HTTP 200 OK
Allow: GET, HEAD, OPTIONS
Content-Type: application/json
Vary: Accept
{
"count": 127182,
"next": "https://api-test.medunigraz.at/v1/research/search/publication/?format=api&limit=20&offset=126900",
"previous": "https://api-test.medunigraz.at/v1/research/search/publication/?format=api&limit=20&offset=126860",
"results": [
{
"text": "\n61916\nExpression of the neuropeptide Y Y1 receptor in the CNS of rat and of wild-type and Y1 receptor knock-out mice. Focus on immunohistochemical localization.\n\nKopp, J\n\nXu, ZQ\n\nZhang, X\n\nPedrazzini, T\n\nHerzog, H\n\nKresse, A\n\nWong, H\n\nWalsh, JH\n\nHökfelt, T\n\nBeiträge in Fachzeitschriften\nISI:000176021900002\n12031341.0\n10.1016/S0306-4522(01)00463-8\nNone\nThe distribution of neuropeptide Y (NPY) Y1 receptor-like immunoreactivity (Y1R-LI) has been studied in detail in the CNS of rat using a rabbit polyclonal antibody against the C-terminal 13 amino acids of the rat receptor protein. The indirect immunofluorescence technique with tyramide signal amplification has been employed. For specificity and comparative reasons Y1 knock-out mice and wild-type controls were analyzed. The distribution of Y1R mRNA was also studied using in situ hybridization. A limited comparison between Y1R-LI and NPY-LI was carried out.A widespread and abundant distribution of Y1R-LI, predominantly in processes but also in cell bodies, was observed. In fact, Y1R-LI was found in most regions of the CNS with a similar distribution pattern between rat and wild-type mouse. This staining was specific in the sense that it was absent in adjacent sections following preadsorption of the antibody with 10(-5) M of the antigenic peptide, and that it could not be observed in sections of the Y1 KO mouse. In contrast, the staining obtained with an N-terminally directed Y1R antiserum did not disappear, strongly suggesting unspecificity. In brief, very high levels of Y1R-LI were seen in the islands of Calleja, the anterior olfactory nucleus, the molecular layer of the dentate gyrus, parts of the habenula, the interpeduncular nucleus, the mammillary body, the spinal nucleus of the trigeminal, caudal part, the paratrigeminal nucleus, and superficial layers of the dorsal horn. High levels were found in most cortical areas, many thalamic nuclei, some subnuclei of the amygdaloid complex, the hypothalamus and the nucleus of the stria terminalis, the nucleus of the solitary tract, the parabrachial nucleus, and the inferior olive. Moderate levels of Y1R-LI were detected in the cornu Ammonis and the subicular complex, many septal, some thalamic and many brainstem regions. Y1R staining of processes, often fiber and/or dot-like, and occasional cell bodies was also seen in tracts, such as the lateral lemniscus, the rubrospinal tract and the spinal tract of the trigeminal. There was in general a good overlap between Y1R-LI and NPY-LI, but some exceptions were found. Thus, some areas had NPY innervation but apparently lacked Y1Rs, whereas in other regions Y1R-LI, but no or only few NPY-positive nerve endings could be detected.Our results demonstrate that NPY signalling through the Y1R is common in the rat (and mouse) CNS. Mostly the Y1R is postsynaptic but there are also presynaptic Y1Rs. Mostly there is a good match between NPY-releasing nerve endings and Y1Rs, but 'volume transmission' may be 'needed' in some regions. Finally, the importance of using proper control experiments for immunohistochemical studies on seven-transmembrane receptors is stressed.\n\nKresse, Adelheid\n\n\n"
},
{
"text": "\n156457\nSafety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer's disease: a randomised, double-blind, placebo-controlled, phase 1 trial.\n\nNovak, P\n\nSchmidt, R\n\nKontsekova, E\n\nZilka, N\n\nKovacech, B\n\nSkrabana, R\n\nVince-Kazmerova, Z\n\nKatina, S\n\nFialova, L\n\nPrcina, M\n\nParrak, V\n\nDal-Bianco, P\n\nBrunner, M\n\nStaffen, W\n\nRainer, M\n\nOndrus, M\n\nRopele, S\n\nSmisek, M\n\nSivak, R\n\nWinblad, B\n\nNovak, M\n\nBeiträge in Fachzeitschriften\nISI:000391910800011\n27955995.0\n10.1016/S1474-4422(16)30331-3\nNone\nNeurofibrillary pathology composed of tau protein is a main correlate of cognitive impairment in patients with Alzheimer's disease. Immunotherapy targeting pathological tau proteins is therefore a promising strategy for disease-modifying treatment of Alzheimer's disease. We have developed an active vaccine, AADvac1, against pathological tau proteins and assessed it in a phase 1 trial.\n We did a first-in-man, phase 1, 12 week, randomised, double-blind, placebo-controlled study of AADvac1 with a 12 week open-label extension in patients aged 50-85 years with mild-to-moderate Alzheimer's disease at four centres in Austria. We randomly assigned patients with a computer-generated sequence in a 4:1 ratio overall to receive AADvac1 or placebo. They received three subcutaneous doses of AADvac1 or placebo from masked vaccine kits at monthly intervals, and then entered the open-label phase, in which all patients were allocated to AADvac1 treatment and received another three doses at monthly intervals. Patients, carers, and all involved with the trial were masked to treatment allocation. The primary endpoint was all-cause treatment-emergent adverse events, with separate analyses for injection site reactions and other adverse events. We include all patients who received at least one dose of AADvac1 in the safety assessment. Patients who had a positive IgG titre against the tau peptide component of AADvac1 at least once during the study were classified as responders. The first-in-man study is registered with EU Clinical Trials Register, number EudraCT 2012-003916-29, and ClinicalTrials.gov, number NCT01850238; the follow-up study, which is ongoing, is registered with EU Clinical Trials Register, number EudraCT 2013-004499-36, and ClinicalTrials.gov, number NCT02031198.\n This study was done between June 9, 2013, and March 26, 2015. 30 patients were randomly assigned in the double-blind phase: 24 patients to the AADvac1 group and six to the placebo group. A total of 30 patients received AADvac1. Two patients withdrew because of serious adverse events. The most common adverse events were injection site reactions after administration (reported in 16 [53%] vaccinated patients [92 individual events]). No cases of meningoencephalitis or vasogenic oedema occurred after administration. One patient with pre-existing microhaemorrhages had newly occurring microhaemorrhages. Of 30 patients given AADvac1, 29 developed an IgG immune response. A geometric mean IgG antibody titre of 1:31415 was achieved. Baseline values of CD3+ CD4+ lymphocytes correlated with achieved antibody titres.\n AADvac1 had a favourable safety profile and excellent immunogenicity in this first-in-man study. Further trials are needed to corroborate the safety assessment and to establish proof of clinical efficacy of AADvac1.\n AXON Neuroscience SE.\n Copyright © 2017 Elsevier Ltd. All rights reserved.\n\nRopele, Stefan\n\nSchmidt, Reinhold\n\n\n"
},
{
