Mineralisation patterns in the subchondral bone plate of the humeral head

Purpose: Pathologic changes of the glenohumeral joint, like a long-standing overloading or an accident often lead to severe glenohumeral osteoarthritis, and a glenohumeral joint replacement could be necessary. Joint instability and glenoid loosening are the most common post-operative complications, which can be caused by eccentric loading of the glenoid, if the humeral head is malcentered. If these malcentered cases could be identified pre-operatively, the pathologic position of the humeral head could be fixed intra-operatively and complication may be prevented. Computed tomography osteoabsorptiometry (CT-OAM) is a useful method to determine the distribution of mineralisation in the subchondral bone as a marker for the long-term loading history of a joint. The objective of this study was to gain information about the mineralisation distribution in the subchondral bone plate of the humeral head. Methods: By the use of CT-OAM, the distribution of the subchondral mineralisation of 69 humeral heads was investigated and groups of mineralisation patterns were built. To evaluate if differences in age exist, the mean values of the two groups were compared using t test. Results: 49 humeral heads (71% of 69 specimens) showed bicentric subchondral mineralisation patterns with ventral and dorsal maxima, 20 humeral heads (29% of 69 specimens) could be classified as monocentric with a centro-dorsal maximum. We found no statistical significant difference between the age of the monocentric and the bicentric group on a significance level of 95%. Conclusion: We could show that stress distribution at the humeral head is typically bicentric with a ventral and dorsal maximum. However, other mineralisation patterns may occur under pathologic circumstances. The pre-operative identification of such cases by the use of CT-OAM could help to improve the post-operative results in shoulder surger

Shared knowledge and the formal housing process in Namibia

PhD ThesisThis study investigates issues related to housing in the period immediately preceding Namibia's independence in 1990. A formal housing process was inherited from the colonial era and during the decade before independence, this process became the one that was applied to provide housing for low-income people. Indigenous Namibians were excluded from decision making and participating in their own housing process in the municipal areas. Policies of apartheid maintained cultural distances and contributed to a condition of lack of shared knowledge concerning the formal housing process. To solve the housing problem, an increased role by low-income people in the housing process is emphasised by international agencies, as well as the new Namibian government through its National Housing Policy and the housing strategy. In the context of policy and strategy proposals based on this emphasis, lack of shared knowledge is identified as the research problem for this thesis. This follows from the argument that shared knowledge is important to enable people to take actions in solving their own housing problems. This lack of shared knowledge is investigated through aspects of the formal housing process dealing with the commercialisation of housing and the creation of the domestic environment. The research is done by using a combination of qualitative and quantitative methods, which include fieldwork in various urban areas in Namibia. It was determined that a limited awareness concerning certain financial and contractual aspects exists among house buyers. On the other hand, the domestic environment designs are based on principles of 'closed domesticated environments' for nuclear family and 'suburbs' for domestic purposes only, which do not reflect the way of life of the people occupying the houses. This is illustrated by an in-depth comparison of the socio-spatial characteristics of domestic environments designed on these principles, with those inhabited and created by the inhabitants themselves. To conclude, proposals are made in context of housing developments after independence. It is proposed that increased participation by low-income people can only overcome this lack of shared knowledge, if the housing process is made more accessible to people. An accessible process also has to be developed in partnership with people in need of shelter

Petrogenesis of kyanite-quartz segregations in mica schists of the Western Tatra Mountains (Slovakia)

In the Tatra Mountains (Slovakia) metamorphic complex, kyanite-quartz segregations with biotite-rich selvage occur in mylonitized mica schists. In this paper, the problem of fluid flow and aluminium mobility during the uplift of the crystalline massif, and the position of the segregations in the history of Western Tatra metamorphic complex, is adressed. The reaction Alm + Rt Ilm + Ky + Qtz is considered to be the result of a pressure drop from above to below 9 kbar. Ti-in-biotite geothermometry shows the temperature range to be 579- 639ºC that is related to heating and decompression associated with granite intrusion. Major-element mass-balance calculations show that Al remained stable in the selvage + segregation system whereas other elements (e.g. Cr, HFSE) were mobilized. The kyanite-quartz segregations formed from local fluids generated during dehydration of the metapelitic rocks during uplift. The main mechanism was likely diffusion-driven mass-transfer into extensionrelated cracks

