Targeting Tregs in Juvenile Idiopathic Arthritis and Juvenile Dermatomyositis-Insights From Other Diseases

Regulatory T cells (Tregs) are believed to be dysfunctional in autoimmunity. Juvenile idiopathic arthritis (JIA) and juvenile dermatomyositis (JDM) result from a loss of normal immune regulation in specific tissues such as joints or muscle and skin, respectively. Here, we discuss recent findings in regard to Treg biology in oligo-/polyarticular JIA and JDM, as well as what we can learn about Treg-related disease mechanism, treatment and biomarkers in JIA/JDM from studies of other diseases. We explore the potential use of Treg immunoregulatory markers and gene signatures as biomarkers for disease course and/or treatment success. Further, we discuss how Tregs are affected by several treatment strategies already employed in the therapy of JIA and JDM and by alternative immunotherapies such as anti-cytokine or co-receptor targeting. Finally, we review recent successes in using Tregs as a treatment target with low-dose IL-2 or cellular immunotherapy. Thus, this mini review will highlight our current understanding and identify open questions in regard to Treg biology, and how recent findings may advance biomarkers and new therapies for JIA and JDM

Targeting Tregs in Juvenile Idiopathic Arthritis and Juvenile Dermatomyositis—Insights From Other Diseases

Regulatory T cells (Tregs) are believed to be dysfunctional in autoimmunity. Juvenile idiopathic arthritis (JIA) and juvenile dermatomyositis (JDM) result from a loss of normal immune regulation in specific tissues such as joints or muscle and skin, respectively. Here, we discuss recent findings in regard to Treg biology in oligo-/polyarticular JIA and JDM, as well as what we can learn about Treg-related disease mechanism, treatment and biomarkers in JIA/JDM from studies of other diseases. We explore the potential use of Treg immunoregulatory markers and gene signatures as biomarkers for disease course and/or treatment success. Further, we discuss how Tregs are affected by several treatment strategies already employed in the therapy of JIA and JDM and by alternative immunotherapies such as anti-cytokine or co-receptor targeting. Finally, we review recent successes in using Tregs as a treatment target with low-dose IL-2 or cellular immunotherapy. Thus, this mini review will highlight our current understanding and identify open questions in regard to Treg biology, and how recent findings may advance biomarkers and new therapies for JIA and JDM

Development of a computerized 2D rating scale for continuous and simultaneous evaluation of two dimensions of a sensory stimulus

INTRODUCTION One-dimensional rating scales are widely used in research and in the clinic to assess individuals' perceptions of sensory stimuli. Although these scales provide essential knowledge of stimulus perception, their limitation to one dimension hinders our understanding of complex stimuli. METHODS To allow improved investigation of complex stimuli, a two-dimensional scale based on the one-dimensional Gracely Box Scale was developed and tested in healthy participants on a visual and an auditory task (rating changes in brightness and size of circles and rating changes in frequency and sound pressure of sounds, which was compared to ratings on one-dimensional scales). Before performing these tasks, participants were familiarized with the intensity descriptors of the two-dimensional scale by completing two tasks. First, participants sorted the descriptors based on their judgment of the intensity of the descriptors. Second, participants evaluated the intensity of the descriptors by pressing a button for the duration they considered matching the intensity of the descriptors or squeezing a hand grip dynamometer as strong as they considered matching the intensity of the descriptors. RESULTS Results from these tasks confirmed the order of the descriptors as displayed on the original rating scale. Results from the visual and auditory tasks showed that participants were able to rate changes in the physical attributes of visual or auditory stimuli on the two-dimensional scale as accurately as on one-dimensional scales. DISCUSSION These results support the use of a two-dimensional scale to simultaneously report multiple dimensions of complex stimuli

Development of a computerized 2D rating scale for continuous and simultaneous evaluation of two dimensions of a sensory stimulus

Introduction: One-dimensional rating scales are widely used in research and in the clinic to assess individuals’ perceptions of sensory stimuli. Although these scales provide essential knowledge of stimulus perception, their limitation to one dimension hinders our understanding of complex stimuli. Methods: To allow improved investigation of complex stimuli, a two-dimensional scale based on the one-dimensional Gracely Box Scale was developed and tested in healthy participants on a visual and an auditory task (rating changes in brightness and size of circles and rating changes in frequency and sound pressure of sounds, which was compared to ratings on one-dimensional scales). Before performing these tasks, participants were familiarized with the intensity descriptors of the two-dimensional scale by completing two tasks. First, participants sorted the descriptors based on their judgment of the intensity of the descriptors. Second, participants evaluated the intensity of the descriptors by pressing a button for the duration they considered matching the intensity of the descriptors or squeezing a hand grip dynamometer as strong as they considered matching the intensity of the descriptors. Results: Results from these tasks confirmed the order of the descriptors as displayed on the original rating scale. Results from the visual and auditory tasks showed that participants were able to rate changes in the physical attributes of visual or auditory stimuli on the two-dimensional scale as accurately as on one-dimensional scales. Discussion: These results support the use of a two-dimensional scale to simultaneously report multiple dimensions of complex stimuli