"text": "\n168414\nPeriodontal health and gingival diseases and conditions on an intact and a reduced periodontium: Consensus report of workgroup 1 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions.\n\nChapple, ILC\n\nMealey, BL\n\nVan Dyke, TE\n\nBartold, PM\n\nDommisch, H\n\nEickholz, P\n\nGeisinger, ML\n\nGenco, RJ\n\nGlogauer, M\n\nGoldstein, M\n\nGriffin, TJ\n\nHolmstrup, P\n\nJohnson, GK\n\nKapila, Y\n\nLang, NP\n\nMeyle, J\n\nMurakami, S\n\nPlemons, J\n\nRomito, GA\n\nShapira, L\n\nTatakis, DN\n\nTeughels, W\n\nTrombelli, L\n\nWalter, C\n\nWimmer, G\n\nXenoudi, P\n\nYoshie, H\n\nBeiträge in Fachzeitschriften\nISI:000435795300006\n29926499.0\n10.1111/jcpe.12940\nNone\nPeriodontal health is defined by absence of clinically detectable inflammation. There is a biological level of immune surveillance that is consistent with clinical gingival health and homeostasis. Clinical gingival health may be found in a periodontium that is intact, i.e. without clinical attachment loss or bone loss, and on a reduced periodontium in either a non-periodontitis patient (e.g. in patients with some form of gingival recession or following crown lengthening surgery) or in a patient with a history of periodontitis who is currently periodontally stable. Clinical gingival health can be restored following treatment of gingivitis and periodontitis. However, the treated and stable periodontitis patient with current gingival health remains at increased risk of recurrent periodontitis, and accordingly, must be closely monitored. Two broad categories of gingival diseases include non-dental plaque biofilm-induced gingival diseases and dental plaque-induced gingivitis. Non-dental plaque biofilm-induced gingival diseases include a variety of conditions that are not caused by plaque and usually do not resolve following plaque removal. Such lesions may be manifestations of a systemic condition or may be localized to the oral cavity. Dental plaque-induced gingivitis has a variety of clinical signs and symptoms, and both local predisposing factors and systemic modifying factors can affect its extent, severity, and progression. Dental plaque-induced gingivitis may arise on an intact periodontium or on a reduced periodontium in either a non-periodontitis patient or in a currently stable "periodontitis patient" i.e. successfully treated, in whom clinical inflammation has been eliminated (or substantially reduced). A periodontitis patient with gingival inflammation remains a periodontitis patient (Figure 1), and comprehensive risk assessment and management are imperative to ensure early prevention and/or treatment of recurrent/progressive periodontitis. Precision dental medicine defines a patient-centered approach to care, and therefore, creates differences in the way in which a "case" of gingival health or gingivitis is defined for clinical practice as opposed to epidemiologically in population prevalence surveys. Thus, case definitions of gingival health and gingivitis are presented for both purposes. While gingival health and gingivitis have many clinical features, case definitions are primarily predicated on presence or absence of bleeding on probing. Here we classify gingival health and gingival diseases/conditions, along with a summary table of diagnostic features for defining health and gingivitis in various clinical situations.\n © 2018 American Academy of Periodontology and European Federation of Periodontology.\n\nWimmer, Gernot\n\n\n"
},
{
"text": "\n143495\nEvaluation of the prognostic significance of perirenal fat invasion and tumor size in patients with pT1-pT3a localized renal cell carcinoma in a comprehensive multicenter study of the CORONA project. Can we improve prognostic discrimination for patients with stage pT3a tumors?\n\nBrookman-May, SD\n\nMay, M\n\nWolff, I\n\nZigeuner, R\n\nHutterer, GC\n\nCindolo, L\n\nSchips, L\n\nDe Cobelli, O\n\nRocco, B\n\nDe Nunzio, C\n\nTubaro, A\n\nComan, I\n\nTruss, M\n\nDalpiaz, O\n\nFeciche, B\n\nFigenshau, RS\n\nMadison, K\n\nSánchez-Chapado, M\n\nSantiago Martin, Mdel C\n\nSalzano, L\n\nLotrecchiano, G\n\nZastrow, S\n\nWirth, M\n\nSountoulides, P\n\nShariat, S\n\nWaidelich, R\n\nStief, C\n\nGunia, S\n\nCORONA Project\n\nEuropean Association of Urology (EAU) Young Academic Urologists (YAU) Renal Cancer Group\n\nBeiträge in Fachzeitschriften\nISI:000352143100023\n25684695.0\n10.1016/j.eururo.2014.11.055\nNone\nThe current TNM system for renal cell carcinoma (RCC) merges perirenal fat invasion (PFI) and renal vein invasion (RVI) as stage pT3a despite limited evidence concerning their prognostic equivalence. In addition, the prognostic value of PFI compared to pT1-pT2 tumors remains controversial.\n To analyze the prognostic significance of PFI, RVI, and tumor size in pT1-pT3a RCC.\n Data for 7384 pT1a-pT3a RCC patients were pooled from 12 centers. Patients were grouped according to stages and PFI/RVI presence as follows: pT1-2N0M0 (n=6137; 83.1%), pT3aN0M0 + PFI (n=1036; 14%), and pT3aN0M0 (RVI ± PFI; n=211; 2.9%).\n Radical nephrectomy or nephron-sparing surgery (NSS) (1992-2010).\n Cancer-specific survival was estimated using the Kaplan-Meier method. Univariate and multivariate Cox proportional-hazards regression models, as well as sensitivity and discrimination analyses, were used to evaluate the impact of clinicopathologic parameters on cancer-specific mortality (CSM).\n Compared to stage pT1-2, patients with stage pT3a RCC were significantly more often male (59.4% vs 53.1%) and older (64.9 vs 62.1 yr), more often had clear cell RCC (85.2% vs 77.7%), Fuhrman grade 3-4 (29.4% vs 13.4%), and tumor size >7 cm (39.1% vs 13%), and underwent NSS less often (7.5% vs 36.6%; all p<0.001). According to multivariate analysis, CSM was significantly higher for the PFI and RVI ± PFI groups compared to pT1-2 patients (hazard ratio [HR] 1.94 and 2.12, respectively; p<0.001), whereas patients with PFI only and RVI ± PFI did not differ (HR 1.17; p=0.316). Tumor size instead enhanced CSM by 7% per cm in stage pT3a (HR 1.07; p<0.001) with a 7 cm cutoff yielding the highest prediction accuracy.\n Since the prognostic impact of PFI and RVI on CSM seems to be comparable, merging both as stage pT3a RCC might be justified. Enhanced prognostic discrimination of stage pT3a RCC appears to be possible by applying a tumor size cutoff of 7 cm within an alternative staging system.\n Prognosis prediction for patients with localized renal cell carcinoma up to stage pT3a can be enhanced by including tumor size with a cutoff of 7 cm as an additional parameter in the TNM classification system.\n Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.\n\nDalpiaz, Orietta\n\nHutterer, Georg\n\nZigeuner, Richard\n\n\n"
},
{
"text": "\n168415\nPeriodontal health and gingival diseases and conditions on an intact and a reduced periodontium: Consensus report of workgroup 1 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions.\n\nChapple, ILC\n\nMealey, BL\n\nVan Dyke, TE\n\nBartold, PM\n\nDommisch, H\n\nEickholz, P\n\nGeisinger, ML\n\nGenco, RJ\n\nGlogauer, M\n\nGoldstein, M\n\nGriffin, TJ\n\nHolmstrup, P\n\nJohnson, GK\n\nKapila, Y\n\nLang, NP\n\nMeyle, J\n\nMurakami, S\n\nPlemons, J\n\nRomito, GA\n\nShapira, L\n\nTatakis, DN\n\nTeughels, W\n\nTrombelli, L\n\nWalter, C\n\nWimmer, G\n\nXenoudi, P\n\nYoshie, H\n\nBeiträge in Fachzeitschriften\nISI:000435799100006\n29926944.0\n10.1002/JPER.17-0719\nNone\nPeriodontal health is defined by absence of clinically detectable inflammation. There is a biological level of immune surveillance that is consistent with clinical gingival health and homeostasis. Clinical gingival health may be found in a periodontium that is intact, i.e. without clinical attachment loss or bone loss, and on a reduced periodontium in either a non-periodontitis patient (e.g. in patients with some form of gingival recession or following crown lengthening surgery) or in a patient with a history of periodontitis who is currently periodontally stable. Clinical gingival health can be restored following treatment of gingivitis and periodontitis. However, the treated and stable periodontitis patient with current gingival health remains at increased risk of recurrent periodontitis, and accordingly, must be closely monitored. Two broad categories of gingival diseases include non-dental plaque biofilm-induced gingival diseases and dental plaque-induced gingivitis. Non-dental plaque biofilm-induced gingival diseases include a variety of conditions that are not caused by plaque and usually do not resolve following plaque removal. Such lesions may be manifestations of a systemic condition or may be localized to the oral cavity. Dental plaque-induced gingivitis has a variety of clinical signs and symptoms, and both local predisposing factors and systemic modifying factors can affect its extent, severity, and progression. Dental plaque-induced gingivitis may arise on an intact periodontium or on a reduced periodontium in either a non-periodontitis patient or in a currently stable "periodontitis patient" i.e. successfully treated, in whom clinical inflammation has been eliminated (or substantially reduced). A periodontitis patient with gingival inflammation remains a periodontitis patient (Figure 1), and comprehensive risk assessment and management are imperative to ensure early prevention and/or treatment of recurrent/progressive periodontitis. Precision dental medicine defines a patient-centered approach to care, and therefore, creates differences in the way in which a "case" of gingival health or gingivitis is defined for clinical practice as opposed to epidemiologically in population prevalence surveys. Thus, case definitions of gingival health and gingivitis are presented for both purposes. While gingival health and gingivitis have many clinical features, case definitions are primarily predicated on presence or absence of bleeding on probing. Here we classify gingival health and gingival diseases/conditions, along with a summary table of diagnostic features for defining health and gingivitis in various clinical situations.