Variation in mitochondrial DNA levels in muscle from normal controls. Is depletion of mtDNA in patients with mitochondrial myopathy a distinct clinical syndrome?

Summary Recent studies have identified a group of patients with cytochrome oxidase (COX) deficiency presenting in infancy associated with a deficiency of mtDNA in muscle or other affected tissue (Moraes et al 1991). We used a novel approach to compare the level of mitochondrial (mtDNA) compared to nuclear DNA in skeletal muscle from a group of patients and controls, based on dot blots that were hybridized with a mtDNA probe labelled with³⁵S[dCTP] and a reference nuclear DNA probe labelled with [³²P]dCTP.The ratio of mtDNA to nuclear DNA varied in samples from different muscles of the same individual. Secondly, fetal muscle had very low levels of mtDNA compared to nuclear DNA, and data from older controls (cross-sectional rather than sequential) suggest that this increases rapidly over the first 3 months after birth and thereafter more slowly. Four patients with COX deficiency had levels of mtDNA that were below the age-specific range defined by normal quadriceps muscle. The clinical features of two of these patients were similar to earlier case reports of mtDNA depletion. In three patients the clinical course was relatively benign compared to cases that have previously been described.Levels of mtDNA in skeletal muscle from some patients with other forms of muscle disease were also found to be low, suggesting that mtDNA depletion, possibly related to depletion of mitochondria, may be a relatively non-specific response of muscle to various pathological processes. However, there does appear to be a distinctive group of young patients with reduced cytochrome oxidase activity in muscle, in whom marked mtDNA depletion reflects the primary defect.     

Long-term risk of adverse cardiovascular outcomes associated with cutaneous lupus erythematosus: a nationwide cohort study

Clinical Rheumatology - Autoimmune diseases, including systemic lupus erythematosus, have been associated with a substantial risk of cardiovascular morbidity and mortality. However, data on the...     

Workplace Bullying and Suicidal Ideation: A 3-Wave Longitudinal Norwegian Study

Objectives. We examined whether victimization from bullying is related to an increased risk of suicidal ideation over time and whether suicidal ideation is related to subsequent bullying.Methods. In a longitudinal study (2005–2010), we used well-established single-item measures to assess victimization from bullying and suicidal ideation. We used latent Markov models to determine forward and reverse relationships between variables at 3 time points with 2 or 3 years between the measurement points among a randomized nationwide sample of 1846 employees in Norway.Results. Victimization from bullying was associated with subsequent suicidal ideation (odds ratio = 2.05; 95% confidence interval = 1.08, 3.89). Suicidal ideation at baseline was not related to subsequent victimization from workplace bullying.Conclusions. Workplace bullying may be a precursor to suicidal ideation, whereas suicidal ideation seems to have no impact on subsequent risk of being bullied. Regulations against bullying should be integrated into work-related legislation and public health policies.Suicide is a leading cause of death around the globe. Estimates show that more than 800 000 people take their own lives every year.1 In Norway (with a population of 5 165 802) there are about 530 reported suicides every year.2 In the United States, 12 suicide deaths per 100 000 people were reported in 2010, making suicide the 10th leading cause of death among Americans.3 Altogether, 1719 employees committed suicide in US workplaces between 2003 and 2010.4Although psychiatric disorders are involved in the majority of suicide attempts,5 most psychiatric patients do not commit suicide. A psychiatric disorder alone is, therefore, an insufficient condition for suicide.6 To identify other risk factors, we must look beyond the presence of a psychiatric syndrome and understand the underlying factors of suicide and suicidal ideation. Among many potential causes, exposure to workplace bullying has been proposed to be an important predictor of both suicidal ideation and actual suicide.7,8To date, bullying as an antecedent to suicide has been examined only with anecdotal evidence9,10 and cross-sectional research designs.11,12 Einarsen et al.13 established that severely bullied workers were 6 times more likely than nonbullied workers to report suicidal ideations. Sterud et al.8 found that workplace bullying was positively associated with suicidal ideation in a nationwide sample of 1022 Norwegian ambulance personnel. Bullying was more strongly associated with suicidal ideation than were gender, neuroticism, anxiety, somatic complaints, depersonalization, and job dissatisfaction.Cross-sectional research cannot provide adequate evidence for anything more than that suicidal ideation is a correlate of bullying. To understand the directional nature of the association, longitudinal research is needed. In this representative, longitudinal study, we contribute to the literature by examining whether victimization from bullying is related to increased risk of suicidal ideation over time and whether suicidal ideation is related to subsequent bullying.Workplace bullying refers to a situation in which 1 or several individuals persistently perceive themselves to be on the receiving end of negative actions from superiors or co-workers and in which the targets find it difficult to defend themselves against these actions.14,15 Following this definition, there are 3 main characteristics of workplace bullying: (1) an employee becomes the target of systematic negative and unwanted social behavior in the workplace; (2) the exposure occurs over a prolonged period, often with ever more escalating intensity and frequency in the attacks; and (3) targets feel they cannot easily escape the situation or stop the unwanted treatment. This third characteristic, the feeling of being victimized by the harassment, distinguishes bullying from other forms of mistreatment in the workplace.15 Globally, about 11% of workers perceive themselves as victims of bullying,16 and 5% of the Norwegian working population is victimized by bullying at any time.17The interpersonal theory of suicide (ITS)5 provides a theoretical foundation for how exposure to such bullying may be related to suicide. The theory posits that fundamental to suicidal ideation and behavior is that an individual has both the desire and the ability to die by suicide.18 With regard to the desire to die, displayed through suicidal ideation, the ITS asserts that when people over a prolonged period perceive themselves to be socially alienated from others and simultaneously feel that they are a burden on others, they develop a desire for death.19 As for the ability to commit suicide, displayed through suicidal behavior, the ITS proposes that people who are repeatedly exposed to painful and provocative events will lose any fear of pain, injury, and death and thereby be able to overcome the instinct of self-preservation.Because of its focus on persistent exposure to painful events and social alienation, the ITS strongly suggests that repeated and long-term exposure to negative treatment and social exclusion from one’s peers or supervisors at work constitutes a risk factor for suicidal ideation and behavior.Although previous research has assumed bullying to be an antecedent to suicidal ideation, it is possible that the established cross-sectional association reflects a relationship in which suicidal ideation is a precursor to bullying. Two different mechanisms can explain such a reverse association. First, employees with suicidal ideation may report less favorable work characteristics because their distress makes them evaluate their work environment increasingly more negatively.20 Second, employees with suicidal ideations may elicit aggressive behavior in others because their psychological state creates aversive feelings among co-workers and supervisors.21,22To provide better indications of how workplace bullying is related to suicidal ideation, we investigated direct forward and reverse associations with longitudinal data. We tested the following hypotheses:

