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Purpose: Radioiodine I-131 (RAI) is the therapy of choice for differentiated thyroid cancer (DTC). Between 5% and 15% of DTC patients become RAI refractory, due to the loss of expression/function of iodide metabolism components, especially the Na/I symporter (NIS). We searched for a miRNA profile associated with RAI-refractory DTC to identify novel biomarkers that could be potential targets for redifferentiation therapy. Methods: We analyzed the expression of 754 miRNAs in 26 DTC tissues: 12 responsive (R) and 14 non-responsive (NR) to RAI therapy. We identified 15 dysregulated miRNAs: 14 were upregulated, while only one (miR-139-5p) was downregulated in NR vs. R tumors. We investigated the role of miR-139-5p in iodine uptake metabolism. We overexpressed miR-139-5p in two primary and five immortalized thyroid cancer cell lines, and we analyzed the transcript and protein levels of NIS and its activation through iodine uptake assay and subcellular protein localization. Results: The finding of higher intracellular iodine levels and increased cell membrane protein localization in miR-139-5p overexpressing cells supports the role of this miRNA in the regulation of NIS function. Conclusions: Our study provides evidence of miR-139-5p involvement in iodine uptake metabolism and suggests its possible role as a therapeutic target in restoring iodine uptake in RAI-refractory DTC.

A multicystic intraventricular tumour of the right ventricular atrium was incidentally diagnosed on follow-up imaging of a 61-year-old man with a history of prostatic adenocarcinoma. Surgical resection of the lesion was performed after a one-year radio-clinical follow-up due to progressive expansion of the lesion size and a rising prostate specific antigen blood-level. Morphological features with papillary pattern on pathological examination were compatible with malignant adenocarcinoma or choroid plexus carcinoma. The immunoprofile was conclusive for an exceptional choroid plexus metastasis (CPM) of a prostatic adenocarcinoma. To our knowledge, this is the first report of a proven prostatic origin of a CPM.

Iron overload may promote the progression of HIV infection and AIDS. Excessive iron in the body may promote oxidation and impair the immune system. Researchers studied iron dynamics in 49 HIV patients with thalassemia, a genetic blood disorder, nine years after they tested positive for HIV. Thirty-one percent of patients with high serum ferritin levels, indicating substantial iron stores, progressed to stage IV infection, compared to 16% of those with lower ferritin levels. Desferrioxamine therapy slowed progression of the infection.

Sudden liquidity or solvency problems by a bank in interbank clearing networks may preclude settlement of its creditors' claims, thus putting at risk settlement of other institutions. An examination of the potential size of the 'domino effect' in the Italian netting system simulated a network participant's settlement failure and measured the impact on the rest of the network. Results revealed that the average number of systemic crises is small and that the systemic crises themselves are small, in terms of number of institutions involved and of monetary losses. These indicate that the differences are primarily due to the much smaller volume of funds involved in the Italian system and to structural differences.

Objectives: To assess the impact of a screening programme for haemoglobinopathies which was organised from 1978 to 1985 in high secondary schools of the Marseille region. Methods: Several variables that [...]

Ultraviolet (UV) radiation is considered to be an important environmental factor in the clinical course of children with juvenile dermatomyositis (DM). We aimed to evaluate the association between UV radiation and severe disease outcomes in juvenile DM. This is a cross‐sectional study of patients with juvenile DM enrolled in the US multicenter Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry from 2010 to 2015. The mean UV index (UVI) in the calendar month prior to symptom onset in each subject's zip code was calculated from daily satellite solar noon measurements. Multivariable logistic regression was used to model the relationship between the mean UVI and calcinosis as well as other outcomes of severe disease. Covariates included sex, race, age, time to diagnosis, disease duration, and latitude. In a multivariable model, there was no association between the mean UVI and calcinosis. African American race was associated with a 3‐fold greater odds of calcinosis. However, there was a significant statistical interaction between race and mean UVI. Accounting for this interaction, the odds of calcinosis markedly decreased in African American subjects and steadily increased in non–African American subjects over a range of increasing the mean UVI. Higher mean UVI was associated with decreased odds of using biologics or nonmethotrexate disease‐modifying antirheumatic drugs and skin ulceration. We described a novel association between UV radiation, calcinosis, and race in a large cohort of patients with juvenile DM. This study furthers our knowledge of the role of UV radiation in the clinical course of juvenile DM and highlights the complex interplay between genes and environment in the clinical phenotypes and development of calcinosis in children with juvenile DM.

We investigate the relaxation dynamics of protein–polymer conjugates by neutron scattering spectroscopy to understand to which extent the coating of a protein by a polymer can replace water in promoting thermal structural fluctuations. For this purpose, we compare the dynamics of protein–polymer mixtures to that of conjugates with a variable number of polymers covalently attached to the protein. Results show that the flexibility of the protein is larger in protein–polymer mixtures than in native protein or in conjugates, even in the dry state. Upon hydration, both the native protein and the conjugate show equivalent dynamics, suggesting that the polymer grafted on the protein surface adsorbs all water molecules.

Aim of this study was to evaluate the association between body mass index (BMI) and aggressive features of differentiated thyroid cancer (DTC) in a prospective cohort. Patients with DTC were prospectively enrolled at a tertiary referral center and grouped according to their BMI. Aggressive clinic-pathological features were analyzed following the American Thyroid Association Initial Risk Stratification System score. The cohort was composed of 432 patients: 5 (1.2%) were underweight, 187 (43.3%) normal weight, 154 (35.6%) overweight, 68 (15.7%) grade 1 obese, 11 (2.5%) grade 2 obese and 7 (1.6%) grade 3 obese. No single feature of advanced thyroid cancer was more frequent in obese patients than in others. No significant correlation was found between BMI, primary tumor size (Spearman’s ρ− 0.02; p= 0.71) and ATA Initial Risk Stratification System score (ρ0.03; p= 0.49), after adjustment for age. According to the multivariate logistic regression analysis, male gender and pre-surgical diagnosis of cancer were significant predictors of cancer with high or intermediate–high recurrence risk according to the ATA system (OR 2.06 and 2.51, respectively), while older age at diagnosis was a protective factor (OR 0.98), and BMI was not a predictor. BMI was a predictor of microscopic extrathyroidal extension only (OR 1.06). Obesity was not associated with aggressive features in this prospective, European cohort of patients with DTC.

