Subclinical atherosclerosis and its progression are modulated by PLIN2 through a feed-forward loop between LXR and autophagy.

BACKGROUND: Hyperlipidaemia is a major risk factor for cardiovascular disease, and atherosclerosis is the underlying cause of both myocardial infarction and stroke. We have previously shown that the Pro251 variant of perilipin-2 reduces plasma triglycerides and may therefore be beneficial to reduce atherosclerosis development. OBJECTIVE: We sought to delineate putative beneficial effects of the Pro251 variant of perlipin-2 on subclinical atherosclerosis and the mechanism by which it acts. METHODS: A pan-European cohort of high-risk individuals where carotid intima-media thickness has been assessed was adopted. Human primary monocyte-derived macrophages were prepared from whole blood from individuals recruited by perilipin-2 genotype or from buffy coats from the Karolinska University hospital blood central. RESULTS: The Pro251 variant of perilipin-2 is associated with decreased intima-media thickness at baseline and over 30 months of follow-up. Using human primary monocyte-derived macrophages from carriers of the beneficial Pro251 variant, we show that this variant increases autophagy activity, cholesterol efflux and a controlled inflammatory response. Through extensive mechanistic studies, we demonstrate that increase in autophagy activity is accompanied with an increase in liver-X-receptor (LXR) activity and that LXR and autophagy reciprocally activate each other in a feed-forward loop, regulated by CYP27A1 and 27OH-cholesterol. CONCLUSIONS: For the first time, we show that perilipin-2 affects susceptibility to human atherosclerosis through activation of autophagy and stimulation of cholesterol efflux. We demonstrate that perilipin-2 modulates levels of the LXR ligand 27OH-cholesterol and initiates a feed-forward loop where LXR and autophagy reciprocally activate each other; the mechanism by which perilipin-2 exerts its beneficial effects on subclinical atherosclerosis.

Updated European Consensus Statement on diagnosis and treatment of adult ADHD.

Background Attention-deficit/hyperactivity disorder (ADHD) is among the most common psychiatric disorders of childhood that often persists into adulthood and old age. Yet ADHD is currently underdiagnosed and undertreated in many European countries, leading to chronicity of symptoms and impairment, due to lack of, or ineffective treatment, and higher costs of illness. Methods The European Network Adult ADHD and the Section for Neurodevelopmental Disorders Across the Lifespan (NDAL) of the European Psychiatric Association (EPA), aim to increase awareness and knowledge of adult ADHD in and outside Europe. This Updated European Consensus Statement aims to support clinicians with research evidence and clinical experience from 63 experts of European and other countries in which ADHD in adults is recognized and treated. Results Besides reviewing the latest research on prevalence, persistence, genetics and neurobiology of ADHD, three major questions are addressed: (1) What is the clinical picture of ADHD in adults? (2) How should ADHD be properly diagnosed in adults? (3) How should adult ADHDbe effectively treated? Conclusions ADHD often presents as a lifelong impairing condition. The stigma surrounding ADHD, mainly due to lack of knowledge, increases the suffering of patients. Education on the lifespan perspective, diagnostic assessment, and treatment of ADHD must increase for students of general and mental health, and for psychiatry professionals. Instruments for screening and diagnosis of ADHD in adults are available, as are effective evidence-based treatments for ADHD and its negative outcomes. More research is needed on gender differences, and in older adults with ADHD.

Utility of single versus multiple breath washout in adult asthma.

Nitrogen multiple breath washout (N2 MBW) is a sensitive method to identify peripheral airway involvement in asthma, but is a time-consuming test. The N2 vital capacity single breath (VC SBW) test offers greater time efficiency, but concordance with N2 MBW is poorly understood. The prevalence of peripheral airway abnormality was determined by N2 MBW and N2 SBW tests in 194 asthmatic subjects aged 18-1 years. N2 MBW data were related to findings in 400 healthy controls, aged 17-71 years, while N2 SBW data were compared to findings in 224 healthy controls, aged 15-65 years, to derive equipment-specific reference values. Amongst asthmatic subjects, relationships between N2 SBW and N2 MBW outcomes were studied. N2 SBW relationship with clinical history, spirometry, blood eosinophils and fraction exhaled nitric oxide (FENO) data was also explored. The prevalence of peripheral airway involvement (i.e. abnormal ventilation distribution) determined by N2 SBW-derived phase III slope (N2 SIII ) was 24·7%, compared to 44% determined by N2 MBW-derived lung clearance index (LCI) (P<0·001). Predictors of abnormal N2 SIII were older age, smoking history and lower FEV1. N2 SBW offers lower sensitivity than N2 MBW to detect small airway dysfunction in adult asthma, but may be a marker of more severe disease.