\n © 2018 American Academy of Periodontology and European Federation of Periodontology.\n\nWimmer, Gernot\n\n\n"
},
{
"text": "\n168789\nWhole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation.\n\nBis, JC\n\nJian, X\n\nKunkle, BW\n\nChen, Y\n\nHamilton-Nelson, KL\n\nBush, WS\n\nSalerno, WJ\n\nLancour, D\n\nMa, Y\n\nRenton, AE\n\nMarcora, E\n\nFarrell, JJ\n\nZhao, Y\n\nQu, L\n\nAhmad, S\n\nAmin, N\n\nAmouyel, P\n\nBeecham, GW\n\nBelow, JE\n\nCampion, D\n\nCantwell, L\n\nCharbonnier, C\n\nChung, J\n\nCrane, PK\n\nCruchaga, C\n\nCupples, LA\n\nDartigues, JF\n\nDebette, S\n\nDeleuze, JF\n\nFulton, L\n\nGabriel, SB\n\nGenin, E\n\nGibbs, RA\n\nGoate, A\n\nGrenier-Boley, B\n\nGupta, N\n\nHaines, JL\n\nHavulinna, AS\n\nHelisalmi, S\n\nHiltunen, M\n\nHowrigan, DP\n\nIkram, MA\n\nKaprio, J\n\nKonrad, J\n\nKuzma, A\n\nLander, ES\n\nLathrop, M\n\nLehtimäki, T\n\nLin, H\n\nMattila, K\n\nMayeux, R\n\nMuzny, DM\n\nNasser, W\n\nNeale, B\n\nNho, K\n\nNicolas, G\n\nPatel, D\n\nPericak-Vance, MA\n\nPerola, M\n\nPsaty, BM\n\nQuenez, O\n\nRajabli, F\n\nRedon, R\n\nReitz, C\n\nRemes, AM\n\nSalomaa, V\n\nSarnowski, C\n\nSchmidt, H\n\nSchmidt, M\n\nSchmidt, R\n\nSoininen, H\n\nThornton, TA\n\nTosto, G\n\nTzourio, C\n\nvan der Lee, SJ\n\nvan Duijn, CM\n\nValladares, O\n\nVardarajan, B\n\nWang, LS\n\nWang, W\n\nWijsman, E\n\nWilson, RK\n\nWitten, D\n\nWorley, KC\n\nZhang, X\n\nAlzheimer’s Disease Sequencing Project\n\nBellenguez, C\n\nLambert, JC\n\nKurki, MI\n\nPalotie, A\n\nDaly, M\n\nBoerwinkle, E\n\nLunetta, KL\n\nDestefano, AL\n\nDupuis, J\n\nMartin, ER\n\nSchellenberg, GD\n\nSeshadri, S\n\nNaj, AC\n\nFornage, M\n\nFarrer, LA\n\nBeiträge in Fachzeitschriften\nISI:000553251700020\n30108311.0\n10.1038/s41380-018-0112-7\nPMC6375806\nThe Alzheimer's Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5, 40 late-onset Alzheimer disease (AD) cases and 5, 96 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50, 00 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2, 78 cases, 7, 62 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9, 43 cases, 11, 27 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10-7), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10-7), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10-6). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.\n\nSchmidt, Helena\n\nSchmidt, Reinhold\n\n\n"
},
{
"text": "\n176393\nEvaluation of the Central Vein Sign as a Diagnostic Imaging Biomarker in Multiple Sclerosis.\n\nSinnecker, T\n\nClarke, MA\n\nMeier, D\n\nEnzinger, C\n\nCalabrese, M\n\nDe Stefano, N\n\nPitiot, A\n\nGiorgio, A\n\nSchoonheim, MM\n\nPaul, F\n\nPawlak, MA\n\nSchmidt, R\n\nKappos, L\n\nMontalban, X\n\nRovira, À\n\nEvangelou, N\n\nWuerfel, J\n\nMAGNIMS Study Group\n\nBeiträge in Fachzeitschriften\nISI:000505186000008\n31424490.0\n10.1001/jamaneurol.2019.2478\nPMC6704746\nThe central vein sign has been proposed as a specific imaging biomarker for distinguishing between multiple sclerosis (MS) and not MS, mainly based on findings from ultrahigh-field magnetic resonance imaging (MRI) studies. The diagnostic value of the central vein sign in a multicenter setting with a variety of clinical 3 tesla (T) MRI protocols, however, remains unknown.\n To evaluate the sensitivity and specificity of various central vein sign lesion criteria for differentiating MS from non-MS conditions using 3T brain MRI with various commonly used pulse sequences.\n This large multicenter, cross-sectional study enrolled participants (n = 648) of ongoing observational studies and patients included in neuroimaging research databases of 8 neuroimaging centers in Europe. Patient enrollment and MRI data collection were performed between January 1, 2010, and November 30, 2016. Data analysis was conducted between January 1, 2016, and April 30, 2018. Investigators were blinded to participant diagnosis by a novel blinding procedure.\n Occurrence of central vein sign was detected on 3T T2*-weighted or susceptibility-weighted imaging. Sensitivity and specificity were assessed for these MRI sequences and for different central vein sign lesion criteria, which were defined by the proportion of lesions with central vein sign or by absolute numbers of lesions with central vein sign.\n A total of 606 participants were included in the study after exclusion of 42 participants. Among the 606 participants, 413 (68.2%) were women. Patients with clinically isolated syndrome and relapsing-remitting MS (RRMS) included 235 women (66.6%) and had a median (range) age of 37 (14.7-61.4) years, a median (range) disease duration of 2 (0-33) years, and a median (range) Expanded Disability Status Scale score of 1.5 (0-6.5). Patients without MS included 178 women (70.4%) and had a median (range) age of 54 (18-83) years. A total of 4447 lesions were analyzed in a total of 487 patients: 690 lesions in 98 participants with clinically isolated syndrome, 2815 lesions in 225 participants with RRMS, 54 lesions in 13 participants with neuromyelitis optica spectrum disorder, 54 lesions in 14 participants with systemic lupus erythematosus, 121 lesions in 29 participants with migraine or cluster headache, 240 lesions in 20 participants with diabetes, and 473 lesions in 88 participants with other types of small-vessel disease. The sensitivity was 68.1% and specificity was 82.9% for distinguishing MS from not MS using a 35% central vein sign proportion threshold. The 3 central vein sign lesion criteria had a sensitivity of 61.9% and specificity of 89.0%. Sensitivity was higher when an optimized T2*-weighted sequence was used.\n In this study, use of the central vein sign at 3T MRI yielded a high specificity and a moderate sensitivity in differentiating MS from not MS; international, multicenter studies may be needed to ascertain whether the central vein sign-based criteria can accurately detect MS.\n\nEnzinger, Christian\n\nSchmidt, Reinhold\n\n\n"
},
{
