Maternally inherited Leigh syndrome.

A 6 1/2-year-old girl had developmental regression, and Leigh syndrome was diagnosed. A second girl born to the same mother after heterologous artificial insemination also lost acquired skills and died at 2 1/2 years of age; neuropathologic examination confirmed the diagnosis of Leigh syndrome. Tissues from both children and from the mother had a point mutation at nucleotide 8993 in the adenosinetriphosphatase 6-gene of mitochondrial DNA. This family illustrates that Leigh syndrome can be transmitted by maternal inheritance.

Rather than words: Philip Larkin's 'High Windows'

Discussion of possible origins and analogues, including Milton, Herbert and Mallarmé, of the image in Larkin's famous poem.

Proteomic and Metabolomic Analyses of Mitochondrial Complex I-deficient Mouse Model Generated by Spontaneous B2 Short Interspersed Nuclear Element (SINE) Insertion into NADH Dehydrogenase (Ubiquinone) Fe-S Protein 4 (Ndufs4) Gene.

Eukaryotic cells generate energy in the form of ATP, through a network of mitochondrial complexes and electron carriers known as the oxidative phosphorylation system. In mammals, mitochondrial complex I (CI) is the largest component of this system, comprising 45 different subunits encoded by mitochondrial and nuclear DNA. Humans diagnosed with mutations in the gene NDUFS4, encoding a nuclear DNA-encoded subunit of CI (NADH dehydrogenase ubiquinone Fe-S protein 4), typically suffer from Leigh syndrome, a neurodegenerative disease with onset in infancy or early childhood. Mitochondria from NDUFS4 patients usually lack detectable NDUFS4 protein and show a CI stability/assembly defect. Here, we describe a recessive mouse phenotype caused by the insertion of a transposable element into Ndufs4, identified by a novel combined linkage and expression analysis. Designated Ndufs4(fky), the mutation leads to aberrant transcript splicing and absence of NDUFS4 protein in all tissues tested of homozygous mice. Physical and behavioral symptoms displayed by Ndufs4(fky/fky) mice include temporary fur loss, growth retardation, unsteady gait, and abnormal body posture when suspended by the tail. Analysis of CI in Ndufs4(fky/fky) mice using blue native PAGE revealed the presence of a faster migrating crippled complex. This crippled CI was shown to lack subunits of the "N assembly module", which contains the NADH binding site, but contained two assembly factors not present in intact CI. Metabolomic analysis of the blood by tandem mass spectrometry showed increased hydroxyacylcarnitine species, implying that the CI defect leads to an imbalanced NADH/NAD(+) ratio that inhibits mitochondrial fatty acid β-oxidation.

Altered NKG2D function in NK cells induced by chronic exposure to NKG2D ligand-expressing tumor cells.

NKG2D is an activation receptor that allows natural killer (NK) cells to detect diseased host cells. The engagement of NKG2D with corresponding ligand results in surface modulation of the receptor and reduced function upon subsequent receptor engagement. However, it is not clear whether in addition to modulation the NKG2D receptor complex and/or its signaling capacity is preserved. We show here that the prolonged encounter with tumor cell-bound, but not soluble, ligand can completely uncouple the NKG2D receptor from the intracellular mobilization of calcium and the exertion of cell-mediated cytolysis. However, cytolytic effector function is intact since NKG2D ligand-exposed NK cells can be activated via the Ly49D receptor. While NKG2D-dependent cytotoxicity is impaired, prolonged ligand exposure results in constitutive interferon gamma (IFNgamma) production, suggesting sustained signaling. The functional changes are associated with a reduced presence of the relevant signal transducing adaptors DNAX-activating protein of 10 kDa (DAP-10) and killer cell activating receptor-associated protein/DNAX-activating protein of 12 kDa (KARAP/DAP-12). That is likely the consequence of constitutive NKG2D engagement and signaling, since NKG2D function and adaptor expression is restored to normal when the stimulating tumor cells are removed. Thus, the chronic exposure to tumor cells expressing NKG2D ligand alters NKG2D signaling and may facilitate the evasion of tumor cells from NK cell reactions.

