Can the trabecular bone score be considered as a major clinical risk factor of osteoporotic fractures? A meta-like analysis.

To have an added value over BMD, a CRF of osteoporotic fracture must be predictable of the fracture, independent of BMD, reversible and quantifiable. Many major recognized CRF exist. Out of these factors many of them are indirect factor of bone quality. TBS predicts fracture independently of BMD as demonstrated from previous studies. The aim of the study is to verify if TBS can be considered as a major CRF of osteoporotic fracture. Existing validated datasets of Caucasian women were analyzed. These datasets stem from different studies performed by the authors of this report or provided to our group. However, the level of evidence of these studies will vary. Thus, the different datasets were weighted differently according to their design. This meta-like analysis involves more than 32000 women (≥50years) with 2000 osteoporotic fractures from two prospective studies (OFELY&MANITOBA) and 7 cross-sectional studies. Weighted relative risk (RR) for TBS was expressed for each decrease of one standard deviation as well as per tertile difference (TBS=1.300 and 1.200) and compared with those obtained for the major CRF included in FRAX®. Overall TBS RR obtained (adjusted for age) was 1.79 [95%CI-1.37-2.37]. For all women combined, RR for fracture for the lowest compared with the middle TBS tertile was 1.55[1.46-1.68] and for the lowest compared with the highest TBS tertile was 2.8[2.70-3.00]. TBS is comparable to most of the major CRF and thus could be used as one of them. Further studies have to be conducted to confirm these first findings.

Evolution of anaesthesia care and related events between 1996 and 2010 in a developed country

Background: Anaesthesia Databank Switzerland (ADS) is a voluntary data registry introduced in 1996. The goal was to promote quality in anaesthesiology. Methods: Analysis of routinely recorded adverse events. Internal and external benchmark comparisons between anaesthesia departments. Results: In 2010, the database included 2'158'735 anaesthetic procedures. Forty-four anaesthesia departments were participating to the data collection in 2010. Over time, the number of patients in older age groups increased, the largest group being patients aged 50 to 64 years. Over time, the percentage of patients with ASA physical status score 1 decreased while the number of ASA 2 or 3 patients increased. The most frequent co-morbidities were hypertension (21%), smoking (16%), allergy (15%), and obesity (12%). Between 1996 and 2010, 146'459 adverse events were recorded, of which 34% were cardiovascular, 7% respiratory, 39% specific to anaesthesia and 17% nonspecific. The overall proportion of adverse events decreased over time, whatever their severity. Conclusion: The ADS routine data collection contributes to monitoring the trends of anaesthesia care in Switzerland.

Sleep disorders in children with cerebral palsy.

To determine the frequency and predictors of sleep disorders in children with cerebral palsy (CP) we analyzed the responses of 173 parents who had completed the Sleep Disturbance Scale for Children. The study population included 100 males (57.8%) and 73 females (42.2%; mean age 8y 10mo [SD 1y 11mo]; range 6y-11y 11mo). Eighty-three children (48.0%) had spastic diplegia, 59 (34.1%) congenital hemiplegia, 18 (10.4%) spastic quadriplegia, and 13 (7.5%) dystonic/dyskinetic CP. Seventy-three children (42.2%) were in Gross Motor Function Classification System Level I, 33 (19.1%) in Level II, 30 (17.3%) in Level III, 23 (13.3%) in Level IV, and 14 (8.1%) in Level V. Thirty children (17.3%) had epilepsy. A total sleep problem score and six factors indicative of the most common areas of sleep disorder in childhood were obtained. Of the children in our study, 23% had a pathological total sleep score, in comparison with 5% of children in the general population. Difficulty in initiating and maintaining sleep, sleep-wake transition, and sleep breathing disorders were the most frequently identified problems. Active epilepsy was associated with the presence of a sleep disorder (odds ratio [OR]=17.1, 95% confidence interval [CI] 2.5-115.3), as was being the child of a single-parent family (OR=3.9, 95% CI 1.3-11.6). Disorders of initiation and maintenance of sleep were more frequent in children with spastic quadriplegia (OR=12.9, 95% CI 1.9-88.0), those with dyskinetic CP (OR=20.6, 95% CI 3.1-135.0), and those with severe visual impairment (OR=12.5, 95% CI 2.5-63.1). Both medical and environmental factors seem to contribute to the increased frequency of chronic sleep disorders in children with CP.

