Block of death-receptor apoptosis protects mouse cytomegalovirus from macrophages and is a determinant of virulence in immunodeficient hosts.

The inhibition of death-receptor apoptosis is a conserved viral function. The murine cytomegalovirus (MCMV) gene M36 is a sequence and functional homologue of the human cytomegalovirus gene UL36, and it encodes an inhibitor of apoptosis that binds to caspase-8, blocks downstream signaling and thus contributes to viral fitness in macrophages and in vivo. Here we show a direct link between the inability of mutants lacking the M36 gene (ΔM36) to inhibit apoptosis, poor viral growth in macrophage cell cultures and viral in vivo fitness and virulence. ΔM36 grew poorly in RAG1 knockout mice and in RAG/IL-2-receptor common gamma chain double knockout mice (RAGγC(-/-)), but the depletion of macrophages in either mouse strain rescued the growth of ΔM36 to almost wild-type levels. This was consistent with the observation that activated macrophages were sufficient to impair ΔM36 growth in vitro. Namely, spiking fibroblast cell cultures with activated macrophages had a suppressive effect on ΔM36 growth, which could be reverted by z-VAD-fmk, a chemical apoptosis inhibitor. TNFα from activated macrophages synergized with IFNγ in target cells to inhibit ΔM36 growth. Hence, our data show that poor ΔM36 growth in macrophages does not reflect a defect in tropism, but rather a defect in the suppression of antiviral mediators secreted by macrophages. To the best of our knowledge, this shows for the first time an immune evasion mechanism that protects MCMV selectively from the antiviral activity of macrophages, and thus critically contributes to viral pathogenicity in the immunocompromised host devoid of the adaptive immune system

Health related quality of life of obese adolescents in Kuwait

Obesity impairs health related quality of life (HRQL) in adolescents, but most evidence in this area has mostly come from western societies. We wanted to test the hypothesis that obesity impairs HRQL in Kuwaiti adolescents, and to test for differences in HRQL assessed by self-report and parent-proxy report. In 500 Kuwaiti 10-14 year olds HRQL was assessed using the Peds QL (TM) with both adolescent self-reports (n = 500) and parent-proxy reports (n = 374). Obesity was not significantly associated with HRQL in regression analysis. In a paired comparison of 98 pairs of obese adolescents vs. 98 healthy weight peers, impairment of HRQL reached significance only for physical score (95% CI = -1.5, -9.4), not for psychosocial score or total score. In a paired comparison of parent-proxy vs. self-reports for the obese adolescents, total score (95% CI = -4.9, -10.9), physical score (95% CI = -3.2, -11.0), and psychosocial score (95% CI = -4.2, -10.8) were all significantly lower in the parent reports. Obesity is not associated with marked impairment of HRQL in adolescents in Kuwait, in contrast to studies in western societies. This may reflect cultural differences in attitudes towards obesity

The experience of taking methotrexate for juvenile idiopathic arthritis: results of a cross-sectional survey with children and young people

Background: Children and young people (CYP) with juvenile idiopathic arthritis (JIA) are known to have impaired health-related quality of life (HRQoL), which is improved significantly for many by treatment with methotrexate (MTX). However, a significant proportion of CYP experience difficulties in taking MTX, which may reduce its potential benefits for HRQoL. The aim of this research was to examine how CYP with JIA perceive MTX treatment and how this relates to HRQoL. Methods: CYP aged 8-16 years taking MTX for JIA completed an adapted Parent Adherence Report Questionnaire, which contains 100mm visual analogue scales, to assess difficulty taking MTX, adherence, frequency of negative reactions and helpfulness of MTX. They also completed the Pediatric Quality of Life Inventory (PedsQL) Generic and Rheumatology scales. We collected data on age, gender, JIA course, disease duration, MTX duration of use, route and dose. Number of inflamed and limited joints were indicators of disease severity. Results: 116 CYP participated. Most considered MTX helpful (median 87; interquartile range (IQR) 50.75–98) and reported adherence was high (median 98; IQR 90–100). There was greater variability on scores for difficulty (median 22; IQR 2–69) and frequency of negative reactions (median 14.5; IQR 1.25–80). Mean (S.D.) scores on the PedsQL Physical and Psychosocial subscales were 71.63 (24.02) and 71.78 (19.59) respectively, indicating poorer HRQoL than that reported by healthy children. After controlling for demographic and disease variables, poorer physical HRQoL was significantly accounted for by greater difficulty in taking MTX. Poorer psychosocial HRQoL was significantly accounted for by subcutaneous MTX administration, a lower rating of MTX helpfulness and a greater reported difficulty in taking MTX. Conclusions: Taking MTX for JIA was viewed as helpful by most CYP but HRQoL was poorer in those who reported greater difficulty in taking MTX

Triad3a induces the degradation of early necrosome to limit RipK1-dependent cytokine production and necroptosis.

