Modulation of β-Catenin Signaling by Glucagon Receptor Activation

The glucagon receptor (GCGR) is a member of the class B G protein–coupled receptor family. Activation of GCGR by glucagon leads to increased glucose production by the liver. Thus, glucagon is a key component of glucose homeostasis by counteracting the effect of insulin. In this report, we found that in addition to activation of the classic cAMP/protein kinase A (PKA) pathway, activation of GCGR also induced β-catenin stabilization and activated β-catenin–mediated transcription. Activation of β-catenin signaling was PKA-dependent, consistent with previous reports on the parathyroid hormone receptor type 1 (PTH1R) and glucagon-like peptide 1 (GLP-1R) receptors. Since low-density-lipoprotein receptor–related protein 5 (Lrp5) is an essential co-receptor required for Wnt protein mediated β-catenin signaling, we examined the role of Lrp5 in glucagon-induced β-catenin signaling. Cotransfection with Lrp5 enhanced the glucagon-induced β-catenin stabilization and TCF promoter–mediated transcription. Inhibiting Lrp5/6 function using Dickkopf-1(DKK1) or by expression of the Lrp5 extracellular domain blocked glucagon-induced β-catenin signaling. Furthermore, we showed that Lrp5 physically interacted with GCGR by immunoprecipitation and bioluminescence resonance energy transfer assays. Together, these results reveal an unexpected crosstalk between glucagon and β-catenin signaling, and may help to explain the metabolic phenotypes of Lrp5/6 mutations

Gender differences in health care use among the elderly population in areas of Norway and Finland. A cross-sectional analysis based on the HUNT study and the FINRISK Senior Survey

BACKGROUND: The aim of the study was to examine gender differences in the self-reported use of health care services by the elderly in rural and metropolitan areas of two Nordic countries with slightly different health care systems: Finland and Norway. METHODS: Population based, cross-sectional surveys conducted in Nord-Tröndelag Norway (1995–97) and in rural and metropolitan areas of Finland (1997) were employed. In the Norwegian data, a total of 7,919 individuals, aged 65–74 years old were included, and the Finnish data included 1,500 individuals. The outcome variables comprised whether participants had visited a general practitioner or a specialist, or had received hospital care or physiotherapy during the past 12 months. Gender differences in the use of health care services were analysed by multiple logistic regression, controlling for health status and socio-demographic characteristics. RESULTS: In Norway, elderly women visited a specialist or were hospitalised less often than men. In Finland, elderly women used all health care services except hospital care more often than men. In Norway, less frequent use of specialist care by women was not associated with self-reported health or chronic diseases. CONCLUSION: The findings revealed differences in self-reported use of secondary care among different genders in areas of Norway and Finland

Exome chip analyses in adult attention deficit hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable childhood-onset neuropsychiatric condition, often persisting into adulthood. The genetic architecture of ADHD, particularly in adults, is largely unknown. We performed an exome-wide scan of adult ADHD using the Illumina Human Exome Bead Chip, which interrogates over 250 000 common and rare variants. Participants were recruited by the International Multicenter persistent ADHD CollaboraTion (IMpACT). Statistical analyses were divided into 3 steps: (1) gene-level analysis of rare variants (minor allele frequency (MAF)<1%); (2) single marker association tests of common variants (MAFgreater than or equal to1%), with replication of the top signals; and (3) pathway analyses. In total, 9365 individuals (1846 cases and 7519 controls) were examined. Replication of the most associated common variants was attempted in 9847 individuals (2077 cases and 7770 controls) using fixed-effects inverse variance meta-analysis. With a Bonferroni-corrected significance level of 1.82E−06, our analyses of rare coding variants revealed four study-wide significant loci: 6q22.1 locus (P=4.46E−08), where NT5DC1 and COL10A1 reside; the SEC23IP locus (P=6.47E−07); the PSD locus (P=7.58E−08) and ZCCHC4 locus (P=1.79E−06). No genome-wide significant association was observed among the common variants. The strongest signal was noted at rs9325032 in PPP2R2B (odds ratio=0.81, P=1.61E−05). Taken together, our data add to the growing evidence of general signal transduction molecules (NT5DC1, PSD, SEC23IP and ZCCHC4) having an important role in the etiology of ADHD. Although the biological implications of these findings need to be further explored, they highlight the possible role of cellular communication as a potential core component in the development of both adult and childhood forms of ADHD

Older Norwegians' understanding of loneliness

This interpretive study explored older people's understanding of loneliness and what they considered appropriate and effective ways of dealing with it. Thirty elderly people were interviewed in-depth; 12 described themselves as “lonely” and 18 as “not lonely.” We found a striking difference in the way “lonely” and “not lonely” people talked about loneliness. The “not lonely” participants described loneliness as painful, caused by the person's negative way of behaving and a state they should pull themselves out of. The “lonely” participants also described loneliness as painful, and gave more detailed descriptions of loneliness as disconnection from others, from their former home and from today's society. The “lonely” participants were more reserved and subdued in trying to explain loneliness, attributing it partly to themselves, but mostly to the lack of social contact with important others. Some felt able to handle their loneliness, while others felt unable to cope. This study underlines the importance of subjective experiences in trying to understand a phenomenon like loneliness and of developing support for lonely older people unable to cope on their own

Exome-wide association analysis reveals novel coding sequence variants associated with lipid traits in Chinese

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Neoadjuvant chemotherapy in breast cancer-response evaluation and prediction of response to treatment using dynamic contrast-enhanced and diffusion-weighted MR imaging

Objective To explore the predictive value of MRI parameters and tumour characteristics before neoadjuvant chemotherapy (NAC) and to compare changes in tumour size and tumour apparent diffusion coefficient (ADC) during treatment, between patients who achieved pathological complete response (pCR) and those who did not. Methods Approval by the Regional Ethics Committee and written informed consent were obtained. Thirty-one patients with invasive breast carcinoma scheduled for NAC were enrolled (mean age, 50.7; range, 37–72). Study design included MRI before treatment (Tp0), after four cycles of NAC (Tp1) and before surgery (Tp2). Data in pCR versus non-pCR groups were compared and cut-off values for pCR prediction were evaluated. Results Before NAC, HER2 overexpression was the single significant predictor of pCR (p=0.006). At Tp1 ADC, tumour size and changes in tumour size were all significantly different in the pCR and non-pCR groups. Using 1.42×10−3 mm2/s as the cut-off value for ADC, pCR was predicted with sensitivity and specificity of 88% and 80%, respectively. Using a cut-off value of 83% for tumour volume reduction, sensitivity and specificity for pCR were 91% and 80%. Conclusion ADC, tumour size and tumour size reduction at Tp1 were strong independent predictors of pCR