To investigate clinical manifestations of juvenile systemic sclerosis (SSc; scleroderma), including disease characteristics and patient quality of life, using the multinational Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry. Patients with juvenile SSc were prospectively enrolled between 2010 and 2013. The diagnosis of juvenile SSc was determined by the enrolling pediatric rheumatologist, with the requirement for disease onset prior to age 18 years. Collected data included demographics, disease characteristics, medication exposure, and quality of life metrics. In total, 64 patients with juvenile SSc were enrolled a median of 3.6 years after disease onset, which occurred at a median age of 10.3 years. The most common organ manifestations were dermatologic and vascular, followed by musculoskeletal, gastrointestinal, and pulmonary; in 38% of patients, ≥4 organ systems were affected. Patients with juvenile SSc had significantly more disability at enrollment compared with CARRALegacy Registry patients with juvenile idiopathic arthritis, dermatomyositis, or systemic lupus erythematosus. Although physician‐reported measures correlated most closely with arthritis, dermatologic manifestations, and pulmonary manifestations, poor patient‐reported measures were associated with gastrointestinal involvement. During >50 person‐years of follow‐up, most organ manifestations remained stable, and no mortality or development of new solid organ involvement after enrollment was reported. In the first multicenter prospective cohort of patients with juvenile SSc in North America, the disease burden was high: multiorgan manifestations were common, and functional disability was greater than that observed in patients with other childhood‐onset rheumatic diseases. Gastrointestinal involvement had the greatest impact on quality of life.

Purpose: A controversy exists regarding the prognostic value of coronary artery calcification (CAC) found on electron beam-CT (EBCT) screening. Selection of inappropriate age ranges may affect the test value. Methods: [...]

We study the standard deviation of water saturation SDSas function of the mean saturation 〈S〉by a stochastic model of unsaturated flow, which is based on the first‐order solution of the three‐dimensional Richards equation. The model assumes spatially variable soil properties, following a given geostatistical description, and it explicitly accounts for the different scales involved in the determination of the spatial properties of saturation: the extent L, i.e., the domain size, the spacing Δ among measurements, and the dimension ℓassociated to the sampling measurement. It is found that the interplay between those scales and the correlation scale Iof the hydraulic properties rules the spatial variability of saturation. A “scale effect” manifests for small to intermediate L/I, for which SDSincrease with the extent L. This nonergodic effect depends on the structural and hydraulic parameters as well as the scales of the problem, and it is consistent with a similar effect found in field experiments. In turn, the influence of the scale ℓis to decrease the saturation variability and increase its spatial correlation. Although the solution focuses on the medium heterogeneity as the main driver for the spatial variability of saturation, neglecting other important components, it explicitly links the spatial variation of saturation to the hydraulic properties of the soil, their spatial variability, and the sampling schemes; it can provide a useful tool to assess the impact of scales on the saturation variability, also in view of the several applications that involve the saturation variability. We study the spatial variability of soil moisture by a three‐dimensional stochastic model of unsaturated flowThe model accounts for the three relevant scales: extent, spacing among measurements, support scale of the latterInterplay between the scales and the correlation of the hydraulic properties rules the variability of saturation, a scale effect manifests

Prompt treatment for lupus is important to prevent morbidity. A potential barrier to early treatment of pediatric lupus is delayed presentation to a pediatric rheumatologist. To better understand factors contributing to delayed presentation among pediatric lupus patients, we examined differences in demographic and clinical characteristics of lupus patients within the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry with regard to time between symptom onset and presentation to a pediatric rheumatologist. We analyzed data from 598 CARRALegacy Registry participants for differences between those who presented early (within <1 month of symptom onset), between 1–3 months (typical presentation), with moderate delays (3–12 months), and with severe delays (≥1 year). Factors associated with early presentation, moderate delay, and severe delay were determined by multinomial logistic regression. Forty‐four percent of patients presented early, while 23% had moderate delays and 9% had severe delays. Family history of lupus, absence of discoid rash, and location in a state with a higher density of pediatric rheumatologists were associated with earlier presentation. Younger age, low household income (<$25,000 per year), and a family history of lupus were associated with severe delay. Delays to care ≥1 year exist in a notable minority of pediatric lupus patients from the CARRALegacy Registry. In this large and diverse sample of patients, access to care and family resources played an important role in predicting time to presentation to a pediatric rheumatologist.

The physio-pathologic interrelationships between endothelium and GvHD have been better elucidated and have led to definition of the entity ‘endothelial GvHD’ as an essential early phase prior to the clinical presentation of acute GvHD. Using the CellSearch system, we analyzed circulating endothelial cells (CEC) in 90 allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients at the following time-points: T1 (pre-conditioning), T2 (pre-transplant), T3 (engraftment), T4 (onset of GvHD) and T5 (1 week after steroid treatment). Although CEC changes in allo-HSCT represent a dynamic phenomenon influenced by many variables (that is, conditioning, immunosuppressive treatments, engraftment syndrome and infections), we showed that CEC peaks were constantly seen at onset of acute GvHD and invariably returned to pre-transplant values after treatment response. Since we showed that CEC changes during allo-HSCT has rapid kinetics that may be easily missed if blood samples are drawn at pre-fixed time-points, we rather suggest an ‘on demand’ evaluation of CEC counts right at onset of GvHD clinical symptoms to possibly help differentiate GvHD from other non-endothelial complications. We confirm that CEC changes are a suitable biomarker to monitor endothelial damage in patients undergoing allo-transplantation and hold the potential to become a useful tool to support GvHD diagnosis (ClinicalTrials.gov NCT02064972).

C-peptide has been shown to exert several, previously unknown, biological effects. A recent cross-sectional study demonstrated an association between low C-peptide serum levels and low lumbar bone density of postmenopausal women not affected by diabetes. To date, very little research attention has been directed toward the association between C-peptide and osteoporotic fractures. To contribute toward filling this gap, we investigated the association between C-peptide and fractures in postmenopausal women. A cohort of 133 non-diabetic postmenopausal women with and without a history of fractures was evaluated in this cross-sectional investigation. Standardized interviews were performed to gather information on the patients’ fracture history. All of the participants underwent a bone mineral density assessment by DXA, radiographs, and a serum C-peptide measurement. Thirty-four women presented fractures. Bivariate analysis revealed an inverse correlation between C-peptide and fractures (r= −0.27, p= 0.002). A significant difference in mean C-peptide levels was also found between women with vs.without fractures (p= 0.01, adjusted for age, BMI and glucose). Logistic regression analysis showed that C-peptide levels, femoral and vertebral BMD were all negatively associated with fracture status (B= −1.097, ES = 0.401, p= 0.006, 95% CI 0.15–0.73; B= −15.6, SE = 4.17, p< 0.001, CI 0.001–0.002; B= −24.8, SE = 5.23, p< 0.001, CI 0001–0.002; respectively). This study confirms an inverse association between serum C-peptide levels and a history of fractures in postmenopausal women without diabetes. These results suggest that C-peptidemay exert an effect on bone mineral density. However, further large-scale studies are needed to corroborate this finding and investigate the potential underlying mechanisms involved.

