Improvements in knee biomechanics during walking are associated with increased physical activity after total knee arthroplasty

Total knee arthroplasty (TKA) in people with knee osteoarthritis increases knee‐specific and general physical function, but it has not been established if there is a relationship between changes in these elements of functional ability. This study investigated changes and relationships between knee biomechanics during walking, physical activity, and use of time after TKA. Fifteen people awaiting TKA underwent 3D gait analysis before and six months after surgery. Physical activity and use of time were determined in free‐living conditions from a high resolution 24‐h activity recall. After surgery, participants displayed significant improvements in sagittal plane knee biomechanics and improved their physical activity profiles, standing for 105 more minutes (p = 0.001) and performing 64 min more inside chores on average per day (p = 0.008). Changes in sagittal plane knee range of motion (ROM) and peak knee flexion positively correlated with changes in total daily energy expenditure, time spent undertaking moderate to vigorous physical activity, inside chores and passive transport (r = 0.52–0.66, p = 0.005–0.047). Restoration of knee function occurs in parallel and is associated with improvements in physical activity and use of time after TKA. Increased functional knee ROM is required to support improvements in total and context specific physical activity. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1818–1825, 2015.     

Mapping the relationship between subgenual cingulate cortex functional connectivity and depressive symptoms across adolescence

Changes in the functional connectivity of the subgenual anterior cingulate cortex (SGC) have been linked with depressive symptoms. The aim of this study was to map this relationship across mid to late adolescence. Employing a longitudinal functional magnetic resonance imaging (fMRI) design, associations between patterns of resting-state SGC functional connectivity and symptoms of depression were examined at two time points in an initial sample of 72 adolescents. Using a region-of-interest approach, these associations were evaluated cross-sectionally and longitudinally. Cross-sectionally, weaker SGC functional connectivity with the posterior cingulate cortex (PCC), angular gyrus and dorsal prefrontal cortex at baseline, and weaker SGC connectivity with the dorsomedial prefrontal cortex (DMPFC) and ventromedial prefrontal cortex at follow-up, were associated with higher depressive symptoms. Longitudinally, a decrease in SGC functional connectivity with DMPFC, PCC, angular gyrus and middle temporal gyrus was associated with higher depressive symptoms at follow-up. The observation of weaker SGC connectivity predicting increased symptoms contrasts with the majority of resting-state fMRI studies in clinically depressed populations. Taken together with these past studies, our findings suggest depression-related changes in SGC functional connectivity may differ across developmental and illness stages.     

Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1β

Gain-of-function mutations that activate the innate immune system can cause systemic autoinflammatory diseases associated with increased IL-1β production. This cytokine is activated identically to IL-18 by an intracellular protein complex known as the inflammasome; however, IL-18 has not yet been specifically implicated in the pathogenesis of hereditary autoinflammatory disorders. We have now identified an autoinflammatory disease in mice driven by IL-18, but not IL-1β, resulting from an inactivating mutation of the actin-depolymerizing cofactor Wdr1. This perturbation of actin polymerization leads to systemic autoinflammation that is reduced when IL-18 is deleted but not when IL-1 signaling is removed. Remarkably, inflammasome activation in mature macrophages is unaltered, but IL-18 production from monocytes is greatly exaggerated, and depletion of monocytes in vivo prevents the disease. Small-molecule inhibition of actin polymerization can remove potential danger signals from the system and prevents monocyte IL-18 production. Finally, we show that the inflammasome sensor of actin dynamics in this system requires caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain, and the innate immune receptor pyrin. Previously, perturbation of actin polymerization by pathogens was shown to activate the pyrin inflammasome, so our data now extend this guard hypothesis to host-regulated actin-dependent processes and autoinflammatory disease.Autoinflammatory syndromes are caused by dysregulation of the innate immune system, frequently affecting the inflammasome or other pathogen recognition pathways and leading to the overproduction of active IL-1β and IL-18 (Masters et al., 2009). To date, there are at least 12 known genetic causes of autoinflammatory disease, including familial Mediterranean fever (FMF), hyper-IgD syndrome, and cryopyrin-associated periodic syndrome. Therapeutic options for these diseases include nonsteroidal antiinflammatory drugs, corticosteroids, colchicine (for FMF), anti-TNF, and direct blockade of IL-1, which can be highly efficacious (Masters et al., 2009; Caso et al., 2013). IL-18 and IL-1β are produced in many cells, including monocytes and macrophages (Okamura et al., 1995; Ushio et al., 1996). IL-18 and IL-1β are produced as precursors and do not have a signal peptide to facilitate their secretion; instead, they are activated and released extracellularly as mature proteins after cleavage by caspase-1 (Li et al., 1995; Ghayur et al., 1997; Gu et al., 1997). Despite these similarities, there is no known hereditary autoinflammatory disease where the pathology is caused exclusively by IL-18.The inflammasome is an intracellular molecular platform that forms in response to pathogen- or danger-associated molecular patterns (DAMPs), leading to recruitment and activation of caspase-1 (Martinon et al., 2002; Schroder and Tschopp, 2010). A growing number of inflammasomes have been reported, each nucleated by a different innate immune receptor, such as NLRP1 (Martinon et al., 2000; Boyden and Dietrich, 2006), NLRP3 (Agostini et al., 2004), NLRC4 (Franchi et al., 2006), pyrin (Chae et al., 2011), and AIM2 (Hornung et al., 2009). Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is a key adaptor used by most of these innate immune receptors to interact with and recruit caspase-1 (Srinivasula et al., 2002). Activating mutations in NLRP3 result in increased IL-1β and IL-18 production, which can be prevented in mice by deleting caspase-1 or ASC. Furthermore, deleting either the IL-18R or the IL-1R can both independently protect mice from this NLRP3-mediated autoinflammatory disease (Brydges et al., 2013). For the FMF protein, pyrin, activating mutations induce ASC-dependent but NLRP3-independent IL-1β activation and cause severe autoinflammation in mice (Chae et al., 2011). Interestingly, pyrin interacts with ASC, microtubules, and actin filaments (Mansfield et al., 2001; Richards et al., 2001; Waite et al., 2009), and it has recently been shown that modification of RhoGTPases by bacterial toxins can trigger the pyrin inflammasome, perhaps via modulation of actin dynamics (Xu et al., 2014). This raises the fascinating prospect of a link between perturbations in the actin cytoskeleton and autoinflammatory disease.Wdr1 is required for disassembly of actin filaments in conjunction with the actin-depolymerizing factor/cofilin family of proteins. Mice homozygous for a hypomorphic allele of Wdr1 (Wdr1^rd/rd) exhibit spontaneous autoinflammatory disease and thrombocytopenia (Kile et al., 2007). Both defects have been suggested to result from a disruption in actin dynamics. Thrombocytopenia results from defects in megakaryocytes, a cell type that is entirely dependent on a functional cytoskeleton to shed platelets (Patel et al., 2005). Wdr1 mutant mice also exhibit neutrophilia; however, the critical inflammatory mediators and cell types important for the development of inflammation in this genetic condition are unclear (Kile et al., 2007). Intriguingly, Wdr1 was found to be secreted after caspase-1 activation (Keller et al., 2008).We examined the role of key inflammatory mediators that drive autoinflammation in Wdr1^rd/rd mice and demonstrated that this disease is IL-18 dependent, but IL-1 independent. As expected, this IL-18 is produced by the inflammasome; however, it is not produced from neutrophils or macrophages, but instead only from monocytes. Finally, we found that the autoinflammatory disease was mediated by pyrin, providing evidence that this innate immune receptor recognizes alterations in the actin polymerization pathway.     

