Changed sleep according to weighted blanket adherence in a 16-week sleep intervention among children with attention-deficit/hyperactivity disorder.

STUDY OBJECTIVES: To examine differences in sample characteristics and longitudinal sleep outcomes according to weighted blanket adherence. METHODS: Children with attention-deficit/hyperactivity disorder (ADHD) (n =94), mean age 9.0 (sd 2.2, range 6-14) participated in a 16-week sleep intervention with weighted blankets (WB). Children were classified as WB adherent (use of WB ≥ 4 nights/week) or non-adherent (use of WB ≤ 3 nights/week). Changes in objectively measured sleep by actigraphy, parent-reported sleep problems (Children's Sleep Habits Questionnaire (CSHQ)) and child-reported Insomnia Severity Index (ISI) were evaluated according to adherence with mixed effect models. Gender, age, and ADHD subtype were examined as potential moderators. RESULTS: Children adherent to WBs (48/94) showed an early response in sleep outcomes and an acceptance of the WB after four weeks of use as well as a decrease in parent- (CSHQ) (-5.73, P = .000) and child-reported sleep problems (ISI) (-4.29, P = .005) after 16 weeks. The improvement in sleep was larger among WB adherent vs. non-adherent (between-group difference: CSHQ: -2.09, P = .038; ISI: -2.58, P =.007). Total sleep time was stable for children adherent to WB but decreased for non-adherent (between-group difference: +16.90, P = .019). CONCLUSIONS: An early response in sleep and acceptance of the WB predicted later adherence to WBs. Improvements in sleep were more likely among WB adherents vs. non-adherents. Children with ADHD may thus benefit from using WBs to handle their sleep problems.

The efficacy of weighted blankets for sleep in children with attention-deficit/hyperactivity disorder-A randomized controlled crossover trial.

Weighted blankets are a non-pharmacological intervention for treating sleep and anxiety problems in children with attention-deficit/hyperactivity disorder. However, research on the efficacy of weighted blankets is sparse. The aim of this randomized controlled trial with a crossover design (4 + 4 weeks) was to evaluate the efficacy of weighted blankets on sleep among children with attention-deficit/hyperactivity disorder and sleeping problems. Children diagnosed with uncomplicated Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition attention-deficit/hyperactivity disorder with verified sleep problems were randomized to start with either a weighted blanket or a lighter control blanket. Data collection was performed at weeks 0, 4 and 8 using actigraphy, questionnaires and a daily sleep diary. T-tests were used to evaluate efficacy. The study included 94 children with attention-deficit/hyperactivity disorder (mean age 9.0 [sd 2.2] years; 54 [57.4%] boys). Weighted blankets had a significant effect on total sleep time (mean diff. 7.72 min, p = 0.027, Cohen's d = 0.24), sleep efficiency (mean diff. 0.82%, p = 0.038, Cohen's d = 0.23) and wake after sleep onset (mean diff. -2.79 min, p = 0.015, Cohen's d = -0.27), but not on sleep-onset latency (p = 0.432). According to our exploratory subgroup analyses, weighted blankets may be especially beneficial for improving total sleep time in children aged 11-14 years (Cohen's d = 0.53, p = 0.009) and in children with the inattentive attention-deficit/hyperactivity disorder subtype (Cohen's d = 0.58, p = 0.016). Our results suggest that weighted blankets may improve children's sleep and could be used as an alternative to pharmacological sleep interventions.

Experiences of Using Weighted Blankets among Children with ADHD and Sleeping Difficulties.

Introduction: Sleeping difficulties are common in children with attention deficit hyperactivity disorder (ADHD). A sleep intervention with weighted blankets was designed to increase current understanding of using weighted blankets to target children's individual needs in connection with sleep and daytime functioning. Aim: To explore how children with ADHD and sleeping difficulties experience the use of weighted blankets. Methods: An explorative qualitative design in which 26 children with ADHD and sleeping difficulties, 6-15 years old, were interviewed about a sleep intervention with weighted blankets. Four categories emerged from qualitative content analysis. Results: Children's experiences revealed that the use of weighted blankets 1) requires a commitment, by adjusting according to needs and preferences and adapting to the environment; 2) improves emotional regulation by feeling calm and feeling safe; 3) changes sleeping patterns by creating new routines for sleep and improving sleep quality; and 4) promotes everyday participation by promoting daily function and balancing activity and sleep. Conclusions: Using weighted blankets promoted children's management of daily life with ADHD and sleeping difficulties. Occupational therapists can improve the assessment and delivery of weighted blankets tailored to individual needs based on increased knowledge from the children themselves.