Age and origin of fluorapatite-rich dyke from Baranec Mt. (Tatra Mts., Western Carpathians) : a key to understanding of the post-orogenic processes and element mobility

On the southeastern slope of the Baranec Mount in the Western Tatra Mountains (Slovakia) an apatite-rich pegmatite-like segregation was found in the subvertical fault zone cutting metapelitic rocks. Two zones: felsic (F) and mafic (M) were found, differing in mineral assemblages and consequently in chemistry. Fluorapatite crystals yield a LA-ICP-MS U-Pb age of 328.6 ± 2.4 Ma. A temperature decrease from 634 °C to 454 °C at a pressure around 500 to 400 MPa with oxygen fugacity increasing during crystallization are the possible conditions for formation of the pegmatite-like segregation, while secondary alterations took place in the temperature range of 340-320 °C. The Sr-Nd isotope composition of both apatite and whole rock point toward a crustal origin of the dike in question, suggesting partial melting of (P, F, H2O)-rich metasedimentary rocks during prolonged decompression of the Tatra Massif. The original partial melt (felsic component) was mixed with an external (F, H2O)-rich fluid, carrying Fe and Mg fluxed from more mafic metapelites and crystallizing as biotite and epidote in the mafic component of the dyke

Multiple allosteric effectors control the affinity of DasR for its target sites

peer reviewe

Rosetting T cells in Hodgkin lymphoma are activated by immunological synapse components HLA class II and CD58

A unique feature of Hodgkin lymphoma (HL) is the presence of CD4+ T cells that surround, protect, and promote survival of tumor cells. The adhesion molecules involved in this so-called T-cell rosetting are important components of the immunological synapse (IS). However, it is unknown whether this synapse is fully assembled and leads to T-cell activation by enabling interaction between the T-cell receptor (TCR) and human leukocyte antigen class II (HLA-II). We established a novel rosetting model by coculturing HLA-II-matched peripheral blood mononuclear cells with HL cell lines and showed IS formation with activation of rosetting T cells. HLA-II downregulation by class II transactivator knockout did not affect the extent of rosetting, but almost completely abrogated T-cell activation. Intriguingly, the level of CD58 expression correlated with the extent of rosette formation, and CD58 knockout or CD2 blockade reduced both rosette formation and T-cell activation. The extension of our findings to primary HL tissue by immunohistochemistry and proximity ligation assays showed interaction of CD2 with CD58 and of TCR-associated CD4 with HLA-II. In conclusion, T-cell rosetting in HL is established by formation of the IS, and activation of rosetting T cells critically depends on the interaction of both TCR-HLA-II and CD2-CD58

Meeting the WHO 90% target : antiretroviral treatment efficacy in Poland is associated with baseline clinical patient characteristics

Introduction: Modern combined antiretroviral therapies (cART) allow to effectively suppress HIV-1 viral load, with the 90% virologic success rate, meeting the WHO target in most clinical settings. The aim of this study was to analyse antiretroviral treatment efficacy in Poland and to identify variables associated with virologic suppression. Methods: Cross-sectional data on 5152 (56.92% of the countrywide treated at the time-point of analysis) patients on cART for more than six months with at least one HIV-RNA measurement in 2016 were collected from 14 Polish centres. Patients’ characteristics and treatment type-based outcomes were analysed for the virologic suppression thresholds of <50 and <200 HIV-RNA copies/ml. CART was categorized into two nucleos(t)ide (2NRTI) plus non-nucleoside reverse transcriptase (NNRTI) inhibitors, 2NRTI plus protease (PI) inhibitor, 2NRTI plus integrase (InI) inhibitor, nucleos(t)ide sparing PI/r+InI and three drug class regimens. For statistics Chi-square and U-Mann Whitney tests and adjusted multivariate logistic regression models were used. Results: Virologic suppression rates of <50 copies/mL were observed in 4672 (90.68%) and <200 copies/mL in 4934 (95.77%) individuals. In univariate analyses, for the suppression threshold <50 copies/mL higher efficacy was noted for 2NRTI+NNRTI-based combinations (94.73%) compared to 2NRTI+PI (89.93%), 2NRTI+InI (90.61%), nucleos(t)ide sparing PI/r+InI (82.02%) and three drug class regimens (74.49%) (p < 0.0001), with less pronounced but significant differences for the threshold of 200 copies/mL [2NRTI+NNRTI-97.61%, 2NRTI+PI-95.27%, 2NRTI+InI-96.61%, PI/r+InI- 95.51% and 86.22% for three drug class cART) (p < 0.0001). However, in multivariate model, virologic efficacy for viral load <50 copies/mL was similar across treatment groups with significant influence by history of AIDS [OR:1.48 (95%CI:1.01–2.17) if AIDS diagnosed, p = 0.046], viral load < 5 log copies/mL at care entry [OR:1.47 (95%CI:1.08–2.01), p = 0.016], baseline lymphocyte CD4 count ≥200 cells/µL [OR:1.72 (95%CI:1.04–2.78), p = 0.034] and negative HCV serology [OR:1.97 (95%CI:1.29–2.94), p = 0.002]. For viral load threshold <200 copies/mL higher likelihood of virologic success was only associated with baseline lymphocyte CD4 count ≥200 cells/µL [OR:2.08 (95%CI:1.01–4.35), p = 0.049] and negative HCV status [OR:2.84 (95%CI:1.52–5.26), p = 0.001]. Conclusions: Proportion of virologically suppressed patients is in line with WHO treatment target confirming successful application of antiretroviral treatment strategy in Poland. Virological suppression rates depend on baseline patient characteristics, which should guide individualized antiretroviral tre0atment decisions

