Functional Impairment of Human Myeloid Dendritic Cells during Schistosoma haematobium Infection

Chronic Schistosoma infection is often characterized by a state of T cell hyporesponsiveness of the host. Suppression of dendritic cell (DC) function could be one of the mechanisms underlying this phenomenon, since Schistosoma antigens are potent modulators of dendritic cell function in vitro. Yet, it remains to be established whether DC function is modulated during chronic human Schistosoma infection in vivo. To address this question, the effect of Schistosoma haematobium infection on the function of human blood DC was evaluated. We found that plasmacytoid (pDC) and myeloid DC (mDC) from infected subjects were present at lower frequencies in peripheral blood and that mDC displayed lower expression levels of HLA-DR compared to those from uninfected individuals. Furthermore, mDC from infected subjects, but not pDC, were found to have a reduced capacity to respond to TLR ligands, as determined by MAPK signaling, cytokine production and expression of maturation markers. Moreover, the T cell activating capacity of TLR-matured mDC from infected subjects was lower, likely as a result of reduced HLA-DR expression. Collectively these data show that S. haematobium infection is associated with functional impairment of human DC function in vivo and provide new insights into the underlying mechanisms of T cell hyporesponsiveness during chronic schistosomiasis

Heritability and Phenotypic Variation of Canine Hip Dysplasia Radiographic Traits in a Cohort of Australian German Shepherd Dogs

Canine Hip Dysplasia (CHD) is a common, painful and debilitating orthopaedic disorder of dogs with a partly genetic, multifactorial aetiology. Worldwide, potential breeding dogs are evaluated for CHD using radiographically based screening schemes such as the nine ordinally-scored British Veterinary Association Hip Traits (BVAHTs). The effectiveness of selective breeding based on screening results requires that a significant proportion of the phenotypic variation is caused by the presence of favourable alleles segregating in the population. This proportion, heritability, was measured in a cohort of 13,124 Australian German Shepherd Dogs born between 1976 and 2005, displaying phenotypic variation for BVAHTs, using ordinal, linear and binary mixed models fitted by a Restricted Maximum Likelihood method. Heritability estimates for the nine BVAHTs ranged from 0.14–0.24 (ordinal models), 0.14–0.25 (linear models) and 0.12–0.40 (binary models). Heritability for the summed BVAHT phenotype was 0.30±0.02. The presence of heritable variation demonstrates that selection based on BVAHTs has the potential to improve BVAHT scores in the population. Assuming a genetic correlation between BVAHT scores and CHD-related pain and dysfunction, the welfare of Australian German Shepherds can be improved by continuing to consider BVAHT scores in the selection of breeding dogs, but that as heritability values are only moderate in magnitude the accuracy, and effectiveness, of selection could be improved by the use of Estimated Breeding Values in preference to solely phenotype based selection of breeding animals

Preclinical evaluation of transcriptional targeting strategies for carcinoma of the breast in a tissue slice model system

INTRODUCTION: In view of the limited success of available treatment modalities for metastatic breast cancer, alternative and complementary strategies need to be developed. Adenoviral vector mediated strategies for breast cancer gene therapy and virotherapy are a promising novel therapeutic platform for the treatment of breast cancer. However, the promiscuous tropism of adenoviruses (Ads) is a major concern. Employing tissue specific promoters (TSPs) to restrict transgene expression or viral replication is an effective way to increase specificity towards tumor tissues and to reduce adverse effects in non-target tissues such as the liver. In this regard, candidate breast cancer TSPs include promoters of the genes for the epithelial glycoprotein 2 (EGP-2), cyclooxygenase-2 (Cox-2), α-chemokine SDF-1 receptor (stromal-cell-derived factor, CXCR4), secretory leukoprotease inhibitor (SLPI) and survivin. METHODS: We employed E1-deleted Ads that express the reporter gene luciferase under the control of the promoters of interest. We evaluated this class of vectors in various established breast cancer cell lines, primary breast cancer cells and finally in the most stringent preclinical available substrate system, constituted by precision cut tissue slices of human breast cancer and liver. RESULTS: Overall, the CXCR4 promoter exhibited the highest luciferase activity in breast cancer cell lines, primary breast cancer cells and breast cancer tissue slices. Importantly, the CXCR4 promoter displayed a very low activity in human primary fibroblasts and human liver tissue slices. Interestingly, gene expression profiles correlated with the promoter activities both in breast cancer cell lines and primary breast cancer cells. CONCLUSION: These data suggest that the CXCR4 promoter has an ideal 'breast cancer-on/liver-off' profile, and could, therefore, be a powerful tool in Ad vector based gene therapy or virotherapy of the carcinoma of the breast

