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Unreported Missense Mutation in the Dimerization Domain of ADA2 Leads to ADA2 Deficiency Associated with Severe Oral Ulcers and Neutropenia in a Female Somalian Patient - Addendum to the Genotype-Phenotype Puzzle B The electropherogram of the reverse strand of ADA2 of patient and her heterozygous daughter. c The white blood count (WBC) measured in giga per liter (G/L) of the patient before and after the switch from cyclosporine A to TNF- blocking therapy. Despite this treatment, granulocyte levels could only be maintained at low-normal levels with continuous cortisone treatment and the patient was hospitalized several times in the subsequent 2 years for oral ulcers and severe bacterial skin abscesses. [Extracted from the article]

Mean opinion score (MOS) has become a very popular indicator of perceived media quality. While there is a clear benefit to such a 'reference quality indicator' and its widespread acceptance, MOS is often applied without sufficient consideration of its scope or limitations. In this paper, we critically examine MOS and the various ways it is being used today. We highlight common issues with both subjective and objective MOS and discuss a variety of alternative approaches that have been proposed for media quality measurement. [ABSTRACT FROM AUTHOR]

Caspase-1 is a unique cysteine protease playing central roles in innate immunity. Pathogens, stress, and damage signals induce activation of caspase-1, typically mediated by proximity-induced autoproteolysis in multimeric protein complexes called the inflammasome. Active caspase-1 induces secretion of pro-inflammatory cytokines and mediates pyroptosis, a programmed pro-inflammatory cell death, thereby initiating an immune response finally leading to pathogen clearance. Excessive activation of caspase-1 is the underlying cause for rare diseases such as periodic fever syndromes, and more common disorders, including atherosclerosis, type 2 diabetes, and gout. Beside these well-known pro-inflammatory functions, active caspase-1 also has anti-inflammatory and protective functions contributing to cell survival, reduced inflammatory cytokine signaling, and improved outcomes in mouse models of burn injury or trauma and shock. Furthermore, naturally occurring procaspase-1 variants with reduced or abrogated enzymatic activity mediate enhanced inflammatory signaling and have been associated to autoinflammatory symptoms. Here, we review functions of caspase-1 focusing on anti-inflammatory signaling pathways and discuss the role of enzymatically inactive caspase-1 as disease-promoting factors in autoinflammatory diseases. Moreover, we illustrate differential requirements for autoproteolysis and enzymatic activity in caspase-1 functions. [ABSTRACT FROM AUTHOR]

Slam events experienced by high-speed catamarans in irregular waves were characterised through experiments using a hydroelastic segmented model. The model was designed to represent the dynamic behaviour of the full-scale Incat 112 m vessel and to allow the measurement of the slam load on the centrebow and wet deck. It was tested in irregular head seas at two speeds relating to Froude numbers of 0.32 and 0.60. Nearly 300 slams were identified in the test data and analysed with respect to kinematic parameters. Slams were found to have a large range of magnitudes, with the largest equivalent to 1785 tonnes full scale (approximately 70% of vessel displacement); however, the majority of events were of relatively low severity. Differences in slam characteristics were found for the two model speeds tested; slams at the slower speed generally occurred further forward on the hull, prior to the wave crest and with a bow down pitch angle. Immersion of the centrebow to the two-dimensional filling height of the cross-section between the centrebow and demihulls is shown to be a better indicator of slam occurrence than immersion to the top of the archway. [ABSTRACT FROM AUTHOR]

Traceability—the ability to follow the life of software artifacts—is a topic of great interest to software developers in general, and to requirements engineers and model-driven developers in particular. This article aims to bring those stakeholders together by providing an overview of the current state of traceability research and practice in both areas. As part of an extensive literature survey, we identify commonalities and differences in these areas and uncover several unresolved challenges which affect both domains. A good common foundation for further advances regarding these challenges appears to be a combination of the formal basis and the automated recording opportunities of MDD on the one hand, and the more holistic view of traceability in the requirements engineering domain on the other hand. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding the study on Alu repeat-induced deletions in chronic granulomatous disease (GGD).

The long-term behaviour of Norwegian glaciers is reflected by the long mass-balance records provided by the Norwegian Water Resources and Energy Directorate. These show positive annual mass balances in the 1980s and 1990s at maritime glaciers followed by rapid mass loss since 2000. This study assesses the influence of various atmospheric variables on mass changes of selected Norwegian glaciers by correlation- and cross-validated stepwise multiple regression analyses. The atmospheric variables are constructed from reanalyses by the National Centers for Environmental Prediction and the European Centre for Medium-Range Weather Forecasts. Transfer functions determined by the multiple regression are applied to predictors derived from a multi-model ensemble of climate projections to estimate future mass-balance changes until 2100. The statistical relationship to the North Atlantic Oscillation (NAO), the strongest predictor, is highest for maritime glaciers and less for more continental ones. The mass surplus in the 1980s and 1990s can be attributed to a strong NAO phase and lower air temperatures during the ablation season. The mass loss since 2000 can be explained by an increase of summer air temperatures and a slight weakening of the NAO. From 2000 to 2100 the statistical model predicts predicts changes for glaciers in more continental settings of c. −20 m w.e. (water equivalent) or 0.2 m w.e./a. The corresponding range for their more maritime counterparts is −0.5 to +0.2 m w.e./a. Results from Bayesian classification of observed atmospheric states associated with high melt or high accumulation in the past into different simulated climates in the future suggest that climatic conditions towards the end of the twenty-first century favour less winterly accumulation and more ablation in summer. The posterior probabilities for high accumulation at the end of the twenty-first century are typically 1.5-3 times lower than in the twentieth century while the posterior probabilities for high melt are often 1.5-3 times higher at the end of the twenty-first century than in the twentieth and early twenty-first century. [ABSTRACT FROM AUTHOR]

