Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura

Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABO and LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes.</p

Natriuretic peptides and integrated risk assessment for cardiovascular disease: an individual-participant-data meta-analysis

BACKGROUND: Guidelines for primary prevention of cardiovascular diseases focus on prediction of coronary heart disease and stroke. We assessed whether or not measurement of N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration could enable a more integrated approach than at present by predicting heart failure and enhancing coronary heart disease and stroke risk assessment. METHODS: In this individual-participant-data meta-analysis, we generated and harmonised individual-participant data from relevant prospective studies via both de-novo NT-proBNP concentration measurement of stored samples and collection of data from studies identified through a systematic search of the literature (PubMed, Scientific Citation Index Expanded, and Embase) for articles published up to Sept 4, 2014, using search terms related to natriuretic peptide family members and the primary outcomes, with no language restrictions. We calculated risk ratios and measures of risk discrimination and reclassification across predicted 10 year risk categories (ie, <5%, 5% to <7·5%, and ≥7·5%), adding assessment of NT-proBNP concentration to that of conventional risk factors (ie, age, sex, smoking status, systolic blood pressure, history of diabetes, and total and HDL cholesterol concentrations). Primary outcomes were the combination of coronary heart disease and stroke, and the combination of coronary heart disease, stroke, and heart failure. FINDINGS: We recorded 5500 coronary heart disease, 4002 stroke, and 2212 heart failure outcomes among 95 617 participants without a history of cardiovascular disease in 40 prospective studies. Risk ratios (for a comparison of the top third vs bottom third of NT-proBNP concentrations, adjusted for conventional risk factors) were 1·76 (95% CI 1·56-1·98) for the combination of coronary heart disease and stroke and 2·00 (1·77-2·26) for the combination of coronary heart disease, stroke, and heart failure. Addition of information about NT-proBNP concentration to a model containing conventional risk factors was associated with a C-index increase of 0·012 (0·010-0·014) and a net reclassification improvement of 0·027 (0·019-0·036) for the combination of coronary heart disease and stroke and a C-index increase of 0·019 (0·016-0·022) and a net reclassification improvement of 0·028 (0·019-0·038) for the combination of coronary heart disease, stroke, and heart failure. INTERPRETATION: In people without baseline cardiovascular disease, NT-proBNP concentration assessment strongly predicted first-onset heart failure and augmented coronary heart disease and stroke prediction, suggesting that NT-proBNP concentration assessment could be used to integrate heart failure into cardiovascular disease primary prevention. FUNDING: British Heart Foundation, Austrian Science Fund, UK Medical Research Council, National Institute for Health Research, European Research Council, and European Commission Framework Programme 7

Zeng bu Wu fang yuan yin /

Special collection from London Missionary Society.; On double leaves, oriental style.; http://nla.gov.au/nla.gen-vn1868384.880-03 Wu fang yüan yin

Dimitri Rostoff as the Chamberlain (centre left), Paul Petroff as The Prince (centre front), Tatiana Riabouchinska as Cinderella (centre right), and artists of the company, in Cendrillon, Covent Garden Russian Ballet, Australian tour, His Majesty's Theatre, Melbourne, ca. 1938 [picture] /

From: Cendrillon (Cinderella) : ballet in three parts after Perrault's fairy tale / music by Frederic d'Erlanger.; Inscription: "N26".; Part of the collection: Hugh P. Hall collection of photographs, 1938-1940.; Performed Sept.-Oct. 1938 and Mar.-Apr. 1939.; Choreography by Michel Fokine ; scenery and costumes by Nathalie Gontcharova ; scenery executed by Prince A. Schervachidze, costumes executed by B. Karinska.; Also available in an electronic version via the Internet at: http://nla.gov.au/nla.pic-vn3995877. One of a collection of photographs taken by Hugh P. Hall of 28 ballet productions performed by the Covent Garden Russian Ballet (toured Australia 1938-1939) and the Original Ballet Russe (toured Australia 1939-1940). These are the second and third of the three Ballets Russes companies which toured Australasia between 1936 and 1940. The photographs were taken from the auditorium during a live performance in His Majesty's Theatre, Melbourne and mounted on cardboard for display purposes. For conservation and storage, the photographs have been demounted. The original arrangement of the photographs has been recorded, and details are available from the Pictures Branch of the National Library

Prevalence of chronic kidney disease based on estimated glomerular filtration rate and proteinuria in Icelandic adults

