Chondrocytes respond to adenosine via A2receptors and activity is potentiated by an adenosine deaminase inhibitor and a phosphodiesterase inhibitor

AbstractObjective To test the mechanisms by which adenosine and adenosine analogues stimulate adenylate cyclase and suppress lipopolysaccharide (LPS)-induced production of nitric oxide (NO) by chondrocytes.Methods Primary chondrocytes isolated from equine articular cartilage were plated in monolayer. Intracellular cyclic-AMP (cAMP) accumulation was measured following exposure to medium containing adenosine, the non-hydrolyzable adenosine analogue N6-methyladenosine, the A2Aspecific agonist N6-(dimethoxyphenyl)-ethyl]adenosine (DPMA), the adenosine deaminase inhibitor erythro-9-(2-Hydroxy-3-nonyl)adenine hydrochloride (EHNA), or forskolin, a potent stimulator of adenylate cyclase. Regulation of NO production by LPS-stimulated chondrocytes, as determined by nitrite concentration, was assessed in the presence of adenosine, N6-methyladenosine, DPMA, the broad agonist 5′-N-ethylcarboxamidoadenosine (NECA), or forskolin. Alternatively, LPS-stimulated chondrocytes were exposed to EHNA or the phosphodiesterase inhibitor rolipram in the presence or absence of supplemental adenosine.Results Adenosine, N6-methyladenosine, DPMA, and forskolin each increased intracellular cAMP accumulation in a concentration-dependent manner and suppressed NO production by LPS-stimulated chondrocytes. NECA also decreased NO production by chondrocytes stimulated with LPS. Incubation with EHNA, to protect endogenously produced adenosine, or rolipram, which prevents the degradation of cAMP, similarly suppressed LPS-stimulated NO production. The addition of exogenous adenosine with EHNA or rolipram further suppressed NO production.Conclusions This study documents functional responses to adenosine by articular chondrocytes. These responses are mimicked by the A2Areceptor agonist, DPMA. Effects were enhanced by protecting adenosine using an adenosine deaminase inhibitor or by potentiating the cAMP response with rolipram. These experiments suggest that adenosine may play a physiological role in regulation of chondrocytes and that adenosine pathways could represent a novel target for therapeutic intervention

Applying refinement to the use of mice and rats in rheumatoid arthritis research

Rheumatoid arthritis (RA) is a painful, chronic disorder and there is currently an unmet need for effective therapies that will benefit a wide range of patients. The research and development process for therapies and treatments currently involves in vivo studies, which have the potential to cause discomfort, pain or distress. This Working Group report focuses on identifying causes of suffering within commonly used mouse and rat ‘models’ of RA, describing practical refinements to help reduce suffering and improve welfare without compromising the scientific objectives. The report also discusses other, relevant topics including identifying and minimising sources of variation within in vivo RA studies, the potential to provide pain relief including analgesia, welfare assessment, humane endpoints, reporting standards and the potential to replace animals in RA research

WIVERN: A new satellite concept to provide global in-cloud winds, precipitation and cloud properties.

A new satellite concept with a conically scanning W-band Doppler radar to provide in-cloud winds, together with estimates of global rainfall, snowfall and cloud properties. This paper presents a conically scanning space-borne Dopplerized 94GHz radar Earth Science mission concept, WIVERN, ‘Wind VElocity Radar Nephoscope’. WIVERN aims to provide global measurements of in-cloud winds using the Doppler shifted radar returns from hydrometeors. The conically scanning radar could provide wind data with daily revisits poleward of 50°, 50-km horizontal resolution and approximately 1km vertical resolution. The measured winds, when assimilated into weather forecasts and provided they are representative of the larger scale mean flow, should lead to further improvements in the accuracy and effectiveness of forecasts of severe weather and better focusing of activities to limit damage and loss of life. It should also be possible to characterize the more variable winds associated with local convection. Polarization diversity would be used to enable high wind speeds to be unambiguously observed; analysis indicates that artifacts associated with polarization diversity are rare and can be identified. Winds should be measurable down to 1 km above the ocean surface and 2 km over land. The potential impact of the WIVERN winds on reducing forecast errors is estimated by comparison with the known positive impact of cloud motion and aircraft winds. The main thrust of WIVERN is observing in-cloud winds, but WIVERN should also provide global estimates of ice water content, cloud cover and vertical distribution continuing the data series started by CloudSat with the conical scan giving increased coverage. As with CloudSat, estimates of rainfall and snowfall rates should be possible. These non-wind products may also have a positive impact when assimilated into weather forecasts

Comparative effectiveness and safety of non-vitamin K antagonists for atrial fibrillation in clinical practice: GLORIA-AF Registry

