Decrease in thyroid adenoma associated (THADA) expression is a marker of dedifferentiation of thyroid tissue

<p>Abstract</p> <p>Background</p> <p><it>Thyroid adenoma associated (THADA) </it>has been identified as the target gene affected by chromosome 2p21 translocations in thyroid adenomas, but the role of THADA in the thyroid is still elusive. The aim of this study was to quantify <it>THADA </it>gene expression in normal tissues and in thyroid hyper- and neoplasias, using real-time PCR.</p> <p>Methods</p> <p>For the analysis <it>THADA </it>and 18S rRNA gene expression assays were performed on 34 normal tissue samples, including thyroid, salivary gland, heart, endometrium, myometrium, lung, blood, and adipose tissue as well as on 85 thyroid hyper- and neoplasias, including three adenomas with a 2p21 translocation. In addition, <it>NIS </it>(<it>sodium-iodide symporter</it>) gene expression was measured on 34 of the pathological thyroid samples.</p> <p>Results</p> <p>Results illustrated that <it>THADA </it>expression in normal thyroid tissue was significantly higher (<it>p </it>< 0.0001, exact Wilcoxon test) than in the other tissues. Significant differences were also found between non-malignant pathological thyroid samples (goiters and adenomas) and malignant tumors (<it>p </it>< 0.001, Wilcoxon test, t approximation), anaplastic carcinomas (ATCs) and all other samples and also between ATCs and all other malignant tumors (<it>p </it>< 0.05, Wilcoxon test, t approximation). Furthermore, in thyroid tumors <it>THADA </it>mRNA expression was found to be inversely correlated with <it>HMGA2 </it>mRNA. <it>HMGA2 </it>expression was recently identified as a marker revealing malignant transformation of thyroid follicular tumors. A correlation between <it>THADA </it>and <it>NIS </it>has also been found in thyroid normal tissue and malignant tumors.</p> <p>Conclusions</p> <p>The results suggest <it>THADA </it>being a marker of dedifferentiation of thyroid tissue.</p

Locating the global financial crisis: variegated neoliberalization in four European cities

Locating the global financial crisis: variegated neoliberalization in four European cities. Territory, Politics, Governance. This paper looks at the variegated impact of the 2008 global financial crisis and the different ways in which local strategic actors imagined and responded to it through a comparative study of Barcelona, Brussels, Leeds and Turin. Drawing on cultural political economy, we see crisis moments as fertile territory for the analysis of variegation in urban neoliberalization processes as they can break path dependencies and open up alternatives. Inspired by the comparative turn in critical urban studies, our case studies are not offered as representative samples but as dense sites to explore the various interpretations and uses of the crisis, particularly at the elite level. This analysis suggests considerable variegation in how the crisis was both felt and interpreted locally across the four cities. The local elites did not regard this as a crisis of or in their own urban growth models, but as something external. However, as the global financial crisis morphed into national sovereign debt crises and austerity programmes, the experience in each city has been relatively similar. The paper concludes by emphasizing the continuity function of specific local actors through the processes of meaning-making in which they engage, something that existing work on variegated neoliberalization has so far overlooked

Host hindrance to HIV-1 replication in monocytes and macrophages

Monocytes and macrophages are targets of HIV-1 infection and play critical roles in multiple aspects of viral pathogenesis. HIV-1 can replicate in blood monocytes, although only a minor proportion of circulating monocytes harbor viral DNA. Resident macrophages in tissues can be infected and function as viral reservoirs. However, their susceptibility to infection, and their capacity to actively replicate the virus, varies greatly depending on the tissue localization and cytokine environment. The susceptibility of monocytes to HIV-1 infection in vitro depends on their differentiation status. Monocytes are refractory to infection and become permissive upon differentiation into macrophages. In addition, the capacity of monocyte-derived macrophages to sustain viral replication varies between individuals. Host determinants regulate HIV-1 replication in monocytes and macrophages, limiting several steps of the viral life-cycle, from viral entry to virus release. Some host factors responsible for HIV-1 restriction are shared with T lymphocytes, but several anti-viral mechanisms are specific to either monocytes or macrophages. Whilst a number of these mechanisms have been identified in monocytes or in monocyte-derived macrophages in vitro, some of them have also been implicated in the regulation of HIV-1 infection in vivo, in particular in the brain and the lung where macrophages are the main cell type infected by HIV-1. This review focuses on cellular factors that have been reported to interfere with HIV-1 infection in monocytes and macrophages, and examines the evidences supporting their role in vivo, highlighting unique aspects of HIV-1 restriction in these two cell types

The CD14+CD16+ monocytes in erysipelas are expandend and show reduced cytokine production.