"text": "\n166374\nThe genotypic and phenotypic spectrum of MTO1 deficiency.\n\nO'Byrne, JJ\n\nTarailo-Graovac, M\n\nGhani, A\n\nChampion, M\n\nDeshpande, C\n\nDursun, A\n\nOzgul, RK\n\nFreisinger, P\n\nGarber, I\n\nHaack, TB\n\nHorvath, R\n\nBarić, I\n\nHusain, RA\n\nKluijtmans, LAJ\n\nKotzaeridou, U\n\nMorris, AA\n\nRoss, CJ\n\nSantra, S\n\nSmeitink, J\n\nTarnopolsky, M\n\nWortmann, SB\n\nMayr, JA\n\nBrunner-Krainz, M\n\nProkisch, H\n\nWasserman, WW\n\nWevers, RA\n\nEngelke, UF\n\nRodenburg, RJ\n\nTing, TW\n\nMcFarland, R\n\nTaylor, RW\n\nSalvarinova, R\n\nvan Karnebeek, CDM\n\nBeiträge in Fachzeitschriften\nISI:000423501300004\n29331171.0\n10.1016/j.ymgme.2017.11.003\nPMC5780301\nMitochondrial diseases, a group of multi-systemic disorders often characterized by tissue-specific phenotypes, are usually progressive and fatal disorders resulting from defects in oxidative phosphorylation. MTO1 (Mitochondrial tRNA Translation Optimization 1), an evolutionarily conserved protein expressed in high-energy demand tissues has been linked to human early-onset combined oxidative phosphorylation deficiency associated with hypertrophic cardiomyopathy, often referred to as combined oxidative phosphorylation deficiency-10 (COXPD10).\n Thirty five cases of MTO1 deficiency were identified and reviewed through international collaboration. The cases of two female siblings, who presented at 1 and 2years of life with seizures, global developmental delay, hypotonia, elevated lactate and complex I and IV deficiency on muscle biopsy but without cardiomyopathy, are presented in detail.\n For the description of phenotypic features, the denominator varies as the literature was insufficient to allow for complete ascertainment of all data for the 35 cases. An extensive review of all known MTO1 deficiency cases revealed the most common features at presentation to be lactic acidosis (LA) (21/34; 62% cases) and hypertrophic cardiomyopathy (15/34; 44% cases). Eventually lactic acidosis and hypertrophic cardiomyopathy are described in 35/35 (100%) and 27/34 (79%) of patients with MTO1 deficiency, respectively; with global developmental delay/intellectual disability present in 28/29 (97%), feeding difficulties in 17/35 (49%), failure to thrive in 12/35 (34%), seizures in 12/35 (34%), optic atrophy in 11/21 (52%) and ataxia in 7/34 (21%). There are 19 different pathogenic MTO1 variants identified in these 35 cases: one splice-site, 3 frameshift and 15 missense variants. None have bi-allelic variants that completely inactivate MTO1; however, patients where one variant is truncating (i.e. frameshift) while the second one is a missense appear to have a more severe, even fatal, phenotype. These data suggest that complete loss of MTO1 is not viable. A ketogenic diet may have exerted a favourable effect on seizures in 2/5 patients.\n MTO1 deficiency is lethal in some but not all cases, and a genotype-phenotype relation is suggested. Aside from lactic acidosis and cardiomyopathy, developmental delay and other phenotypic features affecting multiple organ systems are often present in these patients, suggesting a broader spectrum than hitherto reported. The diagnosis should be suspected on clinical features and the presence of markers of mitochondrial dysfunction in body fluids, especially low residual complex I, III and IV activity in muscle. Molecular confirmation is required and targeted genomic testing may be the most efficient approach. Although subjective clinical improvement was observed in a small number of patients on therapies such as ketogenic diet and dichloroacetate, no evidence-based effective therapy exists.\n Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.\n\nBrunner-Krainz, Michaela\n\n\n"
},
{
"text": "\n130830\nBioactivity of enoxaparin in critically ill patients with normal renal function.\n\nGouya, G\n\nPalkovits, S\n\nKapiotis, S\n\nMadl, C\n\nLocker, G\n\nStella, A\n\nWolzt, M\n\nHeinz, G\n\nBeiträge in Fachzeitschriften\nISI:000309597200010\n23227470.0\n10.1111/j.1365-2125.2012.04285.x\nPMC3495145\nWHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Venous thromboembolism is a frequent complication in critically ill patients that has a negative impact on patient outcomes. Critically ill patients have significantly lower plasma anti-factor-Xa activity levels compared with control patients after administration of subcutaneous heparin. The clinical relevance of the different anti-factor-Xa levels after prophylactic doses of low molecular weight heparin (LMWH) in critically ill patients is not completely understood. WHAT THIS STUDY ADDS The standard dose of 40 mg enoxaparin led to a significant increase in anti-FXa levels in this selected cohort of ICU patients with normal renal function. This study found only subtle pharmacokinetic differences, but a comparable pharmacodynamic action, after enoxaparin administration in critically ill and normal medical ward patients. Thrombin generation with TGA RC-low and TGA RC-high reagents was significantly reduced in ICU and normal ward patients after receiving LMWH. Both readouts appear equally useful for estimating the pharmacodynamics of enoxaparin. The ex vivo model of thrombosis was used for the first time in patients to evaluate the anti-thrombotic activity of LMWH. This method did not show any difference in thrombus formation after administration of enoxaparin in the individual group of patients. Aim In critically ill patients, reduced anti-FXa plasma activity following subcutaneous administration of enoxaparin or nadroparin has been described. In this study, we aimed to investigate the bioactivity of enoxaparin in critically ill patients and controls. Methods A prospective, controlled, open label study was performed on a medical intensive care unit (ICU) and a general medical ward. Fifteen ICU patients (male = 12, median age 52 years [IQR 40-65], with a median Simplified Acute Physiology Score of 30 [IQR 18-52]) and sex- and age-matched medical ward patients were included. The anti-FXa plasma activity was measured after a single subcutaneous dose of 40 mg enoxaparin. The thrombus size of a clot formed in an ex vivo perfusion chamber and endogenous thrombin potential (ETP) were measured. Results The anti-FXa plasma activity increased significantly after enoxaparin administration, with peak levels at 3 h after treatment, but was comparable between the ICU and medical ward groups (median 0.16 IU ml-1[IQR 0-0.22 IU ml-1]vs. 0.2 IU ml-1[IQR 0.15-0.27 IU ml-1], respectively, P= 0.13). The area under the anti-FXa activity curve from 012 h was similar between the groups (median 0.97 IU ml-1 h [IQR 0.59-2.1] and 1.48 IU ml-1 h1[IQR 0.83-1.62], P= 0.42 for the ICU group compared with the control group, respectively). The ETP was lower in the ICU group (P < 0.05) at baseline, but it was comparable at 3 h between the groups. Thrombus size decreased at 3 h compared with predose (P= 0.029) and was not different between the groups. Conclusion Similar bioactivity was achieved with a standard dose of subcutaneous enoxaparin in this selected cohort of ICU and general ward patients with normal renal function.\n\n\n"
},
{
"text": "\n122124\nGenetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies.\n\nTraylor, M\n\nFarrall, M\n\nHolliday, EG\n\nSudlow, C\n\nHopewell, JC\n\nCheng, YC\n\nFornage, M\n\nIkram, MA\n\nMalik, R\n\nBevan, S\n\nThorsteinsdottir, U\n\nNalls, MA\n\nLongstreth, W\n\nWiggins, KL\n\nYadav, S\n\nParati, EA\n\nDestefano, AL\n\nWorrall, BB\n\nKittner, SJ\n\nKhan, MS\n\nReiner, AP\n\nHelgadottir, A\n\nAchterberg, S\n\nFernandez-Cadenas, I\n\nAbboud, S\n\nSchmidt, R\n\nWalters, M\n\nChen, WM\n\nRingelstein, EB\n\nO'Donnell, M\n\nHo, WK\n\nPera, J\n\nLemmens, R\n\nNorrving, B\n\nHiggins, P\n\nBenn, M\n\nSale, M\n\nKuhlenbäumer, G\n\nDoney, AS\n\nVicente, AM\n\nDelavaran, H\n\nAlgra, A\n\nDavies, G\n\nOliveira, SA\n\nPalmer, CN\n\nDeary, I\n\nSchmidt, H\n\nPandolfo, M\n\nMontaner, J\n\nCarty, C\n\nde Bakker, PI\n\nKostulas, K\n\nFerro, JM\n\nvan Zuydam, NR\n\nValdimarsson, E\n\nNordestgaard, BG\n\nLindgren, A\n\nThijs, V\n\nSlowik, A\n\nSaleheen, D\n\nParé, G\n\nBerger, K\n\nThorleifsson, G\n\nThe Australian Stroke Genetics Collaborative, Wellcome Trust Case Control Consortium 2 (WTCCC2)\n\nHofman, A\n\nMosley, TH\n\nMitchell, BD\n\nFurie, K\n\nClarke, R\n\nLevi, C\n\nSeshadri, S\n\nGschwendtner, A\n\nBoncoraglio, GB\n\nSharma, P\n\nBis, JC\n\nGretarsdottir, S\n\nPsaty, BM\n\nRothwell, PM\n\nRosand, J\n\nMeschia, JF\n\nStefansson, K\n\nDichgans, M\n\nMarkus, HS\n\non behalf of the International Stroke Genetics Consortium\n\nBeiträge in Fachzeitschriften\nISI:000310422200011\n23041239.0\n10.1016/S1474-4422(12)70234-X\nPMC3490334\nBackground Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes.\nMethods We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nudeotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls.\nFindings We verified previous associations for cardioembolic stroke near PITX2 (p=2.8x10(-16)) and ZFHX3 (p=2.28x10(-8)), and for large-vessel stroke at a 9p21 locus (p=3.32x10(-5)) and HDAC9 (p=2.03x10(-12)). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at pANDlt;5x10(-6). However, we were unable to replicate any of these novel associations in the replication cohort.\nInterpretation Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes.\n\nSchmidt, Helena\n\nSchmidt, Reinhold\n\n\n"