Background and purpose: Prospectively collected data comparing the safety and effectiveness of individual non-vitamin K antagonists (NOACs) are lacking. Our objective was to directly compare the effectiveness and safety of NOACs in patients with newly diagnosed atrial fibrillation (AF). Methods: In GLORIA-AF, a large, prospective, global registry program, consecutive patients with newly diagnosed AF were followed for 3 years. The comparative analyses for (1) dabigatran vs rivaroxaban or apixaban and (2) rivaroxaban vs apixaban were performed on propensity score (PS)-matched patient sets. Proportional hazards regression was used to estimate hazard ratios (HRs) for outcomes of interest. Results: The GLORIA-AF Phase III registry enrolled 21,300 patients between January 2014 and December 2016. Of these, 3839 were prescribed dabigatran, 4015 rivaroxaban and 4505 apixaban, with median ages of 71.0, 71.0, and 73.0 years, respectively. In the PS-matched set, the adjusted HRs and 95% confidence intervals (CIs) for dabigatran vs rivaroxaban were, for stroke: 1.27 (0.79–2.03), major bleeding 0.59 (0.40–0.88), myocardial infarction 0.68 (0.40–1.16), and all-cause death 0.86 (0.67–1.10). For the comparison of dabigatran vs apixaban, in the PS-matched set, the adjusted HRs were, for stroke 1.16 (0.76–1.78), myocardial infarction 0.84 (0.48–1.46), major bleeding 0.98 (0.63–1.52) and all-cause death 1.01 (0.79–1.29). For the comparison of rivaroxaban vs apixaban, in the PS-matched set, the adjusted HRs were, for stroke 0.78 (0.52–1.19), myocardial infarction 0.96 (0.63–1.45), major bleeding 1.54 (1.14–2.08), and all-cause death 0.97 (0.80–1.19). Conclusions: Patients treated with dabigatran had a 41% lower risk of major bleeding compared with rivaroxaban, but similar risks of stroke, MI, and death. Relative to apixaban, patients treated with dabigatran had similar risks of stroke, major bleeding, MI, and death. Rivaroxaban relative to apixaban had increased risk for major bleeding, but similar risks for stroke, MI, and death. Registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01468701, NCT01671007. Date of registration: September 2013

Anticoagulant selection in relation to the SAMe-TT2R2 score in patients with atrial fibrillation. the GLORIA-AF registry

Aim: The SAMe-TT2R2 score helps identify patients with atrial fibrillation (AF) likely to have poor anticoagulation control during anticoagulation with vitamin K antagonists (VKA) and those with scores >2 might be better managed with a target-specific oral anticoagulant (NOAC). We hypothesized that in clinical practice, VKAs may be prescribed less frequently to patients with AF and SAMe-TT2R2 scores >2 than to patients with lower scores. Methods and results: We analyzed the Phase III dataset of the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), a large, global, prospective global registry of patients with newly diagnosed AF and ≥1 stroke risk factor. We compared baseline clinical characteristics and antithrombotic prescriptions to determine the probability of the VKA prescription among anticoagulated patients with the baseline SAMe-TT2R2 score >2 and ≤ 2. Among 17,465 anticoagulated patients with AF, 4,828 (27.6%) patients were prescribed VKA and 12,637 (72.4%) patients an NOAC: 11,884 (68.0%) patients had SAMe-TT2R2 scores 0-2 and 5,581 (32.0%) patients had scores >2. The proportion of patients prescribed VKA was 28.0% among patients with SAMe-TT2R2 scores >2 and 27.5% in those with scores ≤2. Conclusions: The lack of a clear association between the SAMe-TT2R2 score and anticoagulant selection may be attributed to the relative efficacy and safety profiles between NOACs and VKAs as well as to the absence of trial evidence that an SAMe-TT2R2-guided strategy for the selection of the type of anticoagulation in NVAF patients has an impact on clinical outcomes of efficacy and safety. The latter hypothesis is currently being tested in a randomized controlled trial. Clinical trial registration: URL: https://www.clinicaltrials.gov//Unique identifier: NCT01937377, NCT01468701, and NCT01671007

Developmental adaptation to high altitude hypoxia

Experimental studies on animals and humans exposed to hypoxic stress have been reviewed. These data suggest that the influence of hypoxic stress, and the organism's response to it, are greater during growth than during adulthood. The organism's responses include alterations in the quantity and size of the alveolar units of the lungs, enlargement of the right ventricle of the heart, slower somatic growth as measured by birth weight and body size, increased aerobic capacity during maximal work, and greater control of ventilation. It is postulated that the organism is more sensitive to the influence of environmental factors during growth and development than during adulthood. Consequently, adaptive traits acquired during the developmental period have profound, long-term consequences, which are reflected in the physiological and morphological characteristics of the adult organism. It is concluded that the differences between the highland and lowland natives in their physiological performance and morphology are mostly due to adaptations acquired during the developmental period.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47840/1/484_2005_Article_BF01553707.pd