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"text": "\n99697\nExpression and activation of matrix metalloproteinase-2 (MMP-2) and its co-localization with membrane-type 1 matrix metalloproteinase (MT1-MMP) correlate with melanoma progression\n\nHofmann, UB\n\nWestphal, JR\n\nZendman, AJW\n\nBecker, JC\n\nRuiter, DJ\n\nvan Muijen, GNP\n\nBeiträge in Fachzeitschriften\nISI:000087979900005\nNone\nNone\nNone\nMatrix metalloproteinases (MMPs) and their specific tissue inhibitors (TIMPs) play an important role in cancer cell invasion and metastasis. Recently, it was shown that the presence of activated MMP-2 correlates with melanoma progression in vitro. This activation involves coordinated expression of MMP-2, membrane-type 1 MMP (MT1-MMP), and TIMP-2. To investigate the expression profile of these enzymes in human melanoma, this study used tumour specimens obtained from both a human melanoma xenograft model, consisting of eight melanoma cell lines with different metastatic capacity in nude mice, and 60 fresh human cutaneous melanocytic Lesions comprising all stages of melanocytic tumour progression. MT1-MMP and TIMP-2 mRNA and protein were present in all cell lines. Cell surface expression level of MT1-MMP, as determined by flow cytometry, was similar on all cell lines. In addition, western blot analysis revealed that both inactive and active MT1-MMP protein was expressed by all cell lines. MMP-2 mRNA and the pro-enzyme form of MMP-2 were expressed by all cell lines. Remarkably, the presence of functionally active MMP-2 was restricted to the most aggressive cell lines MV3 and BLM. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of RNA isolated from subcutaneous xenografts revealed MT1-MMP and TIMP-2 mRNA expression in all lesions, whereas MMP-2 mRNA could be detected only in xenografts derived from the highly metastatic cell lines 1F6m, MV3, and BLM. Furthermore, immunohistochemistry demonstrated a marked increase of MMP-2 and MT1-MMP in MV3 and BLM xenografts, whereas TIMP-2 expression showed no evident correlation with metastatic capacity. In human cutaneous melanocytic lesions, MMP-2, MT1-MMP, and TIMP-2 mRNA were detectable by RT-PCR in all lesions. Expression of MMP-2 protein was not detectable, either in common and atypical naevi, or in melanoma in situ by immunohistochemistry. In these lesions, heterogeneous expression of MT1-MMP and TIMP-2 was present in melanocytic cells. In contrast, a large number of MMP-2 and MT1-MMP-positive tumour cells were observed in primary melanomas and melanoma metastases, Double staining experiments and immunohistochemistry on serial sections from the same lesions demonstrated that all tumour cells expressing MMP-2 also expressed MT1-MMP and TIMP-2. Finally, zymography of melanoma metastases revealed that MMP-2 was present in its functionally active form. This study demonstrates that expression of MT1-MMP and TIMP-2 and activation of MMP-2 are correlated with tumour progression both in the xenograft model and in human melanocytic lesions, strongly suggesting that these factors are required for melanoma invasion and metastasis formation. Copyright (C) 2000 John Wiley & Sons, Ltd.\n\n\n"
},
{
"text": "\n154835\nEarly-stage heart failure with preserved ejection fraction in the pig: a cardiovascular magnetic resonance study.\n\nReiter, U\n\nReiter, G\n\nManninger, M\n\nAdelsmayr, G\n\nSchipke, J\n\nAlogna, A\n\nRajces, A\n\nStalder, AF\n\nGreiser, A\n\nMühlfeld, C\n\nScherr, D\n\nPost, H\n\nPieske, B\n\nFuchsjäger, M\n\nBeiträge in Fachzeitschriften\nISI:000386466500001\n27688028.0\n10.1186/s12968-016-0283-9\nPMC5043627\nThe hypertensive deoxy-corticosterone acetate (DOCA)-salt-treated pig (hereafter, DOCA pig) was recently introduced as large animal model for early-stage heart failure with preserved ejection fraction (HFpEF). The aim of the present study was to evaluate cardiovascular magnetic resonance (CMR) of DOCA pigs and weight-matched control pigs to characterize ventricular, atrial and myocardial structure and function of this phenotype model.