Infection with a Brazilian isolate of Zika virus generates RIG‐I stimulatory RNA and the viral NS5 protein blocks type I IFN induction and signalling

Zika virus (ZIKV) is a major public health concern in the Americas. We report that ZIKV infection and RNA extracted from ZIKV infected cells potently activated the induction of type I interferons (IFNs). This effect was fully dependent on the mitochondrial antiviral signalling protein (MAVS), implicating RIG‐I‐like receptors (RLRs) as upstream sensors of viral RNA. Indeed, RIG‐I and the related RNA sensor MDA5 contributed to type I IFN induction in response to RNA from infected cells. We found that ZIKV NS5 from a recent Brazilian isolate blocked type I IFN induction downstream of RLRs and also inhibited type I IFN receptor (IFNAR) signalling. We defined the ZIKV NS5 nuclear localization signal and report that NS5 nuclear localization was not required for inhibition of signalling downstream of IFNAR. Mechanistically, NS5 blocked IFNAR signalling by both leading to reduced levels of STAT2 and by blocking phosphorylation of STAT1, two transcription factors activated by type I IFNs. Taken together, our observations suggest that ZIKV infection induces a type I IFN response via RLRs and that ZIKV interferes with this response by blocking signalling downstream of RLRs and IFNAR

Stereocilia Membrane Deformation: Implications for the Gating Spring and Mechanotransduction Channel

AbstractIn hair cells, although mechanotransduction channels have been localized to tips of shorter stereocilia of the mechanically sensitive hair bundle, little is known about how force is transmitted to the channel. Here, we use a biophysical model of the membrane-channel complex to analyze the nature of the gating spring compliance and channel arrangement. We use a triangulated surface model and Monte Carlo simulation to compute the deformation of the membrane under the action of tip link force. We show that depending on the gating spring stiffness, the compliant component of the gating spring arises from either the membrane alone or a combination of the membrane and a tether that connects the channel to the actin cytoskeleton. If a bundle is characterized by relatively soft gating springs, such as those of the bullfrog sacculus, the need for membrane reinforcement by channel tethering then depends on membrane parameters. With stiffer gating springs, such as those from rat outer hair cells, the channel must be tethered for all biophysically realistic parameters of the membrane. We compute the membrane forces (resultants), which depend on membrane tension, bending modulus, and curvature, and show that they can determine the fate of the channel

Development of Danish version of child oral-health-related quality of life questionnaires (CPQ8–10 and CPQ11–14)

<p>Abstract</p> <p>Background</p> <p>The Child Perceptions Questionnaire (CPQ) is a self-reported questionnaire developed to measure oral health-related quality of life in children. The CPQ aims to improve the description of children's oral health, while taking into consideration the importance of psychological aspects in the concept of health. The CPQ exists in two versions: the CPQ_8–10for children aged 8–10 years and the CPQ_11–14for those aged 11–14 years. The aim of this study was to develop a Danish version of the CPQ_8–10and the CPQ_11–14and to evaluate its validity for use among Danish-speaking children.</p> <p>Methods</p> <p>The instruments were translated from English into Danish in accordance with a recommended translation procedure. Afterwards, they were tested among children aged 8–10 (n = 120) and 11–14 years (n = 225). The validity was expressed by the correlation between overall CPQ scores and i) self-reported assessment of the influence of oral conditions on everyday life (not at all, very little, some, a lot, very much) and ii) the self-reported rating of oral health. Furthermore, groups of children with assumed decreased oral health-related quality of life were compared with children with healthy oral conditions. Finally, we examined the internal consistency.</p> <p>Results</p> <p>The correlation between overall CPQ scores and global assessments of the influence of oral conditions on everyday life showed Spearman correlation coefficients of 0.45, <it>P < 0.001 </it>for CPQ_8–10and 0.50, <it>P < 0.001 </it>for CPQ_11–14. The correlation between overall CPQ scores and the self-reported rating of oral health showed Spearman correlation coefficients of 0.45, <it>P < 0.001 </it>for CPQ_8–10and 0.17, P = 0.010 for CPQ_11–14.</p> <p>The median overall CPQ_8–10scores were 7 for individuals with healthy oral conditions, 5 for individuals with cleft lip and palate, and 15 for individuals with rare oral diseases. The median overall CPQ_11–14scores were 9 for individuals with healthy oral conditions, 9 for individuals with cleft lip and palate, 17.0 for individuals with rare oral diseases, and 22.0 for individuals with fixed orthodontic appliances. There were statistically significant differences between the groups of children with healthy oral conditions and each of the subgroups, except for children with cleft lip and palate.</p> <p>Chronbach'α were 0.82 for CPQ_8–10and 0.87 for CPQ_11–14.</p> <p>Conclusion</p> <p>The results of this study reveal that the Danish CPQ_8–10and CPQ_11–14, seem to be valid instruments for measuring oral health-related quality of life in children although its ability to discriminate between children with cleft lip and palate and healthy children seem to be limited.</p

