Genetic mapping of habitual substance use, obesity-related traits, responses to mental and physical stress, and heart rate and blood pressure measurements reveals shared genes that are overrepresented in the neural synapse

Links between substance use habits, obesity, stress and the related cardiovascular outcomes can be, in part, because of loci with pleiotropic effects. To investigate this hypothesis, we performed genome-wide mapping in 119 multigenerational families from a population in the Saguenay-Lac-St-Jean region with a known founder effect using 58,000 single-nucleotide polymorphisms and 437 microsatellite markers to identify genetic components of the following factors: habitual alcohol, tobacco and coffee use; response to mental and physical stress; obesity-related traits; and heart rate (HR) and blood pressure (BP) measures. Habitual alcohol and/or tobacco users had attenuated HR responses to mental stress compared with non-users, whereas hypertensive individuals had stronger HR and systolic BP responses to mental stress and a higher obesity index than normotensives. Genetic mappings uncovered numerous shared genes among substance use, stress response, obesity and hemodynamic traits, including CAMK4, CNTN4, DLG2, FHIT, GRID2, ITPR2, NOVA1 and PRKCE, forming network of interacting proteins, sharing synaptic function and display higher and patterned expression profiles in brain-related tissues; moreover, pathway analysis of shared genes pointed to long-term potentiation. Subgroup genetic mappings uncovered additional shared synaptic genes, including CAMK4, CNTN5 and DNM3 (hypertension-specific); CNTN4, DNM3, FHIT and ITPR1 (sex-specific), having protein interactions with genes driven from general analysis. In summary, consistent with the observed phenotypic correlations, we found substantial overlap among genomic determinants of these traits in synapse, which supports the notion that the neural synapse may be a shared interface behind substance use, stress, obesity, HR, BP as well as the observed sex- and hypertension-specific genetic differences.     

The production and regulation of IGF and IGFBPs in human adipose tissue cultures

BackgroundAdipocytes express and secrete IGFs and IGFBPs; proteins with important effects on adipocyte homeostasis. However, the factors that control adipocyte generation of IGFs and IGFBPs are not clarified.AimTo identify regulators of the synthesis of IGFs and IGFBs in adipose tissue.MethodsSubcutaneous adipose tissue fragments (500 mg) from 7 healthy lean women were incubated for 48 h following addition of GH (50 μg/l), dexamethasone (DXM, 20 nM), insulin (100 nM), interleukin (IL)-1β (50 ng/l), IL-6 (50 ng/l) and tumor-necrosis factor (TNF)-α (10 ng/l). Outcome parameters included tissue mRNA and culture media IGF and IGFBP levels.ResultsAdipose tissue cultures secreted more IGF-II than IGF-I protein (1.14 ± 0.41 vs. 0.26 ± 0.09 μg/l [mean ± SEM]; P < 0.02). IGF-I mRNA and protein levels were stimulated by GH (to 340% [153; 477] (median [interquartiles]) and 270 ± 26%, respectively; P < 0.003), and inhibited by IL-1β (to 28% [21; 77] and 68 ± 11%, respectively; P < 0.003). TNF-α reduced IGF-I and IGF-II protein levels to 51 ± 8% and 69 ± 8%, respectively (P ≤ 0.002), without affecting mRNA levels. IGF protein levels were unaffected by DXM, insulin and IL-6. All IGFBPs IGFBP-1 were expressed. IGFBP-4 was by far the most predominant IGFBP by immunoassay and WLB revealed two bands at 28 and 24 kDa, most likely representing glycosylated and non-glycosylated IGFBP-4.ConclusionAdipose tissue cultures secrete more IGF-II than IGF-I, and predominantly IGFBP-4. The secretion of IGF-I is affected by GH, IL-1β and TNF-α, whereas IGF-II is affected by TNF-α only. Hence, cytokines may control adipocyte homeostasis by affecting local IGF-generation.     