Differential expansion of circulating human MDSC subsets in patients with cancer, infection and inflammation

Background Myeloid-derived suppressor cells (MDSC) are a functional myeloid cell subset that includes myeloid cells with immune suppressive properties. The presence of MDSC has been reported in the peripheral blood of patients with several malignant and non-malignant diseases. So far, direct comparison of MDSC across different diseases and Centers is hindered by technical pitfalls and a lack of standardized methodology. To overcome this issue, we formed a network through the COST Action Mye-EUNITER (www.mye-euniter.eu) with the goal to standardize and facilitate the comparative analysis of human circulating MDSC in cancer, inflammation and infection. In this manuscript, we present the results of the multicenter study Mye-EUNITER MDSC Monitoring Initiative, that involved 13 laboratories and compared circulating MDSC subsets across multiple diseases, using a common protocol for the isolation, identification and characterization of these cells. Methods We developed, tested, executed and optimized a standard operating procedure for the isolation and immunophenotyping of MDSC using blood from healthy donors. We applied this procedure to the blood of almost 400 patients and controls with different solid tumors and non-malignant diseases. The latter included viral infections such as HIV and hepatitis B virus, but also psoriasis and cardiovascular disorders. Results We observed that the frequency of MDSC in healthy donors varied substantially between centers and was influenced by technical aspects such as the anticoagulant and separation method used. Expansion of polymorphonuclear (PMN)-MDSC exceeded the expansion of monocytic MDSC (M-MDSC) in five out of six solid tumors. PMN-MDSC expansion was more pronounced in cancer compared with infection and inflammation. Programmed death-ligand 1 was primarily expressed in M-MDSC and e-MDSC and was not upregulated as a consequence of disease. LOX-1 expression was confined to PMN-MDSC. Conclusions This study provides improved technical protocols and workflows for the multi-center analysis of circulating human MDSC subsets. Application of these workflows revealed a predominant expansion of PMN-MDSC in solid tumors that exceeds expansion in chronic infection and inflammation

Melanocortin peptides protect chondrocytes from mechanically induced cartilage injury