\n Five anesthetized DOCA and seven control pigs underwent 3 T CMR at rest and during dobutamine stress. Left ventricular/atrial (LV/LA) function and myocardial mass (LVMM), strains and torsion were evaluated from (tagged) cine imaging. 4D phase-contrast measurements were used to assess blood flow and peak velocities, including transmitral early-diastolic (E) and myocardial tissue (E') velocities and coronary sinus blood flow. Myocardial perfusion reserve was estimated from stress-to-rest time-averaged coronary sinus flow. Global native myocardial T1 times were derived from prototype modified Look-Locker inversion-recovery (MOLLI) short-axis T1 maps. After in-vivo measurements, transmural biopsies were collected for stereological evaluation including the volume fractions of interstitium (VV(int/LV)) and collagen (VV(coll/LV)). Rest, stress, and stress-to-rest differences of cardiac and myocardial parameters in DOCA and control animals were compared by t-test.\n In DOCA pigs LVMM (p < 0.001) and LV wall-thickness (end-systole/end-diastole, p = 0.003/p = 0.007) were elevated. During stress, increase of LV ejection-fraction and decrease of end-systolic volume accounted for normal contractility reserves in DOCA and control pigs. Rest-to-stress differences of cardiac index (p = 0.040) and end-diastolic volume (p = 0.042) were documented. Maximal (p = 0.042) and minimal (p = 0.012) LA volumes in DOCA pigs were elevated at rest; total LA ejection-fraction decreased during stress (p = 0.006). E' was lower in DOCA pigs, corresponding to higher E/E' at rest (p = 0.013) and stress (p = 0.026). Myocardial perfusion reserve was reduced in DOCA pigs (p = 0.031). T1-times and VV(int/LV) did not differ between groups, whereas VV(coll/LV) levels were higher in DOCA pigs (p = 0.044).\n LA enlargement, E' and E/E' were the markers that showed the most pronounced differences between DOCA and control pigs at rest. Inadequate increase of myocardial perfusion reserve during stress might represent a metrics for early-stage HFpEF. Myocardial T1 mapping could not detect elevated levels of myocardial collagen in this model.\n The study was approved by the local Bioethics Committee of Vienna, Austria (BMWF-66.010/0091-II/3b/2013).\n\nAdelsmayr, Gabriel\n\nFuchsjäger, Michael\n\nManninger-Wünscher, Martin\n\nReiter, Ursula\n\nScherr, Daniel\n\n\n"
},
{
"text": "\n170200\nMASK 2017: ARIA digitally-enabled, integrated, person-centred care for rhinitis and asthma multimorbidity using real-world-evidence.\n\nBousquet, J\n\nArnavielhe, S\n\nBedbrook, A\n\nBewick, M\n\nLaune, D\n\nMathieu-Dupas, E\n\nMurray, R\n\nOnorato, GL\n\nPépin, JL\n\nPicard, R\n\nPortejoie, F\n\nCosta, E\n\nFonseca, J\n\nLourenço, O\n\nMorais-Almeida, M\n\nTodo-Bom, A\n\nCruz, AA\n\nda Silva, J\n\nSerpa, FS\n\nIllario, M\n\nMenditto, E\n\nCecchi, L\n\nMonti, R\n\nNapoli, L\n\nVentura, MT\n\nDe Feo, G\n\nLarenas-Linnemann, D\n\nFuentes Perez, M\n\nHuerta Villabolos, YR\n\nRivero-Yeverino, D\n\nRodriguez-Zagal, E\n\nAmat, F\n\nAnnesi-Maesano, I\n\nBosse, I\n\nDemoly, P\n\nDevillier, P\n\nFontaine, JF\n\nJust, J\n\nKuna, TP\n\nSamolinski, B\n\nValiulis, A\n\nEmuzyte, R\n\nKvedariene, V\n\nRyan, D\n\nSheikh, A\n\nSchmidt-Grendelmeier, P\n\nKlimek, L\n\nPfaar, O\n\nBergmann, KC\n\nMösges, R\n\nZuberbier, T\n\nRoller-Wirnsberger, RE\n\nTomazic, P\n\nFokkens, WJ\n\nChavannes, NH\n\nReitsma, S\n\nAnto, JM\n\nCardona, V\n\nDedeu, T\n\nMullol, J\n\nHaahtela, T\n\nSalimäki, J\n\nToppila-Salmi, S\n\nValovirta, E\n\nGemicioğlu, B\n\nYorgancioglu, A\n\nPapadopoulos, N\n\nProkopakis, EP\n\nBosnic-Anticevich, S\n\nO'Hehir, R\n\nIvancevich, JC\n\nNeffen, H\n\nZernotti, E\n\nKull, I\n\nMelen, E\n\nWickman, M\n\nBachert, C\n\nHellings, P\n\nPalkonen, S\n\nBindslev-Jensen, C\n\nEller, E\n\nWaserman, S\n\nSova, M\n\nDe Vries, G\n\nvan Eerd, M\n\nAgache, I\n\nCasale, T\n\nDykewickz, M\n\nNaclerio, RN\n\nOkamoto, Y\n\nWallace, DV\n\nMASK