The effect of a pre- and post-operative orthogeriatric service on cognitive function in patients with hip fracture. The protocol of the Oslo Orthogeriatrics Trial

ABSTRACT: BACKGROUND: Hip fracture mainly affect older people. It is associated with high morbidity and mortality, and in particular a high frequency of delirium. Incident delirium following hip fracture is associated with an increased risk of dementia in the following months, but it is still not firmly established whether this is an association or a causal relationship. Orthogeriatric units vary with respect to content and timing of the intervention. One main effect of orthogeriatric care may be the prevention of delirium, especially if preoperative and postoperative care are provided. Thus, the aim of Oslo Orthogeriatric Trial, is to assess whether combined preoperative and postoperative orthogeriatric care can reduce the incidence of delirium and improve cognition following hip fracture. Methods/design: Inclusion and randomisation will take place in the Emergency Department, as soon as possible after admission. All patients with proximal femur fractures are eligible, irrespective of age, pre-fracture function and accommodation, except if the fracture is caused by a high energy trauma or the patient is terminally ill. The intervention is pre-and post-operative orthogeriatric care delivered on a dedicated acute geriatric ward. The primary outcome measure is a composite endpoint combining the Clinical Dementia Rating Scale (CDR) and the 10 word memory task at four months after surgery. Secondary outcomes comprise incident delirium, length of stay, cognition, mobility, place of residence, activities of daily living and mortality, measured at 4 and 12 months after surgery. We have included 332 patients in the period 17th September 2009 to 5th January 2012. DISCUSSION: Our choice of outcome measures and our emphasis of orthogeriatric care in the preoperative as well as the postoperative phase will enable us to provide new knowledge on the impact of orthogeriatric care on cognition. Trials registration: ClinicalTrials.gov NCT01009268.     

Ten-year risk of second hip fracture. A NOREPOS study

BackgroundSecond hip fracture risk is elevated after the first, however whether risk differs with age, by sex or over time is not well known.ObjectiveTo examine the risk of second hip fracture by sex, age and time after first hip fracture.DesignData on all hip fractures in subjects 50 years and older and treated in Norwegian hospitals during 1999–2008 were retrieved. Surgical procedure codes and additional diagnosis codes were used to define incident fractures. Survival analyses with and without adjustment for competing risk of death were used to estimate the risk of second hip fracture.ResultsAmong the 81,867 persons who sustained a first hip fracture, 6161 women and 1782 men suffered a second hip fracture during follow-up. The overall age-adjusted hazard ratio (HR) of a second hip fracture did not differ between the sexes (women versus men, HR = 1.03; 95% confidence interval (CI): 0.98–1.09). Taking competing risk of death into account, the corresponding age-adjusted HR of a second hip fracture was 1.40 (95% CI: 1.33–1.47) in women compared to men. The greater risk in women was due to a higher mortality in men. Based on competing risk analyses, we estimate that 15% of women and 11% of men will have suffered a second hip fracture within 10 years after the first hip fracture. The ten-year cumulative incidence was above 10% in all age-groups, except in men 90 years and older.ConclusionFracture preventive strategies have a large potential in both women and men who suffer their first hip fracture due to the high risk of another hip fracture.     

Muscle phenotype in patients with myotonic dystrophy type 1

Introduction: The pathogenesis of muscle involvement in patients with myotonic dystrophy type 1 (DM1) is not well understood. In this study, we characterized the muscle phenotype in patients with confirmed DM1. Methods: In 38 patients, muscle strength was tested by hand‐held dynamometry. Myotonia was evaluated by a handgrip test and by analyzing the decrement of the compound muscle action potential. Muscle biopsies were assessed for morphological changes and Na⁺‐K⁺ pump content. Results: Muscle strength correlated with a decline in Na⁺‐K⁺ pump content (r = 0.60, P < 0.001) and with CTG expansion. CTG expansion did not correlate with severity of myotonia, proximal histopathological changes, or Na⁺‐K⁺ pump content. Histopathologically, we found few centrally placed nuclei (range 0.2–6.9%). Conclusions: The main findings of this study are that muscle weakness correlated inversely with CTG expansion and that central nuclei are not a prominent feature of proximal muscles in DM1. Muscle Nerve 47:409‐415, 2013     