Development of a Digital Decision Support Tool to Aid Participation of Children With Disabilities in Pediatric Rehabilitation Services: Explorative Qualitative Study.

BACKGROUND: Building a health care system in accordance with the rule of law requires child-centered care, where children and young people, regardless of ability, are allowed to participate in visits with their health care professionals. As part of an overall project focusing on developing and implementing a digital decision support tool to increase the participation of children with disabilities in pediatric rehabilitation, this study brings new knowledge as to how this specific patient group views participation. OBJECTIVE: The aim of this formative study was to explore the experiences of children and young people with disabilities concerning increasing their participation in the pediatric rehabilitation services. METHODS: The formative study had an explorative design, based on a latent qualitative content analysis with an inductive approach. Interviews were conducted with 20 children (6-17 years) and 8 young people (19-30 years) with disabilities about their experiences of participation in pediatric rehabilitation services. RESULTS: A total of 3 categories emerged reflecting the participants' possibilities of participation in the pediatric rehabilitation services: to feel involved, to feel independent, and to work in partnership. To feel involved meant being listened to and being connected, to feel independent meant being admitted and being enabled, and to work in partnership meant being supported and being able to entrust others with the decision making. With the overall theme moving toward empowerment of children in pediatric rehabilitation, a true feeling of participation can be experienced. CONCLUSIONS: The views of children and young people with disabilities are that children should be given the prerequisites for empowerment by being allowed to feel involved and independent as well as to work in partnership to experience true participation in the pediatric rehabilitation services. This finding is essential in the design of a digital decision support tool based on the children's needs and perspectives.

Occupational exposure to particles and incidence of stroke.

OBJECTIVES: This paper aims to investigate the relation between occupational exposure to particles, particle size, and the incidence of ischemic and hemorrhagic stroke. METHODS: The cohort included all manual workers identified from the Swedish National Census in 1980, who were alive as of 1 January 1987. First time events of ischemic or hemorrhagic stroke during the period 1987-2005 were identified through linkage to the Hospital Discharge Register and the National Cause of Death Register. A job-exposure matrix for exposure to small (<1 µm) and large (>1 µm) particles was developed and applied. Hazard ratios (HR) were estimated by Cox regression with adjustment for age, socioeconomic group, and residential area. RESULTS: Increased HR of ischemic stroke were found among both women and men occupationally exposed to small as well as large particles for ≥5 years. The risks were higher for workers exposed for ≥5 years compared to "ever exposed" participants indicating a dose-response relationship, but no trend with exposure intensity was observed. A tentative association between particle exposure and hemorrhagic stroke was also found. CONCLUSIONS: Occupational exposure to small and large particles was associated with increased risks of ischemic stroke. Further studies are needed to explore the relationships between exposure to different types of particles and various doses and the occurrence of stroke among women as well as men.

Incidence of myocardial infarction among cooks and other restaurant workers in Sweden 1987-2005.

OBJECTIVES: The aim of this study was to investigate the incidence of myocardial infarction (MI) among cooks and other restaurant workers. METHODS: A prospective cohort study comprised manual workers in the service sector in the Swedish National Census of 1985, totaling 543 497 women and 233 999 men. Restaurant workers were identified by occupational codes. Information on first time MI during 1987-2005 was obtained from nation-wide registers. We used Cox proportional hazards modeling, with separate analyses for men and women, adjusting for age, hypertension, diabetes, and socioeconomic status. RESULTS: Female cooks, restaurant and kitchen assistants, and wait staff all showed a statistically significant increase in risk of MI [hazard ratio (HR) 1.34, 95% confidence interval (95% CI) 1.21-1.48; HR 1.12, 95% CI 1.03-1.21; and HR 1.25, 95% CI 1.06-1.47, respectively]. No increased risk was found among female cold-buffet managers. Among men, there was no statistically significant increase in risk for any of these occupations. The association was not stronger for subjects working ≥5 years. Group level information on smoking habits showed a similar percentage of daily smokers among female cooks compared to female manual workers in general. CONCLUSIONS: We found an increased risk of MI among female but not male cooks, restaurant and kitchen assistants, and wait staff. The excess risk may be related to occupational factors, but the results do not clearly support the hypothesis of cooking fumes as a risk factor for MI. Job strain could be a potential explanation for the findings.