study group\n\nBeiträge in Fachzeitschriften\nISI:000452619600001\n30386555.0\n10.1186/s13601-018-0227-6\nPMC6201545\nmHealth, such as apps running on consumer smart devices is becoming increasingly popular and has the potential to profoundly affect healthcare and health outcomes. However, it may be disruptive and results achieved are not always reaching the goals. Allergic Rhinitis and its Impact on Asthma (ARIA) has evolved from a guideline using the best evidence-based approach to care pathways suited to real-life using mobile technology in allergic rhinitis (AR) and asthma multimorbidity. Patients largely use over-the-counter medications dispensed in pharmacies. Shared decision making centered around the patient and based on self-management should be the norm. Mobile Airways Sentinel networK (MASK), the Phase 3 ARIA initiative, is based on the freely available MASK app (the Allergy Diary, Android and iOS platforms). MASK is available in 16 languages and deployed in 23 countries. The present paper provides an overview of the methods used in MASK and the key results obtained to date. These include a novel phenotypic characterization of the patients, confirmation of the impact of allergic rhinitis on work productivity and treatment patterns in real life. Most patients appear to self-medicate, are often non-adherent and do not follow guidelines. Moreover, the Allergy Diary is able to distinguish between AR medications. The potential usefulness of MASK will be further explored by POLLAR (Impact of Air Pollution on Asthma and Rhinitis), a new Horizon 2020 project using the Allergy Diary.\n\nRoller-Wirnsberger, Regina\n\nTomazic, Peter Valentin\n\n\n"
},
{
"text": "\n17993\nSingle lamellar mechanics of the human lumbar anulus fibrosus.\n\nHolzapfel, GA\n\nSchulze-Bauer, CA\n\nFeigl, G\n\nRegitnig, P\n\nBeiträge in Fachzeitschriften\nISI:000230753600001\n15778871.0\n10.1007/s10237-004-0053-8\nNone\nThe mechanical behavior of the entire anulus fibrosus is determined essentially by the tensile properties of its lamellae, their fiber orientations, and the regional variation of these quantities. Corresponding data are rare in the literature. The paper deals with an in vitro study of single lamellar anulus lamellae and aims to determine (i) their tensile response and regional variation, and (ii) the orientation of lamellar collagen fibers and their regional variation. Fresh human body-disc-body units (L1-L2, n=11) from cadavers were cut midsagittally producing two hemidisc units. One hemidisc was used for the preparation of single lamellar anulus specimens for tensile testing, while the other one was used for the investigation of the lamellar fiber orientation. Single lamellar anulus specimens with adjacent bone fragments were isolated from four anatomical regions: superficial and deep lamellae (3.9+/-0.21 mm, mean +/- SD, apart from the outer boundary surface of the anulus fibrosus) at ventro-lateral and dorsal positions. The specimens underwent cyclic uniaxial tensile tests at three different strain rates in 0.15 mol/l NaCl solution at 37 degrees C, whereby the lamellar fiber direction was aligned with the load axis. For the characterization of the tensile behavior three moduli were calculated: E(low) (0-0.1 MPa), E(medium) (0.1-0.5 MPa) and E(high) (0.5-1 MPa). Additionally, specimens were tested with the load axis transverse to the fiber direction. From the second hemidisc fiber angles with respect to the horizontal plane were determined photogrammetrically from images taken at six circumferential positions from ventral to dorsal and at three depth levels. Tensile moduli along the fiber direction were in the range of 28-78 MPa (regional mean values). Superficial lamellae have larger E(medium) (p=0.017) and E(high) (p=0.012) than internal lamellae, and the mean value of superficial lamellae is about three times higher than that of deep lamellae. Tensile moduli of ventro-lateral lamellae do not differ significantly from