The thermal limits to life on Earth

Living organisms on Earth are characterized by three necessary features: a set of internal instructions encoded in DNA (software), a suite of proteins and associated macromolecules providing a boundary and internal structure (hardware), and a flux of energy. In addition, they replicate themselves through reproduction, a process that renders evolutionary change inevitable in a resource-limited world. Temperature has a profound effect on all of these features, and yet life is sufficiently adaptable to be found almost everywhere water is liquid. The thermal limits to survival are well documented for many types of organisms, but the thermal limits to completion of the life cycle are much more difficult to establish, especially for organisms that inhabit thermally variable environments. Current data suggest that the thermal limits to completion of the life cycle differ between the three major domains of life, bacteria, archaea and eukaryotes. At the very highest temperatures only archaea are found with the current high-temperature limit for growth being 122 °C. Bacteria can grow up to 100 °C, but no eukaryote appears to be able to complete its life cycle above ∼60 °C and most not above 40 °C. The lower thermal limit for growth in bacteria, archaea, unicellular eukaryotes where ice is present appears to be set by vitrification of the cell interior, and lies at ∼−20 °C. Lichens appear to be able to grow down to ∼−10 °C. Higher plants and invertebrates living at high latitudes can survive down to ∼−70 °C, but the lower limit for completion of the life cycle in multicellular organisms appears to be ∼−2 °

Editorial:T cell regulation by the environment

International audienc

Endogenous opioids contribute to the feeling of pain relief in humans

Endogenous opioids mediate the pleasurable responses to positively reinforcing stimuli such as palatable food. Yet, the reduction or omission of a negative experience can also be rewarding (negative reinforcement). As such, pain relief leads to negative reinforcement and evokes a pleasant feeling in humans. Although it has been shown that the feeling of pleasure associated with positive reinforcement is at least partly mediated through endogenous opioids, it is currently unknown whether similar neurochemical mechanisms are involved in the pleasant feeling evoked by pain relief. In this study, 27 healthy participants completed 2 identical experimental sessions, 1 with placebo and 1 with naltrexone, an endogenous opioid antagonist. Pain relief was induced by superficial cooling after heat stimulation of capsaicin-sensitized skin. Participants rated the relief and pleasantness in response to the cooling. Endogenous opioid blockade by naltrexone decreased relief and pleasantness ratings compared with placebo (P 5 0.0027). This study provides evidence that endogenous opioids play a role in mediating the pleasant feeling of pain relief in humans. Clinically, the rewarding nature of pain relief and its underlying mechanisms require consideration because of their potential reinforcing effects on behaviors that might be beneficial short-term but maladaptive long-term

: Severe Tungiasis in Underprivileged Communities: Case Series from Brazil

Tungiasis is caused by infestation with the sand flea (Tunga penetrans). This ectoparasitosis is endemic in economically depressed communities in South American and African countries. Tungiasis is usually considered an entomologic nuisance and does not receive much attention from healthcare professionals. During a study on tungiasis-related disease in an economically depressed area in Fortaleza, northeast Brazil, we identified 16 persons infested with an extremely high number of parasites. These patients had >50 lesions each and showed signs of intense acute and chronic inflammation. Superinfection of the lesions had led to pustule formation, suppuration, and ulceration. Debilitating sequelae, such as loss of nails and difficulty in walking, were constant. In economically depressed urban neighborhoods characterized by a high transmission potential, poor housing conditions, social neglect, and inadequate healthcare behavior, tungiasis may develop into severe disease

Signature for Pain Recovery IN Teens (SPRINT): protocol for a multisite prospective signature study in chronic musculoskeletal pain

INTRODUCTION: Current treatments for chronic musculoskeletal (MSK) pain are suboptimal. Discovery of robust prognostic markers separating patients who recover from patients with persistent pain and disability is critical for developing patient-specific treatment strategies and conceiving novel approaches that benefit all patients. Given that chronic pain is a biopsychosocial process, this study aims to discover and validate a robust prognostic signature that measures across multiple dimensions in the same adolescent patient cohort with a computational analysis pipeline. This will facilitate risk stratification in adolescent patients with chronic MSK pain and more resourceful allocation of patients to costly and potentially burdensome multidisciplinary pain treatment approaches. METHODS AND ANALYSIS: Here we describe a multi-institutional effort to collect, curate and analyse a high dimensional data set including epidemiological, psychometric, quantitative sensory, brain imaging and biological information collected over the course of 12 months. The aim of this effort is to derive a multivariate model with strong prognostic power regarding the clinical course of adolescent MSK pain and function. ETHICS AND DISSEMINATION: The study complies with the National Institutes of Health policy on the use of a single internal review board (sIRB) for multisite research, with Cincinnati Children's Hospital Medical Center Review Board as the reviewing IRB. Stanford's IRB is a relying IRB within the sIRB. As foreign institutions, the University of Toronto and The Hospital for Sick Children (SickKids) are overseen by their respective ethics boards. All participants provide signed informed consent. We are committed to open-access publication, so that patients, clinicians and scientists have access to the study data and the signature(s) derived. After findings are published, we will upload a limited data set for sharing with other investigators on applicable repositories. TRIAL REGISTRATION NUMBER: NCT04285112

Risk Factors for Tungiasis in Nigeria: Identification of Targets for Effective Intervention

Tungiasis is a parasitic skin disease caused by the sand flea Tunga penetrans. After penetration into the skin, the flea grows and reaches the size of a pea. The disease is a neglected public health problem in endemic areas in Latin America, the Caribbean and Africa, and causes considerable morbidity in the affected communities. We performed a study in a rural community in Nigeria to detect factors associated with tungiasis. People were examined for the presence of sand flea lesions, and a questionnaire was applied. Of the 643 individuals examined, 252 (42.5%) had tungiasis. The most important factors independently associated with the disease were: presence of pigs on the compound (adjusted odds ratio [OR] = 17.98), sand or clay floor inside house (OR = 9.33), and having the common resting place outside the house (OR = 7.14). The regular use of closed footwear (OR = 0.34) and the use of insecticides indoors (OR = 0.2) were protective factors. Our data show that tungiasis in this community is determined to an important extent by some variables that may be a target for interventions