Rock avalanches onto glaciers are rare in Norway. Here, we examine a rock avalanche that spread onto the regenerated Brenndalsbreen, an outlet glacier from Jostedalsbreen ice cap. The rock avalanche is intriguing in that limited information exists with respect to the exact time of failure, location of detachment area, and preparatory and triggering processes. Based on an analysis of ice stratigraphy and photographic documentation, we assess that the event happened between mid-March and June 4, 2010. A potential triggering factor could have been heavy snow and rainfall combined with above freezing air temperatures on March 18–19, 2010. We use digital terrain models to determine that the detachment area is at an almost vertical rock slope in a narrow gorge above Lower Brenndalsbreen. The deposit volume is estimated to 0.130 ± 0.065 Mm3, and the H/L ratio and fahrböschung are 0.45 and 24°, respectively. We apply a Voellmy flow model to confirm the detachment location and volume estimate by producing realistic runout lengths. Although glacial debuttressing may have been a likely preparatory process, the detachment area was exposed for 45–70 years before the rock avalanche occurred. The supraglacial rock avalanche debris was separated into two branches with a distinct melt-out line across the glacier. The debris reached the glacier front in 2019 and 2020, where it started being deposited proglacially while Lower Brenndalsbreen kept receding. The 2010 Brenndalsbreen rock avalanche may not be a unique event, as deposits constituting evidence of an old rock avalanche are currently melting out at the glacier front. [ABSTRACT FROM AUTHOR]

Purpose: Abscess patients frequently receive antibiotic therapy when incision cannot be performed or in addition to incision. However, antibiotic concentrations in human abscesses are widely unknown. Methods: Pharmacokinetics of cefpirome in 12 human abscesses located in different body regions was studied. Cefpirome (2 g) was administered as an intravenous short infusion, and concentrations were measured in plasma over an 8-h period and in abscesses at incision. A pharmacokinetic two-stage model was applied. Results: At abscess incision performed 158 ± 112 min after the start of the infusion, the cefpirome concentrations in the abscess fluid varied markedly, ranging from ≤0.1 (limit of quantification) to 47 (mean 8.4 ± 14.1 ) mg/L. Cefpirome was detectable in nine of 12 abscesses. Maximum concentrations were calculated to be 183 ± 106 mg/L in plasma and 12 ± 16 mg/L in the abscess. A cefpirome concentration of 2 mg/L, which is the minimum concentration inhibiting growth of 90% of the most relevant bacterial pathogens, was exceeded spontaneously in six of 12 abscesses after a single dose. Cefpirome concentrations in the abscess did not correlate with either the pH or the ratio of surface area to volume of the abscesses, nor with plasma pharmacokinetics. Conclusions: Cefpirome may be useful to treat abscess patients because it was detectable in most abscesses after a single dose. However, the penetration of cefpirome into abscesses is extremely variable and cannot be predicted by measuring other available covariates. [ABSTRACT FROM AUTHOR]

We report the case of a 35-years-old renal transplant patient known to have familial Mediterranean fever with serum amyloid A (SAA)-amyloidosis, who presented with his second episode of bilateral pneumonia. As antimicrobials failed to control the first episode of pneumonia and all studies done were non-contributory, we attributed the condition to the highly active Mediterranean fever presumably resistant to colchicine and treated the patient with the interleukin-1 receptor antagonist anakinra: the patient substantially improved by clinical symptoms, chemistry and radiological evidence within no more than 2 days and was discharged in good health after 4 days. [ABSTRACT FROM AUTHOR]

Introduction: Mononuclear cells (MNC) from patients with aplastic anemia (AA) can inhibit hematopoietic colony formation from normal bone marrow (BM) cells. Interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-γ) are considered as soluble mediators of BM suppression in AA. Because of its cytokine synthesis inhibiting action, interleukin-10 (IL-10) could be a potentially useful molecule to modulate the hematopoietic effects of MNC from patients with AA. Methods: Using coculture experiments we studied the effect of recombinant human IL-10 (rhIL-10) on the in vitro hematopoietic suppression by peripheral blood (PB) MNC from AA patients. Results: PBMNC (5 × 10[sup 5]/ml) from seven patients with AA caused a 40-100% reduction of normal burst-forming unit-erythroid (BFU-E) growth and a 38-91% reduction of colonyforming unit-granulocyte/macrophage (CFU-GM) growth, respectively, in semisolid cocultures. IL-10 was highly effective in reversing growth inhibition in these cocultures. Addition of 10 ng/ml IL-10 to cocultures significantly restored growth of BFU-E in all seven cases and growth of CFU-GM in five of seven cases, respectively. The effect was dose dependent and correlated with decreased IFN-γ and TNF-α production in suspension cultures. Using intracellular cytokine staining it was found that increased TNF-α production in AA cells was derived from both CD4+ and CD8+ cells, whereas aberrant IFN-γ synthesis was only detected in CD8+ cells. Conclusion: IL-10 is effective in reversing in vitro hematopoietic suppression by PBMNC from AA patients. These results suggest therapeutic evaluation of rhIL-10 in patients with AA. [ABSTRACT FROM AUTHOR]