Optimizing adalimumab treatment in psoriasis with concomitant methotrexate (OPTIMAP): study protocol for a pragmatic, single-blinded, investigator-initiated randomized controlled trial

markdownabstract__Background:__ The introduction of anti-tumor necrosis factor medications has revolutionized the treatment of psoriasis with achievement of treatment goals (Psoriasis Area and Severity Index score 75, remission) that are not usually met with conventional systemics. Nevertheless, some patients continue to experience persistent disease activity or treatment failure over time. Strategies to optimize treatment outcomes include the use of concomitant methotrexate, which has demonstrated beneficial effects on pharmacokinetics and treatment efficacy in psoriasis and other inflammatory diseases. __Methods:__ This is an investigator-initiated, multicenter randomized controlled trial (RCT) designed to compare the combination treatment of adalimumab and methotrexate with adalimumab monotherapy in patients with psoriasis. The primary outcome is adalimumab drug survival at week 49. Other outcomes include improvement in disease severity and quality of life, tolerability, and safety. Moreover, anti-adalimumab antibodies and adalimumab serum concentrations will be measured and correlations between genotypes and clinical outcomes will be assessed. Patient recruitment started in March 2014. Up to now, 36 patients have been randomized. Many more patients have been (pre)screened. A total of 93 patients is desired to meet an adequate sample size. In our experience, the main limitation for recruitment is prior adalimumab therapy and intolerability or toxicity for methotrexate in the past. __Discussion:__ OPTIMAP is the first RCT to examine combination therapy with adalimumab and methotrexate in a psoriasis population. With data derived from this study we expect to provide valuable clinical data on long-term treatment outcomes. These data will be supported by assessment of the impact of concomitant methotrexate on adalimumab pharmacokinetics. Furthermore, the influence of several single nucleotide polymorphisms on adalimumab response will be analyzed in order to support the development of a more personalized approach for this targeted therapy. Trial registration:NTR4499. Registered on 7 April 2014

Sclerostin: Current Knowledge and Future Perspectives

In recent years study of rare human bone disorders has led to the identification of important signaling pathways that regulate bone formation. Such diseases include the bone sclerosing dysplasias sclerosteosis and van Buchem disease, which are due to deficiency of sclerostin, a protein secreted by osteocytes that inhibits bone formation by osteoblasts. The restricted expression pattern of sclerostin in the skeleton and the exclusive bone phenotype of good quality of patients with sclerosteosis and van Buchem disease provide the basis for the design of therapeutics that stimulate bone formation. We review here current knowledge of the regulation of the expression and formation of sclerostin, its mechanism of action, and its potential as a bone-building treatment for patients with osteoporosis

The Interface Region Imaging Spectrograph (IRIS)

The Interface Region Imaging Spectrograph (IRIS) small explorer spacecraft provides simultaneous spectra and images of the photosphere, chromosphere, transition region, and corona with 0.33-0.4 arcsec spatial resolution, 2 s temporal resolution and 1 km/s velocity resolution over a field-of-view of up to 175 arcsec x 175 arcsec. IRIS was launched into a Sun-synchronous orbit on 27 June 2013 using a Pegasus-XL rocket and consists of a 19-cm UV telescope that feeds a slit-based dual-bandpass imaging spectrograph. IRIS obtains spectra in passbands from 1332-1358, 1389-1407 and 2783-2834 Angstrom including bright spectral lines formed in the chromosphere (Mg II h 2803 Angstrom and Mg II k 2796 Angstrom) and transition region (C II 1334/1335 Angstrom and Si IV 1394/1403 Angstrom). Slit-jaw images in four different passbands (C II 1330, Si IV 1400, Mg II k 2796 and Mg II wing 2830 Angstrom) can be taken simultaneously with spectral rasters that sample regions up to 130 arcsec x 175 arcsec at a variety of spatial samplings (from 0.33 arcsec and up). IRIS is sensitive to emission from plasma at temperatures between 5000 K and 10 MK and will advance our understanding of the flow of mass and energy through an interface region, formed by the chromosphere and transition region, between the photosphere and corona. This highly structured and dynamic region not only acts as the conduit of all mass and energy feeding into the corona and solar wind, it also requires an order of magnitude more energy to heat than the corona and solar wind combined. The IRIS investigation includes a strong numerical modeling component based on advanced radiative-MHD codes to facilitate interpretation of observations of this complex region. Approximately eight Gbytes of data (after compression) are acquired by IRIS each day and made available for unrestricted use within a few days of the observation.Comment: 53 pages, 15 figure

Community mobilization for malaria elimination: application of an open space methodology in Ruhuha sector, Rwanda

Background Despite the significant reduction of malaria transmission in Rwanda, Ruhuha sector is still a highly endemic area for malaria. The objective of this activity was to explore and brainstorm the potential roles of various community stakeholders in malaria elimination. Methods Horizontal participatory approaches such as ‘open space’ have been deployed to explore local priorities, stimulate community contribution to project planning, and to promote local capacity to manage programmes. Two open space meetings were conducted with 62 and 82 participants in years 1 and 2, respectively. Participants included purposively selected community and local organizations’ representatives. Results Malaria was perceived as a health concern by the respondents despite the reported reduction in prevalence from 60 to 20% for cases at the local health centre. Some misconceptions of the cause of malaria and misuse of preventive strategies were noted. Poverty was deemed to be a contributing factor to malaria transmission, with suggestions that improvement of living conditions for poor families might help malaria reduction. Participants expressed willingness to contribute to malaria elimination and underscored the need for constant education, sensitization and mobilization towards malaria control in general. Active diagnosis, preventative strategies and prompt treatment of malaria cases were all mentioned by participants as ways to reduce malaria. Participants suggested that partnership of stakeholders at various levels could speed up programme activities. A community rewards system was deemed important to motivate engaged participants, i.e., community health workers and households. Establishment of malaria clubs in schools settings was also suggested as crucial to speed up community awareness and increase skills towards further malaria reduction. Conclusions This bottom-up approach was found useful in engaging the local community, enabling them to explore issues related to malaria in the area and suggest solutions for sustainable malaria elimination gains