Plasma pituitary hormone levels in severe trauma with or without head injury.

In order to evaluate the effect of head injury in severely traumatized patients on the response of ACTH, GH, PRL, and TSH plasma levels, 36 patients were prospectively studied over 5 consecutive days following injury. They were divided into three groups: Group I, severe isolated head injury (n = 14); Group II, multiple injury combined with severe head injury (n = 12); Group III, multiple injury without head injury (n = 10). No significant trend was observed during the 5 consecutive days. The following changes in plasma levels were observed, compared to normal reference value (median values): ACTH was normal in the three groups; PRL was elevated in Group II and normal in the other groups; GH was elevated in all groups; TSH was elevated in Group III and reduced in Groups I and II. Intergroup comparisons showed significantly lower plasma levels for PRL (p less than 0.05) and TSH (p less than 0.01) in Groups I and II, i.e., head-injured patients, compared to Group III, i.e., traumatized patients without head injury. A relationship was observed between the severity of head injury, as expressed by Glasgow Coma Score, intracranial pressure levels, outcome, and TSH and PRL levels.

Trabecular Bone Score Helps Classifying Women At Riskof Fracture Prospectively In The Ofely Study

Objectives: Trabecular Bone Score (TBS, Med-Imaps, France) is an index of bone microarchitecture calculated from antero-posterior spine DXA scan and reported to be associated with fracture in prior case-control studies and in a large prospective study with the Prodigy DXA device. Our aim was to assess the ability of TBS to predict incident fracture and improve the classification of fracture prospectively in the OFELY study.Materials/Methods: TBS was assessed in 564 postmenopausal women (66±8 years old) from the OFELY cohort, who had a spine DXA scan (QDR 4500A, Hologic, USA) between year 2000 and 2001. During a mean follow up of 7.8±1.3 years, 94 women sustained a fragility fracture.Results: At the time of baseline DXA scan, women with incident fracture were significantly older (70±9 vs. 65± 8 years), had a lower spine BMD (T-score: −1.9±1.2 vs. −1.3±1.3, p<0.001) and spine TBS (−3.1%, p<0.001) than women without incident fracture. After adjustment for age, BMI and the presence of prevalent fracture, the magnitude of fracture prediction was similar for spine BMD (OR=1.42 [1.11;1.82] per SD decrease [95% CI]) and TBS (OR=1.34 [1.04;1.74]) but the combination of TBS and spine BMD did not improve fracture prediction. Spine BMD and TBS were both correlated with age (respectively r=−0.17 and −0.49, p<0.001) and correlated together with 39% of TBS explained by spine BMD (r=0.63, p<0.001). When using the WHO classification, 38% of the fractures occurred in osteoporotic (fracture rate=29%), 47% in osteopenic (fracture rate=16%) and 15% in women with T-score >−1 (fracture rate=9%). By classifying our population in tertiles of TBS, we found that 47% of the fractures occurred in the lowest tertile of TBS (fracture rate=23%) and 39% of the fracture that occurred in osteopenic women were in the lowest tertile of TBS.Conclusions: Spine BMD and TBS predicted fractures equally well. The addition of TBS to spine BMD added only limited information on fracture risk prediction in our cohort when considering the all range of BMD. Nevertheless combining the osteopenic T-score and the lowest TBS helped defining a subset of osteopenic women at higher risk of fracture.Disclosure of Interest: None declared.

Recombinant human insulin-like growth factor I (rhIGF-I) for the treatment of amyotrophic lateral sclerosis/motor neuron disease.

