia dell'ischemia critica nell'uremico in terapia dialitica.

The cardiovascular disease is largely increased in chronic renal failure and the patients have a 10-20 times higher mortality respect normal population. Besides habitual risk-factors they add the mineral metabolism alterations, iperomocisteine and chronical vessel flogosis. In these patients the vascular disease is often lately diagnosed, but early diagnosis would be extremely important to establish appropriate pharmacologic or surgical treatment (PTA or by pass). The basic diagnostic methods are still digital angiography, angio-NMR or angio-CT. In our experience appears that dialysed patients present high total mortality and re-vascolarization (particularly for peripheral occlusive disease) gives less guarantee of success. During last years endovascular surgery procedures extremely improved short-term prognosis for these patients. When there is no space for the re-vascolarization and the situation is strongly compromised by the presence of extended gangrene or infected lesion, amputation is still indicated and can be considered the only possible solution.

Progresión a necrólisis epidérmica tóxica por uso de lamotrigina: A propósito de un caso / Progression to toxic epidermal necrolysis by using lamotrigina: In connection of a case

El Síndrome de Stevens Johnson (SSJ), el Síndrome de Superposición (SSJ/ NET) y la Necrólisis Epidérmica Tóxica (NET) son formas clínicas cutáneo-mucosas graves, desencadenadas por fármacos y muy frecuentemente por anticonvulsivantes. Comunicamos el caso de una paciente medicada por su epilepsia, quién presentó un cuadro incipiente de SSJ empeorando rápidamente hasta derivar en la NET. A pesar de la gravedad, la paciente respondió satisfactoriamente a altas dosis de corticoides sistémicos desde el comienzo y por las medidas de soporte del equipo médico multidisciplinario del hospital.

The Stevens Johnson Syndrome, the Overlape Syndrome (SSJ / NET), and the Toxic Epidermal Necrolysis are clinical cutaneous mucouse forms due to drugs administration and most frequently due caused by antiepileptic. We communicate the case of a patient treated with lamotrigina for epilepsy, who presented an incipient case of Stevens Johnson Syndrome, worsened rapidly causing a Toxic Epidermal Necrolysis. Nevertheless, the patient gained a satisfactory answer due to high doses of corticoids, which were given from the beginning as well as the measures and the support of the whole medical team of the hospital.

High serum levels of soluble Fas (sFas) in CKD patients: effects of renal clearance, reabsorption and synthesis.

PURPOSE: Increased serum concentrations of soluble Fas (sFas) have been reported in patients with chronic kidney disease (CKD). However, little is known about the renal clearance of sFas, whether sFas is reabsorbed in the renal tubules, or the behavior of sFas synthesis in CKD. MATERIALS AND METHODS: We studied 69 patients with CKD (60+/-15 years old, creatinine clearance 37+19 ml/min/1.73 m2) and 14 healthy subjects (61+/-17 years, creatinine clearance 79+/-24 ml/min/1.73 m2). ELISA was used to measure the levels of sFas (pg/mL) and retinol binding protein (RBP - mg/L). RT-PCR was used to quantify sFasmRNA of leukocytes. RESULTS: Serum sFas levels were significantly higher in patients with CKD (2781+/-1214 vs. 2196+/-773, p=0.02). The concentrations of sFas in 24-hour urine samples (23+/-27 vs. 40+/-17, p=0.006) and sFas Clearance (0.019+/-0.022 vs. 0.036+/-0.020, p=0.01) were significantly lower in patients with CKD. sFas clearance correlated with creatinine clearance (r=0.25, p=0.02). Urine concentrations of RBP correlated with sFas concentrations in the urine (r=0.80, p<0.001). sFasmRNA were higher in patients with CKD (3.9+/-1.8 vs. 2.5+/-0.9, p<0.001). CONCLUSIONS: In CKD patients, the decrease in renal function is followed by a decrease in sFas clearance and an increase in serum sFas. In patients with proximal tubule dysfunction (high urinary RBP concentrations), urinary sFas is also increased, suggesting that sFas is reabsorbed by the proximal tubule. It is possible that an increase in sFas synthesis also contributes to the increase of serum sFas concentrations in uremia.

Discovery of a 25-cm asteroid clast in the giant Morokweng impact crater, South Africa.