Extracorporeal shock waves down-regulate the expression of interleukin-10 and tumor necrosis factor-alpha in osteoarthritic chondrocytes

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to investigate the effects of extra corporeal shock waves (ESW) therapy on the metabolism of healthy and osteoarthritic human chondrocytes, and particularly on the expression of IL-10, TNF-alpha and beta1 integrin.</p> <p>Methods</p> <p>Human adult articular cartilage was obtained from 9 patients (6 male and 3 females), with primary knee osteoarthritis (OA), undergoing total joint replacement and from 3 young healthy donors (HD) (2 males, 1 female) with joint traumatic fracture. After isolation, chondrocytes underwent ESW treatment (electromagnetic generator system, MINILITH SL1, STORZ MEDICAL) at different parameters of impulses, energy levels and energy flux density. After that, chondrocytes were cultured in 24-well plate in DMEM supplemented with 10% FCS for 48 hours and then beta₁integrin surface expression and intracellular IL-10 and TNF-alpha levels were evaluated by flow-cytometry.</p> <p>Results</p> <p>At baseline, osteoarthritic chondrocytes expressed significantly lower levels of beta1 integrin and higher levels and IL-10 and TNF-alpha levels. Following ESW application, while beta1 integrin expression remain unchanged, a significant decrease of IL-10 and TNF-alpha intracellular levels was observed both in osteoarthritic and healthy chondrocytes. IL-10 levels decreased at any impulses and energy levels, while a significant reduction of TNF-alpha was mainly found at middle energies.</p> <p>Conclusion</p> <p>Our study confirmed that osteoarthritic chondrocytes express low beta₁integrin and high TNF-alpha and IL-10 levels. Nonetheless, ESW treatment application down-regulate the intracellular levels of TNF-alpha and IL-10 by chondrocytes, suggesting that ESW might restore TNF-alpha and IL-10 production by osteoarthritic chondrocytes at normal levels. However, further in vivo and in vitro studies are necessary to establish if ESW can represent a viable option in the treatment of OA.</p

Cross-language differences in fundamental frequency range: a comparison of English and German

This paper presents a systematic comparison of various measures of f0 range in female speakers of English and German. F0 range was analysed along two dimensions, level (i.e. overall f0 height) and span (extent of f0 modulation within a given speech sample). These were examined using two types of measures, one based on 'long-term distributional' (LTD) methods, and the other based on specific landmarks in speech that are linguistic in nature ('linguistic' measures). The various methods were used to identify whether and on what basis or bases speakers of these two languages differ in f0 range. Findings yielded significant cross-language differences in both dimensions of f0 range, but effect sizes were found to be larger for span than for level, and for linguistic than for LTD measures. The linguistic measures also uncovered some differences between the two languages in how f0 range varies through an intonation contour. 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Talking Less during Social Interactions Predicts Enjoyment: A Mobile Sensing Pilot Study

Can we predict which conversations are enjoyable without hearing the words that are spoken? A total of 36 participants used a mobile app, My Social Ties, which collected data about 473 conversations that the participants engaged in as they went about their daily lives. We tested whether conversational properties (conversation length, rate of turn taking, proportion of speaking time) and acoustical properties (volume, pitch) could predict enjoyment of a conversation. Surprisingly, people enjoyed their conversations more when they spoke a smaller proportion of the time. This pilot study demonstrates how conversational properties of social interactions can predict psychologically meaningful outcomes, such as how much a person enjoys the conversation. It also illustrates how mobile phones can provide a window into everyday social experiences and well-being

Bone refilling in cortical bone multicellular units: Insights into tetracycline double labelling from a computational model

Bone remodelling is carried out by `bone multicellular units' (BMUs) in which active osteoclasts and active osteoblasts are spatially and temporally coupled. The refilling of new bone by osteoblasts towards the back of the BMU occurs at a rate that depends both on the number of osteoblasts and on their secretory activity. In cortical bone, a linear phenomenological relationship between matrix apposition rate (MAR) and BMU cavity radius is found experimentally. How this relationship emerges from the combination of complex, nonlinear regulations of osteoblast number and secretory activity is unknown. Here, we extend our previous mathematical model of cell development within a single BMU to investigate how osteoblast number and osteoblast secretory activity vary along the BMU's closing cone. MARs predicted by the model are compared with data from tetracycline double labelling experiments. We find that the linear phenomenological relationship observed in these experiments between MAR and BMU cavity radius holds for most of the refilling phase simulated by our model, but not near the start and end of refilling. This suggests that at a particular bone site undergoing remodelling, bone formation starts and ends rapidly. Our model also suggests that part of the observed cross-sectional variability in tetracycline data may be due to different bone sites being refilled by BMUs at different stages of their lifetime. The different stages of a BMU's lifetime depend on whether the cell populations within the BMU are still developing or have reached a quasi-steady state while travelling through bone. We find that due to their longer lifespan, active osteoblasts reach a quasi-steady distribution more slowly than active osteoclasts. We suggest that this fact may locally enlarge the Haversian canal diameter (due to a local lack of osteoblasts compared to osteoclasts) near the BMU's point of origin.Comment: 16 pages, 6 figures, 3 tables. V3: minor changes: added 2 paragraphs (BMU cavity in Section 2 and Model Robustness in Section 4), references [52,54