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldBACKGROUND: The purpose of this study was to compare three different equations to calculate estimated glomerular filtration rate (eGFR) based on serum creatinine (SCr) and to estimate the prevalence of chronic kidney disease (CKD) in the Icelandic population. METHODS: This was a cross-sectional study using data from the Reykjavik Heart Study. GFR was estimated with three equations: Equation I was based on 1/SCr; Equation II based on the Cockcroft-Gault equation; and Equation III was the modified MDRD equation. The eGFR calculated with Equation III and proteinuria were used to estimate the prevalence of CKD. The prevalence was age-standardized to the truncated world population. We used chi-square and ANCOVA to compare the group with low eGFR to age-matched controls. RESULTS: The subjects consisted of 9229 males and 10,027 females, aged 33-85 years. The equations performed very differently. Equation I showed women with higher eGFR than men and little change with age. Equation II showed men with higher eGFR than women and marked decline in eGFR with age. Equation III was similar to Equation II but the decline in eGFR with age was not as great. Regardless of the equation used, most subjects (63.7-80.7%) had an eGFR in the range of 60-89 ml/min/1.73 m2. Using Equation III, age-standardized prevalence of low eGFR for the population aged 35-80+ years was estimated to be 4.7 and 11.6% for men and women, respectively. The proportion of subjects with eGFR <60 ml/min/1.73 m2 increased with advancing age. An additional 2.39% of men and 0.89% of women had proteinuria. The prevalence of renal and cardiovascular risk factors including proteinuria, hypertension, lipid abnormalities and markers of inflammation was higher among those with low eGFR than age-matched controls. CONCLUSIONS: GFR estimates and the prevalence of CKD are dependent on the equation used to calculate eGFR. Unexpectedly, a low proportion of the Icelandic population had normal kidney function according to the eGFR regardless of the equation used. These equations may not be useful in epidemiological research

Exclusive characteristics of graft survival and risk factors in recipients with immunoglobulin A nephropathy: a retrospective analysis of registry data

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldBACKGROUND: Some studies have claimed that patients with immunoglobulin A (IgA) nephropathy have better graft survival than other renal graft recipients, whereas others have rejected this statement. We have addressed this paradox in the present study. METHODS: In all, 1,207 patients with IgA nephropathy who received a primary cadaveric renal graft from 1990 to 2002 were identified in the Eurotransplant database. For comparison, we analyzed 7,935 patients with nonglomerular diseases. Death-censored graft survival was calculated using Kaplan Meier estimates and a multivariable Cox regression analysis was used for risk calculations. RESULTS: Death-censored graft survival was superior in patients with IgA nephropathy in the first period after transplantation. After 3 years posttransplant, however, there was an accelerated decline in graft survival in recipients with IgA nephropathy. The fully adjusted risk of graft loss in the first year was increased by 40% in the control group compared to IgA nephropathy (hazard ratio [HR] 1.40, 95% CI 1.12-1.75), whereas the risk was significantly lower in the control group after the first year posttransplant (HR 0.75, 95% CI 0.63-0.88). Cold ischemia time, immunization and HLA-DR mismatch were risk factors for graft loss in the control group but not for IgA nephropathy, whereas HLA-AB mismatch was an independent risk factor, exclusively for the IgA nephropathy group. CONCLUSIONS: Recipients with IgA nephropathy have better 1-year graft survival, presumably due to favorable immunological behavior. This benefit was however abolished in the long-term by increased graft loss with time. Studies are needed to explain the difference in graft survival and the reason why different risk factors are involved in graft failure

Exclusive characteristics of graft survival and risk factors in recipients with immunoglobulin A nephropathy: a retrospective analysis of registry data

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldBACKGROUND: Some studies have claimed that patients with immunoglobulin A (IgA) nephropathy have better graft survival than other renal graft recipients, whereas others have rejected this statement. We have addressed this paradox in the present study. METHODS: In all, 1,207 patients with IgA nephropathy who received a primary cadaveric renal graft from 1990 to 2002 were identified in the Eurotransplant database. For comparison, we analyzed 7,935 patients with nonglomerular diseases. Death-censored graft survival was calculated using Kaplan Meier estimates and a multivariable Cox regression analysis was used for risk calculations. RESULTS: Death-censored graft survival was superior in patients with IgA nephropathy in the first period after transplantation. After 3 years posttransplant, however, there was an accelerated decline in graft survival in recipients with IgA nephropathy. The fully adjusted risk of graft loss in the first year was increased by 40% in the control group compared to IgA nephropathy (hazard ratio [HR] 1.40, 95% CI 1.12-1.75), whereas the risk was significantly lower in the control group after the first year posttransplant (HR 0.75, 95% CI 0.63-0.88). Cold ischemia time, immunization and HLA-DR mismatch were risk factors for graft loss in the control group but not for IgA nephropathy, whereas HLA-AB mismatch was an independent risk factor, exclusively for the IgA nephropathy group. CONCLUSIONS: Recipients with IgA nephropathy have better 1-year graft survival, presumably due to favorable immunological behavior. This benefit was however abolished in the long-term by increased graft loss with time. Studies are needed to explain the difference in graft survival and the reason why different risk factors are involved in graft failure