Sleep disorders in boys with Duchenne muscular dystrophy.

Aim:  Determine the frequency and predictors of sleep disorders in boys with Duchenne Muscular Dystrophy (DMD). Method:  Cross-sectional study by postal questionnaire. Sleep disturbances were assessed using the Sleep Disturbance Scale for Children (validated on 1157 healthy children). A total sleep score and six sleep disturbance factors representing the most common sleep disorders were computed. Potential associations between pathological scores and personal, medical and environmental factors were assessed. Results:  Sixteen of 63 boys (25.4%) had a pathological total sleep score compared with 3% in the general population. The most prevalent sleep disorders were disorders of initiating and maintaining sleep (DIMS) 29.7%, sleep-related breathing disorders 15.6% and sleep hyperhydrosis 14.3%. On multivariate analysis, pathological total sleep scores were associated with the need to be moved by a carer (OR = 9.4; 95%CI: 2.2-40.7; p = 0.003) and being the child of a single-parent family (OR = 7.2; 95%CI: 1.5-35.1; p = 0.015) and DIMS with the need to be moved by a carer (OR = 18.0; 95%CI: 2.9-110.6; p = 0.002), steroid treatment (OR = 7.7; 95%CI: 1.4-44.0; p = 0.021) and being the child of a single-parent family (OR = 7.0; 95%CI: 1.3-38.4; p = 0.025). Conclusion:  Sleep disturbances are frequent in boys with DMD and are strongly associated with immobility. Sleep should be systematically assessed in DMD to implement appropriate interventions.

Body mass index, cigarette smoking, and alcohol consumption and cancers of the oral cavity, pharynx, and larynx: modeling odds ratios in pooled case-control data.

Odds ratios for head and neck cancer increase with greater cigarette and alcohol use and lower body mass index (BMI; weight (kg)/height(2) (m(2))). Using data from the International Head and Neck Cancer Epidemiology Consortium, the authors conducted a formal analysis of BMI as a modifier of smoking- and alcohol-related effects. Analysis of never and current smokers included 6,333 cases, while analysis of never drinkers and consumers of < or =10 drinks/day included 8,452 cases. There were 8,000 or more controls, depending on the analysis. Odds ratios for all sites increased with lower BMI, greater smoking, and greater drinking. In polytomous regression, odds ratios for BMI (P = 0.65), smoking (P = 0.52), and drinking (P = 0.73) were homogeneous for oral cavity and pharyngeal cancers. Odds ratios for BMI and drinking were greater for oral cavity/pharyngeal cancer (P < 0.01), while smoking odds ratios were greater for laryngeal cancer (P < 0.01). Lower BMI enhanced smoking- and drinking-related odds ratios for oral cavity/pharyngeal cancer (P < 0.01), while BMI did not modify smoking and drinking odds ratios for laryngeal cancer. The increased odds ratios for all sites with low BMI may suggest related carcinogenic mechanisms; however, BMI modification of smoking and drinking odds ratios for cancer of the oral cavity/pharynx but not larynx cancer suggests additional factors specific to oral cavity/pharynx cancer.

Self-perceived health status and mental health outcomes in young adults born with less than 1000 g.

AIM: To assess self-perceived health status and mental health outcomes of former extremely low-birth-weight (ELBW) infants at young adulthood compared with community norms and to analyse predictors of poor outcome. METHODS: Fifty-five ELBW adults, 18 men (33%), with median (range) gestational age of 28.7 (25.0-34.0) weeks and birth weight of 930 (680-990) grams, born in Switzerland, were included. They self-rated their health status and mental health at a mean (range) age of 23.3 (21.8-25.9) years. Health status was measured by the Medical Outcomes Study Short Form-36 questionnaire and mental health by the Brief Symptom Inventory. RESULTS: The mean scores for both outcome measures were in the normal range. However, the study group self-rated significantly higher physical health status and lower mental health status compared with the community norms, and scores for self-perceived mental health tended to be worse in the former. ELBW adults reported more problems in socio-emotional role functioning compared with the community norms. Female sex was associated with poorer and bronchopulmonary dysplasia with better mental health status. CONCLUSION: Health status and mental health of former ELBW adults were overall satisfying. However, the comparison with the community norms revealed differences, which may be important for parental and patient counselling and developing support strategies.