According to the recent definition proposed by the Consensus conference on Acute Dialysis Quality Initiative Group, the term cardio-renal syndrome (CRS) has been used to define different clinical conditions in which heart and kidney dysfunction overlap.

Les inhibiteurs de la pompe à protons (IPP) sont fréquemment utilisés chez les patients atteints de cancer. Pourtant, en diminuant l’acidité gastrique, ils peuvent perturber l’absorption de nombreux médicaments administrés par voie orale. Une diminution de l’efficacité anti-tumorale de plusieurs inhibiteurs de tyrosine kinase a été suggérée dans des études de pharmacocinétique et en vie réelle. Peu de données ont été publiées concernant les thérapies ciblées anti-BRAF/anti-MEK. La Food and Drug Administration (FDA) estime qu’on ne connaît pas l’effet de la prise d’IPP sur l’efficacité du dabrafénib, et la Société européenne d’oncologie médicale (ESMO) recommande donc d’éviter la prise d’IPP au cours d’un traitement par dabrafénib. De plus, les IPP inhibent le cytochrome P450 3A4 (CYP3A4) et pourraient donc entraîner un surdosage et une toxicité du vemuraéenib et du cobimétinib qui sont des substrats du CYP3A4.

Non-functioning (NF) pancreatic neuroendocrine tumors (pNET) often have an indolent outcome. A consensus to submit patients with large (>2 cm) NF-pNET to surgery already exists; but a conservative approach for small (≤2 cm) NF neoplasms has been proposed. To identify prognostic factors for survival and progression free survival (PFS) of NF-pNET, evaluating whether surgery may be avoided for small NF-pNET. Retrospective study of 77 consecutive patients with pNET submitted to surgery, of which 60 were NF. Pathological tissues were revised according to the 2000 and 2010 WHO classifications. Risk factors for survival and PFS were evaluated using the Kaplan–Meier method and the Cox regression model. The 8-year cause-specific survival of NF-pNET was 79.3 %. At univariate analysis, high grading, high staging, large tumors, angioinvasion and peri-pancreatic infiltration were significantly associated with a shorter survival; at multivariate analysis only peri-pancreatic infiltration was significantly associated with a shorter NF-pNET survival. Most small NF-pNET were grade 1 (74 %), compared to large NF-pNET (27 %). Distant metastases were present in 29.7 % (n= 11) and 17.4 % (n= 4) of patients with large or small NF-pNET, respectively; among the 19 small NF-pNET without metastasis, five had a local malignancy (lymph node metastasis or local infiltration); thus, 39 % of the 23 NF-pNET, turned out to have a malignant potential. Among NF-pNET, large neoplasms were associated with worse outcomes; however, small NF-pNET do not seem to have an invariable benign behavior. Whether surgery should be avoided in all patients with small NF-pNET is questionable.

This study focuses on the analyses of field‐scale water flow originating from a drywell, using the 3‐D Richards equation for the local description of the flow in a spatially heterogeneous, combined vadose zone‐groundwater flow system. Realistic features of the flow system, that is, height of the groundwater table, records of the time‐dependent rainfall data, spatial heterogeneity of soil hydraulic properties and flow‐controlled attributes, as well as man‐controlled characteristics of the drywell, were considered in the analyses. The effect of (a) the depth‐dependency of the soil type, (b) the vertical position of the drywell's screen, and (c) the mode of water injection to the drywell (constant or time‐dependent), on the performance of the drywell, were examined. Results, and in particular those related to the importance of the soil type depth‐dependency with regard to the drywell performance, can be explained by the physics of flow in unsaturated soils of differing soil texture. Of specific significance is the transition zone between the two different soil types in the case in which the spatially‐heterogeneous coarse‐textured soil overlies the spatially heterogeneous fine‐textured soil. In this case, when most of the drywell screen is located within this transition zone and when the flow is transient and non‐monotonous, the downward flow from the drywell is maximized. Although this study is site‐specific, we believe that its results are novel and relevant for sandy to sandy‐clay soils associated with managed aquifer recharge technology based on a device whose vertical axis is perpendicular to the soil layering. Flow from a drywell is simulated for six 3‐D spatially heterogeneous, vadose zone ‐ groundwater (VZ‐GW) flow setupsFlows controlled by rain dynamics and constant injection scenarios are simulatedFine textured layer at the lower part of the drywell will maximize downward fluxes Flow from a drywell is simulated for six 3‐D spatially heterogeneous, vadose zone ‐ groundwater (VZ‐GW) flow setups Flows controlled by rain dynamics and constant injection scenarios are simulated Fine textured layer at the lower part of the drywell will maximize downward fluxes

Acromegaly usually occurs as a sporadic disease, but it may be a part of familial pituitary tumor syndromes in rare cases. Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene have been associated with a predisposition to familial isolated pituitary adenoma. The aim of the present study was to evaluate the AIPgene in a patient with gigantism and in her relatives. Direct sequencing of AIPgene was performed in fourteen members of the family, spanning among three generations. The index case was an 18-year-old woman with gigantism due to an invasive GH-secreting pituitary adenoma and a concomitant tall-cell variant of papillary thyroid carcinoma. A novel germline mutation in the AIPgene (c.685C>T, p.Q229X) was identified in the proband and in two members of her family, who did not present clinical features of acromegaly or other pituitary disorders. Eleven subjects had no mutation in the AIPgene. Two members of the family with clinical features of acromegaly refused either the genetic or the biochemical evaluation. The Q229X mutation was predicted to generate a truncated AIP protein, lacking the last two tetratricopeptide repeat domains and the final C-terminal α-7 helix. We identified a new AIPgermline mutation predicted to produce a truncated AIP protein, lacking its biological properties due to the disruption of the C-terminus binding sites for both the chaperones and the client proteins of AIP.

The presence of the sodium/iodide symporter (NIS) is the prerequisite for the use of the radioiodine in the treatment of thyroid cancer. Thus, stimulators of NIS expression and function are currently investigated in cellular models of various human malignancies, also including extrathyroid cancers. In this study, we analyzed the effects of the histone deacetylase inhibitors (HDACi), suberoylanilide hydroxamic acid (SAHA) and valproic acid (VPA), on NIS expression and function in rat Leydig testicular carcinoma cells (LC540). LC540 cells were exposed to SAHA 3 μM and VPA 3 mM (alone and in combination), and cell viability evaluated by MTT assay and cell counting, NIS mRNA and protein levels by using, respectively, real-time RT-PCR and western blotting. NIS function was evaluated by iodide uptake assay. We found that both HDACi were able to stimulate the transcription of NISgene, but not its protein expression, while the association of SAHA and VPA increased both NIS transcript and protein levels, resulting in significant sixfold enhancement of radioiodine uptake capacity of LC540 cells. These data demonstrate the presence of an epigenetic control of NIS expression in Leydig tumor cells, suggesting the possibility to use the combination of these two HDACi for a radioiodine-based treatment of these malignancies.