Actions of "antioxidants" in the protection against atherosclerosis.

This review addresses the role of oxidative processes in atherosclerosis and its resulting cardiovascular disease by focusing on the outcome of antioxidant interventions. Although there is unambiguous evidence for the presence of heightened oxidative stress and resulting damage in atherosclerosis, it remains to be established whether this represents a cause or a consequence of the disease. This critical question is complicated further by the increasing realization that oxidative processes, including those related to signaling, are part of normal cell function. Overall, the results from animal interventions suggest that antioxidants provide benefit neither generally nor consistently. Where benefit is observed, it appears to be achieved at least in part via modulation of biological processes such as increase in nitric oxide bioavailability and induction of protective enzymes such as heme oxygenase-1, rather than via inhibition of oxidative processes and lipid oxidation in the arterial wall. Exceptions to this may be situations of multiple/excessive stress, the relevance of which for humans is not clear. This interpretation is consistent with the overall disappointing outcome of antioxidant interventions in humans and can be rationalized by the spatial compartmentalization of cellular oxidative signaling and/or damage, complex roles of oxidant-producing enzymes, and the multifactorial nature of atherosclerosis.

Occupational exposure to particles and incidence of acute myocardial infarction and other ischaemic heart disease.

BACKGROUND: Ambient particulate air pollution has been linked to cardiovascular disease. Occupational particle exposure levels may be several times higher than ambient levels but has been less studied. OBJECTIVES: The authors investigated the association between occupational exposure to particles and the incidence of ischaemic heart disease (IHD). METHODS: The cohort included all manual workers in the Swedish national census of 1980 with information on demographic data and occupation. Information on hospital admissions for acute myocardial infarction or other IHDs and cause of death were obtained from nation-wide registers. A job-exposure matrix for exposure to small (<1 µm) and large (>1 µm) particles was developed. HRs were calculated with Cox regression with adjustment for sex, age, socioeconomic group and urban/rural residential area. RESULTS: Exposure to small particles was associated with an increased HR for acute myocardial infarction of 1.12 (95% CI 1.09 to 1.15), and HR for exposure to large particles was 1.14 (95% CI 1.10 to 1.18). The association was somewhat stronger for workers exposed to small particles for more than 5 years, 1.21 (95% CI 1.11 to 1.31), but no trend with exposure intensity was found. The risk associated with exposure to small particles was higher among women than among men, 1.30 (95% CI 1.12 to 1.51) and 1.10 (95% CI 1.07 to 1.14), respectively. Findings were essentially similar for other IHDs. CONCLUSIONS: This explorative study gives some support to the hypothesis that occupational exposure to particles increases the risk of acute myocardial infarction and other IHD. The findings must be interpreted cautiously due to lack of smoking data.

Sustained expression of heme oxygenase-1 alters iron homeostasis in nonerythroid cells.

Heme oxygenases initiate the catabolism of heme, releasing carbon monoxide, iron, and biliverdin. Sustained induction of heme oxygenase-1 (HO-1) in nonerythroid cells plays a key role in many pathological processes, yet the effect of long-term HO-1 expression on cellular iron metabolism in the absence of exogenous heme is poorly understood. Here we report that in a model nonerythroid cell, both transient and stable HO-1 expression increased heme oxygenase activity, but total cellular heme content was decreased only with transient enzyme expression. Sustained HO-1 activity increased the expression of both the mitochondrial iron importer mitoferrin-2 and the rate-limiting enzyme in heme synthesis, aminolevulinate synthase-1, and it augmented the mitochondrial content of heme. Also, the expression of transferrin receptor-1 and the activities of iron-regulatory proteins 1 and 2 decreased, whereas total labile iron and the regulatory activity of the heme-binding transcription factor Bach1 were unaltered. In addition, stable, but not transient, HO-1 expression decreased the activities of aconitase, as well as increasing proteasomal degradation of ferritin. Together, our results reveal a novel and coordinated adaptive response of nonerythroid cells to sustained HO-1 induction that has an impact on cellular iron homeostasis.

Both thioredoxin 2 and glutaredoxin 2 contribute to the reduction of the mitochondrial 2-Cys peroxiredoxin Prx3.