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

Background: An in-depth understanding of the fundamental principles that regulate thyroid hormone homeostasis is critical for the development of new diagnostic and treatment ap-proaches for patients with thyroid disease. Summary: Important clinical practices in use today for the treatment of patients with hypothy-roidism, hyperthyroidism, or thyroid cancer, are the result of laboratory discoveries made by scientists investigating the most basic aspects of thyroid structure and molecular biology. In this document, a panel of experts commissioned by the American Thyroid Association makes a se-ries of recommendations related to the study of thyroid hormone economy and action. These recommendations are intended to promote standardization of study design, which should in turn increase the comparability and reproducibility of experimental findings. Conclusions: It is expected that adherence to these recommendations by investigators in the field will facilitate progress towards a better understanding of the thyroid gland and thyroid hormone dependent processes

Dutch perfusion incident survey

Background: Cardiopulmonary bypass procedures remain complex, involving many potential risks. Therefore, a nationwide retrospective study was conducted to gain insight into the number of incidents and accidents in Dutch adult perfusion practice. Methods: An anonymous postal survey (85 questions about hardware, disposables, fluids and medication, air emboli, anticoagulation, practice, and safety measures) was sent to all Dutch perfusionists involved in adult cardiovascular perfusion during 2006 and 2007. To guarantee complete anonymity, respondents were asked to return the survey to a notary who discarded personal information. Results: The net response rate was 72% and covered 23,500 perfusions. Individual respondents performed 240 +/- 103 perfusions during the 2-year study period and had 13.8 +/- 8.7 years of practical experience. The incident rate was 1 per 15.6 perfusions and the adverse event rate was 1 per 1,236 perfusions. The three most reported incidents were: (1) persistent inability to raise the activated coagulation time above 400s during perfusion (184 incidents); (2) an allergic or anaphylactic reaction to drugs, fluids, or blood products (114 incidents); and (3) clotting formation in the extracorporeal circuit (74 incidents). Furthermore, pre-bypass safety measures showed no statistically significant association with the reported incidents. Conclusions: In comparison with data from the recent literature, the reported number of incidents is high. Nevertheless, the adverse outcome rate is well matched to other published surveys. The relatively high response rate conveys the impression that the Dutch perfusionist is vigilant and willing to report incidents. Hence, a web-based Dutch perfusion incident registration system is recommended

Anxiety as social practice

This paper advances a theory of anxiety as social practice. Distinguishing between individual anxieties and anxiety as a social condition, the paper suggests that anxiety has not been subject to the same level of theoretical scrutiny as related concepts such as risk, trust, or fear. Drawing on the existential philosophy of Kierkegaard, Nietzsche, and Heidegger, the paper shows how contemporary anxieties involve the recognition of our own mortality and the destabilisation of established systems of meaning. The paper then turns to practice theory to show how social anxieties can be understood as events that rupture the fabric of everyday life, creating specific subjects and objects, ‘framed’ by different communities of practice, and becoming institutionalised to varying degrees. Focusing on a range of food-related anxieties, the paper explores the geographical and historical constitution of social anxiety, examining the process of anxiety formation and the factors that inhibit or enhance its social and spatial diffusion

Platelet leukocyte gel facilitates bone substitute growth and autologous bone growth in a goat model

The aim of this study is to evaluate multiple conditions on the formation of bone growth in a goat model. We prepared from a unit of whole blood, platelet-leukocyte gel (PLG) to stimulate bone formation, based on the release of platelet growth factors. Two 3-compartment cages containing autologous bone, calcium phosphate, and trabecular metal were implanted onto goat spinal transverse processes. One cage was treated with PLG, prepared according to a standardized protocol. An untreated cage served as a control. To monitor bone formation overtime, fluorochrome markers were administered at 2, 3, and 5 weeks. Animals were sacrificed at 9 weeks after implantation. Bone growth in these 3-compartments cages was examined by histology and histomorphometry of nondecalcified sections using traditional light and epifluorescent microscopy. Compared to the control samples, bone growth in the PLG-treated autologous bone and calcium phosphate samples was significantly more. Fairly little bone growth was seen in PLG treated or untreated trabecular metal scaffolds. The results obtained from this goat model suggest a potential role for the application of autologous PLG during surgeries in which autologous bone grafts or calcium phosphate scaffolds are used

Reduced frequencies of mDC and pDC in blood from <i>S. haematobium</i>-infected subjects.

<p>(A) Blood DC were identified in fixed PBMC as HLA-DR⁺/CD14⁻/CD19⁻ cells and subsequently subdivided into mDC and pDC on the basis of positive staining for BDCA-1 and BDCA-2, respectively. Data from one representative donor is shown. (B) Frequencies of blood DC subsets in total PBMC (C) and their surface expression of HLADR, CD80, CD86 and CCR7 was determined by following the gating strategy shown in (A). (B) Box and whiskers with 10–90% percentile are shown. (C) Bars represent mean + SD. (B+C) Each group represents data from 20 donors.</p