},
{
"text": "\n182071\nLiver Phenotypes of European Adults Heterozygous or Homozygous for Pi∗Z Variant of AAT (Pi∗MZ vs Pi∗ZZ genotype) and Noncarriers.\n\nSchneider, CV\n\nHamesch, K\n\nGross, A\n\nMandorfer, M\n\nMoeller, LS\n\nPereira, V\n\nPons, M\n\nKuca, P\n\nReichert, MC\n\nBenini, F\n\nBurbaum, B\n\nVoss, J\n\nGutberlet, M\n\nWoditsch, V\n\nLindhauer, C\n\nFromme, M\n\nKümpers, J\n\nBewersdorf, L\n\nSchaefer, B\n\nEslam, M\n\nBals, R\n\nJanciauskiene, S\n\nCarvão, J\n\nNeureiter, D\n\nZhou, B\n\nWöran, K\n\nBantel, H\n\nGeier, A\n\nDirrichs, T\n\nStickel, F\n\nTeumer, A\n\nVerbeek, J\n\nNevens, F\n\nGovaere, O\n\nKrawczyk, M\n\nRoskams, T\n\nHaybaeck, J\n\nLurje, G\n\nChorostowska-Wynimko, J\n\nGenesca, J\n\nReiberger, T\n\nLammert, F\n\nKrag, A\n\nGeorge, J\n\nAnstee, QM\n\nTrauner, M\n\nDatz, C\n\nGaisa, NT\n\nDenk, H\n\nTrautwein, C\n\nAigner, E\n\nStrnad, P\n\nEuropean Alpha-1 Liver Study Group\n\nBeiträge in Fachzeitschriften\nISI:000561918600021\n32376409.0\n10.1053/j.gastro.2020.04.058\nNone\nHomozygosity for the Pi∗Z variant of the gene that encodes the alpha-1 antitrypsin peptide (AAT), called the Pi∗ZZ genotype, causes a liver and lung disease called alpha-1 antitrypsin deficiency. Heterozygosity (the Pi∗MZ genotype) is a risk factor for cirrhosis in individuals with liver disease. Up to 4% of Europeans have the Pi∗MZ genotype; we compared features of adults with and without Pi∗MZ genotype among persons without preexisting liver disease.\n We analyzed data from the European Alpha-1 Liver Cohort, from 419 adults with the Pi∗MZ genotype, 309 adults with the Pi∗ZZ genotype, and 284 individuals without the variant (noncarriers). All underwent a comprehensive evaluation; liver stiffness measurements (LSMs) were made by transient elastography. Liver biopsies were analyzed to define histologic and biochemical features associated with the Pi∗Z variant. Levels of serum transaminases were retrieved from 444, 42 participants, available in the United Kingdom biobank.\n In the UK biobank database, levels of serum transaminases were increased in subjects with the Pi∗MZ genotype compared with noncarriers. In the Alpha-1 Liver Cohort, adults with Pi∗MZ had lower levels of gamma-glutamyl transferase in serum and lower LSMs than adults with the Pi∗ZZ variant, but these were higher than in noncarriers. Ten percent of subjects with the Pi∗MZ genotype vs 4% of noncarriers had LSMs of 7.1 kPa or more (adjusted odds ratio, 4.8; 95% confidence interval, 2.0-11.8). Obesity and diabetes were the most important factors associated with LSMs ≥7.1 kPa in subjects with the Pi∗MZ genotype. AAT inclusions were detected in liver biopsies of 63% of subjects with the Pi∗MZ genotype, vs 97% of subjects with the Pi∗ZZ genotype, and increased with liver fibrosis stages. Subjects with the Pi∗MZ genotype did not have increased hepatic levels of AAT, whereas levels of insoluble AAT varied among individuals.\n Adults with the Pi∗MZ genotype have lower levels of serum transaminases, fewer AAT inclusions in liver, and lower liver stiffness than adults with the Pi∗ZZ genotype, but higher than adults without the Pi∗Z variant. These findings should help determine risk of subjects with the Pi∗MZ genotype and aid in counseling.\n Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.\n\nDenk, Helmut\n\nHaybäck, Johannes\n\n\n"
},
{
"text": "\n168834\nMRI-Guided Thrombolysis for Stroke with Unknown Time of Onset.\n\nThomalla, G\n\nSimonsen, CZ\n\nBoutitie, F\n\nAndersen, G\n\nBerthezene, Y\n\nCheng, B\n\nCheripelli, B\n\nCho, TH\n\nFazekas, F\n\nFiehler, J\n\nFord, I\n\nGalinovic, I\n\nGellissen, S\n\nGolsari, A\n\nGregori, J\n\nGünther, M\n\nGuibernau, J\n\nHäusler, KG\n\nHennerici, M\n\nKemmling, A\n\nMarstrand, J\n\nModrau, B\n\nNeeb, L\n\nPerez de la Ossa, N\n\nPuig, J\n\nRingleb, P\n\nRoy, P\n\nScheel, E\n\nSchonewille, W\n\nSerena, J\n\nSunaert, S\n\nVillringer, K\n\nWouters, A\n\nThijs, V\n\nEbinger, M\n\nEndres, M\n\nFiebach, JB\n\nLemmens, R\n\nMuir, KW\n\nNighoghossian, N\n\nPedraza, S\n\nGerloff, C\n\nWAKE-UP Investigators\n\nBeiträge in Fachzeitschriften\nISI:000441659100005\n29766770.0\n10.1056/NEJMoa1804355\nNone\nUnder current guidelines, intravenous thrombolysis is used to treat acute stroke only if it can be ascertained that the time since the onset of symptoms was less than 4.5 hours. We sought to determine whether patients with stroke with an unknown time of onset and features suggesting recent cerebral infarction on magnetic resonance imaging (MRI) would benefit from thrombolysis with the use of intravenous alteplase.\n In a multicenter trial, we randomly assigned patients who had an unknown time of onset of stroke to receive either intravenous alteplase or placebo. All the patients had an ischemic lesion that was visible on MRI diffusion-weighted imaging but no parenchymal hyperintensity on fluid-attenuated inversion recovery (FLAIR), which indicated that the stroke had occurred approximately within the previous 4.5 hours. We excluded patients for whom thrombectomy was planned. The primary end point was favorable outcome, as defined by a score of 0 or 1 on the modified Rankin scale of neurologic disability (which ranges from 0 [no symptoms] to 6 [death]) at 90 days. A secondary outcome was the likelihood that alteplase would lead to lower ordinal scores on the modified Rankin scale than would placebo (shift analysis).\n The trial was stopped early owing to cessation of funding after the enrollment of 503 of an anticipated 800 patients. Of these patients, 254 were randomly assigned to receive alteplase and 249 to receive placebo. A favorable outcome at 90 days was reported in 131 of 246 patients (53.3%) in the alteplase group and in 102 of 244 patients (41.8%) in the placebo group (adjusted odds ratio, 1.61; 95% confidence interval [CI], 1.09 to 2.36; P=0.02). The median score on the modified Rankin scale at 90 days was 1 in the alteplase group and 2 in the placebo group (adjusted common odds ratio, 1.62; 95% CI, 1.17 to 2.23; P=0.003). There were 10 deaths (4.1%) in the alteplase group and 3 (1.2%) in the placebo group (odds ratio, 3.38; 95% CI, 0.92 to 12.52; P=0.07). The rate of symptomatic intracranial hemorrhage was 2.0% in the alteplase group and 0.4% in the placebo group (odds ratio, 4.95; 95% CI, 0.57 to 42.87; P=0.15).\n In patients with acute stroke with an unknown time of onset, intravenous alteplase guided by a mismatch between diffusion-weighted imaging and FLAIR in the region of ischemia resulted in a significantly better functional outcome and numerically more intracranial hemorrhages than placebo at 90 days. (Funded by the European Union Seventh Framework Program; WAKE-UP ClinicalTrials.gov number, NCT01525290; and EudraCT number, 2011-005906-32 .).\n\nFandler-Höfler, Simon\n\nFazekas, Franz\n\nGattringer, Thomas\n\n\n"
},
{