the tensile moduli of dorsal lamellae, and E(low) is generally indifferent with respect to the anatomical region. Tensile moduli transverse to the fiber direction were about two orders of magnitude smaller (0.22+/-0.2 MPa, mean +/- SD, n=5). Tensile properties are not correlated significantly with donor age. Only small viscoelastic effects were observed. The regional variation of lamellar fiber angle phi is described appropriately by a regression line |phi|=23.2 + 0.130 x alpha (r(2)=0.55, p<0.001), where alpha is the polar angle associated with the circumferential position. The single anulus lamella may be seen as the elementary structural unit of the anulus fibrosus, and exhibits marked anisotropy and distinct regional variation of tensile properties and fiber angles. These features must be considered for appropriate physical and numerical modeling of the anulus fibrosus.\n\nRegitnig, Peter\n\n\n"
},
{
"text": "\n170885\nQualitative and Quantitative DNA- and RNA-Based Analysis of the Bacterial Stomach Microbiota in Humans, Mice, and Gerbils.\n\nWurm, P\n\nDörner, E\n\nKremer, C\n\nSpranger, J\n\nMaddox, C\n\nHalwachs, B\n\nHarrison, U\n\nBlanchard, T\n\nHaas, R\n\nHögenauer, C\n\nGorkiewicz, G\n\nFricke, WF\n\nBeiträge in Fachzeitschriften\nISI:000455120400021\n30505943.0\n10.1128/mSystems.00262-18\nPMC6247015\nClinical interventions in the stomach have been linked to fecal microbiota alterations, suggesting a function of the stomach in gastrointestinal (GI) homeostasis. We sought to determine the taxonomic bacterial biogeography of the upper GI tract, including different sites within the human stomach (cardia, corpus, and antrum), adjacent upstream (esophagus) and downstream (duodenum) locations, and luminal contents (aspirate), as well as whole-stomach samples from mice and gerbils. Qualitative and quantitative DNA- and RNA-based taxonomic microbiota analyses were combined to study the relationship of relative and absolute bacterial abundances and transcriptionally active bacterial microbiota components in the stomach of humans and mice. Stomach microbiota compositions resembled those of esophagus and duodenum. However, along the descending GI tract, the relative abundances of specific oropharyngeal commensals decreased (Streptococcus) or increased (Rothia mucilaginosa, Porphyromonas, and Lachnospiraceae). Furthermore, the compositional similarity (weighted UniFrac) between stomach aspirates and esophageal biopsy samples increased with gastric Streptococcus relative abundance. In both human aspirate and mouse stomach samples, Firmicutes were more abundant among transcriptionally active bacteria than Bacteroidetes. The relative abundance of Firmicutes in the stomach was negatively correlated and that of Bacteroidetes was positively correlated with absolute bacterial abundance, suggesting a disproportionate increase of Bacteroidetes over Firmicutes at higher bacterial densities. Human, mouse, and gerbil stomach samples showed similarities at higher taxonomic levels but differences at lower taxonomic levels. Our findings suggest selective enrichment and depletion of specific bacterial taxa in the stomach and Firmicutes being transcriptionally more active than Bacteroidetes that increase in relative abundance with total bacterial load. IMPORTANCE Clinical stomach interventions, such as acid inhibition or bypass surgery, have been linked to fecal microbiota alterations. We demonstrate that the stomach microbiota largely overlaps those of adjacent gastrointestinal locations and identify gradual decreases and increases in the relative abundances of specific bacteria within the stomach, suggesting selective enrichment and depletion. Moreover, similarities between stomach and esophagus samples are proportional to the concentrations of Streptococcus (Firmicutes) in the stomach. The relative abundance of Firmicutes in the stomach, compared to that of Bacteroidetes, is increased in RNA relative to DNA, indicating higher transcriptional activity. Moreover, increased absolute bacterial loads are associated with decreased relative abundance of Firmicutes and higher relative abundance of Bacteroidetes. Our findings characterize the stomach microbiota as influenced by Bacteroidetes influx against a background of transcriptionally more active Firmicutes. Human, mouse, and gerbil stomach microbiotas differ at lower taxonomic levels, which might affect the utility of these model organisms.\n\nGorkiewicz, Gregor\n\nHoegenauer, Christoph\n\nWurm, Philipp\n\n\n"