BACKGROUND: Recombinant human insulin-like growth factor I (rhIGF-I) is a possible disease modifying therapy for amyotrophic lateral sclerosis (ALS, which is also known as motor neuron disease (MND)). OBJECTIVES: To examine the efficacy of rhIGF-I in affecting disease progression, impact on measures of functional health status, prolonging survival and delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival in ALS. Occurrence of adverse events was also reviewed. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (21 November 2011), CENTRAL (2011, Issue 4), MEDLINE (January 1966 to November 2011) and EMBASE (January 1980 to November 2011) and sought information from the authors of randomised clinical trials and manufacturers of rhIGF-I. SELECTION CRITERIA: We considered all randomised controlled clinical trials involving rhIGF-I treatment of adults with definite or probable ALS according to the El Escorial Criteria. The primary outcome measure was change in Appel Amyotrophic Lateral Sclerosis Rating Scale (AALSRS) total score after nine months of treatment and secondary outcome measures were change in AALSRS at 1, 2, 3, 4, 5, 6, 7, 8, 9 months, change in quality of life (Sickness Impact Profile scale), survival and adverse events. DATA COLLECTION AND ANALYSIS: Each author independently graded the risk of bias in the included studies. The lead author extracted data and the other authors checked them. We generated some missing data by making ruler measurements of data in published graphs. We collected data about adverse events from the included trials. MAIN RESULTS: We identified three randomised controlled trials (RCTs) of rhIGF-I, involving 779 participants, for inclusion in the analysis. In a European trial (183 participants) the mean difference (MD) in change in AALSRS total score after nine months was -3.30 (95% confidence interval (CI) -8.68 to 2.08). In a North American trial (266 participants), the MD after nine months was -6.00 (95% CI -10.99 to -1.01). The combined analysis from both RCTs showed a MD after nine months of -4.75 (95% CI -8.41 to -1.09), a significant difference in favour of the treated group. The secondary outcome measures showed non-significant trends favouring rhIGF-I. There was an increased risk of injection site reactions with rhIGF-I (risk ratio 1.26, 95% CI 1.04 to 1.54). . A second North American trial (330 participants) used a novel primary end point involving manual muscle strength testing. No differences were demonstrated between the treated and placebo groups in this study. All three trials were at high risk of bias. AUTHORS' CONCLUSIONS: Meta-analysis revealed a significant difference in favour of rhIGF-I treatment; however, the quality of the evidence from the two included trials was low. A third study showed no difference between treatment and placebo. There is no evidence for increase in survival with IGF1. All three included trials were at high risk of bias.

French version of the addiction severity index (5th Edition): validity and reliability among Swiss opiate-dependent patients. French validation of the Addiction Severity Index.

OBJECTIVE: The aim of the study was to validate a French adaptation of the 5th version of the Addiction Severity Index (ASI) instrument in a Swiss sample of illicit drug users. PARTICIPANTS AND SETTING: The participants in the study were 54 French-speaking dependent patients, most of them with opiates as the drug of first choice. Procedure: Analyses of internal consistency (convergent and discriminant validity) and reliability, including measures of test-retest and inter-observer correlations, were conducted. RESULTS: Besides good applicability of the test, the results on composite scores (CSs) indicate comparable results to those obtained in a sample of American opiate-dependent patients. Across the seven dimensions of the ASI, Cronbach's alpha ranged from 0.42 to 0.76, test-retest correlations coefficients ranged from 0.48 to 0.98, while for CSs, inter-observer correlations ranged from 0.76 to 0.99. CONCLUSIONS: Despite several limitations, the French version of the ASI presents acceptable criteria of applicability, validity and reliability in a sample of drug-dependent patients.

