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Mutations in the Recombination Activating Gene 1 (RAG1) can cause a wide variety of clinical and immunological phenotypes in humans, ranging from absence of T and B lymphocytes to occurrence of autoimmune manifestations associated with expansion of oligoclonal T cells and production of autoantibodies. Although the mechanisms underlying this phenotypic heterogeneity remain poorly understood, some genotype-phenotype correlations can be made. Currently, mouse models of Rag deficiency are restricted to RAG1-/- mice and to knock-in models carrying severe missense mutations. The Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)/Cas9 system is a novel and powerful gene-editing strategy that permits targeted introduction of DNA double strand breaks with high efficiency through simultaneous delivery of the Cas9 endonuclease and a guide RNA (gRNA). Here, we report on CRISPR-based, single-step generation and characterization of mutant mouse models in which gene editing was attempted around residue 838 of RAG1, a region whose functional role had not been studied previously.

Mindreading accounts of social cognition typically claim that we cannot directly perceive the mental states of other agents and therefore have to exercise certain cognitive capacities in order to infer them. In recent years this view has been challenged by proponents of the direct social perception (DSP) thesis, who argue that the mental states of other agents can be directly perceived. In this paper we show, first, that the main disagreement between proponents of DSP and mindreading accounts has to do with the so-called 'sandwich model' of social cognition. Although proponents of DSP are critical of this model, we argue that they still seem to accept the distinction between perception, cognition and action that underlies it. Second, we contrast the sandwich model of social cognition with an alternative theoretical framework that is becoming increasingly popular in the cognitive neurosciences: Bayesian Predictive Coding (BPC). We show that the BPC framework renders a principled distinction between perception, cognition and action obsolete, and can accommodate elements of both DSP and mindreading accounts., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background and Purpose: (18)F-fluoroazomycinarabinoside ((18)F-FAZA) is a promising hypoxia radiopharmaceutical agent with outstanding biokinetic parameters. We aimed to determine the accuracy of (18)F-FAZA-PET/CT scan in detecting hypoxic regions within the tumor using immunohistochemical markers in a pilot study., Patients and Methods: Eleven patients with primary or recurrent laryngeal squamous cell carcinoma were indicated for total laryngectomy (TLE). Patients underwent (18)F-FAZA-PET/CT scan before TLE. Hypoxic regions inside the laryngeal tumor were determined. After TLE, regions with high uptake on (18)F-FAZA-PET scan were selected for immunohistochemical examination for exogenous (pimonidazole) and endogenous (HIF1α, CA-IX and GLUT-1) hypoxia markers. To assess the accuracy of (18)F-FAZA-PET scanning, radiopharmacon accumulation was related with immunohistochemical expression of hypoxia markers., Results: Inter- and intratumoral heterogeneity of tumor hypoxia was observed on (18)F-FAZA-PET scan. Nine of the eleven tumors were hypoxic with (18)F-FAZA-PET. Hypoxia could also be detected with pimonidazole, HIF1α, CA-IX and GLUT-1 expression in some tumors. No clear association was observed between (18)F-FAZA uptake and hypoxia markers., Conclusions: This pilot study could not prove the accuracy of (18)F-FAZA-PET in determining hypoxic subvolumes in laryngeal cancer. Further study is required to investigate the benefit of (18)F-FAZA-PET imaging in radiotherapy planning., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Research in postoperative mortality is scarce. Insight into mortality and cause of death might improve and innovate perioperative care. The objective for this study was to report the 24-hour and 30-day overall, and surgery and anaesthesia-related, in-hospital mortality at a tertiary paediatric hospital., Methods: All patients <18 yr old who underwent anaesthesia with or without surgery between January 1, 2006, and December 31, 2012, at the Wilhelmina Children's Hospital, Utrecht, The Netherlands, were included in this retrospective cohort study. Causes of death within 30 days were identified and tabulated into four major categories according to principal cause., Results: A total of 45,182 anaesthetics were administered during this 7-yr period. The all-cause 24-hour hospital mortality was 13.1 per 10,000 anaesthetics (95% CI: 9.9-16.8) and the all-cause 30-day in-hospital mortality was 41.6 per 10,000 anaesthetics (95% CI: 35.9-48.0). In total five patients were partially contributable to anaesthesia (30-day mortality: 1.1/10,000, 95% CI: 0.4-2.6) and four patients were partially contributable to surgery (30-day mortality: 0.9/10,000, 95% CI: 0.2-2.3). Mortality was higher in neonates and infants, children with ASA physical status III and IV, and emergency- and cardiothoracic surgery., Conclusions: Neonates and infants, children with ASA physical status III or poorer, and emergency- and cardiothoracic surgery are associated with a higher postoperative mortality. Anaesthesia- or surgery-related complications contribute to mortality in only a small amount of the deaths, indicating the relative safety of paediatric surgical and anaesthetic procedures., (© The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Tumor hypoxia is known to be associated with poor clinical outcome; therefore, patients with hypoxic tumors might benefit from more intensive treatment approaches. This is particularly true for patients with head and neck cancer. Pretreatment assessment of hypoxia in tumors would be desirable, not only to predict prognosis but also to select patients for more aggressive treatment.As an alternative to the invasive polarographic needle electrode method, there is the possibility of using PET with radiopharmaceuticals visualizing hypoxia. Most hypoxia imaging studies on head and cancer have been performed using F-labeled fluoromisonidazole (F-FMISO). A chemically related molecule, F-fluoroazomycin-arabinoside (F-FAZA), seems to have superior kinetic properties and may therefore be the radiopharmaceutical of choice.This minireview summarizes the published literature on animal and human F-FAZA PET studies. Furthermore, future perspectives on how individualized treatment could be applied in patients with hypoxic head and neck tumors are discussed, for instance, the use of hypoxia sensitizers or special intensity-modulated radiation therapy techniques achieving tumor subvolume dose escalation.