The chaperonin CCT8 controls proteostasis essential for T cell maturation, selection, and function

T cells rely for their development and function on the correct folding and turnover of proteins generated in response to a broad range of molecular cues. In the absence of the eukaryotic type II chaperonin complex, CCT, T cell activation induced changes in the proteome are compromised including the formation of nuclear actin filaments and the formation of a normal cell stress response. Consequently, thymocyte maturation and selection, and T cell homeostatic maintenance and receptor-mediated activation are severely impaired. In the absence of CCT-controlled protein folding, Th2 polarization diverges from normal differentiation with paradoxical continued IFN-γ expression. As a result, CCT-deficient T cells fail to generate an efficient immune protection against helminths as they are unable to sustain a coordinated recruitment of the innate and adaptive immune systems. These findings thus demonstrate that normal T cell biology is critically dependent on CCT-controlled proteostasis and that its absence is incompatible with protective immunity

Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability

Topoisomerase 3α (TOP3A) is an enzyme that removes torsional strain and interlinks between DNA molecules. TOP3A localises to both the nucleus and mitochondria, with the two isoforms playing specialised roles in DNA recombination and replication respectively. Pathogenic variants in TOP3A can cause a disorder similar to Bloom syndrome, which results from bi-allelic pathogenic variants in BLM, encoding a nuclear-binding partner of TOP3A. In this work, we describe 11 individuals from 9 families with an adult-onset mitochondrial disease resulting from bi-allelic TOP3A gene variants. The majority of patients have a consistent clinical phenotype characterised by bilateral ptosis, ophthalmoplegia, myopathy and axonal sensory-motor neuropathy. We present a comprehensive characterisation of the effect of TOP3A variants, from individuals with mitochondrial disease and Bloom-like syndrome, upon mtDNA maintenance and different aspects of enzyme function. Based on these results, we suggest a model whereby the overall severity of the TOP3A catalytic defect determines the clinical outcome, with milder variants causing adult-onset mitochondrial disease and more severe variants causing a Bloom-like syndrome with mitochondrial dysfunction in childhood

Preoperative medical treatment in Cushing&apos;s syndrome : frequency of use and its impact on postoperative assessment : data from ERCUSYN

Background: Surgery is the definitive treatment of Cushing's syndrome (CS) but medications may also be used as a first-line therapy. Whether preoperative medical treatment (PMT) affects postoperative outcome remains controversial. Objective: (1) Evaluate how frequently PMT is given to CS patients across Europe; (2) examine differences in preoperative characteristics of patients who receive PMT and those who undergo primary surgery and (3) determine if PMT influences postoperative outcome in pituitary-dependent CS (PIT-CS). Patients and methods: 1143 CS patients entered into the ERCUSYN database from 57 centers in 26 countries. Sixty-nine percent had PIT-CS, 25% adrenal-dependent CS (ADR-CS), 5% CS from an ectopic source (ECT-CS) and 1% were classified as having CS from other causes (OTH-CS). Results: Twenty per cent of patients took PMT. ECT-CS and PIT-CS were more likely to receive PMT compared to ADR-CS (P < 0.001). Most commonly used drugs were ketoconazole (62%), metyrapone (16%) and a combination of both (12%). Median (interquartile range) duration of PMT was 109 (98) days. PIT-CS patients treated with PMT had more severe clinical features at diagnosis and poorer quality of life compared to those undergoing primary surgery (SX) (P < 0.05). Within 7 days of surgery, PIT-CS patients treated with PMT were more likely to have normal cortisol (P < 0.01) and a lower remission rate (P < 0.01). Within 6 months of surgery, no differences in morbidity or remission rates were observed between SX and PMT groups. Conclusions: PMT may confound the interpretation of immediate postoperative outcome. Follow-up is recommended to definitely evaluate surgical results

