Prevalence of shift work disorder among hospital personnel: A cross‐sectional study using objective working hour data

The prevalence of shift work disorder (SWD) has been studied using self‐reported data and the International Classification of Sleep Disorders, Second Edition (ICSD‐2) criteria. We examined the prevalence in relation to ICSD‐2 and ICSD‐3 criteria, work schedules and the number of non‐day shifts (work outside 06:00–18:00 hours) using objective working‐hours data. Secondly, we explored a minimum cut‐off for the occurrence of SWD symptoms. Hospital shift workers without (n = 1,813) and with night shifts (n = 2,917) and permanent night workers (n = 84) answered a survey (response rate 69%) on SWD and fatigue on days off. The prevalence of SWD was calculated for groups with ≥1, ≥3, ≥5 and ≥7 monthly non‐day shifts utilizing the working hours registry. ICSD‐3‐based SWD prevalence was 2.5%–3.7% (shift workers without nights), 2.6%–9.5% (shift workers with nights) and 6.0% (permanent night workers), depending on the cut‐off of non‐day shifts (≥7–1/month, respectively). The ICSD‐2‐based prevalence was higher: 7.1%–9.2%, 5.6%–33.5% and 16.7%, respectively. The prevalence was significantly higher among shift workers with than those without nights (p‐values <.001) when using the cut‐offs of ≥1–3 non‐day shifts. Shift workers with nights who had ≥3 days with ICSD‐3‐based SWD symptoms/month more commonly had fatigue on days off (49.3%) than those below the cut‐off (35.8%, p < .05). The ICSD‐3 criteria provided lower estimates for SWD prevalence than ISCD‐2 criteria, similarly to exclusion of employees with the fewest non‐day shifts. The results suggest that a plausible cut‐off for days with ICSD‐3‐based SWD symptoms is ≥3/month, resulting in 3%–6% prevalence of SWD.     

Patients’ and next-of-kins’ attitudes towards compulsory psychiatric care

The introduction of a new Civil Commitment Act in Sweden in 1992 involved a shift of emphasis from medical to judicial authority. Little is known about general patient attitudes to compulsory care. The aim of the study was to study possible differences in attitudes, before and after the mental health law reform, among involuntarily and voluntarily admitted patients and their next-of-kins towards involuntary psychiatric admission. Samples of 84 committed and 84 voluntarily admitted patients in 1991 and 118 committed and 117 voluntarily admitted patients in 1997–99 were interviewed within 5 days from admission and at discharge, or after 3 weeks of care. Samples of 64 next-of-kins to the committed patients and 69 next-of-kins to the voluntarily admitted patients in 1991, and 73 and 89 next-of-kins, respectively, in 1997–99 were interviewed approximately 1 month after the admission. Few changes in attitudes were found between the two study occasions. A majority of all patients stated that it should be possible to compulsorily admit patients, and a great majority of the patients and the next-of kins stated that decisions regarding compulsory admission should be taken by doctors. Most patients and next-of-kins regarded decisions about involuntary psychiatric care mainly as a medical matter. Strong support for coercion in order to protect the patient and others was found among next-of-kins. The law reform was not reflected in attitudinal differences.     

Mitochondrial encephalomyopathy and retinoblastoma explained by compound heterozygosity of SUCLA2 point mutation and 13q14 deletion