Systematic identification and stratification of help-seeking school-aged youth with mental health problems: a novel approach to stage-based stepped-care

We investigated whether a novel visitation model for school-aged youth with mental health problems based on a stage-based stepped-care approach facilitated a systematic identification and stratification process without problems with equity in access. The visitation model was developed within the context of evaluating a new transdiagnostic early treatment for youth with anxiety, depressive symptoms, and/or behavioural problems. The model aimed to identify youth with mental health problems requiring an intervention, and to stratify the youth into three groups with increasing severity of problems. This was accomplished using a two-phase stratification process involving a web-based assessment and a semi-structured psychopathological interview of the youth and parents. To assess problems with inequity in access, individual-level socioeconomic data were obtained from national registers with data on both the youth participating in the visitation and the background population. Altogether, 573 youth and their parents took part in the visitation process. Seventy-five (13%) youth had mental health problems below the intervention threshold, 396 (69%) were deemed eligible for the early treatment, and 52 (9%) had symptoms of severe mental health problems. Fifty (9%) youth were excluded for other reasons. Eighty percent of the 396 youth eligible for early treatment fulfilled criteria of a mental disorder. The severity of mental health problems highlights the urgent need for a systematic approach. Potential problems in reaching youth of less resourceful parents, and older youth were identified. These findings can help ensure that actions are taken to avoid equity problems in future mental health care implementations.

     

Social context, the struggle with uncertainty, and subjective risk as meaning-rich constructs for explaining HBP noncompliance

OBJECTIVE: To identify the reasons for which people fail to take blood-pressure-lowering medication regularly, a qualitative study was conducted. METHODS: Interviews lasting approximately 90 min were conducted with 27 patients (15 women, 12 men) aged 40-70. The verbatim of the 27 interviews was first read and divided into segments with explanatory value. This was followed by the production of a final text in vignette form for all interviews. An integrative, analytical phase consisted of identifying trends, significant central themes, regularities, and divergences in the vignettes. RESULTS: Analysis revealed the explanatory power that 3 broad groups of subjective meanings could hold for given medication noncompliance scenarios. These scenarios are expressing the role of: (1) stress and living conditions in the occasional skipping or deferral of medication-taking; (2) doubt as the motivating factor for transitory, irregular medication use; (3) subjective risk as the motivating factor for persistent irregular use. CONCLUSION: Life and social contexts, doubt and risk subsume extremely meaning-rich constructs that can help identify dilemmas facing people about medication-taking. PRACTICE IMPLICATIONS: By discussing these dimensions with their patients, health professionals will be better able to understand patient medication behaviors that sometimes run counter to their recommendations.     

Self-actualization and poststroke rehabilitation

Rehabilitation is influenced by the individual's abilities and resources and extent to which they are used. This study explored self-actualization (capacity to maximize use of one's abilities and resources) in 37 individuals attending in-patient rehabilitation following a stroke by (1) comparing the level of self-actualization of the participants to the level of self-actualization of 562 healthy community-dwelling individuals without stroke; (2) assessing changes in the level of self-actualization during rehabilitation (admission vs. discharge); and (3) exploring the relationships between self-actualization and changes in functional independence during rehabilitation, length of stay in the rehabilitation unit and change in living environment at discharge. Self-actualization was assessed with the measure of actualization of potential. The results showed that individuals with stroke had significantly lower self-actualization levels (P<0.001) than community-dwelling individuals without stroke. Self-actualization levels remained stable during rehabilitation (P=0.07). No significant relationships were found between self-actualization and changes in functional independence (P=0.36), length of stay (P=0.82) or change in living environment (P=0.65). This study suggests that many individuals with stroke are poorly actualized and self-actualization levels do not improve during rehabilitation. Further studies are needed to explore the relationship between self-actualization and other outcome measures in poststroke rehabilitation such as depressive symptoms or social participation.