Novel methodology to perform sulfur hexafluoride (SF6)-based multiple-breath wash-in and washout in infants using current commercially available equipment.

Multiple-breath inert gas washout (MBW) is ideally suited for early detection and monitoring of serious lung disease, such as cystic fibrosis, in infants and young children. Validated commercial options for the MBW technique are limited, and suitability of nitrogen (N2)-based MBW is of concern given the detrimental effect of exposure to pure O2 on infant breathing pattern. We propose novel methodology using commercially available N2 MBW equipment to facilitate 4% sulfur hexafluoride (SF6) multiple-breath inert gas wash-in and washout suitable for the infant age range. CO2, O2, and sidestream molar mass sensor signals were used to accurately calculate SF6 concentrations. An improved dynamic method for synchronization of gas and respiratory flow was developed to take into account variations in sidestream sample flow during MBW measurement. In vitro validation of triplicate functional residual capacity (FRC) assessments was undertaken under dry ambient conditions using lung models ranging from 90 to 267 ml, with tidal volumes of 28-79 ml, and respiratory rates 20-60 per minute. The relative mean (SD, 95% confidence interval) error of triplicate FRC determinations by washout was -0.26 (1.84, -3.86 to +3.35)% and by wash-in was 0.57 (2.66, -4.66 to +5.79)%. The standard deviations [mean (SD)] of percentage error among FRC triplicates were 1.40 (1.14) and 1.38 (1.32) for washout and wash-in, respectively. The novel methodology presented achieved FRC accuracy as outlined by current MBW consensus recommendations (95% of measurements within 5% accuracy). Further clinical evaluation is required, but this new technique, using existing commercially available equipment, has exciting potential for research and clinical use.

Social inequality and age-specific gender differences in overweight and perception of overweight among Swedish children and adolescents: a cross-sectional study.

BACKGROUND: Overweight among children and adolescents related to social inequality, as well as age and gender differences, may contribute to poor self-image, thereby raising important public health concerns. This study explores social inequality in relation to overweight and perception of overweight among 263 boys and girls, age 7 to 17, in Växjö, Sweden. METHODS: Data were obtained through a questionnaire and from physical measurements of height, weight and waist circumference [WC]. To assess social, age and gender differences in relation to overweight, the independent sample t- and chi-square tests were used, while logistic regression modeling was used to study determinants for perception of overweight. RESULTS: Social inequality and gender differences as they relate to high ISO-BMI [Body Mass Index for children] and WC were associated with low maternal socioeconomic status [SES] among boys < 13 years [mean age = 10.4; n = 65] and with low paternal education level among boys ≥ 13 years [mean age = 15.0; n = 39] [p < 0.05]. One suggested explanation for this finding is maternal impact on boys during childhood and the influence of the father as a role model for adolescent boys. The only association found among girls was between high ISO-BMI in girls ≥ 13 years [mean age = 15.0; n = 74] and low paternal occupational status. Concerning perception of overweight, age and gender differences were found, but social inequality was not the case. Among boys and girls < 13 years, perception of overweight increased only when overweight was actually present according to BMI or WC [p < 0.01]. Girls ≥ 13 years [mean age = 15.0] were more likely to unrealistically perceive themselves as overweight or "too fat," despite factual measurements to the contrary, than boys [p < 0.05] and girls < 13 years [mean age = 10.4; n = 83] [p < 0.001]. CONCLUSIONS: The association between social inequality and overweight in adolescence in this study is age- and gender-specific. Gender differences, especially in perception of overweight, tend to increase with age, indicating that adolescence is a crucial period. When planning interventions to prevent overweight and obesity among children and adolescents, parental SES as well as age and gender-specific differences in social norms and perception of body weight status should be taken into account.