Facteurs Influençant la Progression du Score EDSS dans la Sclérose en Plaques Récurrente-Rémittente

Introduction : la Sclérose en plaques (SEP) est le prototype de désordre auto-immun du système nerveux central. Avec environ 110 malades par 100'000 habitants, la Suisse est considérée un pays à haute prévalence. Chez environ 80% des patients, la maladie débute par la forme récurrente- rémittente (RR), où des poussées aiguës s'intercalent avec des périodes de rémission. Cette phase se conclut dans son évolution naturelle généralement en une phase secondairement progressive, pendant laquelle le déficit progresse en l'absence de poussée. Sur le plan physiopathologique, deux phénomènes interagissent : l'atteinte inflammatoire démyélinisante et l'atteinte neurodégénerative. La première est { l'origine des poussées aiguës, la deuxième se manifeste cliniquement par la progression irréversible du déficit neurologique. En Suisse les immunomodulateurs ont été utilisés comme thérapies de fond pour la SEP à partir des années 1995. Leur effet sur le taux de poussées a été largement démontré, tandis que leur efficacité sur l'évolution de la maladie à long terme reste ouverte. Le moyen le plus répandu pour quantifier le niveau du handicap neurologique est la Kurtzke Expanded Disability Status Scale (EDSS). Cette échelle évalue les troubles neurologiques en les classifiant de 0 (examen normal) à 10 (décès) avec des marches de demi-points. Notre recherche à voulu identifier des facteurs cliniques précoces { valeur prédictif sur l'évolution du déficit neurologique permanent, ainsi qu'analyser le moment d'introduction du traitement pour extraire des informations utiles { la décision thérapeutique. Méthodes : Exploitation de la base de données iMed-CHUV comptant 1150 patients SEP (dont 622 SEP RR) pour analyser rétrospectivement, dans la SEP RR, l'influence de différentes variables cliniques précoces (taux de poussées pendant les premières deux années de maladie, intervalle entre les deux premières poussées, sévérité et site anatomique de la première poussée, déficit résiduel après la première poussée) et de deux caractéristiques liées { l'instauration du traitement immunosuppresseur de fond (âge et délai d'introduction) sur l'évolution du déficit neurologique vers un score EDSS ≥4.0. Les variables ont été testées avec la méthode d'estimation de taux de survie Kaplan-Meier. Résultats: 349 patients avec SEP RR possédaient les critères nécessaires pour faire partie de l'analyse, le suivi moyen étant de 8.26 ans (SD 4.77). Un taux de poussées élevé pendant les premiers 2 ans (>1 vs ≤1) et un long intervalle entre les 2 premiers épisodes (>36 vs >12-36 vs ≤12) étaient significativement associés au risque de progression du déficit neurologique vers un score EDSS de 4.0 ou plus (log Rank P=0.016 et P=0.008 respectivement). Par contre ni le site anatomique de la première poussée ni l'âge d'introduction du traitement immunomodulateur n'avaient d'influence significative sur la progression du déficit neurologique (log rank P=0.370 et P=0.945 respectivement). Etonnamment une introduction rapide du traitement était associée à une plus forte progression du déficit neurologique (log rank P=0.032), montrant qu'une partie des patients a une évolution bénigne même en l'absence de traitement. Conclusions : L'activité inflammatoire précoce, dont le niveau peut être estimé par indices précoces comme le taux de poussées et l'intervalle entre les deux premières poussées, mais non le site de primo-manifestation prédit la progression ultérieure du déficit neurologique. Ces indices doivent être utilisés en combinaison avec les informations fournies par l'IRM pour l'individuation et le traitement précoce des patients à risque, indépendamment de leur âge. En raison des effets indésirables et des coûts élevés, les thérapies doivent cibler de façon spécifique les classes à risque, et épargner les patients avec évolution lente.

Symptomatic intracranial hemorrhage after stroke thrombolysis: the SEDAN score.