In human peripheral blood the classical CD14++DR+ monocytes and the pro-inflammatory CD14+CD16+DR++ monocytes can be distinguished. In erysipelas we found strongly increased numbers of CD14+CD16+ monocytes on the day of diagnosis (day 1) in 11 patients with an average of 150.5&plusmn;76.0 cells/&mu;l, while 1 patient had low levels (35 cells/&mu;l, control donors 48.8&plusmn;19.8 cells/&mu;l). The classical monocytes were only moderately elevated in the erysipelas patients (factor 1.7 as compared to controls). Patients exhibited increased body temperature, erythrocyte sedimentation rate and increased serum levels for C-reactive protein (CRP), IL-6 and macrophage-colony-stimulating factor. Among these, body temperature and CRP showed a significant correlation to the numbers of CD14+CD16+ monocytes. In 4 of 4 patients with high levels of CD14+CD16+ monocytes, these levels returned to that seen in controls by day 5 of antibiotic therapy. Determination of intracellular TNF was performed by three-color immunofluorescence and flow cytometry after ex vivo stimulation withlipoteichoic acid, a typical constituent of streptococci. Here, patient CD14+DR++ pro-inflammatory monocytes showed a twofold lower level of intracellular TNF. By contrast, expression of TNF was unaltered in the classical CD14++ monocytes. These data show that in erysipelas the pro-inflammatory CD14+CD16+DR++ monocytes are substantially expanded and selectively tolerant to stimulation by streptococcal products. &nbsp

Mechanism of glucocorticoid-induced depletion of human CD14+CD16+ monocytes.

Abstract: Healthy donors infused with high doses of glucocorticoids [GCs; methyl-prednisolone (MP); 500 mg/day for 3 days] suffer a selective depletion of the CD14CD16 monocytes such that these cells are reduced by 95 % on day 5. In vitro studies revealed that at 11 h of culture in the presence of 105 M MP, no depletion was ob-served as yet, but a reduction by 80 % was seen after 24 h. In dose-response analysis, MP still led to a 50 % reduction of CD14CD16 monocytes at 107 M. Depletion could not be overcome by ad-dition of the cytokines interleukin-1 or macro-phage-colony stimulating factor, and it was inde-pendent of CD95. Depletion was, however, inhibited by the caspase 3,8 blocker z-Val-Ala-Asp, suggest-ing that cell death occurs in a caspase-dependent manner. Furthermore, blockade of depletion by RU-486 indicates that the intracellular GC recep-tor (GCR) is involved. Measurement of GCR by flow cytometry revealed a 50 % higher level of expression in the CD14CD16 monocytes. Our studies show a selective depletion of CD14CD16 monocytes by GC treatment in vivo and in vitro, an effect to which the modestly increased level of GCR may contribute

The Proinflammatory CD14+CD16+DR++ Monocytes Are a Major Source of TNF1.

In human blood two monocyte populations can be distinguished, i.e.,, the CD14(++)CD16(-)DR(+) classical monocytes and the CD14(+)CD16(+)DR(++) proinflammatory monocytes that account for only 10% of all monocytes. We have studied TNF production in these two types of cells using three-color immunofluorescence and flow cytometry on whole peripheral blood samples stimulated with either LPS or with the bacterial lipopeptide S-(2,3-bis(palmityloxy)-(2-RS)-propyl)-N-palmitoyl-(R)-Cys-(S)-Ser-(S)-LVS4_ OH,trihydrochloride (Pam3Cys). After stimulation with LPS the median fluorescence intensity for TNF protein was 3-fold higher in the proinflammatory monocytes when compared with the classical monocytes. After stimulation with Pam3Cys they almost exclusively responded showing 10-fold-higher levels of median fluorescence intensity for TNF protein. The median fluorescence intensity, for Toll-like receptor 2 cell surface protein was found 2-fold higher on CD14(+)CD16(+)DR(++) &#39; monocytes, which may explain, in part, the higher Pam3Cys-induced TNF production by these cells. When analyzing secretion of TNF protein into the supernatant in PBMCs after depletion of CD16(+) monocytes we found a reduction of LPS-induced TNF by 28% but Pam3Cys-induced TNF was reduced by 64%. This indicates that the minor population of CD14+CD16+ monocytes are major producers of TNF in human blood

Clinical and genetic spectra of autosomal dominant tubulointerstitial kidney disease due to mutations in UMOD and MUC1.

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is an increasingly recognized cause of end-stage kidney disease, primarily due to mutations in UMOD and MUC1. The lack of clinical recognition and the small size of cohorts have slowed the understanding of disease ontology and development of diagnostic algorithms. We analyzed two registries from Europe and the United States to define genetic and clinical characteristics of ADTKD-UMOD and ADTKD-MUC1 and develop a practical score to guide genetic testing. Our study encompassed 726 patients from 585 families with a presumptive diagnosis of ADTKD along with clinical, biochemical, genetic and radiologic data. Collectively, 106 different UMOD mutations were detected in 216/562 (38.4%) of families with ADTKD (303 patients), and 4 different MUC1 mutations in 72/205 (35.1%) of the families that are UMOD-negative (83 patients). The median kidney survival was significantly shorter in patients with ADTKD-MUC1 compared to ADTKD-UMOD (46 vs. 54 years, respectively), whereas the median gout-free survival was dramatically reduced in patients with ADTKD-UMOD compared to ADTKD-MUC1 (30 vs. 67 years, respectively). In contrast to patients with ADTKD-UMOD, patients with ADTKD-MUC1 had normal urinary excretion of uromodulin and distribution of uromodulin in tubular cells. A diagnostic algorithm based on a simple score coupled with urinary uromodulin measurements separated patients with ADTKD-UMOD from those with ADTKD-MUC1 with a sensitivity of 94.1%, a specificity of 74.3% and a positive predictive value of 84.2% for a UMOD mutation. Thus, ADTKD-UMOD is more frequently diagnosed than ADTKD-MUC1, ADTKD subtypes present with distinct clinical features, and a simple score coupled with urine uromodulin measurements may help prioritizing genetic testing