Associations between Campylobacter levels on chicken skin, underlying muscle, caecum and packaged fillets.

A study was performed with the aim to investigate associations between Campylobacter in chicken caecum, carcass skin, underlying breast muscle and packaged breast fillets. Samples were taken from 285 chickens from 57 flocks and analysed according to ISO 10272. Campylobacter spp. were isolated from caecal samples from 41 flocks. From birds of the same 41 flocks Campylobacter could be detected and quantified in 194 (68%) skin samples. Moreover, Campylobacter spp. were enumerated in 13 (5%) underlying muscle samples originating from 9 of the 41 flocks. The mean number of Campylobacter spp. in the 194 skin samples which could be counted was 2.3 log cfu/g and for the 13 underlying muscle samples 1.3 log cfu/g. Campylobacter could only be quantified in those breast muscle samples with a finding in corresponding skin sample. Five packaged chicken fillets were taken from each 25 of the 57 flocks and analysed both quantitatively and qualitatively. In qualitative analysis Campylobacter was detected in 79 (63%) fillets from 16 flocks and quantified in 24 (19%) samples from 11 flocks. The results showed a significant association (P < 0.05) between findings of Campylobacter on carcass skin (log cfu/g) and the proportion of Campylobacter positive breast muscle samples.

Asthma phenotypes and lung function up to 16 years of age-the BAMSE cohort.

BACKGROUND: Asthma is a disease affecting many locations throughout the airway. Most studies have used spirometry as the primary assessment of airway obstruction, a method that may be less sensitive in regard to peripheral airway obstruction. The aim of this study was to elucidate the associations between asthma phenotypes based on age of onset and duration of symptoms, and (i) spirometry and (ii) small airway involvement measured by impulse oscillometry (IOS) in adolescence. METHODS: Children and adolescents taking part in BAMSE, a prospective birth cohort study, performed spirometry at 8 and 16 years and IOS at 16 years of age. Based on data collected in questionnaires, children were categorized into the following groups: 'never asthma', 'early transient asthma', 'early persistent asthma', and 'late onset asthma'. RESULTS: Compared with the never asthma group, all asthma groups were associated with lower FEV1 at 16 years of age (early transient-119 ml, 95% confidence interval -204 to -34; early persistent-410 ml, 95%CI -533; -287; and late onset-148 ml, 95%CI -237; -58). Between 8 and 16 years, significantly less increase in FEV1 was observed in the early persistent and late onset groups. The small airway index 'R5-20 ' was significantly associated with active asthma at 16 years, but not transient asthma. CONCLUSIONS: All asthma phenotypes studied were negatively associated with FEV1 in adolescence. IOS measurements indicated that active asthma could be associated with small airway impairments. These results provide new insights into the physiology underlying wheezing phenotypes based on age of onset and duration of disease.

Slow and fast lung compartments in cystic fibrosis measured by nitrogen multiple-breath washout.

Imaging studies describe significant ventilation defects across a wide range of cystic fibrosis (CF) related lung disease severity. These are unfortunately poorly reflected by phase III slope analysis-derived Scond and Sacin from multiple-breath washout (MBW). Methodology extending previous two-lung compartment model-based analysis is presented describing size and function of fast- and slow-ventilating lung compartments from nitrogen (N2) MBW and correlation to obstructive lung disease severity. In 37 CF subjects (forced expiratory volume in 1 s [FEV1] mean [SD] 84.8 [19.9] % predicted; abnormal lung clearance index [LCI] in 36/37, range 7.28-18.9) and 74 matched healthy controls, volume and specific ventilation of both fast and slowly ventilated lung compartments were derived from N2-based MBW with commercial equipment. In healthy controls lung emptying was characterized by a large compartment constituting 75.6 (8.4)% of functional residual capacity (FRC) with a specific ventilation (regional alveolar tidal volume/regional lung volume) of 13.9 (3.7)% and a small compartment with high specific ventilation (48.4 [15.7]%). In CF the slowly ventilated lung compartment constituted 51.9(9.1)% of FRC, with low specific ventilation of 5.3 (2.4)%. Specific ventilation of the slowly ventilated lung compartment showed stronger correlation with LCI (r2 = 0.70, P < 0.001) vs. Sacin (r2 = 0.44, P < 0.001) or Scond (no significant correlation). Overventilation of the fast lung compartment was no longer seen in severe CF lung disease. Magnitude and function of under- and overventilated lung volumes can be derived from routine N2 MBW in CF. Reported values agree with previous modelling-derived estimates of impaired ventilation and offer improved correlation to disease severity, compared with SnIII analysis.

