Patterns and determinants of response to novel therapies in juvenile and adult-onset polyarthritis

Biological and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) have revolutionized the management of multiple rheumatic inflammatory conditions. Amongst these, polyarticular Juvenile-Idiopathic Arthritis (pJIA) and Rheumatoid Arthritis (RA) display similarities in terms of disease pathophysiology and response pattern to b/tsDMARDs. Indeed, therapeutic efficacy of novel targeted drugs is variable among individual patients, in both RA and pJIA. Mechanisms and determinants of this heterogeneous response are diverse and complex, such that development of true “precision”-medicine strategies has proven highly challenging. In this review, we will discuss pathophysiological, patient-specific, drug-specific and environmental factors contributing to individual therapeutic response in polyarticular JIA in comparison to what is known in RA. Although some biomarkers have been identified that stratify for the likelihood of either therapeutic response or non-response, few have proved useful in clinical practice so far, likely due to the complexity of treatment-response mechanisms. Consequently, we propose a pragmatic, patient-centered and clinically-based approach, i.e. personalized instead of biomarker-based precision medicine in JIA

Single vortex-antivortex pair in an exciton polariton condensate

In a homogeneous two-dimensional system at non-zero temperature, although there can be no ordering of infinite range, a superfluid phase is predicted for a Bose liquid. The stabilization of phase in this superfluid regime is achieved by the formation of bound vortex-antivortex pairs. It is believed that several different systems share this common behaviour, when the parameter describing their ordered state has two degrees of freedom, and the theory has been tested for some of them. However, there has been no direct experimental observation of the phase stabilization mechanism by a bound pair. Here we present an experimental technique that can identify a single vortex-antivortex pair in a two-dimensional exciton polariton condensate. The pair is generated by the inhomogeneous pumping spot profile, and is revealed in the time-integrated phase maps acquired using Michelson interferometry, which show that the condensate phase is only locally disturbed. Numerical modelling based on open dissipative Gross-Pitaevskii equation suggests that the pair evolution is quite different in this non-equilibrium system compared to atomic condensates. Our results demonstrate that the exciton polariton condensate is a unique system for studying two-dimensional superfluidity in a previously inaccessible regime

A primary current distribution model of a novel micro-electroporation channel configuration

Traditional macro and micro-electroporation devices utilize facing electrodes, which generate electric fields inversely proportional to their separation distance. Although the separation distances in micro-electroporation devices are significantly smaller than those in macro-electroporation devices, they are limited by cell size. Because of this, significant potential differences are required to induce electroporation. These potential differences are often large enough to cause water electrolysis, resulting in electrode depletion and bubble formation, both of which adversely affect the electroporation process. Here, we present a theoretical study of a novel micro-electroporation channel composed of an electrolyte flowing over a series of adjacent electrodes separated by infinitesimally small insulators. Application of a small, non-electrolysis inducing potential difference between the adjacent electrodes results in radially-varying electric fields that emanate from these insulators, causing cells flowing through the channel to experience a pulsed electric field. This eliminates the need for a pulse generator, making a minimal power source (such as a battery) the only electrical equipment that is needed. A non-dimensional primary current distribution model of the novel micro-electroporation channel shows that decreasing the channel height results in an exponential increase in the electric field magnitude, and that cells experience exponentially greater electric field magnitudes the closer they are to the channel walls. Finally, dimensional primary current distribution models of two potential applications, water sterilization and cell transfection, demonstrate the practical feasibility of the novel micro-electroporation channel

An investigation of factors associated with the health and well-being of HIV-infected or HIV-affected older people in rural South Africa

BackgroundDespite the severe impact of HIV in sub-Saharan Africa, the health of older people aged 50+ is often overlooked owing to the dearth of data on the direct and indirect effects of HIV on older people's health status and well-being. The aim of this study was to examine correlates of health and well-being of HIV-infected older people relative to HIV-affected people in rural South Africa, defined as participants with an HIV-infected or death of an adult child due to HIV-related cause. MethodsData were collected within the Africa Centre surveillance area using instruments adapted from the World Health Organization (WHO) Study on global AGEing and adult health (SAGE). A stratified random sample of 422 people aged 50+ participated. We compared the health correlates of HIV-infected to HIV-affected participants using ordered logistic regressions. Health status was measured using three instruments: disability index, quality of life and composite health score. ResultsMedian age of the sample was 60 years (range 50-94). Women HIV-infected (aOR 0.15, 95% confidence interval (CI) 0.08-0.29) and HIV-affected (aOR 0.20, 95% CI 0.08-0.50), were significantly less likely than men to be in good functional ability. Women's adjusted odds of being in good overall health state were similarly lower than men's; while income and household wealth status were stronger correlates of quality of life. HIV-infected participants reported better functional ability, quality of life and overall health state than HIV-affected participants. Discussion and Conclusions The enhanced healthcare received as part of anti-retroviral treatment as well as the considerable resources devoted to HIV care appear to benefit the overall well-being of HIV-infected older people; whereas similar resources have not been devoted to the general health needs of HIV uninfected older people. Given increasing numbers of older people, policy and programme interventions are urgently needed to holistically meet the health and well-being needs of older people beyond the HIV-related care system. <br/