},
{
"text": "\n174552\nMobile technology offers novel insights into the control and treatment of allergic rhinitis: The MASK study.\n\nBédard, A\n\nBasagaña, X\n\nAnto, JM\n\nGarcia-Aymerich, J\n\nDevillier, P\n\nArnavielhe, S\n\nBedbrook, A\n\nOnorato, GL\n\nCzarlewski, W\n\nMurray, R\n\nAlmeida, R\n\nFonseca, J\n\nCosta, E\n\nMalva, J\n\nMorais-Almeida, M\n\nPereira, AM\n\nTodo-Bom, A\n\nMenditto, E\n\nStellato, C\n\nVentura, MT\n\nCruz, AA\n\nStelmach, R\n\nda Silva, J\n\nLarenas-Linnemann, D\n\nFuentes-Pérez, JM\n\nHuerta-Villalobos, YR\n\nEmuzyte, R\n\nKvedariene, V\n\nValiulis, A\n\nKuna, P\n\nSamolinski, B\n\nKlimek, L\n\nMösges, R\n\nPfaar, O\n\nShamai, S\n\nAnnesi-Maesano, I\n\nBosse, I\n\nDemoly, P\n\nFontaine, JF\n\nCardona, V\n\nMullol, J\n\nValero, A\n\nRoller-Wirnsberger, RE\n\nTomazic, PV\n\nChavannes, NH\n\nFokkens, WJ\n\nReitsma, S\n\nBewick, M\n\nRyan, D\n\nSheikh, A\n\nHaahtela, T\n\nToppila-Salmi, S\n\nValovirta, E\n\nMakris, M\n\nPapadopoulos, NG\n\nProkopakis, EP\n\nPsarros, F\n\nCingi, C\n\nGemicioğlu, B\n\nYorgancioglu, A\n\nBosnic-Anticevich, S\n\nO'Hehir, RE\n\nBachert, C\n\nHellings, PW\n\nPugin, B\n\nBindslev-Jensen, C\n\nEller, E\n\nKull, I\n\nMelén, E\n\nWickman, M\n\nDe Vries, G\n\nvan Eerd, M\n\nAgache, I\n\nAnsotegui, IJ\n\nDykewicz, MS\n\nCasale, T\n\nWallace, D\n\nWaserman, S\n\nLaune, D\n\nBousquet, J\n\nMASK study group\n\nBeiträge in Fachzeitschriften\nISI:000473432800017\n30951790.0\n10.1016/j.jaci.2019.01.053\nNone\nMobile health can be used to generate innovative insights into optimizing treatment to improve allergic rhinitis (AR) control.\n A cross-sectional real-world observational study was undertaken in 22 countries to complement a pilot study and provide novel information on medication use, disease control, and work productivity in the everyday life of patients with AR.\n A mobile phone app (Allergy Diary, which is freely available on Google Play and Apple stores) was used to collect the data of daily visual analogue scale (VAS) scores for (1) overall allergic symptoms; (2) nasal, ocular, and asthma symptoms; (3) work; and (4) medication use by using a treatment scroll list including all allergy medications (prescribed and over-the-counter) customized for 22 countries. The 4 most common intranasal medications containing intranasal corticosteroids and 8 oral H1-antihistamines were studied.\n Nine thousand one hundred twenty-two users filled in 112, 54 days of VASs in 2016 and 2017. Assessment of days was informative. Control of days with rhinitis differed between no (best control), single (good control for intranasal corticosteroid-treated days), or multiple (worst control) treatments. Users with the worst control increased the range of treatments being used. The same trend was found for asthma, eye symptoms, and work productivity. Differences between oral H1-antihistamines were found.\n This study confirms the usefulness of the Allergy Diary in accessing and assessing behavior in patients with AR. This observational study using a very simple assessment tool (VAS) on a mobile phone had the potential to answer questions previously thought infeasible.\n Copyright © 2019 American Academy of Allergy, Asthma & Immunology. All rights reserved.\n\nRoller-Wirnsberger, Regina\n\nTomazic, Peter Valentin\n\n\n"
},
{