L’avènement des thérapies ciblées a considérablement amélioré le pronostic des patients atteints de mélanome avancé. Cependant la mise en route d’une thérapie personnalisée est parfois retardée par la nécessité de détecter une mutation ciblable dans la tumeur, telle que des mutations de BRAF. Ce délai peut s’allonger par des impératifs incompressibles de demande de désarchivage, envoi, réception d’une biopsie antérieure, ou d’organisation d’une nouvelle biopsie avec temps de fixation, inclusion, extraction d’ADN. L’ADN tumoral circulant est une alternative connue et plus rapide, spécifique mais peu sensible en cas de faible charge tumorale. Cependant il n’est pas rare d’observer des tumeurs ulcéro-hémorragiques, dont l’ADN pourrait être excrété en plus grande quantité en surface que dans la circulation générale. Nous rapportons les premiers cas d’identification de mutations somatiques à partir de simple soluté de rinçage d’exsudat tumoral.

Les mélanomes cutanés présentent une charge mutationnelle (CM) moyenne élevée en raison des mutations induites par les rayonnements ultraviolets (UV). La CM est un facteur prédictif de la réponse à l’immunothérapie par anti PD-1 mais n’est pas encore accessible en routine. L’héliodermie étant le résultat d’une exposition répétée et cumulée aux UV, nous avons émis l’hypothèse que les signes d’héliodermie en périphérie de la cicatrice d’exérèse du mélanome primitif pourraient être prédictifs de la réponse aux anti PD-1.

FSH receptor (FSHR) expression is restricted to gonads, where it drives FSH-dependent cell differentiation; in addition, FSHR plays an important role in the regulation of ovarian angiogenesis. Recently, FHSR expression has been shown in blood vessels of various tumors. However, pancreatic neuroendocrine tumors (p-NET), which have high-degree blood supply, were not included in that study. The aim of this study was to evaluate FSHR expression in p-NET. FSHR expression was evaluated in tumor samples from 30 patients with p-NET by immunohistochemistry and Western blot; fluorescence microscopy was used to localize FSHR in specific cells from tissue samples. von Willebrand factor (vWF) and chromograninA (chrA) was used as blood vessel and NET cells marker, respectively, to co-localize FSHR. FSHR expression was detected in all p-NET by immunohistochemistry. Western blot confirmed FSHR expression on p-NET although different FSHR isoforms, ranging from 240 kD to 55 kD were found in the samples studied. Surprisingly, FSHR co-localized with chrA but not with vWF, suggesting that neoplastic cells of neuroendocrine origin rather than blood vessels expressed FSHR. No relationship was found between degree of FSHR expression and histology of p-NET. FSHR may be aberrantly expressed in neoplastic cells from p-NET and not in tumor blood vessels; however, its biological significance as well as its clinical relevance remains to be elucidated.

The article presents a study which assesses the survival and habitat choices of hand-reared orphaned bats. The study was done on 21 bats in 2 years, where they were sent on an area that is different from the rescue site and were evaluated in terms of foraging, roosting, and commuting. Results proved that hand-raised orphaned bats can adapt to unfamiliar areas and show a strong short-term survival, where the bats seek food often in urban areas.

The aim of this study was to determine the effects of 3 antibiotics used for pulmonary pathologies added in the feed of weaned pigs on growth performance, commensal microbiota, and immune response. At weaning, a total of 72 pigs were randomly assigned by BW and litter to 1 of the following diets: control (typical weaning diet), control + 400 mg of tilmicosin/kg, control + 600 mg of amoxicillin/kg, and control + 300 mg of doxycycline/kg. Individually penned pigs were slaughtered after 3 wk (12 pigs/treatment) or 4 wk (6 pigs/treatment). During the fourth week, all pigs received the control diet to test the residual effect of the antimicrobial supplementation. The antibiotic supplementation increased growth and feed intake during the first week (P< 0.01) and over the first 3 wk combined (P< 0.05). Gain-to-feed ratio tended to improve during the first week (P= 0.076) by the antibiotics compared with the control. Among the antibiotic treatments, no difference was observed in ADG and feed intake, which were also unchanged by the diet in the fourth week. The fecal enterobacteria counts were increased by amoxicillin on d 14 and 21 (P< 0.05 and 0.01, respectively) and were decreased by tilmicosin (P< 0.001) compared with the control. Amoxicillin decreased lactic acid bacteria (P< 0.01) counts compared with the control. The antibiotic supplementation tended to decrease total bacteria variability in the jejunum (Shannon index, P= 0.091) compared with the control. The antibiotic treatment decreased the mean total serum IgM concentration (P= 0.016) after 3 wk and did not change the mucosal histomorphometry of the small intestine. For tilmicosin, the observed positive action on piglet performance and feed intake can originate by the decreased costs of immune activation determined by the action on intestinal microbiota. For amoxicillin and doxycycline, the observation on intestinal and fecal microbiota seems to be not sufficient to explain their growth-promoting effect.

Background: Agents capable of increasing radioiodine concentration by stimulating the sodium/iodide symporter (NIS) expression have been extensively investigated for the treatment of certain well-differentiated breast cancers. Aim: In this study, we analyzed the regulation of the NIS and lactoperoxidase (LPO) gene expression in 4 different human breast cancer cell lines, representative of different histotypes of breast cancer. Methods: MCF-7, T-47D, MDA-MB231, and HCC-1937 (the latter carrying the BRCA-1 mutation) were exposed to different stimulators and the levels of NIS and LPO mRNA measured by a quantitative RT-PCR. Results: AII-trans-Retinoic Acid (RA), Dexamethasone (DEX), Trichostatin A (TSA), and Sodium Butyrate (NaB) induced the expression of NIS mRNA in MCF-7 and T-47D cell lines, whereas HCC-1937 and MBA-MB231 were slightly responsive only to the histone-deacetylase inhibitors TSA and NaB. Minor stimulatory effects were detected on LPO mRNA in MCF-7 and T-47D treated with TSA and NaB or RA only in MCF-7, while no effect was detectable in the other two cell lines. Conclusions: These data indicate that retinoic acid, alone or in combination with DEX, as well as HDAC-inhibitors are very promising agents for a radioiodine-based therapy in a large spectrum of breast cancers, including neoplasms from both basal and ductal cells, especially for the well-differentiated estrogen-dependent tumors. Other molecules or other drug combinations should be tested to extend the same strategy to the less differentiated and more aggressive tumor cells, including those carrying the BRCAmutation.