ETS1 Mediates MEK1/2-Dependent Overexpression of Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) in Human Cancer Cells

EGFR-MEK-ERK signaling pathway has an established role in promoting malignant growth and disease progression in human cancers. Therefore identification of transcriptional targets mediating the oncogenic effects of the EGFR-MEK-ERK pathway would be highly relevant. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently characterized human oncoprotein. CIP2A promotes malignant cell growth and is over expressed at high frequency (40–80%) in most of the human cancer types. However, the mechanisms inducing its expression in cancer still remain largely unexplored. Here we present systematic analysis of contribution of potential gene regulatory mechanisms for high CIP2A expression in cancer. Our data shows that evolutionary conserved CpG islands at the proximal CIP2A promoter are not methylated both in normal and cancer cells. Furthermore, sequencing of the active CIP2A promoter region from altogether seven normal and malignant cell types did not reveal any sequence alterations that would increase CIP2A expression specifically in cancer cells. However, treatment of cancer cells with various signaling pathway inhibitors revealed that CIP2A mRNA expression was sensitive to inhibition of EGFR activity as well as inhibition or activation of MEK-ERK pathway. Moreover, MEK1/2-specific siRNAs decreased CIP2A protein expression. Series of CIP2A promoter-luciferase constructs were created to identify proximal −27 to −107 promoter region responsible for MEK-dependent stimulation of CIP2A expression. Additional mutagenesis and chromatin immunoprecipitation experiments revealed ETS1 as the transcription factor mediating stimulation of CIP2A expression through EGFR-MEK pathway. Thus, ETS1 is probably mediating high CIP2A expression in human cancers with increased EGFR-MEK1/2-ERK pathway activity. These results also suggest that in addition to its established role in invasion and angiogenesis, ETS1 may support malignant cellular growth via regulation of CIP2A expression and protein phosphatase 2A inhibition

Behavioral and cognitive interventions to improve treatment adherence and access to HIV care among older adults in sub-Saharan Africa: an updated systematic review

BACKGROUND: Approximately 14% of Africans infected with HIV are over the age of 50, yet few intervention studies focus on improving access to care, retention in care, and adherence to antiretroviral therapy (ART) in this population. A review of the published literature until 2012, found no relevant ART management and care interventions for older people living with HIV (OPLHIV) in sub-Saharan Africa. The aim of this systematic review is to update the original systematic review of intervention studies on OPLHIV, with a focus on evidence from sub-Saharan Africa. METHODS: We conducted a systematic review of the available published literature from 2012 to 2017 to explore behavioral and cognitive interventions addressing access to ART, retention in HIV care and adherence to ART in sub-Saharan Africa that include older adults (50+). We searched three databases (MEDLINE, EMBASE, and Education Resources Information Center) using relevant Medical Subject Headings (MeSH) terms as well as a manual search of the reference lists. No language restrictions were placed. We identified eight articles which were analyzed using content analysis with additional information obtained directly from the corresponding authors. RESULTS AND DISCUSSION: There were no studies that exclusively focused on OPLHIV. Three studies referred only to participants being over 18 years and did not specify age categories. Therefore, it is unclear whether these studies actively considered people living with HIV over the age of 50. Although the studies sampled older adults, they lacked sufficient data to draw conclusions about the relevance of the outcomes of this group. CONCLUSIONS: These findings underscore the need to increase the evidence-base of which interventions will work for older Africans on ART

Determinants of cardiac troponin T elevation in COPD exacerbation – a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Cardiac Troponin T (cTnT) elevation during exacerbations of chronic obstructive pulmonary disease (COPD) is associated with increased mortality the first year after hospital discharge. The factors associated with cTnT elevation in COPD are not known.</p> <p>Methods</p> <p>From our hospital's database, all patients admitted with COPD exacerbation in 2000–03 were identified. 441 had measurement of cTnT performed. Levels of cTnT ≥ 0.04 μg/l were considered elevated. Clinical and historical data were retrieved from patient records, hospital and laboratory databases. Odds ratios for cTnT elevation were calculated using logistic regression.</p> <p>Results</p> <p>120 patients (27%) had elevated cTnT levels. The covariates independently associated with elevated cTnT were increasing neutrophil count, creatinine concentration, heart rate and Cardiac Infarction Injury Score (CIIS), and decreasing hemoglobin concentration. The adjusted odds ratios (95% confidence intervals in parentheses) for cTnT elevation were 1.52 (1.20–1.94) for a 5 × 10⁶/ml increase in neutrophils, 1.21 (1.12–1.32) for a 10 μmol/l increase in creatinine, 0.80 (0.69–0.92) for a 1 mg/dl increase in hemoglobin, 1.24 (1.09–1.42) for a 10 beats/minute increase in heart rate and 1.44 (1.15–1.82) for a 10 point increase in CIIS.</p> <p>Conclusion</p> <p>Multiple factors are associated with cTnT elevation, probably reflecting the wide panorama of comorbid conditions typically seen in COPD. The positive association between neutrophils and cTnT elevation is compatible with the concept that an exaggerated inflammatory response in COPD exacerbation may predispose for myocardial injury.</p