"text": "\n324\nBEP/VIP in children and adolescents with malignant non-testicular germ cell tumors. A comparison of the results of treatment of therapy studies MAKEI 83/86 and 89P/89\n\nGöbel, U\n\nCalaminus, G\n\nTeske, C\n\nBamberg, M\n\nBökkerink, JP\n\nHaas, RJ\n\nHolschneider, AM\n\nJanka-Schaub, G\n\nJürgens, H\n\nMittler, U\n\nBeiträge in Fachzeitschriften\nISI:A1993LQ62200006\n7690864.0\n10.1055/s-2007-1025232\nNone\nThe treatment regimen of the ongoing cooperative study for non testicular germ cell tumors (MAKEI 89 of the German Society of Pediatric Oncology and Hematology), was stratified as in MAKEI 83 and 86 according to histology, localisation and stage. In the 1989 study, vinblastine was replaced by etoposide, resulting in a chemotherapeutic regimen of 3 to 4 courses BEP and 3 to 4 courses VIP in patients with stage I to IV. Total chemotherapy was reduced for 25%. In children under 1 year of age, bleomycin was omitted and bleomycin dose was reduced to 50%. In children up to 2 years because of two toxic deaths due to bleomycin who were registered in MAKEI 89 Pilot phase. Until Jan. 31, 1993, 230 patients were registered in the MAKEI 89 pilot study and the MAKEI 89 study, containing 186 protocol and 44 follow-up patients (patients with intracranial tumors are excluded for the review). 78 of the registered patients had a teratoma, 9 of these 78 patients suffered from a relapse. In 7 of 9 patients a lasting second remission has been achieved. 12 patients offered with germinoma. 1 of 12 patients had a recurrence but is in second remission. 47 patients had malignant non germinomatous germ cell tumors with an event free survival of 91 +/- 0.4%. 2 of the 47 patients relapsed and died. Toxicity was mainly hematologic without evidence of long term effects. Bleomycin induced pulmotoxicity (WHO grade IV) was documented in 1 protocol patient (see above). Nephrotoxicity with a grade III (WHO) decrease of creatinine clearance was found in 25% of the documented patients with a fast return to normal values after the end of therapy in most of the children. For the follow-up MAKEI 93 study, different topics are defined. 1. The value of chemotherapy for immature teratoma has to be discussed. 2. In invasive immature teratoma in children over 1 year of age, the effectiveness of chemotherapy should be proved. 3. Germinomas show high platinum sensitivity, therefore a platinum based chemotherapy has to be examined for this risk group. 4. The value of a wait and see strategy similar to the proved regimen in the French germ cell tumor protocol has to be verified in patients with stage I non germinomatous germ cell tumors. 5. An intensification of chemotherapy in patients with malignant stage III and IV non germinomatous germ cell tumors has to be examined as a new therapeutic approach for this risk group.\n\nUrban, Ernst-Christian\n\n\n"
},
{
"text": "\n166717\nDaily allergic multimorbidity in rhinitis using mobile technology: A novel concept of the MASK study.\n\nBousquet, J\n\nDevillier, P\n\nAnto, JM\n\nBewick, M\n\nHaahtela, T\n\nArnavielhe, S\n\nBedbrook, A\n\nMurray, R\n\nvan Eerd, M\n\nFonseca, JA\n\nMorais Almeida, M\n\nTodo Bom, A\n\nMenditto, E\n\nPassalacqua, G\n\nStellato, C\n\nTriggiani, M\n\nVentura, MT\n\nVezzani, G\n\nAnnesi-Maesano, I\n\nBourret, R\n\nBosse, I\n\nCaimmi, D\n\nCartier, C\n\nDemoly, P\n\nJust, J\n\nPortejoie, F\n\nSiroux, V\n\nViart, F\n\nBergmann, KC\n\nKeil, T\n\nKlimek, L\n\nMösges, R\n\nPfaar, O\n\nShamai, S\n\nZuberbier, T\n\nMullol, J\n\nValero, A\n\nSpranger, O\n\nTomazic, PV\n\nKowalski, ML\n\nKuna, P\n\nKupczyk, M\n\nRaciborski, F\n\nSamolinski, B\n\nToppila-Salmi, SK\n\nValovirta, E\n\nCruz, AA\n\nSarquis-Serpa, F\n\nda Silva, J\n\nStelmach, R\n\nLarenas-Linnemann, D\n\nRodriguez Gonzalez, M\n\nBurguete Cabañas, MT\n\nKvedariene, V\n\nValiulis, A\n\nChavannes, NH\n\nFokkens, WJ\n\nRyan, D\n\nSheikh, A\n\nBachert, C\n\nHellings, PW\n\nVandenPlas, O\n\nBallardini, N\n\nKull, I\n\nMelén, E\n\nWestman, M\n\nWickman, M\n\nBindslev-Jensen, C\n\nEller, E\n\nBosnic-Anticevich, S\n\nO'Hehir, RE\n\nAgache, I\n\nBieber, T\n\nCasale, T\n\nGemicioğlu, B\n\nIvancevich, JC\n\nDe Vries, G\n\nSorensen, M\n\nYorgancioglu, A\n\nLaune, D\n\nMACVIA working group\n\nBeiträge in Fachzeitschriften\nISI:000438710600004\n29569295.0\n10.1111/all.13448\nNone\nMultimorbidity in allergic airway diseases is well known, but no data exist about the daily dynamics of symptoms and their impact on work. To better understand this, we aimed to assess the presence and control of daily allergic multimorbidity (asthma, conjunctivitis, rhinitis) and its impact on work productivity using a mobile technology, the Allergy Diary.