Lipophilic derivatives of the anticancer drug paclitaxel (PTX) were prepared by means of its conjugation to lipoamino acid (LAA) residues, with the aim of increasing drug accumulation in tumor cells. PTX was linked to the methyl esters of norleucine (C6) or 2-aminodecanoic acid (C10). A succinic acid group was used as a spacer to link the 2-hydroxyl group of PTX and the LAA residue, respectively by means of an ester and an amide bond. The in vitro anticancer activity of the prodrugs was tested on a human thyroid anaplastic cancer cell line (ARO). The intracellular uptake kinetics of free PTX and its prodrugs was assessed by HPLC. PTX-LAA prodrugs showed a noticeable cytotoxic activity against ARO cells at shorter incubation time (12 h) and lower doses (0.01-0.1 M) than PTX. Intracellular accumulation experiments indicated an improvement of drug concentration inside these cells, related to the block of the cellular expulsion by means of multi drug resistance efflux complex and improved physicochemical features that allowed the greater passive cellular membrane permeation. The enhanced activity of PTX-LAA prodrugs, in terms of potency and onset of the effect, as well as the interesting intracellular accumulation data suggest that these compounds can be further tested as possible alternatives to PTX for the treatment of resistant cancer cells.

There is no effective treatment for recurrent or metastatic medullary thyroid carcinoma (MTC), a tumor arising from thyroid C-cells commonly presenting an inherited or acquired RET mutation. In this study we examined the sensitivity of two human MTC cell lines to novel pyrazolo-pyrimidine derivates, able to inhibit src-family tyrosine kinase activity. In TT cells [carrying the multiple endocrine neoplasia (MEN)2A Ret mutation Cys 634Trp] and MZ-CRC-1 cells (carrying the MEN2B RET mutation Met891Thr), one of these compounds, namely Si 34, determined a significant growth inhibitory effect (approximately 90% vscontrol for TT, 80% vscontrol for MZ-CRC-1) mainly due to enhanced cell mortality after a 6-day incubation. At concentrations that increased cell mortality, neither biochemical or morphological characteristics of apoptosis were detected in TT and MZ-CRC-1 cells treated with Si 34. These results, when confirmed in other in vivopreclinical models, suggest that this novel tyrosine kinase inhibitor may be useful for the treatment of MTC.

Amiodarone perturbs thyroid function, causing overt hypothyroidism or hyperthyroidism in 15% of patients. Changes in thyroid function are likely due, at least in part, to amiodarone and/or desethylamiodarone (DEA) concentration into the thyroid gland, but mechanisms whereby the drug uptake occurred are not known. Thyroidal (FRTL-5) or non-thyroidal [Chinese hamster ovary wild-type (CHOwt) or CHO stably transfected with NIS (CHONIS)] cells were exposed to 10 μM amiodarone or DEA. Cellular content of both drugs was measuredby HPLC and normalized by protein concentration. Cellular concentration of the two drugs was higher in FRTL-5 (mean±SD 17.2±1.2 μg/mg protein of amiodarone and 18.9±0.7 μg/mg protein of DEA)than in CHO-NIS and CHOwt cells (10.8±0.8 μg/mg protein and 12.8±0.2 gmg/mg protein, respectively, of amiodarone (p<0.004); 11.9±0.1 μg/mg protein and 11±0.2 μg/mg protein, respectively, of DEA (p<0.0002). DEA concentration was higher than that of amiodarone in all cell lines (p<0.002). Differences between FRTL-5 and CHO cell lines were not dependent on TSH: in fact, cellular content of either drug did not change in the presence or absence of TSH in the culture medium. NIS did not intervene in amiodarone or DEA entry into thyroid cells, since amiodarone and DEA content was the same in CHOwt and CHO-NIS cells; in addition, KClO4inhibited NIS function, but had no effect on drug uptake by the cells. At variance, 80 μM DEA reduced 125I uptake by CHO-NIS cells by 40% at 30 min without affecting cell viability. In conclusion, mechanisms whereby amiodarone is taken up by thyroid cells remain largely unknown, but the two main factors involved in thyroid-specific cellular transport, ie, NIS and TSH, seem to be excluded.

We report a case of a male patient thyroidectomized for follicular thyroid carcinoma and presenting extremely elevated serum thyrotropin levels under L-T4suppressive therapy. Administration of L-T3in increasing amounts resulted in a significant decrease of serum TSH levels. The nature of the possible molecular defects underlying this unusual condition and pitfalls arising from the failure of L-T4therapy to inhibit TSH secretion in a patient in postsurgical follow-up for follicular carcinoma are discussed.

Differential protein arrays between nuclear extracts of human thyroid cell lines obtained from tumors with different degree of differentiation were exploited to define molecular alterations occurring during thyroid tumor progression. Nuclear extracts from the well differentiated TPC-1 (from papillary carcinoma) and the poorly differentiated ARO (from anaplastic carcinoma) cells showed an overall similar pattern of protein expression as revealed by two-dimensional gel electrophoresis analysis. However, manganese-superoxide dismutase (Mn-SOD) was clearly identified by mass spectrometry procedures as significantly less expressed in ARO compared to TPC-1 cells. A reduced expression of Mn-SOD in the nuclear compartment was confirmed by Western blot and immunofluorescence analysis. A similar expression pattern of nuclear Mn-SOD was detected by immunohistochemistry in human thyroid tumors, with the lowest or absent detection in anaplastic carcinomas. Moreover, the levels of nuclear Mn-SOD in tumor cells were lower than in the normal thyrocytes. These data indicate that an altered nuclear expression of Mn-SOD parallels, together with changes in other elements of the antioxidant protective system, the loss of differentiation occurring during the progression of thyroid tumors.