Mutations in SUCLA2, encoding the ß-subunit of succinyl-CoA synthetase of Krebs cycle, are one cause of mitochondrial DNA depletion syndrome. Patients have been reported to have severe progressive childhood-onset encephalomyopathy, and methylmalonic aciduria, often leading to death in childhood. We studied two families, with children manifesting with slowly progressive mitochondrial encephalomyopathy, hearing impairment and transient methylmalonic aciduria, without mtDNA depletion. The other family also showed dominant inheritance of bilateral retinoblastoma, which coexisted with mitochondrial encephalomyopathy in one patient. We found a variant in SUCLA2 leading to Asp333Gly change, homozygous in one patient and compound heterozygous in one. The latter patient also carried a deletion of 13q14 of the other allele, discovered with molecular karyotyping. The deletion spanned both SUCLA2 and RB1 gene regions, leading to manifestation of both mitochondrial disease and retinoblastoma. We made a homology model for human succinyl-CoA synthetase and used it for structure–function analysis of all reported pathogenic mutations in SUCLA2. On the basis of our model, all previously described mutations were predicted to result in decreased amounts of incorrectly assembled protein or disruption of ADP phosphorylation, explaining the severe early lethal manifestations. However, the Asp333Gly change was predicted to reduce the activity of the otherwise functional enzyme. On the basis of our findings, SUCLA2 mutations should be analyzed in patients with slowly progressive encephalomyopathy, even in the absence of methylmalonic aciduria or mitochondrial DNA depletion. In addition, an encephalomyopathy in a patient with retinoblastoma suggests mutations affecting SUCLA2.Mitochondrial diseases are caused by genetic defects in nuclear or mitochondrial DNA (mtDNA) that disrupt function of the respiratory chain, compromising the synthesis of ATP. Most childhood-onset phenotypes are caused by autosomal recessive mutations in nuclear-encoded mitochondrial proteins. Mitochondrial diseases can manifest at any age, with almost any symptom, in almost any tissue, although the tissues with the largest dependence on oxidative energy supply, such as the central nervous system, sensory organs and skeletal muscle,¹ are most commonly affected. The wide clinical and genetic heterogeneity with overlapping phenotypes makes the diagnostics of mitochondrial diseases challenging.²mtDNA depletion syndrome is associated with many clinical phenotypes and has a variable genetic background. It can be caused by several nuclear genes, which typically impair mtDNA replication, repair or nucleotide synthesis.³ One of these genes is SUCLA2, encoding the β-subunit of the Krebs cycle enzyme ADP-forming succinyl-CoA synthetase (SCS-A). SCS catalyzes the reversible conversion of succinyl-CoA to succinate, accompanied by substrate-level phosphorylation of ADP or GDP.⁴ The enzyme is a heterodimer composed of a catalytic α-subunit, encoded by SUCLG1 and a β-subunit that determines the enzymes'' substrate specificity for either ADP (SUCLA2) or GDP (SUCLG2). SCS is widely expressed in mammalian tissues, with predominance of either the ADP- or GDP-forming form in each tissue. SUCLG1 is ubiquitously expressed, whereas expression of SUCLA2 dominates in catabolic tissues, in which the main source of energy is ATP, such as the brain, and is induced in heart and skeletal muscle.^{4, 5} Patients with SUCLA2 mutations typically have progressive childhood-onset Leigh-like encephalomyopathy associated with dystonia, hypotonia, sensorineural hearing deficit, lesions of the basal ganglia, depletion of mtDNA and methylmalonic aciduria.^{3, 6} Over 20 patients and five different mutations in SUCLA2 have been described.^{6, 7, 8, 9, 10}We report here molecular basis of mitochondrial encephalomyopathy, also combined with bilateral retinoblastoma, in patients with clinical symptoms or signs previously described in association with SUCLA2 mutations: encephalomyopathy with hearing deficit and methylmalonic aciduria.     

Laminin isoforms in fetal and adult human adrenal cortex

Laminin has been proposed to influence the function of human adrenal cortex. We have studied the distribution of laminin (Ln) chains using immunofluorescence in human fetal and adult adrenal cortex. In the fetal gland Ln alpha2- and alpha5-chains were weakly expressed in the definitive zone, whereas Ln alpha4-, beta1-, and gamma1-chains occurred around vessels. In the adult gland, Ln alpha2-, alpha5-, and gamma1-chains were found in epithelial basement membranes (BM) in all cortical zones, Ln alpha4-chain in vessels, Ln beta1-chain in outer zone, and Ln beta2-chain in the two inner zones of the cortex, respectively. Among the integrins in adult gland, integrin alpha(3)-subunit was confined to basal surfaces of cortical cells, alpha(6) to vessels, alpha(1) to the stroma, and alpha(2) diffusely to epithelial cells. Lutheran glycoprotein and dystroglycan occurred in the fetal gland diffusely in the definitive zone and throughout the epithelium in the adult. The isoform composition of BM of the adult adrenal gland is distinct, with Ln-2 and -10 in BM of the outer zone and Ln-4 and -11 in BM of the two inner zones. The results suggest that integrin alpha(3)beta(1) and Lutheran are candidate receptors for Ln-10 and -11, whereas dystroglycan probably binds Ln-2 and -4.     

A Post‐Hoc Comparison of the Utility of Sanger Sequencing and Exome Sequencing for the Diagnosis of Heterogeneous Diseases

The advent of massive parallel sequencing is rapidly changing the strategies employed for the genetic diagnosis and research of rare diseases that involve a large number of genes. So far it is not clear whether these approaches perform significantly better than conventional single gene testing as requested by clinicians. The current yield of this traditional diagnostic approach depends on a complex of factors that include gene‐specific phenotype traits, and the relative frequency of the involvement of specific genes. To gauge the impact of the paradigm shift that is occurring in molecular diagnostics, we assessed traditional Sanger‐based sequencing (in 2011) and exome sequencing followed by targeted bioinformatics analysis (in 2012) for five different conditions that are highly heterogeneous, and for which our center provides molecular diagnosis. We find that exome sequencing has a much higher diagnostic yield than Sanger sequencing for deafness, blindness, mitochondrial disease, and movement disorders. For microsatellite‐stable colorectal cancer, this was low under both strategies. Even if all genes that could have been ordered by physicians had been tested, the larger number of genes captured by the exome would still have led to a clearly superior diagnostic yield at a fraction of the cost.