Over the last couple of decades, most neuroscientific research on social cognition has been dominated by a third-person paradigm in which participating subjects are not actively engaging with other agents but merely observe them. Recently this paradigm has been challenged by researchers who promote a second-person approach to social cognition, and emphasize the importance of dynamic, real-time interactions with others. The present article's contribution to this debate is twofold. First, we critically analyze the second-person challenge to social neuroscience, and assess the various ways in which the distinction between second- versus third-person modes of social cognition has been articulated. Second, we put forward an alternative conceptualization of this distinction-one that gives pride of place to the notion of reciprocity. We discuss the implications of our proposal for neuroscientific studies on social cognition.

Objectives: To analyze available evidence on vaccinations in paediatric patients with rheumatic and autoinflammatory diseases. This evidence formed the basis of the recently constructed European League against Rheumatism (EULAR) recommendations for vaccination of these patients., Methods: A systematic literature review in the MEDLINE and EMBASE databases was conducted using various terms for vaccinations, paediatric rheumatic and autoinflammatory diseases and immunosuppressive drugs. Only papers on paediatric patients (<18 years of age) were selected. A panel of 13 experts in the field graded methodological quality and extracted data using predefined criteria., Results: 27 papers were available. No studies were found on autoinflammatory diseases. 14 studies considered live-attenuated vaccines. Evidence so far supports the safety and immunogenicity of non-live composite vaccines, although studies were underpowered to accurately assess safety. Live-attenuated vaccines did not cause disease flares or severe adverse events, not even in patients on methotrexate and low dose glucocorticosteroids. Seven patients on anti-TNFalpha therapy were described receiving the live-attenuated measles, mumps, rubella (n=5) or varicella (n=2) booster without severe adverse events., Conclusions: Data on safety and efficacy of vaccinations in paediatric patients with rheumatic diseases is reassuring, but too limited to draw definite conclusions. More research is needed on the safety and efficacy of especially live-attenuated vaccines in patients with rheumatic and autoinflammatory diseases using high dose immunosuppressive drugs., (Copyright © 2011 Elsevier B.V. All rights reserved.)