Objective: Expression of peroxisome proliferator-activated receptor (PPAR)γ in normal pituitary seems to be restricted to ACTH-secreting cells. The aim of the study was to evaluate the expression of PPARγ in normal human pituitary tissue and to study its localization in the pituitary secreting cells. Materials and methods: Normal pituitary tissue samples were obtained form 11 patients with non-secreting adenoma who underwent surgical excision of the tumor. Expression of PPAR? was evaluated by immunostaining and western blotting; localization of PPAR? in each pituitary secreting cell lineage was evaluated by double immunofluorescence using confocal microscopy. Pituitary non-functioning adenomas served as Controls. Results: PPARγ was highly expressed in all pituitary samples with a (mean±SD) 81±6.5% of stained cells; expression of PPARγ was confirmed by western blotting. Non-functioning pituitary adenomas had 74±11% PPAR? positive cells. Expression of PPARγ was either in cytoplasm or nuclei. In addition, treatment of GH3 cells, with a PPARγ ligand was associated with traslocation of the receptor from cytoplasm into the nucleus. Double immunostaining revealed that every pituitary secreting cell (GH, TSH, LH, FSH, PRL and ACTH) had PPARγ expressed. Discussion: The present study demonstrated that PPARγ is highly expressed in every normal pituitary secreting cell lineage. It can translocate into the nucleus by ligand binding; however, its role in pituitary hormone regulation remains to be elucidated.

Primary hyperparathyroidism (pHPT) is a common endocrine disease that in more than 95% of cases is sporadic and only in some cases is caused by inherited disorders, isolated or as part of multiple endocrine neoplasia (MEN1 and 2). Somatic mutations of MEN1 gene have also been described in sporadic parathyroid tumors. In our study, we examined the presence of alterations in MEN1 gene in a series of 39 patients who had undergone surgery for sporadic pHPT (35 with parathyroid adenoma or hyperplasia, 4 with a carcinoma). A genotype-phenotype correlation was also analysed. After DNA extraction from paraffin-embedded tissues, we amplified by PCR and sequenced the exons 2–10 of the MEN1 gene. Somatic MEN1 mutations were detected in 6 of the 35 patients with a benign parathyroid lesion examined (17.1%), whereas no alterations were found in the carcinomas. Four novel MEN1 gene mutations were identified as follows: one frameshift mutation (222insT, exon 2), one frameshift deletion (912delTA, exon 5), one in-frame deletion (835del18, exon 4) and one missense mutation (P291A, exon 6). In addition, one missense mutation (L89R, exon 2) and one nonsense mutation (Q536X, exon 10) were previously reported. Moreover, two polymorphisms were also found: one allele carried a R171Q polymorphism (1/39 tumors), while a D418D polymorphism (GAC/GAT) was found in 15 and 8 tumors in hetero (CT) and homozygosity (TT), respectively. In no case (mutations and/or polymorphisms) did we find a genotype-phenotype correlation. In conclusion, our data demonstrate the presence of somatic alterations of the MEN1 tumor suppressor gene in about one fifth of benign sporadic parathyroid tumors. The absence of a genotype-phenotype correlation, however, suggests the involvement of other genetic/epigenetic factors for the full expression of the disease.

The functional role of the sodium iodide symporter (NIS) in extrathyroidal tissues was investigated by examining its mRNA and protein expression, together with the evidence of radioiodine (131I) uptake in 302 patients who underwent 131I total body scanning, following the administration of high doses of 131I for a papillary or follicular thyroid carcinoma. By using a real-time kinetic quantitative RT-PCR and immunohistochemistry, the expression of NIS protein was detected mainly in secretory tissues. In parallel, 131I uptake was evidenced in the majority of patients in the salivary glands (in 39%) and stomach (in 78%), but was found in breast in only 4 young female patients. These data demonstrate a strong correlation between the organ radioactivity distribution, as observed in vivo, and NIS protein expression. Interestingly, 131I is rarely concentrated by mammary glands, even when large doses are administered. Moreover, a 131I transfer in secretion fluids may represent a potential source of contamination responsible for false positive images and diagnostic pitfalls.

OBJECTIVE: The objective of the study was to evaluate the expression and functional activity of Peroxisome proliferator-activated receptor (PPAR) gamma in pituitary adenomas from 14 consecutive acromegalic patients and to establish its role in apoptosis. SUBJECTS AND METHODS: Fourteen consecutive acromegalic patients were enrolled in the study. Wistar-Furth rats were used for in vivo studies. Expression of PPARgamma was evaluated by RT-PCR and Western blot. Apoptosis and cell cycle were assessed by FACS analysis. The effects of PPARgamma ligands on transcriptional regulation of GH gene were evaluated by RT-PCR and electromobility shift assay. RESULTS: PPARgamma was expressed in all human GH-secreting adenoma (GH-oma), in normal pituitary tissue samples (39+/-24% and 78+/-5% of immunostained nuclei respectively; P<0.0002; ANOVA), and in rat GH-secreting (GH3) cells. A PPRE-containing reporter plasmid transfected into GH3 cells was activated by ciglitazone or rosiglitazone (TZDs), indicating that PPARgamma was functionally active. Treatment of GH3 cells with TZDs increased apoptosis in a dose-dependent manner (P=0.0003) and arrested cell proliferation, reducing the number of cells in the S-phase (P<0.0001 vs untreated cells). TZDs increased the expression of TRAIL, leaving unaffected that of p53 and Bax. TZDs reduced GH concentrations in the culture media from 43.7+/-5.4 ng/ml to 2.1+/-0.3 ng/ml (P<0.0001) and in cell extracts (P<0.004). PPARgamma-RXRalpha heterodimers bound to GH promoter, inhibiting its activity and reducing GH mRNA levels (1.8 x 10(6) vs 5.7 x 10(6) transcripts respectively vs untreated cells; P<0.002). Subcutaneous GH-oma developed in rats injected with GH3 cells; tumor growth increased in placebo-treated rats and to a lesser extent in TZDs-treated animals (24.1+/-2.0 g, and 14.8+/-4.2 g respectively, P<0.03). Serum GH concentrations were lower in TZDs-treated rats than in controls (871+/-67 ng/ml vs 1.309+/-238 ng/ml; P<0.05). CONCLUSIONS: The results of this study indicate that PPARgamma controls GH transcription and secretion as well as apoptosis and growth of GH-oma; thus, TZDs have the potential of a useful tool in the complex therapeutic management of acromegalic patients.