OBJECTIVE: A study was undertaken to develop a score for assessing risk for symptomatic intracranial hemorrhage (sICH) in ischemic stroke patients treated with intravenous (IV) thrombolysis. METHODS: The derivation cohort comprised 974 ischemic stroke patients treated (1995-2008) with IV thrombolysis at the Helsinki University Central Hospital. The predictive value of parameters associated with sICH (European Cooperative Acute Stroke Study II) was evaluated, and we developed our score according to the magnitude of logistic regression coefficients. We calculated absolute risks and likelihood ratios of sICH per increasing score points. The score was validated in 828 patients from 3 Swiss cohorts (Lausanne, Basel, and Geneva). Performance of the score was tested with area under a receiver operating characteristic curve (AUC-ROC). RESULTS: Our SEDAN score (0 to 6 points) comprises baseline blood Sugar (glucose; 8.1-12.0 mmol/l [145-216 mg/dl] = 1; >12.0 mmol/l [>216 mg/dl] = 2), Early infarct signs (yes = 1) and (hyper)Dense cerebral artery sign (yes = 1) on admission computed tomography scan, Age (>75 years = 1), and NIH Stroke Scale on admission (≥10 = 1). Absolute risk for sICH in the derivation cohort was: 1.4%, 2.9%, 8.5%, 12.2%, 21.7%, and 33.3% for 0, 1, 2, 3, 4, and 5 score points, respectively. In the validation cohort, absolute risks were similar (1.0%, 3.5%, 5.1%, 9.2%, 16.9%, and 27.8%, respectively). AUC-ROC was 0.77 (0.71-0.83; p < 0.001). INTERPRETATION: Our SEDAN score reliably assessed risk for sICH in IV thrombolysis-treated patients with anterior- and posterior circulation ischemic stroke, and it can support clinical decision making in high-risk patients. External validation of the score supports its generalization.

Extent of Hypoattenuation On CT Angiography Source Images In Basilar Artery Occlusion: Prognostic Accuracy Of Posterior Circulation ASPECTS And The Pons-midbrain Score In The Basilar Artery International Cooperation Study

Background: The posterior circulation Acute Stroke Prognosis Early CT Score (pc-ASPECTS) and the combined Pons-midbrain score quantify the extent of early ischemic changes in the posterior circulation. We compared the prognostic accuracy of both scores if applied to CT angiography (CTA) source images (CTA-SI) of patients in the Basilar Artery International Cooperation Study (BASICS).Methods: BASICS was a prospective, observational, multi-centre, registry of consecutive patients who presented with acute symptomatic basilar artery occlusion (BAO). Functional outcome was assessed at 1 month. We applied pc-ASPECTS and the combined Pons-midbrain score to CTA-SI by 3-reader-consensus. Readers were blinded to clinical data. We performed multivariable logistic regression analysis, adjusting for thrombolysis, baseline NIHSS score and age, and used the output to derive ROC curves to compare the ability of both scores to discriminate patients with favourable (modified Rankin Scale [mRS] scores 0-3) from patients with unfavourable (mRS scores 4-6) functional outcome.Results: We reviewed CTAs of 158 patients (64% men, mean age 65 _ 15 years, median NIHSS score 25 [0-38], median GCS score 7 [3-15], median onset-to-CTA time 234 minutes [11-7380]). At 1 month, 40 (25%) patients had a favourable outcome, 49 (31%) had an unfavourable outcome (mRS score 4-5) and 69 (44%) were deceased. Both techniques of assessing CTA-SI hypoattenuation in the posterior circulation showed equally good discriminative value in predicting final outcome (C-statistics; area under ROC curve 0.74 versus 0.75, respectively; p_0.37). Pc-ASPECTS dichotomized at _6 versus _6 was an independent predictor of favourable functional outcome (RR _ 2.2; CI95 1.1-4.7; p _ 0.034).Conclusion: Compared to the combined Pons-midbrain score, the pc-ASPECTS score has similar prognostic accuracy to identify patients with a favourable functional outcome in BASICS. Dichotomized pc-ASPECTS (_6 versus _6) is an independent predictor of favourable functional outcome in this population. Author Disclosures: V. Puetz: None. A. Khomenko: None. M.D. Hill: None. I. Dzialowski: None. P. Michel: None. C. Weimar: None. C.A.C. Wijman: None. H. Mattle: None. K. Muir: None. T. Pfefferkorn: None. D. Tanne: None. S. Engelter: None. K. Szabo: None. A. Algra: None. A.M. Demchuk: None. W.J. Schonewille: None.