Understanding the molecular signaling in programmed cell death is vital to a practical understanding of inflammation and immune cell function. Here we identify a previously unrecognized mechanism that functions to downregulate the necrosome, a central signaling complex involved in inflammation and necroptosis. We show that RipK1 associates with RipK3 in an early necrosome, independent of RipK3 phosphorylation and MLKL-induced necroptotic death. We find that formation of the early necrosome activates K48-ubiquitin-dependent proteasomal degradation of RipK1, Caspase-8, and other necrosomal proteins. Our results reveal that the E3-ubiquitin ligase Triad3a promotes this negative feedback loop independently of typical RipK1 ubiquitin editing enzymes, cIAPs, A20, or CYLD. Finally, we show that Triad3a-dependent necrosomal degradation limits necroptosis and production of inflammatory cytokines. These results reveal a new mechanism of shutting off necrosome signaling and may pave the way to new strategies for therapeutic manipulation of inflammatory responses

Health-related quality of life of children with attention-deficit/hyperactivity disorder versus children with diabetes and healthy controls

The impact of attention-deficit/hyperactivity disorder (ADHD) on health-related quality of life (HRQoL) is reported to be similar to that of other mental health and physical disorders. In this cross-sectional study, we hypothesized that children with ADHD and children with type 1 diabetes mellitus (T1DM) would have significantly worse HRQoL compared with healthy children, and that better clinical status in ADHD and T1DM would be associated with better HRQoL. Children were recruited from three outpatient services in Scotland. Responses to two frequently used validated HRQoL instruments, the Paediatric Quality of Life Inventory (PedsQL) and Child Health and Illness Profile-child edition (CHIP-CE), were obtained from parents/carers and children (6–16 years) with/without ADHD or T1DM. Child and parent/carer-completed HRQoL measurements were evaluated for 213 children with ADHD, 58 children with T1DM and 117 healthy children (control group). Significantly lower self and parent/carer ratings were observed across most PedsQL (P < 0.001) and CHIP-CE (P < 0.05) domains (indicating reduced HRQoL) for the ADHD group compared with the T1DM and control groups. Parent/carer and child ratings were significantly correlated for both measures of HRQoL (PedsQL total score: P < 0.001; CHIP-CE all domains: P < 0.001), but only with low-to-moderate strength. Correlation between ADHD severity and HRQoL was significant with both PedsQL and CHIP-CE for all parent/carer (P < 0.01) and most child (P < 0.05) ratings; more ADHD symptoms were associated with poorer HRQoL. These data demonstrate that ADHD has a significant impact on HRQoL (as observed in both parent/carer and child ratings), which seems to be greater than that for children with T1DM

Six years beyond pediatric trauma: child and parental ratings of children’s health-related quality of life in relation to parental mental health

Purpose: To examine the relationship between child self-report and parent proxy report of health-related quality of life (HRQL) and how parents’ mental health status relates to the HRQL ratings 6 years after minor to severe injury of the child. Materials and methods: This cross-sectional cohort study was performed at a regional pediatric trauma center in Stockholm, Sweden. The PedsQL 4.0 versions for ages 5–7, 8–12, and 13–18 years were completed by 177 child–parent dyads 6 years after injury to the child. The parents also rated their own mental health through the mental health domain (MH) in the SF-36 Health Survey. Results: The children’s median age was 13 years (IQR 10–16 years), 54 % were males, and the median ISS was 5 (IQR 2–9). Most of the parents were female (77 %), born in Sweden (79 %), and half had university degrees. There was no statistically significant difference between child self-report and parent proxy report in any of the PedsQL 4.0 scales or summary scales. The levels of agreement between child self-report and parent proxy reports were excellent (ICC ≥ 0.80) for all scales with the exception of emotional functioning (ICC 0.53) which also was the scale with the lowest internal consistency in child self-report (α 0.60). Multiple regression analyses showed that worse parental mental health status correlated with worse child self-report and parent proxy report of children’s HRQL. Conclusions: Children and their parents’ reports on child’s HRQL were in agreement. Decreased mental health in parents was associated with lower scores on parent proxy reports and child self-reports of HRQL after injury. The current investigation highlights the possible relationship between parent’s mental health status and children’s HRQL long after an injury, which should be considered in future investigations and in clinical care