• Hypothesis 1: Victimization from bullying is associated with an increased risk of later suicidal ideation.
• Hypothesis 2: Suicidal ideation is associated with an increased risk of later victimization from bullying.

     

Ritual circumcision and risk of autism spectrum disorder in 0- to 9-year-old boys: national cohort study in Denmark

Objective

Based on converging observations in animal, clinical and ecological studies, we hypothesised a possible impact of ritual circumcision on the subsequent risk of autism spectrum disorder (ASD) in young boys.

Design

National, register-based cohort study.

Setting

Denmark.

Participants

A total of 342,877 boys born between 1994 and 2003 and followed in the age span 0–9 years between 1994 and 2013.

Main outcome measures

Information about cohort members’ ritual circumcisions, confounders and ASD outcomes, as well as two supplementary outcomes, hyperkinetic disorder and asthma, was obtained from national registers. Hazard ratios (HRs) with 95% confidence intervals (CIs) associated with foreskin status were obtained using Cox proportional hazards regression analyses.

Results

With a total of 4986 ASD cases, our study showed that regardless of cultural background circumcised boys were more likely than intact boys to develop ASD before age 10 years (HR = 1.46; 95% CI: 1.11–1.93). Risk was particularly high for infantile autism before age five years (HR = 2.06; 95% CI: 1.36–3.13). Circumcised boys in non-Muslim families were also more likely to develop hyperkinetic disorder (HR = 1.81; 95% CI: 1.11–2.96). Associations with asthma were consistently inconspicuous (HR = 0.96; 95% CI: 0.84–1.10).

Conclusions

We confirmed our hypothesis that boys who undergo ritual circumcision may run a greater risk of developing ASD. This finding, and the unexpected observation of an increased risk of hyperactivity disorder among circumcised boys in non-Muslim families, need attention, particularly because data limitations most likely rendered our HR estimates conservative. Considering the widespread practice of non-therapeutic circumcision in infancy and childhood around the world, confirmatory studies should be given priority.