Muscle-directed mechanosensory feedback activates egg-laying circuit activity and behavior in Caenorhabditis elegans.

Mechanosensory feedback of the internal reproductive state drives decisions about when and where to reproduce.1 For instance, stretch in the Drosophila reproductive tract produced by artificial distention or from accumulated eggs regulates the attraction to acetic acid to ensure optimal oviposition.2 How such mechanosensory feedback modulates neural circuits to coordinate reproductive behaviors is incompletely understood. We previously identified a stretch-dependent homeostat that regulates egg laying in Caenorhabditis elegans. Sterilized animals lacking eggs show reduced Ca2+ transient activity in the presynaptic HSN command motoneurons that drive egg-laying behavior, while animals forced to accumulate extra eggs show dramatically increased circuit activity that restores egg laying.3 Interestingly, genetic ablation or electrical silencing of the HSNs delays, but does not abolish, the onset of egg laying,3,4,5 with animals recovering vulval muscle Ca2+ transient activity upon egg accumulation.6 Using an acute gonad microinjection technique to mimic changes in pressure and stretch resulting from germline activity and egg accumulation, we find that injection rapidly stimulates Ca2+ activity in both neurons and muscles of the egg-laying circuit. Injection-induced vulval muscle Ca2+ activity requires L-type Ca2+ channels but is independent of presynaptic input. Conversely, injection-induced neural activity is disrupted in mutants lacking the vulval muscles, suggesting "bottom-up" feedback from muscles to neurons. Direct mechanical prodding activates the vulval muscles, suggesting that they are the proximal targets of the stretch-dependent stimulus. Our results show that egg-laying behavior in C. elegans is regulated by a stretch-dependent homeostat that scales postsynaptic muscle responses with egg accumulation in the uterus.

Proteomic Basis of Symbiosis: A Heterologous Partner Fails to Duplicate Homologous Colonization in a Novel Cnidarian- Symbiodiniaceae Mutualism.

Reef corals and sea anemones form symbioses with unicellular symbiotic dinoflagellates. The molecular circumventions that underlie the successful intracellular colonization of hosts by symbionts are still largely unknown. We conducted proteomic analyses to determine molecular differences of Exaiptasia pallida anemones colonized by physiologically different symbiont species, in comparison with symbiont-free (aposymbiotic) anemones. We compared one homologous species, Symbiodinium linucheae, that is natively associated with the clonal Exaiptasia strain (CC7) to another heterologous species, Durusdinium trenchii, a thermally tolerant species that colonizes numerous coral species. This approach allowed the discovery of a core set of host genes that are differentially regulated as a function of symbiosis regardless of symbiont species. The findings revealed that symbiont colonization at higher densities requires circumvention of the host cellular immunological response, enhancement of ammonium regulation, and suppression of phagocytosis after a host cell in colonized. Furthermore, the heterologous symbionts failed to duplicate the same level of homologous colonization within the host, evidenced by substantially lower symbiont densities. This reduced colonization of D. trenchii correlated with its inability to circumvent key host systems including autophagy-suppressing modulators, cytoskeletal alteration, and isomerase activity. The larger capability of host molecular circumvention by homologous symbionts could be the result of a longer evolutionary history of host/symbiont interactions, which translates into a more finely tuned symbiosis. These findings are of great importance within the context of the response of reef corals to climate change since it has been suggested that coral may acclimatize to ocean warming by changing their dominant symbiont species.

The effect of concomitant hand osteoarthritis on pain and disease activity in patients with rheumatoid arthritis.

INTRODUCTION: Pain is a core complaint among rheumatoid arthritis (RA) patients, and persistent pain requires treatment adjustments according to current strategies. We aimed to quantify the impact of hand osteoarthritis (OA) on health status and residual pain in patients with RA. METHODS: This cross-sectional survey compared RA patients with and without osteoarthritis of the hand. The main outcome was pain intensity. Other measurements included disease activity scores (the Disease Activity Score 28-joints; the Simplified Disease Activity Index, SDAI; the Clinical Disease Activity Index, CDAI), functional disability and self-reported quality of life, and the proportion of patients with residual pain (Patient Acceptable Symptom State, PASS). RESULTS: Eighty-one patients were analyzed, including 39 with RA and OA and 42 with RA only. The patients were mainly women (94%), with a median disease duration of 13 years. This group also reported a higher intensity of pain (visual analogue scale, VAS 70 mm vs. 30 mm; p = 0.003), higher disease activity (3.89 vs. 2.88; p = 0.001), and greater functional disability irrespective of treatment and comorbidities. A strong correlation (r2 = 0.69; p < 0.001) between pain and disease activity was observed, although no differences in pain were observed between groups according to disease activity categories. Patients with RA and OA had a higher proportion of residual pain (59% vs. 29%; p = 0.006) even in the absence of clinical inflammation. CONCLUSION: The coexistence of RA and hand OA is associated with distorted disease activity measurements in RA. Osteoarthritis contributes to persistent pain and greater disability in patients with RA.

Physician's Experience and Disease Activity Affect the Impact of Ultrasound on the Treatment Decision in Rheumatoid Arthritis.