International nosocomial infection control consortium (INICC) report, data summary of 36 countries, for 2004-2009

The results of a surveillance study conducted by the International Nosocomial Infection Control Consortium (INICC) from January 2004 through December 2009 in 422 intensive care units (ICUs) of 36 countries in Latin America, Asia, Africa, and Europe are reported. During the 6-year study period, using Centers for Disease Control and Prevention (CDC) National Healthcare Safety Network (NHSN; formerly the National Nosocomial Infection Surveillance system [NNIS]) definitions for device-associated health care-associated infections, we gathered prospective data from 313,008 patients hospitalized in the consortium's ICUs for an aggregate of 2,194,897 ICU bed-days. Despite the fact that the use of devices in the developing countries' ICUs was remarkably similar to that reported in US ICUs in the CDC's NHSN, rates of device-associated nosocomial infection were significantly higher in the ICUs of the INICC hospitals; the pooled rate of central line-associated bloodstream infection in the INICC ICUs of 6.8 per 1,000 central line-days was more than 3-fold higher than the 2.0 per 1,000 central line-days reported in comparable US ICUs. The overall rate of ventilator-associated pneumonia also was far higher (15.8 vs 3.3 per 1,000 ventilator-days), as was the rate of catheter-associated urinary tract infection (6.3 vs. 3.3 per 1,000 catheter-days). Notably, the frequencies of resistance of Pseudomonas aeruginosa isolates to imipenem (47.2% vs 23.0%), Klebsiella pneumoniae isolates to ceftazidime (76.3% vs 27.1%), Escherichia coli isolates to ceftazidime (66.7% vs 8.1%), Staphylococcus aureus isolates to methicillin (84.4% vs 56.8%), were also higher in the consortium's ICUs, and the crude unadjusted excess mortalities of device-related infections ranged from 7.3% (for catheter-associated urinary tract infection) to 15.2% (for ventilator-associated pneumonia). Copyright © 2012 by the Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved

Respiratory impairment due to asbestos exposure in brake-lining workers

WOS: 000181780900003PubMed ID: 12648477There is extensive evidence that exposure to asbestos causes pulmonary parenchymal fibrosis, pleural disease, and malignant neoplasm in asbestos-exposed workers. However, few data concerning brake-lining workers are available in the literature. In this study, we aimed to assess the long-term effects of chrysotile asbestos exposure on lung function and the risk of asbestos-related diseases in brake-lining workers. Seventy-four asbestos-exposed workers who processed brake-lining products and 12 unexposed office workers were offered pulmonary function tests (spirometry and transfer factor) in 1992 and 1999. In 1999, the mean duration of asbestos exposure was 10.00+/-4.07 and 11.02+/-4.81 years (7-31 years) in nonsmoking and smoking asbestos workers, respectively. Transfer factor (T-L, CO) and transfer coefficient (K-CO) decline were significant in the 7-year follow-up in both smoking and nonsmoking asbestos workers. However, lung function indices of the control group, whom were all current smokers; were also found to be decreased, including FEF75, T-L, CO and K-CO. We found minimal reticular changes in 10 asbestos workers who were all current smokers, they underwent high-resolution computed tomography scans of the chest and we found that they had peribronchial thickening resulting from smoking. As a conclusion, even in the absence of radiographic asbestosis, T-L, CO and K-CO may decrease after a mean 10-year duration of exposure to asbestos in brake-lining workers and this is more noticeable with cigarette burden. (C) 2003 Elsevier Science (USA). All rights reserved