Introduction Mechanical injury can greatly influence articular cartilage, propagating inflammation, cell injury and death – risk factors for the development of osteoarthritis. Melanocortin peptides and their receptors mediate anti-inflammatory and pro-resolving mechanisms in chondrocytes. This study aimed to investigate the potential chondroprotective properties of α-MSH and [DTRP8]-γ-MSH in mechanically injured cartilage explants, their ability to inhibit pro-inflammatory and stimulate anti-inflammatory cytokines in in situ and in freshly isolated articular chondrocytes. Methods The effect of melanocortins on in situ chondrocyte viability was investigated using confocal laser scanning microscopy of bovine articular cartilage explants, subjected to a single blunt impact (1.14 N, 6.47 kPa) delivered by a drop tower. Chondroprotective effects of α-MSH, [DTRP8]-γ-MSH and dexamethasone on cytokine release by TNF-α-activated freshly isolated articular chondrocytes/mechanically injured cartilage explants were investigated by ELISA. Results A single impact to cartilage caused discreet areas of chondrocyte death, accompanied by pro-inflammatory cytokine release; both parameters were modulated by α-MSH, [DTRP8]-γ-MSH and dexamethasone. Melanocortin pre-treatment of TNF-α-stimulated freshly isolated chondrocytes resulted in a bell-shaped inhibition in IL-1β, IL-6 and IL-8, and elevation of IL-10 production. The MC3/4 antagonist, SHU9119, abrogated the effect of [DTRP8]-γ-MSH but not α-MSH on cytokine release. Conclusion Melanocortin peptide pre-treatment prevented chondrocyte death following mechanical impact to cartilage and led to a marked reduction of pro-inflammatory cytokines, whilst prompting the production of anti-inflammatory/pro-resolving cytokine IL-10. Development of small molecule agonists towards melanocortin receptors could thus be a viable approach for preventing chondrocyte inflammation and death within cartilage and represent an alternative approach for the treatment of osteoarthritis

Circulating Osteopontin and Prediction of Hepatocellular Carcinoma Development in a Large European Population.

We previously identified osteopontin (OPN) as a promising marker for the early detection of hepatocellular carcinoma (HCC). In this study, we investigated the association between prediagnostic circulating OPN levels and HCC incidence in a large population-based cohort. A nested case-control study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. During a mean follow-up of 4.8 years, 100 HCC cases were identified. Each case was matched to two controls and OPN levels were measured in baseline plasma samples. Viral hepatitis, liver function, and α-fetoprotein (AFP) tests were also conducted. Conditional logistic regression models were used to calculate multivariable odds ratio (OR) and 95% confidence intervals (95% CI) for OPN levels in relation to HCC. Receiver operating characteristics curves were constructed to determine the discriminatory accuracy of OPN alone or in combination with other liver biomarkers in the prediction of HCC. OPN levels were positively associated with HCC risk (per 10% increment, ORmultivariable = 1.30; 95% CI, 1.14-1.48). The association was stronger among cases diagnosed within 2 years of follow-up. Adding liver function tests to OPN improved the discriminatory performance for subjects who developed HCC (AUC = 0.86). For cases diagnosed within 2 years, the combination of OPN and AFP was best able to predict HCC risk (AUC = 0.88). The best predictive model for HCC in this low-risk population is OPN in combination with liver function tests. Within 2 years of diagnosis, the combination of OPN and AFP best predicted HCC development, suggesting that measuring OPN and AFP could identify high-risk groups independently of a liver disease diagnosis. Cancer Prev Res; 9(9); 758-65. ©2016 AACR.This work was supported by NIH R01 CA120719 to LB and by the French National Cancer Institute (Institut National du Cancer; INCA) grant number 2009-139 to MJ. The coordination of EPIC is financially supported by the European Commission (DG-SANCO); and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer; Institut Gustave Roussy; Mutuelle Générale de l’Education Nationale; and Institut National de la Santé et de la Recherche Médicale (INSERM) (France); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum (DKFZ); and Federal Ministry of Education and Research (Germany); Hellenic Health Foundation (Greece); Italian Association for Research on Cancer (AIRC); National Research Council; and AIRE-ONLUS Ragusa, AVIS Ragusa, Sicilian Government (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS); Netherlands Cancer Registry (NKR); LK Research Funds; Dutch Prevention Funds; Dutch ZON (Zorg Onderzoek Nederland); World Cancer Research Fund (WCRF); and Statistics Netherlands (the Netherlands); European Research Council (ERC) (grant number ERC-2009-AdG 232997) and Nordforsk; and Nordic Center of Excellence Programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS); Regional Governments of Andalucía, Asturias, Basque Country, Murcia (No. 6236) and Navarra; and ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society; Swedish Scientific Council; and Regional Government of Skåne and Västerbotten (Sweden); Cancer Research UK; Medical Research Council; Stroke Association; British Heart Foundation; Department of Health; Food Standards Agency; and Wellcome Trust (UK). Reagents for the hepatitis infection determinations were kindly provided by Abbott Diagnostics Division, Lyon, France.This is the author accepted manuscript. The final version is available from the American Association for Cancer Research via http://dx.doi.org/10.1158/1940-6207.CAPR-15-043