Pendred syndrome and the enlarged vestibular aqueduct (EVA) are considered phenotypic variations of the same entity due to mutations in the SLC26A4 (pendrin) gene. Pendred syndrome consists in sensorineural deafness, goiter and impaired thyroid hormone synthesis while in EVA thyroid function seems to be preserved. The aim of this study was to evaluate thyroid function and morphology and to look for mutations in the SLC26A4 gene in patients presented with EVA. Among 57 consecutive patients with sensorineural deafness 15 with EVA, as assessed by magnetic resonance imaging (MRI), were identified and studied. A complete evaluation of thyroid function including thyroid echography and perchlorate discharge test was carried out in all patients with EVA; all exons of the SLC26A4 gene were amplified from peripheral leukocytes and directly sequenced, using specific intronic primers. Out of 15 patients with EVA, goiter was present in 8 (53%), hypothyroidism in 7 (47%), increased serum thyroglobulin levels in 8 (53%) and a positive perchlorate discharge test in 10 (67%). Nine alleles of the SLC26A4 gene were mutated: 2 novel mutations (L465W and G497R) and 4 already known mutations (T410M, R409H, T505N and IVS1001+1G>A) were found. Four subjects were compound heterozygous and 1 heterozygous (G497R/wt). All patients harbouring mutations in the SLC26A4 gene had goiter and a positive perchlorate discharge test: 3 were slightly hypothyroid and 2 euthyroid. The remaining 10 patients had no mutations in the SLC26A4 gene: 4 of them were hypothyroid, 2 with goiter and positive perchlorate discharge test, 2 without goiter and with negative perchlorate discharge test. Two patients without mutations were euthyroid with positive perchlorate discharge test. Patients with mutations in the SLC26A4 gene had larger thyroid volume (p<0.002), higher serum thyroglobulin (Tg) levels (p<0.002) and greater radioiodine discharge after perchlorate (p=0.09) than patients without mutations. The results of the present study lend support to the concept that all patients with mutated SLC26A4 gene have abnormalities of thyroid function tests.

Causative gain-of-function mutations of the RET tyrosine-kinase receptor gene have been reported in more than 95% of inherited cases of medullary thyroid carcinoma (MTC; OMIM# 155240). Most RET activating mutations are clustered in mutational “hot spots” in exons 10, 11, 13, 14, 15 and 16 and are usually detected by single- strand conformation polymorphism (SSCP) followed by direct sequencing. To improve sensitivity, time and costs of mutational screening we have developed a denaturing high performance chromatography (DHPLC) protocol, based on the detection of heteroduplex molecules by ion-pair reverse-phase liquid chromatography under partially denaturing conditions. The mutational screening of RET exons 10, 11, 13–16 was performed in a total of 111 subjects, including 45 MTC patients and 49 relatives with known RET mutations and 17 individuals, being at risk of hereditary MTC and carrying unknown RET alleles. Heteroduplex peaks with a distinct and reproducible DHPLC elution profile allowed the detection of both rare and common RET mutations. Overall, the DHPLC-based methodology showed a high level of sensitivity and accuracy, nearing 100%. Furthermore, our protocol showed the ability to identify: 1) all the mutated codons of RET located in the “hot spots” domain; 2) the different point mutations occurring in the same codon of RET gene; 3) less frequent or rare mutations; 4) polymorphisms. As such, it can be proposed as a relatively simple and highly accurate method for a rapid genetic testing for members of MTC families.

Steroids may have a powerful role in neuronal degeneration. Recent research has revealed that steroids may influence the onset and progression of some retinal disorders as well as neurodegenerative diseases and, as in brain, they accumulate in the retina via a local synthesis (neurosteroids) and metabolism of blood-circulating steroid hormones. Their crucial role as neurodegenerative and neuroprotective agents has been also upheld in a retinal excitotoxic paradigm. These findings are reviewed especially from the emerging perspective that after an insult local changes in steroidogenic responses and consequent neurosteroid availability might turn out to be offensive or defensive cellular adaptations for the potentiation or prevention of neuronal death.

Peroxisome proliferator activated receptor (PPAR)γ plays a pivotal role in regulating adipocyte differentiation and metabolism, but also has an antiproliferative effect in several tissues, including colonic mucosa, where it is highly expressed. Loss-of-function mutations have been reported in about 10% of sporadic primary colon cancer. Acromegalic patients have an increased prevalence of colonic neoplasms and lower PPARγ levels in the colonic mucosa. Thus, PPARγ may act as a tumor suppressor gene, and its reduced expression or loss-of-function mutations may contribute to tumorigenesis. In this study the expression and mutations of the PPARγ gene in the colonic polyps and mucosa outside polyps were investigated in 10 acromegalic and 17 non-acromegalic patients. PPARγ expression was evaluated by RT-PCR. PPARγ was expressed in each sample, but expression appeared to be lower in polyps than in mucosa outside polyps from either acromegalic or non-acromegalic patients. All exons of the PPARγ gene were directly sequenced after PCR amplification: no mutations were found either in acromegalic or in non-acromegalic patients. In conclusion, the results of this preliminary study suggest that the lower expression of PPARγ rather than somatic mutations of this gene is involved in colonic tumorigenesis.

Polychlorinated biphenyls (PCBs) are environmental contaminants which may affect thyroid function. PCBs may reduce serum thyroid hormone (TH) concentrations by either displacing T4from TH transport proteins or increasing its hepatic metabolism. The reduced serum T4causes neurological and growth defects in animals exposed to PCBs during the perinatal period, which can partially be reverted by T4administration. In addition to a hypothyroid-like syndrome, a direct action of PCBs on TH-sensitive genes has been postulated. In the present study the effects of Aroclor 1254 (ARO), a mixture of PCBs, on transcription of TH-dependent genes were investigated. A reporter plasmid containing the TH-responsive element (TRE) of malic enzyme (ME) gene was used in transient transfections to assess the responsiveness to ARO. ARO (10 μM) reduced the CAT activity by about 50% and competed with T3to reduce the induction of transcription. Cotransfection of TH receptor (TR) and a wild type TRE was required to reveal ARO inhibitiry effect, which was abolished by a mock reaction not containing TR or by a mutated TRE. ARO reduced the 125I-T3binding to TR by 30%, but did not affect the interaction of TR with a 32P-labeled TRE in gel shift assay. ARO is likely to produce a conformational change in in vitrotranslated TR, leading to its increased proteolysis by trypsin. These results demonstrate that ARO interacts with TR, thereby affecting the transcription of TH-sensitive genes, and provide a molecular basis to further explain the complex effects of PCBs on TH disruption.

BACKGROUND: Various clinical and experimental findings support the concept that human chorionic gonadotropin (hCG) can stimulate iodide uptake in thyroid cells. DESIGN: We investigated the molecular mechanisms underlying the effects of hCG on iodide uptake, and particularly its action on the expression of Na+/I- symporter (NIS) mRNA and protein. METHODS: Iodide uptake was analyzed in FTRL-5 cells by measuring (125)I concentrations in cells after a 30-min exposure to 0.1 microCi carrier-free Na (125)I in the presence or absence of hCG or, for control purposes, TSH. Expression of NIS mRNA and NIS protein synthesis were evaluated, respectively, with a semiquantitative 'multiplex' RT-PCR method and Western blot analysis. RESULTS: Iodide uptake was increased by hCG in a dose- and time-dependent manner: maximal effects were observed after 72 h of stimulation. The effect was cAMP dependent and paralleled that of TSH, although it lacked the early cycloheximide-independent component seen with TSH, and its peak effect was lower. Semiquantitative multiplex RT-PCR revealed that hCG produced a significant increase in NIS mRNA levels that was detectable after 4 h and peaked after 48 h. In contrast, in TSH-stimulated FRTL-5 cells, maximum NIS mRNA expression was observed after 24 h of stimulation. Western blot analysis demonstrated that hCG also caused a 2.5-fold increase over basal values in NIS protein levels, which was similar to that observed after TSH stimulation although the peak effects of the latter hormone were less marked and occurred earlier. CONCLUSION: Our data demonstrated that hCG stimulates iodide uptake in FRTL-5 cells by increasing NIS mRNA and protein levels. Thus, the functional status of the thyroid may be influenced by hCG-dependent changes in NIS expression occurring during pregnancy.