Meteorites provide a sample of Solar System bodies and so constrain the types of objects that have collided with Earth over time. Meteorites analysed to date, however, are unlikely to be representative of the entire population and it is also possible that changes in their nature have occurred with time. Large objects are widely believed to be completely melted or vaporized during high-angle impact with the Earth. Consequently, identification of large impactors relies on indirect chemical tracers, notably the platinum-group elements. Here we report the discovery of a large (25-cm), unaltered, fossil meteorite, and several smaller fragments within the impact melt of the giant (> 70 km diameter), 145-Myr-old Morokweng crater, South Africa. The large fragment (clast) resembles an LL6 chondrite breccia, but contains anomalously iron-rich silicates, Fe-Ni sulphides, and no troilite or metal. It has chondritic chromium isotope ratios and identical platinum-group element ratios to the bulk impact melt. These features allow the unambiguous characterization of an impactor at a large crater. Furthermore, the unusual composition of the meteorite suggests that the Morokweng asteroid incorporated part of the LL chondrite parent body not represented by objects at present reaching the Earth.

[Peripheral arteriopathy in ESRD dialysed patients: when and how to intervene]. / L'arteriopatia periferica nel paziente in emodialisi cronica: quando e come intervenire.

Critical limb ischemia secondary to chronic peripheral occlusive disease is common in chronically dialysed patients, with an incidence rate of 25-30%. Atherosclerotic lesions are more frequent in the infrainguinal arteries and long infrapopliteal occlusions often occur. Due to diabetes, hypertension and ischemic cardiopathy, the surgical prognosis is very poor in these patients; medical treatment should always be attempted associated with analgesia, without an excessive delay in surgical therapy if needed. Both spinal stimulation and lumbar simpaticectomy often fail; open and endovascular surgery are the best options before major amputation, which has a high incidence in this patient subgroup. Between 2000 and 2003, 23 chronically dialysed patients underwent surgery. Nine open and 13 endovascular procedures were performed, associated with four immediate and five late minor amputations. Despite an immediate mortality rate of 8.6%, we obtained immediate patency and limb salvage in all cases. In a medium follow-up of 25 months (range 3-36), five thromboses were found in subinguinal procedures; not one in iliac procedures. The five patients underwent major amputation. Another two patients underwent amputation despite arterious patency. Seven patients died due to cardiovascular diseases during the follow-up. Our experience confirms that the association between POAD and dialysis is a prediction factor for medium-term death and that the surgical risk is highly increased. It is important to select patients undergoing surgical treatment to check for the lowest invasivity.

Adaptability and compliance of the obese patient to restrictive gastric surgery in the short term.

BACKGROUND: Low compliance, as well as recurrent vomiting, are often pointed out as the main causes of both postoperative technical complications and poor weight loss. METHODS: 50 patients were examined. All underwent preoperative psychological assessment through an intensive clinical interview. Between October 1999 and January 2000, all the patients underwent vertical banded gastroplasty (VBG). Excess Weight Loss (EWL) was followed, and the number of vomiting episodes was recorded at 1, 3 and 6 months after surgery. RESULTS: 3 different groups of patients could be distinguished: 1) those with no vomiting and good weight loss; 2) those with sporadic vomiting and fairly good weight loss; and 3) those with frequent vomiting and poorer weight loss. However, this last group of patients was not homogeneous and should be divided into 2 subgroups: 1) patients who lose weight, while vomiting; 2) patients who do not lose weight, while vomiting. CONCLUSIONS: The experience of vomiting is a crucial cross-roads. The influence of psychosocial factors was noticed in all patients. The absence of psychosocial stressors, together with realistic expectations and a strong motivation to change, should be considered as reliable and replicable predictors of success. However, even those patients with accentuated psychological difficulties were able to succeed in coping with them, and achieved a good weight outcome, with good effects on the psychic side. Therefore, the evidence of psychological disorders cannot be taken as an absolute criterion of selection/exclusion of candidates for the operation. Accurate presurgical education and postoperative psychological support are likely to increase the patient's compliance and the percentage of successful cases.

60 reoperations on 890 patients after gastric restrictive surgery.

BACKGROUND: Since 1988 we performed gastric restriction operations on 890 patients; 60 required subsequent re-operation. METHODS: The Molina non-adjustable band was discontinued early because of a high percentage of re-operations. Between 1992 and 1995, we performed the Mason vertical banded gastroplasty (VBG) using a 9-cm long vertical staple-line, with a re-operation rate of 15%. Since 1996, we have been performing a 6-cm long vertical staple-line, with a re-operation rate of 0.7%. The MacLean VBG also had a low re-operation rate (0.9%), but the seriousness of its most dangerous complication, perioperative cardia fistula, limited our use of this method to specifically selected cases. With adjustable banding, we have used the Swedish band which produced a low re-operation rate (2.1%), consisting of relatively simple corrective procedures. RESULTS: The re-operations produced results similar to those of first-time operations in terms of weight loss and nutritional status. In particular, after 3 years, re-operated patients had similar weight to those who had been operated upon with the same method initially. CONCLUSIONS: When the surgical procedure was selected with greater astuteness and modified appropriately, the re-operation rate decreased from 17% in the period 1992 to 1995, to 1% in the period 1996 to 2000.