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death

Measuring health-related quality of life in young adolescents: Reliability and validity in the Norwegian version of the Pediatric Quality of Life Inventory™ 4.0 (PedsQL) generic core scales

BACKGROUND: Health-Related Quality of Life (HRQOL) studies concerning children and adolescents are a growing field of research. The Pediatric Quality of Life Inventory (PedsQL™) is considered as a promising HRQOL instrument with the availability of age appropriate versions and parallel forms for both child and parents. The purpose of the current study was to evaluate the psychometric properties of the Norwegian translation of the Pediatric Quality of Life Inventory (PedsQL™) 4.0 generic core scale in a sample of healthy young adolescents. METHODS: A cross-sectional study of 425 healthy young adolescents and 237 of their caregivers participating as a proxy. Reliability was assessed by Cronbach's alpha. Construct validity was assessed using exploratory factor analysis and by exploring the intercorrelations between and among the four PedsQL subscales for adolescents and their parents. RESULTS: All the self-report scales and proxy-report scales showed satisfactory reliability with Cronbach's alpha varying between 0.77 and 0.88. Factor analysis showed results comparable with the original version, except for the Physical Health scale. On average, monotrait-multimethod correlations were higher than multitrait-multimethod correlations. Sex differences were noted on the emotional functioning subscale, girls reported lower HRQOL than boys. CONCLUSION: The Norwegian PedsQL is a valid and reliable generic pediatric health-related Quality of Life measurement that can be recommended for self-reports and proxy-reports for children in the age groups ranging from 13–15 years

Reliability and validity of PedsQL for Portuguese children aged 5–7 and 8–12 years

BACKGROUND: Pediatric Quality of Life Inventory (PedsQL) is a measure to assess health-related quality of life (HRQoL) in children and adolescents. It is formed by 23 items adapted to children age and includes a parent proxy report version. With four multidimensional subscales and three summary scores, it measures health as defined by WHO. The concepts measured by this instrument are ‘physical functioning’ (8 items), ‘emotional functioning’ (5 items), ‘social functioning’ (5 items) and ‘school functioning’ (5 items). It also measures a ‘total scale score’ (23 items), a ‘physical health summary score’ (8 items) and a ‘psychosocial health summary score’ (15 items). The aim of this paper is to present the main results of the cultural adaptation and validation of the PedsQL into European Portuguese. METHODS: The Portuguese version was the result of a forward-backward translation process, with a cognitive debriefing analysis, guaranteeing face validity and semantic equivalence. Children aged 5–7 and 8–12 were randomly selected and were asked to fill a socio-demographic data survey and the Portuguese versions of PedsQL and KINDL, another HRQoL measure for children and adolescents. They were divided into three groups, healthy children, children with type I diabetes and children with spina bifida. The reliability was tested for reproducibility (ICC) and internal consistency (Cronbach’s alpha). The construct validity (known-groups discriminant validity) was supported by differences between self-reports from healthy children and children with chronic conditions, and from children with chronic diseases and their parents. The criterion validity was tested after the correlations of the scores obtained by both children and adolescents HRQoL assessment instruments. RESULTS: A total of 179 children and 97 parents were recruited. PedsQL demonstrated good levels of reproducibility (r > 0.95 in all versions) and acceptable levels of internal consistency with Cronbach’s alpha at 0.70 on most scales. Concordance values between children’s and parents’ perceptions ranged between 0.36 and 0.78 and the correlations with KINDL questionnaire were excellent, supporting concurrent validity. CONCLUSIONS: The Portuguese version of the PedsQL demonstrated acceptable psychometric properties for future research and clinical practice for children aged 5–12