Clinical significance of small airway obstruction markers in patients with asthma.

BACKGROUND: The role of small airway obstruction in the clinical expression of asthma is incompletely understood. OBJECTIVE: We tested the hypotheses that markers of small airway obstruction are associated with (i) increased asthma severity, (ii) impaired asthma control and quality of life and (iii) frequent exacerbations. METHODS: Seventy-four adults with asthma and 18 healthy control subjects underwent impulse oscillometry (IOS), multiple breath inert gas washout (MBW), body plethysmography, single-breath determination of carbon monoxide uptake and spirometry. Patients completed the six-point Asthma Control Questionnaire (ACQ-6) and standardized Asthma Quality of Life Questionnaire [AQLQ(S)]. Asthma severity was classified according to the Global Initiative for Asthma (GINA) treatment steps. RESULTS: The putative small airway obstruction markers Sacin , resistance at 5 Hz minus resistance at 20 Hz (R5-R20) and reactance area (AX) were not independently associated with asthma severity, control, quality of life or exacerbations. In contrast, markers of total (R5) and mean airway resistance of large and small airways (R20) were significantly higher in the severe asthma group compared with the mild-moderate group (0.47 vs. 0.37, P < 0.05 for R5; 0.39 vs. 0.31, P < 0.01 for R20). The strongest independent contributors to ACQ-6 score were R20 and forced expiratory volume in one second (% pred.), and the strongest independent contributors to AQLQ(S) score were R20 and forced vital capacity (% pred.). A history of one or more exacerbations within the previous year was independently associated with R20. CONCLUSIONS AND CLINICAL RELEVANCE: Previously reported markers of small airway obstruction do not appear to be independently associated with asthma disease expression. In contrast, the IOS parameter R20, a marker of mean airway resistance of both large and small airways, appears to have independent clinical significance. These observations require confirmation in prospective longitudinal studies.

Overweight and obese children have lower cortisol levels than normal weight children.

AIM: The stress hormone cortisol is vital to survival, and a disturbed circadian rhythm can be deleterious to health. However, little is known about cortisol levels in healthy children. The aim of this study was to examine cortisol levels in relation to body mass index (BMI), age and sex. METHODS: Salivary samples were collected in early morning, late morning and evening, on four consecutive days, from 342 children aged 6-12 years using Salivette(®) tubes. Samples were analysed using a commercial enzyme immunoassay (EIA). School nurses measured the children's height and weight, and these measurements were used to calculate their BMI. RESULTS: The children displayed a circadian rhythm in cortisol secretion, with morning zeniths and evening nadirs. Average cortisol levels in early morning, late morning and evening were significantly lower in overweight and obese children than in their normal weight counterparts. Cortisol levels did not vary significantly with age or sex. CONCLUSION: Our findings may suggest cortisol suppression in overweight and obese children. We found no evidence that sex or age influences cortisol levels. These findings highlight the need for further research on the relationship between stress and obesity in children.

Child physical abuse and concurrence of other types of child abuse in Sweden-Associations with health and risk behaviors.