TREM-1 deficiency can attenuate disease severity without affecting pathogen clearance.

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a potent amplifier of pro-inflammatory innate immune reactions. While TREM-1-amplified responses likely aid an improved detection and elimination of pathogens, excessive production of cytokines and oxygen radicals can also severely harm the host. Studies addressing the pathogenic role of TREM-1 during endotoxin-induced shock or microbial sepsis have so far mostly relied on the administration of TREM-1 fusion proteins or peptides representing part of the extracellular domain of TREM-1. However, binding of these agents to the yet unidentified TREM-1 ligand could also impact signaling through alternative receptors. More importantly, controversial results have been obtained regarding the requirement of TREM-1 for microbial control. To unambiguously investigate the role of TREM-1 in homeostasis and disease, we have generated mice deficient in Trem1. Trem1(-/-) mice are viable, fertile and show no altered hematopoietic compartment. In CD4(+) T cell- and dextran sodium sulfate-induced models of colitis, Trem1(-/-) mice displayed significantly attenuated disease that was associated with reduced inflammatory infiltrates and diminished expression of pro-inflammatory cytokines. Trem1(-/-) mice also exhibited reduced neutrophilic infiltration and decreased lesion size upon infection with Leishmania major. Furthermore, reduced morbidity was observed for influenza virus-infected Trem1(-/-) mice. Importantly, while immune-associated pathologies were significantly reduced, Trem1(-/-) mice were equally capable of controlling infections with L. major, influenza virus, but also Legionella pneumophila as Trem1(+/+) controls. Our results not only demonstrate an unanticipated pathogenic impact of TREM-1 during a viral and parasitic infection, but also indicate that therapeutic blocking of TREM-1 in distinct inflammatory disorders holds considerable promise by blunting excessive inflammation while preserving the capacity for microbial control.

État de stress post-traumatique chez les mères et chez les pères d'enfants prématurés: similitudes et différences = Prematurity and parental post-traumatic stress disorder: similarities and differences

Objectifs Évaluer et comparer la présence de symptômes de stress post-traumatique, en fonction de la gravité de la prématurité, chez les mères et chez les pères de bébés nés prématurément. Méthode En fonction du score de risque périnatal (PERI) du bébé, les parents des prématurés (âge gestationnel moins de 34 semaines) ont été divisés en deux groupes : les parents de prématurés à faible risque (n = 16) et à haut risque (n = 26). Les symptômes d'intrusion et d'évitement, de l'état de stress post-traumatique, ont été évalués chez les parents à l'aide d'un questionnaire, l'Impact of Event Scale (IES). Leurs réponses ont été comparées à un groupe témoin de parents de nouveau-nés à terme (n = 24). Les différences entre les réponses des mères et des pères, ont été analysées. Résultats Les parents de bébés prématurés sont plus à risque que les parents de nouveau-nés à terme de présenter des symptômes de stress post-traumatique. Les mères en lien avec le fait même de la prématurité du bébé, les pères en lien avec la gravité de la prématurité. Les mères et les pères des prématurés des deux groupes (prématurés à faible risque, prématurés à haut risque) décrivent des symptômes d'intrusion, alors que les symptômes d'évitement sont décrits par toutes les mères, mais seulement par les pères de prématurés à haut risque périnatal. Conclusion La naissance prématurée est susceptible d'entraîner l'apparition de symptômes de stress post-traumatique chez les parents. Les mères et les pères réagissent différemment. Objectives Evaluation of the symptoms of parental post-traumatic stress disorder (PTSD), according to the severity of the prematurity, in mothers and fathers of premature babies. Materials and methods According to the Perinatal Risk Inventory (PERI), the parents of premature infants (gestational age less than 34 weeks) were divided into two groups, parents of a low-risk premature infants (n = 16) and of high-risk premature infants (n = 26). The symptoms of intrusion and avoidance, as a part of the post-traumatic stress disorder, were evaluated by an autoadministrated questionnaire, the Impact of Event Scale (IES). Their responses were compared with a control group of parents of full-term infants (n = 24). The differences in the answers of mothers and fathers were analysed. Results The occurrence of symptoms of post-traumatic stress disorder is increased in parents of preterm infants compared with the control group. Whereas mothers of premature infants are at risk of presenting symptoms of PTSD, linked to the prematurity, with fathers the infant perinatal risk factors play a greater role. The symptoms of intrusion are present in mothers and fathers of preterm infants of both groups. Mothers of both groups present avoidance symptoms, although only fathers of high-risk preterm infants present them. Conclusions Premature birth has an impact on both parents in terms of post-traumatic stress reactions. However, mothers and fathers react in different ways according to the severity of the prematurity.