\n We undertook a 1-year prospective observational study in which 4 210 users and 32 585 days were monitored in 19 countries. Five visual analogue scales (VAS) assessed the daily burden of the disease (i.e., global evaluation, nose, eyes, asthma and work). Visual analogue scale levels <20/100 were categorized as "Low" burden and VAS levels ≥50/100 as "High" burden.\n Visual analogue scales global measured levels assessing the global control of the allergic disease were significantly associated with allergic multimorbidity. Eight hypothesis-driven patterns were defined based on "Low" and "High" VAS levels. There were <0.2% days of Rhinitis Low and Asthma High or Conjunctivitis High patterns. There were 5.9% days with a Rhinitis High-Asthma Low pattern. There were 1.7% days with a Rhinitis High-Asthma High-Conjunctivitis Low pattern. A novel Rhinitis High-Asthma High-Conjunctivitis High pattern was identified in 2.9% days and had the greatest impact on uncontrolled VAS global measured and impaired work productivity. Work productivity was significantly correlated with VAS global measured levels.\n In a novel approach examining daily symptoms with mobile technology, we found considerable intra-individual variability of allergic multimorbidity including a previously unrecognized extreme pattern of uncontrolled multimorbidity.\n © 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.\n\nTomazic, Peter Valentin\n\n\n"
},
{
"text": "\n160192\nVps33b is crucial for structural and functional hepatocyte polarity.\n\nHanley, J\n\nDhar, DK\n\nMazzacuva, F\n\nFiadeiro, R\n\nBurden, JJ\n\nLyne, AM\n\nSmith, H\n\nStraatman-Iwanowska, A\n\nBanushi, B\n\nVirasami, A\n\nMills, K\n\nLemaigre, FP\n\nKnisely, AS\n\nHowe, S\n\nSebire, N\n\nWaddington, SN\n\nPaulusma, CC\n\nClayton, P\n\nGissen, P\n\nBeiträge in Fachzeitschriften\nISI:000399196300017\n28082148.0\n10.1016/j.jhep.2017.01.001\nPMC5387182\nIn the normal liver, hepatocytes form a uniquely polarised cell layer that enables movement of solutes from sinusoidal blood to canalicular bile. Whilst several cholestatic liver diseases with defects of hepatocyte polarity have been identified, the molecular mechanisms of pathogenesis are not well defined. One example is arthrogryposis, renal dysfunction and cholestasis syndrome, which in most patients is caused by VPS33B mutations. VPS33B is a protein involved in membrane trafficking that interacts with RAB11A at recycling endosomes. To understand the pathways that regulate hepatocyte polarity better, we investigated VPS33B deficiency using a novel mouse model with a liver-specific Vps33b deletion.\n To assess functional polarity, plasma and bile samples were collected from Vps33b liver knockout (Vps33bfl/fl-AlfpCre) and control (Vps33bfl/fl) mice; bile components or injected substrates were quantitated by mass spectrometry or fluorometry. For structural analysis, livers underwent light and transmission electron microscopy. Apical membrane and tight junction protein localisation was assessed by immunostaining. Adeno-associated virus vectors were used for in vivo gene rescue experiments.\n Like patients, Vps33bfl/fl-AlfpCre mice showed mislocalisation of ATP-binding cassette proteins that are specifically trafficked to the apical membrane via Rab11a-positive recycling endosomes. This was associated with retention of bile components in blood. Loss of functional tight junction integrity and depletion of apical microvilli were seen in knockout animals. Gene transfer partially rescued these defects.