The proteins from the thioredoxin family are crucial actors in redox signaling and the cellular response to oxidative stress. The major intracellular source for oxygen radicals are the components of the respiratory chain in mitochondria. Here, we show that the mitochondrial 2-Cys peroxiredoxin (Prx3) is not only substrate for thioredoxin 2 (Trx2), but can also be reduced by glutaredoxin 2 (Grx2) via the dithiol reaction mechanism. Grx2 reduces Prx3 exhibiting catalytic constants (K(m), 23.8 µmol·liter(-1); V(max), 1.2 µmol·(mg·min)(-1)) similar to Trx2 (K(m), 11.2 µmol·liter(-1); V(max), 1.1 µmol·(mg·min)(-1)). The reduction of the catalytic disulfide of the atypical 2-Cys Prx5 is limited to the Trx system. Silencing the expression of either Trx2 or Grx2 in HeLa cells using specific siRNAs did not change the monomer:dimer ratio of Prx3 detected by a specific 2-Cys Prx redox blot. Only combined silencing of the expression of both proteins led to an accumulation of oxidized protein. We further demonstrate that the distribution of Prx3 in different mouse tissues is either linked to the distribution of Trx2 or Grx2. These results introduce Grx2 as a novel electron donor for Prx3, providing further insights into pivotal cellular redox signaling mechanisms.

Penultimate selenocysteine residue replaced by cysteine in thioredoxin reductase from selenium-deficient rat liver.

Selenium is an essential micronutrient for humans and animals, and its deficiency can predispose to the development of pathological conditions. This study evaluates the effect of selenium deficiency on the thioredoxin system, consisting of NADPH, selenoprotein thioredoxin reductase (TrxR), and thioredoxin (Trx); and the glutathione system, including NADPH, glutathione reductase, glutathione, and glutaredoxin coupled with selenoprotein glutathione peroxidase (GPx). We particularly investigate whether inactive truncated TrxR is present under selenium-starvation conditions due to reading of the UGA codon as stop. Feeding rats a selenium-deficient diet resulted in a large decrease in activity of TrxR and GPx in rat liver but not in the levels of Trx1 and Grx1. However, selenium deficiency induced mitochondrial Grx2 10-fold and markedly changed the expression of some flavoproteins that are involved in the cellular folate, glucose, and lipid metabolism. Liver TrxR mRNA was nearly unchanged, but no truncated enzyme was found. Instead, a low-activity form of TrxR with a cysteine substituted for the penultimate selenocysteine in the C-terminal active site was identified in selenium-deficient rat liver. These results show a novel mechanism for decoding the UGA stop codon, inserting cysteine to make a full-length enzyme that may be required for selenium assimilation.

Impaired nuclear Nrf2 translocation undermines the oxidative stress response in Friedreich ataxia.

BACKGROUND: Friedreich ataxia originates from a decrease in mitochondrial frataxin, which causes the death of a subset of neurons. The biochemical hallmarks of the disease include low activity of the iron sulfur cluster-containing proteins (ISP) and impairment of antioxidant defense mechanisms that may play a major role in disease progression. METHODOLOGY/PRINCIPAL FINDINGS: We thus investigated signaling pathways involved in antioxidant defense mechanisms. We showed that cultured fibroblasts from patients with Friedreich ataxia exhibited hypersensitivity to oxidative insults because of an impairment in the Nrf2 signaling pathway, which led to faulty induction of antioxidant enzymes. This impairment originated from previously reported actin remodeling by hydrogen peroxide. CONCLUSIONS/SIGNIFICANCE: Thus, the defective machinery for ISP synthesis by causing mitochondrial iron dysmetabolism increases hydrogen peroxide production that accounts for the increased susceptibility to oxidative stress.

Identification, expression pattern, and characterization of mouse glutaredoxin 2 isoforms.

Glutaredoxin 2 (Grx2) is a glutathione-dependent oxidoreductase involved in the maintenance of mitochondrial redox homeostasis. Grx2 was first characterized as mitochondrial protein, but alternative mRNA variants lacking the transit peptide-encoding first exon were demonstrated for human and proposed for mouse. We systematically screened for alternative transcript variants of mouse Grx2. We identified a total of six exons, three constitutive (II, III, and IV), two alternative first exons (exons Ia and Ic), and one single-cassette exon (exon IIIb) located between exons III and IV. Exons Ic and IIIb are not present in the human genome; mice lack human exon Ib. The six exons give rise to five transcript variants that encode three protein isoforms: mitochondrial Grx2a, a cytosolic isoform that is homologous to the cytosolic/nuclear human Grx2c and present in specific cells of many tissues and the testis-specific isoform Grx2d that is unique to mice. Mouse Grx2c can form an iron/sulfur cluster-bridged dimer, is enzymatically active as a monomer, and can donate electrons to ribonucleotide reductase. Testicular cells lack mitochondrial Grx2a but contain cytosolic Grx2. Prominent immunostaining was detected in spermatogonia and spermatids. These results provide evidence for additional functions of Grx2 in the cytosol, in cell proliferation, and in cellular differentiation.