Structural organization and chromosomal localization of the human type II deiodinase gene.

OBJECTIVE: The selenoenzyme type 2 iodothyronine 5' deiodinase (DII) catalyzes the conversion of thyroxine into its active form tri-iodothyronine (T3), modulating thyroid hormone homeostasis in a local, tissue-specific manner. The amphibian, rodent and human cDNAs encoding this enzyme have been recently cloned and expressed. At present, little information regarding the genomic structure of mammalian DII is available. DESIGN AND METHODS: The complete structure, including intron-exon junctions, of the human DII (hDII) gene was obtained by long PCR and rapid amplification of cDNA ends (RACE). Chromosomal assignment of the hDII gene was performed by fluorescence in situ hybridization using a highly specific probe. RESULTS AND CONCLUSIONS: Our data demonstrated that hDII is a single copy gene located on chromosome 14, position 14q24.3. The gene spans over 15 kb, and the 7 kb transcript is encoded by three exons of 149 bp, 273 bp and 6.6 kb separated respectively by two 274 bp and 7.4 kb introns. A restriction map of the hDII gene is also reported. These data will help in further studies of the role of DII in the maintenance of peripheral thyroid hormone homeostasis.

Voltammetric and functional evidence that N-methyl-D-aspartate and substance P mediate rat vascular relaxation via nitrogen monoxide release.

It is known that substance P acts as a vasodilator via activation of the enzyme nitrogen monoxide synthase (NOS) in endothelial tissue and it is suggested that N-methyl-D-aspartate (NMDA) could stimulate nitrogen monoxide (NO) release within nervous tissue. However, the data reported concern NO metabolites (nitrites, nitrates), while there is no clear evidence to date of the action of the latter compound within the aortic tissue. In this study, amperometry with specifically prepared carbon fiber electrodes has been applied to examine the effect of NMDA or substance P upon NO release. In particular, the data obtained confirm that NMDA can stimulate NO release in vivo, in the striatum of anaesthetized rats, and that substance P can stimulate NO release in rat aortic rings (ex vivo experiments). In addition, they indicate that NMDA also stimulates NO release in rat aortic rings. This original data has been confirmed by the observation of a vasorelaxant action of NMDA within noradrenaline precontracted aortic rings. Thus, these experiments provide the first direct evidence that NMDA can mediate vascular relaxation via NO release.

Effect of tryptophan on the early tri-iodothyronine uptake in mouse thymocytes.

OBJECTIVE: We have studied the effect of tryptophan on cellular [(125)I]tri-iodothyronine (T3) uptake by mouse thymocytes. MATERIALS AND METHODS: Mouse thymocytes (20 x 10(6 )cells/ml) were suspended in Krebs-Ringer solution buffered by Tris-HCl and incubation (23 degrees C at pH7.45+/-0.6), in the presence or absence of 1mM tryptophan, was started by adding 25 pM [(125)I]T3. At the end of incubation, samples were cooled in ice, centrifuged over a 30% sucrose cushion and the cell-associated radioactivity was measured in the pellet. RESULTS: Tryptophan reduced both the total and the saturable fraction of [(125)I]T3 uptake by 44% (P=0.0009) and 60% (P=0.0006) respectively, following 1 min of incubation. This effect was specific and dose-dependent, being maximal at 5mM concentration (-82%). In contrast, the pre-exposure of cells to tryptophan for up to 2h had no effect on the subsequent uptake of [(125)I]T3, in the absence of tryptophan. The effect of D-tryptophan on saturable T3 uptake was not different from that obtained using the L-stereoisomer. Tryptophan reduced the V(max) of the initial rate of saturable [(125)I]T3 uptake by two-thirds without affecting the apparent K(m) (2.2 nM) of the process, thus indicating the non-competitive nature of the inhibition. In sodium-free medium the saturable [(125)I]T3 uptake was reduced by 43%. The inhibitory effect of tryptophan on [(125)I]T3 uptake was exerted in both the presence and the absence of sodium. In fact, the inhibitory effect of tryptophan on T3 transport was greater and significantly different (P=0.0046) from that obtained by sodium depletion alone. CONCLUSIONS: Tryptophan interferes with both the sodium-dependent and -independent components of [(125)I]T3 uptake by a dose-dependent, non-competitive mechanism which operates in cis-modality at the plasma membrane level of mouse thymocytes.