"text": "\n1617\nMechanism of hypertriglyceridemia in human apolipoprotein (apo) CIII transgenic mice. Diminished very low density lipoprotein fractional catabolic rate associated with increased apo CIII and reduced apo E on the particles.\n\nAalto-Setälä, K\n\nFisher, EA\n\nChen, X\n\nChajek-Shaul, T\n\nHayek, T\n\nZechner, R\n\nWalsh, A\n\nRamakrishnan, R\n\nGinsberg, HN\n\nBreslow, JL\n\nBeiträge in Fachzeitschriften\nISI:A1992JZ47500033\n1430212.0\n10.1172/JCI116066\nPMC443250\nHypertriglyceridemia is common in the general population, but its mechanism is largely unknown. In previous work human apo CIII transgenic (HuCIIITg) mice were found to have elevated triglyceride levels. In this report, the mechanism for the hypertriglyceridemia was studied. Two different HuCIIITg mouse lines were used: a low expressor line with serum triglycerides of approximately 280 mg/dl, and a high expressor line with serum triglycerides of approximately 1, 00 mg/dl. Elevated triglycerides were mainly in VLDL. VLDL particles were 1.5 times more triglyceride-rich in high expressor mice than in controls. The total amount of apo CIII (human and mouse) per VLDL particle was 2 and 2.5 times the normal amount in low and high expressors, respectively. Mouse apo E was decreased by 35 and 77% in low and high expressor mice, respectively. Under electron microscopy, VLDL particles from low and high expressor mice were found to have a larger mean diameter, 55.2 +/- 16.6 and 58.2 +/- 17.8 nm, respectively, compared with 51.0 +/- 13.4 nm from control mice. In in vivo studies, radiolabeled VLDL fractional catabolic rate (FCR) was reduced in low and high expressor mice to 2.58 and 0.77 pools/h, respectively, compared with 7.67 pools/h in controls, with no significant differences in the VLDL production rates. In an attempt to explain the reduced VLDL FCR in transgenic mice, tissue lipoprotein lipase (LPL) activity was determined in control and high expressor mice and no differences were observed. Also, VLDLs obtained from control and high expressor mice were found to be equally good substrates for purified LPL. Thus excess apo CIII in HuCIIITg mice does not cause reduced VLDL FCR by suppressing the amount of extractable LPL in tissues or making HuCIIITg VLDL a bad substrate for LPL. Tissue uptake of VLDL was studied in hepatoma cell cultures, and VLDL from transgenic mice was found to be taken up much more slowly than control VLDL (P < 0.0001), indicating that HuCIIITg VLDL is not well recognized by lipoprotein receptors. Additional in vivo studies with Triton-treated mice showed increased VLDL triglyceride, but not apo B, production in the HuCIIITg mice compared with controls. Tissue culture studies with primary hepatocytes showed a modest increase in triglyceride, but not apo B or total protein, secretion in high expressor mice compared with controls. In summary, hypertriglyceridemia in HuCIIITg mice appears to result primarily from decreased tissue uptake of triglyceride-rich particles from the circulation, which is most likely due to increased apo CIII and decreased apo E on VLDL particles. the HuCIIITg mouse appears to be a suitable animal model of primary familial hypertriglyceridemia, and these studies suggest a possible mechanism for this common lipoprotein disorder.\n\n\n"
},
{
"text": "\n153337\nAssociation Between Sarcopenia and Nutritional Status in Older Adults: A Systematic Literature Review.\n\nEglseer, D\n\nEminovic, S\n\nLohrmann, C\n\nBeiträge in Fachzeitschriften\nISI:000384989300006\n27337185.0\n10.3928/00989134-20160613-03\nNone\nHOW TO OBTAIN CONTACT HOURS BY READING THIS ARTICLE INSTRUCTIONS 1.2 contact hours will be awarded by Villanova University College of Nursing upon successful completion of this activity. A contact hour is a unit of measurement that denotes 60 minutes of an organized learning activity. This is a learner-based activity. Villanova University College of Nursing does not require submission of your answers to the quiz. A contact hour certificate will be awarded once you register, pay the registration fee, and complete the evaluation form online at http://goo.gl/gMfXaf. To obtain contact hours you must: 1. Read the article, "Association Between Sarcopenia and Nutritional Status in Older Adults: A Systematic Literature Review" found on pages 33-41, carefully noting any tables and other illustrative materials that are included to enhance your knowledge and understanding of the content. Be sure to keep track of the amount of time (number of minutes) you spend reading the article and completing the quiz. 2. Read and answer each question on the quiz. After completing all of the questions, compare your answers to those provided within this issue. If you have incorrect answers, return to the article for further study. 3. Go to the Villanova website listed above to register for contact hour credit. You will be asked to provide your name; contact information; and a VISA, MasterCard, or Discover card number for payment of the $20.00 fee. Once you complete the online evaluation, a certificate will be automatically generated. This activity is valid for continuing education credit until June 30, 2019. CONTACT HOURS This activity is co-provided by Villanova University College of Nursing and SLACK Incorporated. Villanova University College of Nursing is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. ACTIVITY OBJECTIVES 1. Describe the geriatric syndrome of sarcopenia. 2. Identify the outcome of the sarcopenia studies. DISCLOSURE STATEMENT Neither the planners nor the authors have any conflicts of interest to disclose. Sarcopenia is an important geriatric syndrome with high prevalence rates and one of the most common causes of reductions in mobility, quality of life, and increasing dependency on care. The current study examined the relationship between sarcopenia and nutritional status in adults 60 and older. A systematic literature search was conducted, and data from 33 publications were included. The currently available literature indicates that sarcopenia is correlated with poor nutritional status (e.g., low body mass index, unfavorable nutritional risk screening results, decreased nutritional laboratory parameters, anorexia). Comparison of the studies' results were complicated by the lack of a generally accepted definition for sarcopenia, as well as the use of many different instruments to detect sarcopenia. The co-occurrence of malnutrition and sarcopenia is of great relevance. Future scientific work should focus on the formation of consistent definitions and instruments for the detection of sarcopenia to improve data comparisons. [Journal of Gerontological Nursing, 42(7), 33-41.]. \n Copyright 2016, SLACK Incorporated.\n\nEglseer, Doris\n\nEminovic, Sandra\n\nLohrmann, Christa\n\n\n"
},
{
"text": "\n162730\nGenetic variants influencing elevated myeloperoxidase levels increase risk of stroke.\n\nPhuah, CL\n\nDave, T\n\nMalik, R\n\nRaffeld, MR\n\nAyres, AM\n\nGoldstein, JN\n\nViswanathan, A\n\nGreenberg, SM\n\nJagiella, JM\n\nHansen, BM\n\nNorrving, B\n\nJimenez-Conde, J\n\nRoquer, J\n\nPichler, A\n\nEnzinger, C\n\nMontaner, J\n\nFernandez-Cadenas, I\n\nLindgren, A\n\nSlowik, A\n\nSchmidt, R\n\nBiffi, A\n\nRost, N\n\nLangefeld, CD\n\nMarkus, HS\n\nMitchell, BD\n\nWorrall, BB\n\nKittner, SJ\n\nWoo, D\n\nDichgans, M\n\nRosand, J\n\nAnderson, CD\n\nMETASTROKE\n\nNINDS-SiGN Consortium\n\nInternational Stroke Genetics Consortium\n\nBeiträge in Fachzeitschriften\nISI:000414358500021\n28969386.0\n10.1093/brain/awx220\nPMC5841027\nPrimary intracerebral haemorrhage and lacunar ischaemic stroke are acute manifestations of progressive cerebral microvascular disease. Current paradigms suggest atherosclerosis is a chronic, dynamic, inflammatory condition precipitated in response to endothelial injury from various environmental challenges. Myeloperoxidase plays a central role in initiation and progression of vascular inflammation, but prior studies linking myeloperoxidase with stroke risk have been inconclusive. We hypothesized that genetic determinants of myeloperoxidase levels influence the development of vascular instability, leading to increased primary intracerebral haemorrhage and lacunar stroke risk. We used a discovery cohort of 1409 primary intracerebral haemorrhage cases and 1624 controls from three studies, an extension cohort of 12 577 ischaemic stroke cases and 25 643 controls from NINDS-SiGN, and a validation cohort of 10 307 ischaemic stroke cases and 29 326 controls from METASTROKE Consortium with genome-wide genotyping to test this hypothesis. A genetic risk score reflecting elevated myeloperoxidase levels was