Expression pattern of human glutaredoxin 2 isoforms: identification and characterization of two testis/cancer cell-specific isoforms.

The cellular redox state is associated with major cellular processes including differentiation, transformation, and apoptosis. Glutaredoxin 2 (Grx2) is a mitochondrial oxidoreductase suggested to play a critical role in protection against apoptotic stimuli. An alternative Grx2 transcript variant encoding a nonmitochondrial protein (Grx2b) was proposed before, but no data was available on the expression of this isoform. We have systematically investigated the expression of Grx2 transcript variants in human tissues and transformed cell lines. The transcript variant encoding mitochondrial Grx2 (Grx2a) was found to be ubiquitously expressed, emphasizing the general importance of the protein for mitochondrial redox homeostasis. In addition, we confirmed the previously suggested isoform Grx2b and identified a new third isoform (Grx2c) derived from alternative splicing of the Grx2b-encoding transcript. In normal tissue expression of both Grx2b and Grx2c was restricted to testes, but additionally we were able to demonstrate transcripts in various cancer cell lines. Both Grx2b and Grx2c are enzymatically active, but only Grx2c can complex the regulatory iron-sulfur cluster described for Grx2a. Expression of GFP fusion proteins suggested a cytosolic and nuclear localization of both Grx2b and Grx2c. Our findings provide the first evidence for functions of Grx2 outside mitochondria.

Characterization of human glutaredoxin 2 as iron-sulfur protein: a possible role as redox sensor.

Human mitochondrial glutaredoxin 2 (Grx2) is a glutathione-dependent oxidoreductase (active site: Cys-Ser-Tyr-Cys) that facilitates the maintenance of mitochondrial redox homeostasis upon induction of apoptosis by oxidative stress. Here, we have characterized Grx2 as an iron-sulfur center-containing member of the thioredoxin fold protein family. Mossbauer spectroscopy revealed the presence of a four cysteine-coordinated nonoxidizable [2Fe-2S]2+ cluster that bridges two Grx2 molecules via two structural Cys residues to form dimeric holo Grx2. Coimmunoprecipitation of radiolabeled iron with Grx2 from human cell lines indicated the presence of the cluster in vivo. The [2Fe-2S]-bridged dimer was enzymatically inactive, but degradation of the cluster and the resulting monomerization of Grx2 activated the protein. Slow degradation under aerobic conditions was prevented by the presence of glutathione, whereas glutathione disulfide as well as one-electron oxidants or reductants promoted monomerization of Grx2. We propose that the iron-sulfur cluster serves as a redox sensor for the activation of Grx2 during conditions of oxidative stress when free radicals are formed and the glutathione pool becomes oxidized.

Short interfering RNA-mediated silencing of glutaredoxin 2 increases the sensitivity of HeLa cells toward doxorubicin and phenylarsine oxide.

Glutaredoxin (Grx) belongs to the thioredoxin fold superfamily and catalyzes glutathione-dependent oxidoreductions. The recently discovered mitochondrial and nuclear Grx (Grx2) differs from the more abundant cytosolic Grx (Grx1) by its higher affinity toward S-glutathionylated proteins and by being a substrate for thioredoxin reductase. Here, we have successfully established a method to silence the expression of Grx2 in HeLa cells by using short interfering RNA to study its role in the cell. Cells with levels of Grx2 <3% of the control were dramatically sensitized to cell death induced by doxorubicin/adriamycin and phenylarsine oxide but did not show signs of a general increase in oxidative damage with respect to carbonylation and glutathionylation. The ED(50) for doxorubicin dropped from 40 to 0.7 microM and for phenylarsine oxide from 200 to 5 nM. However, no differences were detected after treatment with cadmium, a known inhibitor of Grx1. These results indicate a crucial role of Grx2 in the regulation of the mitochondrial redox status and regulation of cell death at the mitochondrial checkpoint.