BACKGROUND/OBJECTIVE: The aim of this cross-sectional study was to explore which factors affect the impact of musculoskeletal ultrasound (MUS) on the treatment proposal among rheumatologists with different degree of experience. METHODS: Sixteen clinical vignettes summarized data from rheumatoid arthritis (RA) outpatients; vignettes included clinical evaluation and a blank section for a first treatment proposal; MUS information was then added, based on German Ultrasound score, followed by a blank section for treatment re-consideration, if applicable. During a 6 months period, each vignette was concomitantly presented to six trainees and six senior rheumatologists (SR); three SR had ≥15 years of experience. Participants were blinded to colleagues' responses. Appropriated statistics were used. RESULTS: Vignettes included data from female patients, who had a mean ± SD age of 43.3 ± 9 years, 7.6 ± 3.5 years of disease duration and comorbidities (68.8%). MUS induced treatment modification in 24% of evaluations, with similar percentage among SR and trainees. Within SR, more experienced rheumatologists (≥15 years) never translated MUS findings in a different treatment proposal, compared to 34% of those with lesser experience, p ≤ 0.0001. There were 60 clinical scenarios each, with remission and moderate disease activity, and 36 clinical scenarios each, with low and high disease activity. MUS-induced treatment modifications were more frequent in scenarios with low and moderate disease activity, compared to remission and high disease activity, p = 0.008. CONCLUSIONS: Physician's experience and disease activity level affect the impact of MUS on the treatment decision in RA outpatients. RA patients with intermediate disease activity may benefit from MUS incorporation to standard assessments.

Psychometric validation of an empowerment scale for Spanish-speaking patients with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) knowledge has been constructed with studies performed in Caucasians patients; Latin American patients present unique characteristics. Empowerment is a social multidimensional construct that has been associated to better health-related quality of life in RA. There is no validated instrument for use with Spanish-speaking patients. The objective of the study was to adapt the Spanish version of the Health Empowerment Scale (S-HES), which was selected for its psychometric properties and suitability for low-literacy populations, for RA Hispanic patients (RAEH), and to perform its psychometric validation. METHODS: RAEH adaptation, pilot testing, and psychometric validation were performed. Three convenience samples of RA outpatients from a national tertiary care level center were used. For RAEH adaptation, the word "health" was substituted with "RA" in the original S-HES, integrated by 8 items. Pilot testing (in 50 patients) assessed feasibility. Psychometric validation included content validity (nine experts rated item convenience, clarity, and cultural semantic accuracy), internal consistency (in 200 patients, Cronbach's alpha) and test-retest (in a subsample of 50 patients, ICC and 95% CI), construct validity (factor analysis), and face validity (in 20 patients, % of agreement). Patients gave written informed consent. RESULTS: Patients were primarily middle-aged females and had typical long-standing disease, although early disease was represented. In the psychometric validation sample, the majority of the outpatients had autoantibodies; meanwhile, half of them had no evidence of disease activity, with acute reactants phase determinations within normal range. Patients with comorbidities and joint replacement were also included. Experts agreed upon the attributes of content validity: 83-100% considered the item was essential, 100% agreed on the item's clarity and 80-100% on the cultural semantic accuracy. In the pilot sample, ≥ 80% of the patients agreed with the item's clarity and format. In the psychometric validation sample, mean RAEH was 34 (maximum possible score: 40 = highest score). RAEH had a good internal consistency, Cronbach's α = 0.86, and moderately good reliability (ICC [95% CI] test-retest: 0.79 [0.62-0.88]). Factor analysis for construct validity showed a single factor explaining 52% of the variance. Patients agreed with each item content validity (85-100%) and clarity (75-100%). CONCLUSIONS: RAEH was valid and reliable to evaluate empowerment in Spanish-speaking RA patients.

Outcomes after rheumatoid arthritis patients complete their participation in a long-term observational study with tofacitinib combined with methotrexate: practical and ethical implications in vulnerable populations after tofacitinib discontinuation.

To describe disease activity and disability during the first year of follow-up, from rheumatoid arthritis (RA) patients who discontinue tofacitinib after they end participation in a clinical trial. From 2008 to 2016, 36 patients were enrolled in the "Long term follow-up study with tofacitinib (and methotrexate) for RA treatment". At the end of the study, tofacitinib was discontinued and patients were proposed to enter an observational study; 35 agree and had scheduled evaluations at baseline, at 15 and 30 days of follow-up, at month 2 and 3, and thereafter every 3 months. Disease activity was evaluated as per DAS28-ESR and disability as per HAQ. During follow-up, treatment was treat-to-target oriented, only conventional DMARDs were indicated. Descriptive statistics and nonparametric test were used. The study was approved by IRB. Patients were primarily females (N = 34), had median (Q25-75) age of 52 years (45-58), and had received tofacitinib for a median of 7.9 years (6.3-8.3). The proportion of patients with remission and low disease activity decreased from day 30 of follow-up and recovered after 270 days, meanwhile patients with high disease activity increased from 0% at baseline to 6.3% at 1 year. At study entry, 20 patients had remission/low disease activity; during follow-up, 85% deteriorated after (median) 30 days; among them, 23.5% recovered their baseline status after a median of 172.5 days. The HAQ showed a similar behavior, but 66.7% recovered. A substantial proportion of RA patients deteriorated outcomes early after tofacitinib cessation; some patients recovered baseline status with traditional DMARDS.