Constitutively activating germline mutations of the TSH receptor (TSH-R) are considered the cause of hereditary non-autoimmune hyperthyroidism. In this study, 10 members (8 affected and 2 unaffected) of an Italian family with hereditary non-autoimmune hyperthyroidism were investigated for the presence of mutations in the TSH-R gene. The clinical features of the disease were also analyzed. PCRamplified fragments of the TSH-R gene were obtained from genomic DNA extracted from peripheral blood leukocytes of each family member and analyzed by direct nucleotide sequencing and restriction analysis. An identical germline TSH-R mutation was detected in all the patients with hyperthyroidism but in none of the unaffected family members. The mutation was heterozygotic and determined the substitution of valine for methionine (codon 463; ATG —>GTG) in the second transmembrane domain of the TSH-R. When expressed in chinese hamster ovary (CHO) cells, the Val463 mutant TSH-R induced constitutive activation of the TSH receptor. Analysis of the clinical features of our family and those of other families with hereditary non-autoimmune hyperthyroidism, including one with the same Val463 mutation, revealed wide variability in the phenotypical expression of the disease. Our findings indicate that an activating germline mutation in the TSHR gene plays a key role in hereditary non-autoimmune hyperthyroidism although the onset of clinical manifestations and the evolution of the disease seem to depend heavily on other factors, thus far unidentified. The absence of a clear correlation between mutant genotypes and phenotypic expression of the disease currently limits the prognostic value of genetic testing in families with hereditary non-autoimmune hyperthyroidism.

We present a prospective study on the long-term efficacy of percutaneous ethanol injection (PEI) treatment of a large series of symptomatic thyroid cystic nodules (STCN). Ninety-eight patients (72 females and 26 males) were treated. The mean basal volume of the STCN was 35.3 mL. In 92 of 98 patients PEI treatment induced a greater than 50% nodule shrinkage, only 6 of 92 responder patients relapsed at a follow-up of 9 years. Moreover, all the patients had a significant clinical benefit because a significant reduction of the cyst-associated symptoms was recorded. Furthermore, a limited number of sessions was required for the treatment of cysts larger than 40mL (mean ± standard deviation [SD]:2.7 ± 0.75) demonstrating the feasibility of the procedure also in the treatment of large cysts. In conclusion, PEI is an effective and inexpensive procedure with a high patient compliance and long-lasting effects in the treatment of cysts larger than 40mL.

The aetiologies of oral ulceration, disseminated interstitial lymphocytosis syndrome and oral lymphomas have been reviewed, with emphasis on the role of HIV infection in the primary causation or modification of the presentation of these entities. There is a paucity of evidence to explain why oral ulceration is so severe in HIV infection, and why major ulceration affects the oropharynx. A number of mechanisms have been proposed to account for the development of lymphomas in patients with HIV infection, including a genetic predisposition, decreased immunosurveillance due to HIV infection, alteration of endothelial cell function and dysregulation of cytokine networks. From this review, it was concluded that there is a need for a prospective multicentre study, to elucidate the aetiological mechanisms involved in lymphomas of the oral regions in this patient group. It was concluded that, although there is anecdotal evidence implicating tobacco use in the aetiology of the lesions reviewed, this is insufficient to allow definitive statements to be made and further systematic evaluation is indicated.

Objective:to evaluate early and mid-term term results of carotid endarterectomy (CEA) in patient with and without contralateral carotid occlusion.

The transport of a pulse of trifluralin (2,6‐dinitro‐N,N‐dipropyl‐4‐[trifluoromethyl] benzenamime) applied via a subsurfacedripper was analyzed numerically. Results of the analyses suggest that the movement and spread of trifluralin in the soil is considerably retarded by its strong adsorption to the solid phase of the soil. This is particularly so in soils which contain aconsiderable fraction of organic C and in fine‐textured (clayey) soils with low hydraulic conductivity and high water retentivity. Water uptake by plant roots and the resultant rapid decrease of water velocity with increasing distance from the dripper restricts further the downward movement of trifluralin and its potential to pollute the groundwater. The presence of dissolved organic matter (DOM) in the irrigation water may enhance both the movement and the spread of trifluralin in the soil, particularly in coarse‐textured soils with a relatively small fraction of organic C. Because of the strong adsorption of trifluralin to the soil, its concentration in the aqueous phase of the soil is very low and it decreases further with increasing time because of degradation and nonequilibrium sorption. This is particularly so in coarse‐textured soils with a relatively large fraction of organic C. Nevertheless, results of the analyses suggest that for soils of quite widely differing textures and organic C contents, a trifluralin concentration of ct=10−6kg m−3may persist in the vicinity of the dripper for a relatively long period of time (90 d) even with relatively small applied mass (3 × 10−5kg).

OBJECTIVE: The expression of two iodide transporters, the sodium/iodide symporter (NIS) and pendrin, was analyzed in thyroid tissues of patients with toxic multinodular goiter (TMNG) and non-toxic multinodular goiter (MNG). METHODS: The levels of NIS and pendrin proteins were analyzed in total protein extracts from nodular and non-nodular tissues by Western blot. RESULTS: In tissue samples from TMNG, we found an increased expression of NIS (2.5-fold) in the hot nodules, and similar levels between cold nodules and non-nodular tissues. In contrast, the levels of pendrin were slightly increased in both hot and cold nodules from TMNG, and decreased (about twofold) in cold nodules from MNG. We also noticed that there was no relationship between NIS and pendrin expression. CONCLUSIONS: Our data demonstrate that hot nodules from TMNG express a higher number of iodide transporters (mainly NIS), whereas cold nodules from TMNG, but not from MNG, show levels of the two proteins comparable with normal tissue, suggesting a role in vivo of TSH in maintaining the expression of NIS and pendrin protein in normal thyroid tissue. Finally, different mechanisms are involved in the regulation of NIS and pendrin expression.