Isolation of human type 2 deiodinase gene promoter and characterization of a functional cyclic adenosine monophosphate response element.

We analyzed the structure and function of the 5' flanking region of the human type 2 deiodinase (hD2) gene. Two major transcription start sites were identified at -470/-474 from the ATG. The 5' flanking region of hD2 gene efficiently directed transcription in transient transfection studies, using luciferase as reporter gene, in HEK 293 cells. Basal transcriptional activity was significantly reduced by deleting the region containing a canonical cAMP-responsive element (CRE) located -766/-759 from ATG. Forskolin treatment significantly increased luciferase activity in cells transfected with CRE-containing constructs. This effect was abolished in constructs that did not contain CRE or contained the mutagenized CRE. Northern blot analysis in JEG-3 cells revealed that the hD2 messenger RNA was markedly increased after stimulation with cAMP agonist. The electrophoretic mobility shift assay with hD2-CRE probe and HEK 293 nuclear extract showed the occurrence of a DNA-protein complex, which was competed by specific unlabeled oligonucleotides and supershifted by the anti-CREB and anti-CRE modulator-1 antibodies. A-CREB, a dominant negative inhibitor of CREB, completely inhibited forskolin induction of the hD2 promoter. CREB protein, once cotransfected with hD2 promoter construct and pKA in F9 teratocarcinoma cells, which are unresponsive to cAMP, was able to stimulate the hD2 gene transcription. These results indicate the existence of a functional promoter within the 5' flanking region of hD2 gene which is characterized by the presence of a CRE. The specific involvement of CREB in the cAMP-mediated hD2 gene promoter induction also has been demonstrated.

[Thyroid diseases: molecular diagnosis and therapeutic perspectives]. / Tireopatie: diagnostica molecolare e prospettive terapeutiche.

The diagnostic algorithm of thyroid diseases, the most frequent dysendocrine condition, can be today integrated by the newly developed molecular methodologies. From the early diagnostic approaches, centered on the assessment of thyroid function, either by in vivo radioisotopic techniques, or by in vitro radioimmunological measurement of hormone plasma concentrations, it is nowadays possible to precisely define the molecular events triggered by the iodothyronine signal at the level of target tissues. In this brief review will be discussed the recent progresses on cloning and characterization of several genes involved in the regulation of thyroid differentiation, ability to trap iodine, synthesis and secretion of iodothyronines, regulation of thyroid function by TSH, transduction of the hormonal signal to subcellular structures involved in the translation of the hormone message in specific biological, effects such as those on metabolic homeostasis, cell proliferation and differentiation. It will be also discussed the most recent advancements on the genetics of thyroid diseases which have allowed to characterize the molecular basis of several thyropathies such as congenital hypothyroidism, thyroid hormone resistance syndrome, hyperthyroidism or hypothyroidism caused by TSH-receptor alterations, molecular abnormalities of oncogenes or tumor suppressor genes which are associated with benign or malignant thyroid cell transformation. The most recent developments of the diagnostic procedures of thyroid diseases, also in their pre-clinical stage, will be also reviewed together with a brief highlight on the most recent treatment options, centered on prophylactic therapeutic intervention or on the development of gene therapy strategies which will be possibly applied in a near future.

An introduction to benign thyroid disease: pathophysiologic, epidemiologic aspects and diagnostic methodology.

The role of preoperative noninvasive diagnostic procedures in the management of benign thyroid diseases is critically reviewed and on the basis of a series of more than 13,000 thyroid nodules, sequentially examined, the role of preoperative fine needle aspiration (FNA) cytology in discriminating benign from malignant lesions, is assessed. Retrospective studies were performed to determine the diagnostic accuracy of FNA adopted as routine preoperative screening procedure as compared to intraoperative frozen section (FS) analysis. US-guided FNA was shown to be more accurate allowing the preoperative identification of occult or minimal carcinoma: in fact about 3% of malignant thyroid nodules were detected. Moreover, the operation time is reduced, and unnecessary surgical treatments for benign lesions are eliminated, preventing the need of two-stage cancer surgery. FNA is a cost-effective diagnostic tool with about 20% reduction in the cost of care of patients with thyroid nodules. Most recent methods of molecular biology which seem promising in thyroid tissue sampled by FNA to detect malignant lesions missed by conventional cytology and included in the generic category of "follicular proliferation", are analyzed.