constructed from 15 common single nucleotide polymorphisms identified from prior genome-wide studies of circulating myeloperoxidase levels (P < 5 × 10-6). This genetic risk score was used as the independent variable in multivariable regression models for association with primary intracerebral haemorrhage and ischaemic stroke subtypes. We used fixed effects meta-analyses to pool estimates across studies. We also used Cox regression models in a prospective cohort of 174 primary intracerebral haemorrhage survivors for association with intracerebral haemorrhage recurrence. We present effects of myeloperoxidase elevating single nucleotide polymorphisms on stroke risk per risk allele, corresponding to a one allele increase in the myeloperoxidase increasing genetic risk score. Genetic determinants of elevated circulating myeloperoxidase levels were associated with both primary intracerebral haemorrhage risk (odds ratio, 1.07, P = 0.04) and recurrent intracerebral haemorrhage risk (hazards ratio, 1.45, P = 0.006). In analysis of ischaemic stroke subtypes, the myeloperoxidase increasing genetic risk score was strongly associated with lacunar subtype only (odds ratio, 1.05, P = 0.0012). These results, demonstrating that common genetic variants that increase myeloperoxidase levels increase risk of primary intracerebral haemorrhage and lacunar stroke, directly implicate the myeloperoxidase pathway in the pathogenesis of cerebral small vessel disease. Because genetic variants are not influenced by environmental exposures, these results provide new support for a causal rather than bystander role for myeloperoxidase in the progression of cerebrovascular disease. Furthermore, these results support a rationale for chronic inflammation as a potential modifiable stroke risk mechanism, and suggest that immune-targeted therapies could be useful for treatment and prevention of cerebrovascular disease.\n © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.\n\nEnzinger, Christian\n\nPichler, Alexander\n\nSchmidt, Reinhold\n\n\n"
},
{
"text": "\n181888\nTreatment and outcome of 370 cases with spontaneous or post-laser twin anemia-polycythemia sequence managed in 17 fetal therapy centers.\n\nTollenaar, LSA\n\nSlaghekke, F\n\nLewi, L\n\nVille, Y\n\nLanna, M\n\nWeingertner, A\n\nRyan, G\n\nArévalo, S\n\nKhalil, A\n\nBrock, CO\n\nKlaritsch, P\n\nHecher, K\n\nGardener, G\n\nBevilacqua, E\n\nKostyukov, KV\n\nBahtiyar, MO\n\nKilby, MD\n\nTiblad, E\n\nOepkes, D\n\nLopriore, E\n\nCollaborators\n\nBeiträge in Fachzeitschriften\nISI:000564449600008\n32291846.0\n10.1002/uog.22042\nPMC7497010\nTo investigate the antenatal management and outcome in a large international cohort of monochorionic twin pregnancies with spontaneous or post-laser twin anemia-polycythemia sequence (TAPS).\n This study analyzed data of monochorionic twin pregnancies diagnosed antenatally with spontaneous or post-laser TAPS in 17 fetal therapy centers, recorded in the TAPS Registry between 2014 and 2019. Antenatal diagnosis of TAPS was based on fetal middle cerebral artery peak systolic velocity > 1.5 multiples of the median (MoM) in the TAPS donor and < 1.0 MoM in the TAPS recipient. The following antenatal management groups were defined: expectant management, delivery within 7 days after diagnosis, intrauterine transfusion (IUT) (with or without partial exchange transfusion (PET)), laser surgery and selective feticide. Cases were assigned to the management groups based on the first treatment that was received after diagnosis of TAPS. The primary outcomes were perinatal mortality and severe neonatal morbidity. The secondary outcome was diagnosis-to-birth interval.\n In total, 370 monochorionic twin pregnancies were diagnosed antenatally with TAPS during the study period and included in the study. Of these, 31% (n = 113) were managed expectantly, 30% (n = 110) with laser surgery, 19% (n = 70) with IUT (± PET), 12% (n = 43) with delivery, 8% (n = 30) with selective feticide and 1% (n = 4) underwent termination of pregnancy. Perinatal mortality occurred in 17% (39/225) of pregnancies in the expectant-management group, 18% (38/215) in the laser group, 18% (25/140) in the IUT (± PET) group, 10% (9/86) in the delivery group and in 7% (2/30) of the cotwins in the selective-feticide group. The incidence of severe neonatal morbidity was 49% (41/84) in the delivery group, 46% (56/122) in the IUT (± PET) group, 31% (60/193) in the expectant-management group, 31% (57/182) in the laser-surgery group and 25% (7/28) in the selective-feticide group. Median diagnosis-to-birth interval was longest after selective feticide (10.5 (interquartile range (IQR), 4.2-14.9) weeks), followed by laser surgery (9.7 (IQR, 6.6-12.7) weeks), expectant management (7.8 (IQR, 3.8-14.4) weeks), IUT (± PET) (4.0 (IQR, 2.0-6.9) weeks) and delivery (0.3 (IQR, 0.0-0.5) weeks). Treatment choice for TAPS varied greatly within and between the 17 fetal therapy centers.\n Antenatal treatment for TAPS differs considerably amongst fetal therapy centers. Perinatal mortality and morbidity were high in all management groups. Prolongation of pregnancy was best achieved by expectant management, treatment by laser surgery or selective feticide. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.\n © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.\n\nGreimel, Patrick\n\nKlaritsch, Philipp\n\n\n"
},
{
"text": "\n144085\nExome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.\n\nDo, R\n\nStitziel, NO\n\nWon, HH\n\nJørgensen, AB\n\nDuga, S\n\nAngelica Merlini, P\n\nKiezun, A\n\nFarrall, M\n\nGoel, A\n\nZuk, O\n\nGuella, I\n\nAsselta, R\n\nLange, LA\n\nPeloso, GM\n\nAuer, PL\n\nNHLBI Exome Sequencing Project\n\nGirelli, D\n\nMartinelli, N\n\nFarlow, DN\n\nDePristo, MA\n\nRoberts, R\n\nStewart, AF\n\nSaleheen, D\n\nDanesh, J\n\nEpstein, SE\n\nSivapalaratnam, S\n\nHovingh, GK\n\nKastelein, JJ\n\nSamani, NJ\n\nSchunkert, H\n\nErdmann, J\n\nShah, SH\n\nKraus, WE\n\nDavies, R\n\nNikpay, M\n\nJohansen, CT\n\nWang, J\n\nHegele, RA\n\nHechter, E\n\nMarz, W\n\nKleber, ME\n\nHuang, J\n\nJohnson, AD\n\nLi, M\n\nBurke, GL\n\nGross, M\n\nLiu, Y\n\nAssimes, TL\n\nHeiss, G\n\nLange, EM\n\nFolsom, AR\n\nTaylor, HA\n\nOlivieri, O\n\nHamsten, A\n\nClarke, R\n\nReilly, DF\n\nYin, W\n\nRivas, MA\n\nDonnelly, P\n\nRossouw, JE\n\nPsaty, BM\n\nHerrington, DM\n\nWilson, JG\n\nRich, SS\n\nBamshad, MJ\n\nTracy, RP\n\nCupples, LA\n\nRader, DJ\n\nReilly, MP\n\nSpertus, JA\n\nCresci, S\n\nHartiala, J\n\nTang, WH\n\nHazen, SL\n\nAllayee, H\n\nReiner, AP\n\nCarlson, CS\n\nKooperberg, C\n\nJackson, RD\n\nBoerwinkle, E\n\nLander, ES\n\nSchwartz, SM\n\nSiscovick, DS\n\nMcPherson, R\n\nTybjaerg-Hansen, A\n\nAbecasis, GR\n\nWatkins, H\n\nNickerson, DA\n\nArdissino, D\n\nSunyaev, SR\n\nO'Donnell, CJ\n\nAltshuler, D\n\nGabriel, S\n\nKathiresan, S\n\nBeiträge in Fachzeitschriften\nISI:000349098000040\n25487149.0\n10.1038/nature13917\nPMC4319990\nMyocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9, 93 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.\n\nMärz, Winfried\n\n\n"
},
{