Analysis of stop-gain and frameshift variants in human innate immunity genes.

Loss-of-function variants in innate immunity genes are associated with Mendelian disorders in the form of primary immunodeficiencies. Recent resequencing projects report that stop-gains and frameshifts are collectively prevalent in humans and could be responsible for some of the inter-individual variability in innate immune response. Current computational approaches evaluating loss-of-function in genes carrying these variants rely on gene-level characteristics such as evolutionary conservation and functional redundancy across the genome. However, innate immunity genes represent a particular case because they are more likely to be under positive selection and duplicated. To create a ranking of severity that would be applicable to innate immunity genes we evaluated 17,764 stop-gain and 13,915 frameshift variants from the NHLBI Exome Sequencing Project and 1,000 Genomes Project. Sequence-based features such as loss of functional domains, isoform-specific truncation and nonsense-mediated decay were found to correlate with variant allele frequency and validated with gene expression data. We integrated these features in a Bayesian classification scheme and benchmarked its use in predicting pathogenic variants against Online Mendelian Inheritance in Man (OMIM) disease stop-gains and frameshifts. The classification scheme was applied in the assessment of 335 stop-gains and 236 frameshifts affecting 227 interferon-stimulated genes. The sequence-based score ranks variants in innate immunity genes according to their potential to cause disease, and complements existing gene-based pathogenicity scores. Specifically, the sequence-based score improves measurement of functional gene impairment, discriminates across different variants in a given gene and appears particularly useful for analysis of less conserved genes.

Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome.

BACKGROUND: The proinflammatory cytokines interleukin 1beta (IL-1beta) and IL-18 are central players in the pathogenesis of inflammatory bowel disease (IBD). In response to a variety of microbial components and crystalline substances, both cytokines are processed via the caspase-1-activating multiprotein complex, the NLRP3 inflammasome. Here, the role of the NLRP3 inflammasome in experimental colitis induced by dextran sodium sulfate (DSS) was examined. METHODS: IL-1beta production in response to DSS was studied in macrophages of wild-type, caspase-1(-/-), NLRP3(-/-), ASC(-/-), cathepsin B(-/-) or cathepsin L(-/-) mice. Colitis was induced in C57BL/6 and NLRP3(-/-) mice by oral DSS administration. A clinical disease activity score was evaluated daily. Histological colitis severity and expression of cytokines were determined in colonic tissue. RESULTS: Macrophages incubated with DSS in vitro secreted high levels of IL-1beta in a caspase-1-dependent manner. IL-1beta secretion was abrogated in macrophages lacking NLRP3, ASC or caspase-1, indicating that DSS activates caspase-1 via the NLRP3 inflammasome. Moreover, IL-1beta secretion was dependent on phagocytosis, lysosomal maturation, cathepsin B and L, and reactive oxygen species (ROS). After oral administration of DSS, NLRP3(-/-) mice developed a less severe colitis than wild-type mice and produced lower levels of proinflammatory cytokines in colonic tissue. Pharmacological inhibition of caspase-1 with pralnacasan achieved a level of mucosal protection comparable with NLRP3 deficiency. CONCLUSIONS: The NLRP3 inflammasome was identified as a critical mechanism of intestinal inflammation in the DSS colitis model. The NLRP3 inflammasome may serve as a potential target for the development of novel therapeutics for patients with IBD.