Constitutively Activated NLRP3 Inflammasome Causes Inflammation and Abnormal Skeletal Development in Mice

The NLRP3 inflammasome complex is responsible for maturation of the pro-inflammatory cytokine, IL-1β. Mutations in NLRP3 are responsible for the cryopyrinopathies, a spectrum of conditions including neonatal-onset multisystem inflammatory disease (NOMID). While excessive production of IL-1β and systemic inflammation are common to all cryopyrinopathy disorders, skeletal abnormalities, prominently in the knees, and low bone mass are unique features of patients with NOMID. To gain insights into the mechanisms underlying skeletal abnormalities in NOMID, we generated knock-in mice globally expressing the D301N NLRP3 mutation (ortholog of D303N in human NLRP3). NOMID mice exhibit neutrophilia in blood and many tissues, including knee joints, and high levels of serum inflammatory mediators. They also exhibit growth retardation and severe postnatal osteopenia stemming at least in part from abnormally accelerated bone resorption, attended by increased osteoclastogenesis. Histologic analysis of knee joints revealed abnormal growth plates, with loss of chondrocytes and growth arrest in the central region of the epiphyses. Most strikingly, a tissue “spike" was observed in the mid-region of the growth plate in the long bones of all NOMID mice that may be the precursor to more severe deformations analogous to those observed in NOMID patients. These findings provide direct evidence linking a NOMID-associated NLRP3-activating mutation to abnormalities of postnatal skeletal growth and bone remodeling

A labelled discrete choice experiment adds realism to the choices presented: preferences for surveillance tests for Barrett esophagus

<p>Abstract</p> <p>Background</p> <p>Discrete choice experiments (DCEs) allow systematic assessment of preferences by asking respondents to choose between scenarios. We conducted a labelled discrete choice experiment with realistic choices to investigate patients' trade-offs between the expected health gains and the burden of testing in surveillance of Barrett esophagus (BE).</p> <p>Methods</p> <p>Fifteen choice scenarios were selected based on 2 attributes: 1) type of test (endoscopy and two less burdensome fictitious tests), 2) frequency of surveillance. Each test-frequency combination was associated with its own realistic decrease in risk of dying from esophageal adenocarcinoma. A conditional logit model was fitted.</p> <p>Results</p> <p>Of 297 eligible patients (155 BE and 142 with non-specific upper GI symptoms), 247 completed the questionnaire (84%). Patients preferred surveillance to no surveillance. Current surveillance schemes of once every 1–2 years were amongst the most preferred alternatives. Higher health gains were preferred over those with lower health gains, except when test frequencies exceeded once a year. For similar health gains, patients preferred video-capsule over saliva swab and least preferred endoscopy.</p> <p>Conclusion</p> <p>This first example of a labelled DCE using realistic scenarios in a healthcare context shows that such experiments are feasible. A comparison of labelled and unlabelled designs taking into account setting and research question is recommended.</p