According to the BD-model of mindreading, we primarily understand others in terms of beliefs and desires. In this article we review a number of objections against explicit versions of the BD-model, and discuss the prospects of using its implicit counterpart as an explanatory model of early emerging socio-cognitive abilities. Focusing on recent findings on so-called 'implicit' false belief understanding, we put forward a number of considerations against the adoption of an implicit BD-model. Finally, we explore a different way to make sense of implicit false belief understanding in terms of keeping track of affordances.

An aerobic granular sludge (AGS) reactor was run for 280 days to study the competition between Phosphate and Glycogen Accumulating Organisms (PAOs and GAOs) at high temperatures. Numerous researches have proven that in suspended sludge systems PAOs are outcompeted by GAOs at higher temperatures. In the following study a reactor was operated at 30 °C in which the P-removal efficiency declined from 79% to 32% after 69 days of operation when biomass removal for sludge retention time (SRT) control was established by effluent withdrawal. In a second attempt at 24 °C, efficiency of P-removal remained on average at 71 ± 5% for 76 days. Samples taken from different depths of the sludge bed analysed using Fluorescent in situ hybridization (FISH) microscopy techniques revealed a distinctive microbial community structure: bottom granules contained considerably more Accumulibacter (PAOs) compared to top granules that were dominated by Competibacter (GAOs). In a third phase the SRT was controlled by discharging biomass exclusively from the top of the sludge bed. The application of this method increased the P-removal efficiency up to 100% for 88 days at 30 °C. Granules selected near the bottom of the sludge bed increased in volume, density and overall ash content; resulting in significantly higher settling velocities. With the removal of exclusively bottom biomass in phase four, P-removal efficiency decreased to 36% within 3 weeks. This study shows that biomass segregation in aerobic granular sludge systems offers an extra possibility to influence microbial competition in order to obtain a desired population., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

A 52-year-old woman was referred because of maxillary sinusitis. CT-scan showed two migrated dental implants in both maxillary sinuses.

Background: Point mutations within the family of the ras genes are detected in approximately 50% of human colorectal adenomas and carcinomas. Therefore, it is generally accepted that the occurrence of ras-point mutations constitute an important step in colorectal carcinogenesis. In addition, many studies have demonstrated that the tumorigenicity of the human colorectal carcinoma cell line, CaCo 2, strongly increases after transfection with the c-Ha-ras oncogene. This cell line is suitable for gaining more insight into the mechanism of c-Ha-ras induced tumorigenesis., Material and Methods: Proliferation, differentiation, and proteolytic capacity of c-Ha-ras oncogene transfected CaCo 2 cells were studied in vitro., Results: It was found that gelatinolytic capacity and production of urokinasetype plasminogen activator increased, whereas the production of tissue-type plasminogen activator was similar. Proliferative activity, as measured by the potential doubling time, did not alter. The expression of the differentiation markers sucraseiso-maltase, mucin, and chromogranin A was not different from that of the parental CaCo 2 cell line, which indicates that an increased tumorigenic capacity of c Ha-ras oncogene transfected CaCo 2 cells is not accompanied by loss of differentiation., Conclusion: These data demonstrate that the highly increased tumorigenic capacity of c Ha-ras oncogene-transfected CaCo 2 cells is associated with an enchanced proteolytic capacity.

Lactography is a novel technique that allows the continuous on-line registration of brain extracellular lactate in the freely behaving animal and that is based on a fluorimetric enzymatic assay of brain dialysates. Electroconvulsive shock, activation of the glutamate receptor (NMDA-type) and mild stress (immobilization, cold stress or handling) result in transient increases in the efflux of lactate from the rat hippocampus. The increase following immobilization stress was attenuated by the NMDA-receptor antagonist 2-amino-5-phosphopentanoic acid and after several pre-exposures to this stressor. These experiments suggest that mild stress activates glutamatergic neurons, which may be less after habituation to stress.