"text": "\n161468\nRheological characterization of human brain tissue.\n\nBudday, S\n\nSommer, G\n\nHaybaeck, J\n\nSteinmann, P\n\nHolzapfel, GA\n\nKuhl, E\n\nBeiträge in Fachzeitschriften\nISI:000411421400026\n28658600.0\n10.1016/j.actbio.2017.06.024\nNone\nThe rheology of ultrasoft materials like the human brain is highly sensitive to regional and temporal variations and to the type of loading. While recent experiments have shaped our understanding of the time-independent, hyperelastic response of human brain tissue, its time-dependent behavior under various loading conditions remains insufficiently understood. Here we combine cyclic and relaxation testing under multiple loading conditions, shear, compression, and tension, to understand the rheology of four different regions of the human brain, the cortex, the basal ganglia, the corona radiata, and the corpus callosum. We establish a family of finite viscoelastic Ogden-type models and calibrate their parameters simultaneously for all loading conditions. We show that the model with only one viscoelastic mode and a constant viscosity captures the essential features of brain tissue: nonlinearity, pre-conditioning, hysteresis, and tension-compression asymmetry. With stiffnesses and time constants of μ∞=0.7kPa, μ1=2.0kPa, and τ1=9.7s in the gray matter cortex and μ∞=0.3kPa, μ1=0.9kPa and τ1=14.9s in the white matter corona radiata combined with negative parameters α∞ and α1, this five-parameter model naturally accounts for pre-conditioning and tissue softening. Increasing the number of viscoelastic modes improves the agreement between model and experiment, especially across the entire relaxation regime. Strikingly, two cycles of pre-conditioning decrease the gray matter stiffness by up to a factor three, while the white matter stiffness remains almost identical. These new insights allow us to better understand the rheology of different brain regions under mixed loading conditions. Our family of finite viscoelastic Ogden-type models for human brain tissue is simple to integrate into standard nonlinear finite element packages. Our simultaneous parameter identification of multiple loading modes can inform computational simulations under physiological conditions, especially at low to moderate strain rates. Understanding the rheology of the human brain will allow us to more accurately model the behavior of the brain during development and disease and predict outcomes of neurosurgical procedures.\n While recent experiments have shaped our understanding of the time-independent, hyperelastic response of human brain tissue, its time-dependent behavior at finite strains and under various loading conditions remains insufficiently understood. In this manuscript, we characterize the rheology of human brain tissue through a family of finite viscoelastic Ogdentype models and identify their parameters for multiple loading modes in four different regions of the brain. We show that even the simplest model of this family, with only one viscoelastic mode and five material parameters, naturally captures the essential features of brain tissue: its characteristic nonlinearity, pre-conditioning, hysteresis, and tension-compression asymmetry. For the first time, we simultaneously identify a single parameter set for shear, compression, tension, shear relaxation, and compression relaxation loading. This parameter set is significant for computational simulations under physiological conditions, where loading is naturally of mixed mode nature. Understanding the rheology of the human brain will help us predict neurosurgical procedures, inform brain injury criteria, and improve the design of protective devices.\n Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.\n\nHaybäck, Johannes\n\n\n"
},
{
"text": "\n161071\nLarge-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation.\n\nChristophersen, IE\n\nRienstra, M\n\nRoselli, C\n\nYin, X\n\nGeelhoed, B\n\nBarnard, J\n\nLin, H\n\nArking, DE\n\nSmith, AV\n\nAlbert, CM\n\nChaffin, M\n\nTucker, NR\n\nLi, M\n\nKlarin, D\n\nBihlmeyer, NA\n\nLow, SK\n\nWeeke, PE\n\nMüller-Nurasyid, M\n\nSmith, JG\n\nBrody, JA\n\nNiemeijer, MN\n\nDörr, M\n\nTrompet, S\n\nHuffman, J\n\nGustafsson, S\n\nSchurmann, C\n\nKleber, ME\n\nLyytikäinen, LP\n\nSeppälä, I\n\nMalik, R\n\nHorimoto, ARVR\n\nPerez, M\n\nSinisalo, J\n\nAeschbacher, S\n\nThériault, S\n\nYao, J\n\nRadmanesh, F\n\nWeiss, S\n\nTeumer, A\n\nChoi, SH\n\nWeng, LC\n\nClauss, S\n\nDeo, R\n\nRader, DJ\n\nShah, SH\n\nSun, A\n\nHopewell, JC\n\nDebette, S\n\nChauhan, G\n\nYang, Q\n\nWorrall, BB\n\nParé, G\n\nKamatani, Y\n\nHagemeijer, YP\n\nVerweij, N\n\nSiland, JE\n\nKubo, M\n\nSmith, JD\n\nVan Wagoner, DR\n\nBis, JC\n\nPerz, S\n\nPsaty, BM\n\nRidker, PM\n\nMagnani, JW\n\nHarris, TB\n\nLauner, LJ\n\nShoemaker, MB\n\nPadmanabhan, S\n\nHaessler, J\n\nBartz, TM\n\nWaldenberger, M\n\nLichtner, P\n\nArendt, M\n\nKrieger, JE\n\nKähönen, M\n\nRisch, L\n\nMansur, AJ\n\nPeters, A\n\nSmith, BH\n\nLind, L\n\nScott, SA\n\nLu, Y\n\nBottinger, EB\n\nHernesniemi, J\n\nLindgren, CM\n\nWong, JA\n\nHuang, J\n\nEskola, M\n\nMorris, AP\n\nFord, I\n\nReiner, AP\n\nDelgado, G\n\nChen, LY\n\nChen, YI\n\nSandhu, RK\n\nLi, M\n\nBoerwinkle, E\n\nEisele, L\n\nLannfelt, L\n\nRost, N\n\nAnderson, CD\n\nTaylor, KD\n\nCampbell, A\n\nMagnusson, PK\n\nPorteous, D\n\nHocking, LJ\n\nVlachopoulou, E\n\nPedersen, NL\n\nNikus, K\n\nOrho-Melander, M\n\nHamsten, A\n\nHeeringa, J\n\nDenny, JC\n\nKriebel, J\n\nDarbar, D\n\nNewton-Cheh, C\n\nShaffer, C\n\nMacfarlane, PW\n\nHeilmann-Heimbach, S\n\nAlmgren, P\n\nHuang, PL\n\nSotoodehnia, N\n\nSoliman, EZ\n\nUitterlinden, AG\n\nHofman, A\n\nFranco, OH\n\nVölker, U\n\nJöckel, KH\n\nSinner, MF\n\nLin, HJ\n\nGuo, X\n\nMETASTROKE Consortium of the ISGC\n\nNeurology Working Group of the CHARGE Consortium\n\nDichgans, M\n\nIngelsson, E\n\nKooperberg, C\n\nMelander, O\n\nLoos, RJF\n\nLaurikka, J\n\nConen, D\n\nRosand, J\n\nvan der Harst, P\n\nLokki, ML\n\nKathiresan, S\n\nPereira, A\n\nJukema, JW\n\nHayward, C\n\nRotter, JI\n\nMärz, W\n\nLehtimäki, T\n\nStricker, BH\n\nChung, MK\n\nFelix, SB\n\nGudnason, V\n\nAlonso, A\n\nRoden, DM\n\nKääb, S\n\nChasman, DI\n\nHeckbert, SR\n\nBenjamin, EJ\n\nTanaka, T\n\nLunetta, KL\n\nLubitz, SA\n\nEllinor, PT\n\nAFGen Consortium\n\nBeiträge in Fachzeitschriften\nISI:000402062300020\n28416818.0\n10.1038/ng.3843\nPMC5585859\nAtrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17, 31 individuals with atrial fibrillation and 115, 42 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22, 46 cases and 132, 86 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery.\n\nMärz, Winfried\n\n\n"
},
{
"text": "\n168507\nExome Chip Analysis Identifies Low-Frequency and Rare Variants in <i>MRPL38</i> for White Matter Hyperintensities on Brain Magnetic Resonance Imaging.\n\nJian, X\n\nSatizabal, CL\n\nSmith, AV\n\nWittfeld, K\n\nBis, JC\n\nSmith, JA\n\nHsu, FC\n\nNho, K\n\nHofer, E\n\nHagenaars, SP\n\nNyquist, PA\n\nMishra, A\n\nAdams, HHH\n\nLi, S\n\nTeumer, A\n\nZhao, W\n\nFreedman, BI\n\nSaba, Y\n\nYanek, LR\n\nChauhan, G\n\nvan Buchem, MA\n\nCushman, M\n\nRoyle, NA\n\nBryan, RN\n\nNiessen, WJ\n\nWindham, BG\n\nDeStefano, AL\n\nHabes, M\n\nHeckbert, SR\n\nPalmer, ND\n\nLewis, CE\n\nEiriksdottir, G\n\nMaillard, P\n\nMathias, RA\n\nHomuth, G\n\nValdés-Hernández, MDC\n\nDivers, J\n\nBeiser, AS\n\nLangner, S\n\nRice, KM\n\nBastin, ME\n\nYang, Q\n\nMaldjian, JA\n\nStarr, JM\n\nSidney, S\n\nRisacher, SL\n\nUitterlinden, AG\n\nGudnason, VG\n\nNauck, M\n\nRotter, JI\n\nSchreiner, PJ\n\nBoerwinkle, E\n\nvan Duijn, CM\n\nMazoyer, B\n\nvon Sarnowski, B\n\nGottesman, RF\n\nLevy, D\n\nSigurdsson, S\n\nVernooij, MW\n\nTurner, ST\n\nSchmidt, R\n\nWardlaw, JM\n\nPsaty, BM\n\nMosley, TH\n\nDeCarli, CS\n\nSaykin, AJ\n\nBowden, DW\n\nBecker, DM\n\nDeary, IJ\n\nSchmidt, H\n\nKardia, SLR\n\nIkram, MA\n\nDebette, S\n\nGrabe, HJ\n\nLongstreth, WT\n\nSeshadri, S\n\nLauner, LJ\n\nFornage, M\n\nneuroCHARGE Working Group\n\nBeiträge in Fachzeitschriften\nISI:000439576500014\n30002152.0\n10.1161/STROKEAHA.118.020689\nPMC6202149\nWhite matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored.\n In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies.\n At 17q25, we confirmed the association of multiple common variants in TRIM65, FBF1, and ACOX1 (P<6×10-7). We also identified a novel association with 2 low-frequency nonsynonymous variants in MRPL38 (lead, rs34136221; PEA=4.5×10-8) partially independent of known common signal (PEA(conditional)=1.4×10-3). We further identified a locus at 2q33 containing common variants in NBEAL1, CARF, and WDR12 (lead, rs2351524; Pall=1.9×10-10). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency MRPL38 variants (Prs34136221=2.8×10-8).\n Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.\n © 2018 American Heart Association, Inc.\n\nHofer, Edith\n\nSABA, Yasaman\n\nSchmidt, Helena\n\nSchmidt, Reinhold\n\n\n"
}
]
}