OBJECTIVE: To examine the associations between child physical abuse executed by a parent or caretaker and self-rated health problems/risk-taking behaviors among teenagers. Further to evaluate concurrence of other types of abuse and how these alone and in addition to child physical abuse were associated with bad health status and risk-taking behaviors. METHODS: A population-based survey was carried out in 2008 among all the pupils in 2 different grades (15 respectively 17 years old) in Södermanland County, Sweden (n=7,262). The response rate was 81.8%. The pupils were asked among other things about their exposure to child physical abuse, exposure to parental intimate violence, bullying, and exposure to being forced to engage in sexual acts. Adjusted analyses were conducted to estimate associations between exposure and ill-health/risk-taking behaviors. RESULTS: Child physical abuse was associated with poor health and risk-taking behaviors with adjusted odds ratios (OR) ranging from 1.6 to 6.2. The associations were stronger when the pupils reported repeated abuse with OR ranging from 2.0 to 13.2. Also experiencing parental intimate partner violence, bullying and being forced to engage in sexual acts was associated with poor health and risk-taking behaviors with the same graded relationship to repeated abuse. Finally there was a cumulative effect of multiple abuse in the form of being exposed to child physical abuse plus other types of abuse and the associations increased with the number of concurrent abuse. CONCLUSIONS: This study provides strong indications that child abuse is a serious public health problem based on the clear links seen between abuse and poor health and behavioral problems. Consistent with other studies showing a graded relationship between experiences of abuse and poor health/risk-taking behaviors our study shows poorer outcomes for repeated and multiple abuse. Thus, our study calls for improvement of methods of comprehensive assessments, interventions and treatment in all settings where professionals meet young people.

The effect of dornase alfa on ventilation inhomogeneity in patients with cystic fibrosis.

Outcome measures to assess therapeutic interventions in cystic fibrosis (CF) patients with mild lung disease are lacking. Our aim was to determine if the lung clearance index (LCI) can detect a treatment response to dornase alfa in paediatric CF patients with normal spirometry. CF patients between 6-18 yrs of age with FEV(1 )≥ 80% pred were eligible. In a crossover design, 17 patients received 4 weeks of dornase alfa and placebo in a randomised sequence separated by a 4-week washout period. The primary end-point was the change in LCI from dornase alfa versus placebo. A mixed model approach incorporating period-dependent baselines was used. The mean ± sd age was 10.32 ± 3.35 yrs. Dornase alfa improved LCI versus placebo (0.90 ± 1.44; p = 0.022). Forced expiratory flow at 25-75% expired volume measured by % pred and z-scores also improved in subjects on dornase alfa (6.1% ± 10.34%; p = 0.03 and 0.28 ± 0.46 z-score; p = 0.03). Dornase alfa significantly improved LCI. Therefore the LCI may be a suitable tool to assess early intervention strategies in this patient population.

ADHD symptoms and maturity - a follow-up study in school children.

AIM: To test the hypothesis that there is a subgroup of children with attention deficit hyperactivity disorder (ADHD) who show a decline in ADHD-symptoms that is associated with signs of biological maturation, a phenomenon referred to as a 'maturation catch-up'. METHODS: The parents of 147 children who were given an examination in grades one and two 1999-2000 that included assessment of ADHD-symptoms and estimation of skeletal bone-age by use of hand radiographs (which was repeated in the eighth grade), were contacted 2008-2009 and were asked to answer questions concerning ADHD-symptoms and behavioural maturity in their children. The response frequency was 67%. A complete dataset was achieved in 57 children. A reduction of Conners scores for ADHD-symptoms of eight or more between the evaluations was defined as a marked reduction in symptoms. RESULTS: When the children with a marked symptom reduction (n = 6) were compared with children without such a reduction (n = 51), we found a significant difference in skeletal maturation (p < 0.05). CONCLUSION: This study gives support to the theory that there is a group of children with ADHD-symptoms who have a biological maturational-lag who will show a decrease in their ADHD-symptoms as they show a maturation catch-up with increasing age.

Prevalence and characteristics of child physical abuse in Sweden - findings from a population-based youth survey.