Adolescent's suicide attempts: populations at risk, vulnerability, and substance use.

Adolescence corresponds to a transition period that requires adaptation and change capacities and skills. Most young people succeed with this challenge, whereas a minority fail. In order to identify with the teenage culture, become autonomous, and differentiate from their parents, some adolescents choose to use drugs, beginning with the use of cigarettes, alcohol, cannabis, followed by other illicit drugs such as opiates and stimulants. A high proportion of these adolescents attempt suicide, which is the primary cause of death during adolescence in many European countries. Who are the "vulnerable" adolescents? What are the mechanisms that can explain the varieties of drug-use initiation or suicide attempts? Can "protective factors" be identified? What kind of strategies might be developed at a social and political level in order to prevent or to minimize drug abuse and suicide attempts, among other harmful behaviors? These issues will be discussed on the basis of the recent literature and in the light of a recent study carried out in the French-speaking part of Switzerland on large cohorts of adolescent drug users. Unresolved critical issues are noted and future needed research is suggested.

Frailty and use of health and community services by community-dwelling older men: the Concord Health and Ageing in Men Project.

BACKGROUND: frailty is a concept used to describe older people at high risk of adverse outcomes, including falls, functional decline, hospital or nursing home admission and death. The associations between frailty and use of specific health and community services have not been investigated. METHODS: the cross-sectional relationship between frailty and use of several health and community services in the last 12 months was investigated in 1,674 community-dwelling men aged 70 or older in the Concord Health and Ageing in Men study, a population-based study conducted in Sydney, Australia. Frailty was assessed using a modified version of the Cardiovascular Health Study criteria. RESULTS: overall, 158 (9.4%) subjects were frail, 679 (40.6%) were intermediate (pre-frail) and 837 (50.0%) were robust. Frailty was associated with use of health and community services in the last 12 months, including consulting a doctor, visiting or being visited by a nurse or a physiotherapist, using help with meals or household duties and spending at least one night in a hospital or nursing home. Frail men without disability in activities of daily living were twice more likely to have seen a doctor in the previous 2 weeks than robust men (adjusted odds ratio 2.04, 95% confidence interval 1.21-3.44), independent of age, comorbidity and socio-economic status. CONCLUSION: frailty is strongly associated with use of health and community services in community-dwelling older men. The high level of use of medical services suggests that doctors and nurses could play a key role in implementation of preventive interventions.

Exercise prevents fructose-induced hypertriglyceridemia in healthy young subjects.

Excess fructose intake causes hypertriglyceridemia and hepatic insulin resistance in sedentary humans. Since exercise improves insulin sensitivity in insulin-resistant patients, we hypothesized that it would also prevent fructose-induced hypertriglyceridemia. This study was therefore designed to evaluate the effects of exercise on circulating lipids in healthy subjects fed a weight-maintenance, high-fructose diet. Eight healthy males were studied on three occasions after 4 days of 1) a diet low in fructose and no exercise (C), 2) a diet with 30% fructose and no exercise (HFr), or 3) a diet with 30% fructose and moderate aerobic exercise (HFrEx). On all three occasions, a 9-h oral [(13)C]-labeled fructose loading test was performed on the fifth day to measure [(13)C]palmitate in triglyceride-rich lipoprotein (TRL)-triglycerides (TG). Compared with C, HFr significantly increased fasting glucose, total TG, TRL-TG concentrations, and apolipoprotein (apo)B48 concentrations as well as postfructose glucose, total TG, TRL-TG, and [(13)C]palmitate in TRL-TG. HFrEx completely normalized fasting and postfructose TG, TRL-TG, and [(13)C]palmitate concentration in TRL-TG and apoB48 concentrations. In addition, it increased lipid oxidation and plasma nonesterified fatty acid concentrations compared with HFr. These data indicate that exercise prevents the dyslipidemia induced by high fructose intake independently of energy balance.