Hepatic portal venous gas

Differentiating hepatic portal venous gas (HPVG) and pneumobilia on the CT scan can be accomplished by comparing the pattern of intrahepatic air spread. HPVG can be an indicator of significant intra‐abdominal pathology and bowel ischaemia is the most common causative etiology for HPVG.     

A worldwide charter for all children with asthma

Childhood asthma is a huge global health burden. The spectrum of disease, diagnosis, and management vary depending on where children live in the world and how their community can care for them. Global improvement in diagnosis and management has been unsatisfactory, despite ever more evidence‐based guidelines. Guidelines alone are insufficient and need supplementing by government support, changes in policy, access to diagnosis and effective therapy for all children, with research to improve implementation. We propose a worldwide charter for all children with asthma, a roadmap to better education and training which can be adapted for local use. It includes access to effective basic asthma medications. It is not about new expensive medications and biologics as much can be achieved without these. If implemented carefully, the overall cost of care is likely to fall and the global future health and life chance of children with asthma will greatly improve. The key to success will be community involvement together with the local and national development of asthma champions. We call on governments, institutions, and healthcare services to support its implementation.     

Respiratory management of infants with chronic neonatal lung disease beyond the NICU: A position statement from the Thoracic Society of Australia and New Zealand*

Chronic neonatal lung disease (CNLD) is defined as continued need for any form of respiratory support (supplemental oxygen and/or assisted ventilation) beyond 36 weeks PMA. Low‐flow supplemental oxygen facilitates discharge from hospital of infants with CNLD who are hypoxic in air and is widely used despite lack of evidence on the most appropriate minimum mean target oxygen saturations. Furthermore, there are minimal data to guide the home monitoring, titration or weaning of supplemental oxygen in these infants. The purpose of this position statement is to provide a guide for the respiratory management of infants with CNLD, with special emphasis on role and logistics of supplemental oxygen therapy beyond the NICU stay. Reflecting a variety of clinical practices and infant comorbidities (presence of pulmonary hypertension, retinopathy of prematurity and adequacy of growth), it is recommended that the minimum mean target range for SpO₂ during overnight oximetry to be 93–95% with less than 5% of total recording time to be below 90% SpO₂. Safety of short‐term disconnection from supplemental oxygen should be assessed before discharge, with majority of infants with CNLD not ready for discharge until supplemental oxygen requirement is ≤0.5 L/min. Sleep‐time assessment of oxygenation with continuous overnight oximetry is recommended when weaning supplemental oxygen. Palivizumab is considered safe and effective for the reduction of hospital admissions with RSV infection in this group. This statement would be useful for paediatricians, neonatologists, respiratory and sleep physicians and general practitioners managing children with CNLD.