AIM: To examine prevalence rates of child physical abuse perpetrated by a parent/caretaker, abuse characteristics and the extent of disclosures. METHODS: A population-based survey was carried out in 2008 amongst all the pupils in three different grades (n = 8494) in schools in Södermanland County, Sweden. The pupils were asked about their exposure to violence and their experiences of parental intimate-partner violence. Data were analysed with bi- and multivariate models and a comparison between means of accumulating risk factors between three groups were performed. RESULTS: A total of 15.2% of the children reported that they had been hit. There were strong associations between abuse and risk factors and there was a dose-response relationship between risks and reported abuse. It was shown that children who reported parental intimate-partner violence were at a considerably higher risk for abuse than other children and that only 7% of the children exposed to violence had disclosed this to authorities. CONCLUSION: Even though child abuse in Sweden has decreased markedly during the last 40 years, violence against children is still a considerable problem. It is a challenge to develop methods of assessment and interventions that will ensure that the violence and its underlying causes are directly addressed.

Low levels of exhaled nitric oxide are associated with impaired lung function in cystic fibrosis.

Fraction of exhaled nitric oxide (FENO) is often reduced in cystic fibrosis (CF). FENO at different expiratory flows can provide an indication of the site of nitric oxide production. The aim of this study was to examine whether NO parameters are related to overall (FEV(1)) or peripheral (lung clearance index, LCI, measured by multiple breath SF(6) washout) airway function and systemic inflammation in CF. Secondary aim was to compare alveolar NO and bronchial NO flux calculated by two different mathematical models, a linear and a nonlinear method. Thirty-five healthy and 45 CF children were recruited. FENO at 50 ml/sec (FENO(50)) and bronchial NO flux were lower in CF than controls, 9.5 (2.7-38.8) (median (range)) versus 12.4 (5.2-40.1) ppb, P = 0.029, and 391 (97-1772) versus 578 (123-1993) (pl/sec), P = 0.036, respectively. No difference in alveolar NO was shown. The nonlinear method resulted in lower alveolar NO and higher bronchial flux, than the linear method, but the result was closely correlated in both groups. LCI was higher in CF than controls, 8.4 (6.5-12.9) versus 5.9 (5.1-7.8), P < 0.001. FENO(50) was negatively correlated with LCI (r = -0.43; P = 0.003) and positively correlated with FEV(1) (r = 0.42, P = 0.004) in CF. Alveolar NO correlated negatively with inflammatory markers: orosomucoid (r = -0.42, P = 0.005), platelets (r = -0.50, P < 0.001) and white blood cell count (r = -0.48, P = 0.001). In conclusion, FENO(50) and bronchial NO flux are reduced in young CF subjects and low FENO(50) is associated with overall and small airway obstruction. NO parameters derived from the different models were closely related but the values differed slightly.

Decision making about pre-medication to children.

BACKGROUND: Inviting the child to participate in medical decisions regarding common medical procedures might influence the child's behaviour during the procedures. We wanted to study nurse decision-making communication regarding pre-medication before ear, nose and throat (ENT) surgery. METHOD: In total, 102 children (3-6 years) signed for ENT surgery were video-filmed during the pre-medication process. The nurse decision-making communication was identified, transcribed and grouped in six main categories dependent on the level of participation (self-determination, compromise, negotiation, questioning, information, lack of communication). Associations between child factors (age, gender, verbal communication and non-verbal communication) and different nurse decision-making communication were studied. Associations between the decision-making communication and verbal hesitation and/or the child's compliance in taking pre-medication were also studied. RESULTS: Totally, information was the most frequently used category of decision making communication followed by negotiation and questioning. To the children showing signs of shyness, the nurse used more negotiation, questions and self-determination communication and less information. The nurse used more compromise, negotiation and gave less information to children with less compliance. No specific type of nurse decision-making communication was associated with verbal hesitation. The most important predictors for verbal hesitation were none or hesitant eye contact with nurse (OR = 4.5) and placement nearby or in parent's lap (OR = 4.7). Predictors for less compliance in taking pre-medication were verbal hesitation from the child (OR = 22.7) and children who did not give any verbal answer to nurse initial questions (OR = 5.5). CONCLUSION: Decision-making communication could not predict the child's compliance during pre-medication. Although negotiation, questioning and self-determination communication were associated with more unwillingness to take pre-medication. More knowledge is needed about communication to children in medical settings and how it influences the child's behaviours.