\n Vps33b has a key role in establishing structural and functional aspects of hepatocyte polarity and may be a target for gene replacement therapy.\n Hepatocytes are liver cells with tops and bottoms; that is, they are polarised. At their bottoms they absorb substances from blood. They then, at their tops, secrete these substances and their metabolites into bile. When polarity is lost, this directional flow of substances from blood to bile is disrupted and liver disease follows. In this study, using a new mouse model with a liver-specific mutation of Vps33b, the mouse version of a gene that is mutated in most patients with arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome, we investigated how the Vps33b gene product contributes to establishing hepatocyte polarity. We identified in these mice abnormalities similar to those in children with ARC syndrome. Gene transfer could partly reverse the mouse abnormalities. Our work contributes to the understanding of VPS33B disease and hepatocyte polarity in general, and may point towards gene transfer mediated treatment of ARC liver disease.\n Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.\n\nKnisely, Alexander\n\n\n"
},
{
"text": "\n67997\nAutomated detection and characterization of complex fractionated atrial electrograms in human left atrium during atrial fibrillation.\n\nScherr, D\n\nDalal, D\n\nCheema, A\n\nCheng, A\n\nHenrikson, CA\n\nSpragg, D\n\nMarine, JE\n\nBerger, RD\n\nCalkins, H\n\nDong, J\n\nBeiträge in Fachzeitschriften\nISI:000248716200007\n17675074.0\n10.1016/j.hrthm.2007.04.021\nNone\nComplex fractionated atrial electrograms (CFAEs) have been reported as ablative targets for the treatment of atrial fibrillation (AF). However, the process of CFAE identification is highly dependent on the operator's judgment.\n It is the aim of the study to report our initial experience with a novel software algorithm designed to automatically detect CFAEs.\n Nineteen patients (6 female, 58 +/- 8 years) who underwent catheter ablation of paroxysmal (n = 11) or persistent (n = 8) AF were included in the study. During ongoing AF, 100 +/- 15 left atrial (LA) endocardial locations were sampled under the guidance of integrated electroanatomical mapping with computed tomographic images. Bipolar electrograms recorded throughout the LA were analyzed using custom software that allows for automated detection of CFAEs. Interval confidence level (ICL), defined as the number of intervals between consecutive CFAE complexes during 2.5-second recordings, was used to characterize CFAEs. The CFAE sites with an ICL >/=5 were considered as sites with highly repetitive CFAEs, which are thought to be potential ablation targets. For purposes of analysis, the LA was divided into 6 areas: pulmonary vein (PV) ostia, posterior wall, interatrial septum, roof, mitral annulus area, and appendage.\n Among a total of 1, 04 LA locations sampled in 19 patients, 1, 44 (86%) were categorized as CFAE sites, whereas 260 (14%) were categorized as as non-CFAE sites. Thirty-four percent of all CFAE sites were identified as sites with highly repetitive CFAEs. Of these, 24% were located at the interatrial septum, 22% on the posterior wall, 20% at the PV ostia, 18% at the mitral annulus area, 14% on the roof, and 2.7% at the LA appendage. In all patients, highly repetitive CFAE sites were distributed in 4 or more areas of the LA. Persistent AF patients had more highly repetitive CFAE sites on the posterior wall than paroxysmal AF patients (30% +/- 7.3% vs 14% +/- 8.2%, P < .001). There was a strong trend toward more highly repetitive CFAE sites located at the PV ostia in patients with paroxysmal AF compared with persistent AF patients (24% +/- 13% vs 13% +/- 7.7%, P = .05).\n With the use of custom software, CFAE complexes were identified in more than 80% of the LA endocardial locations. LA sites with highly repetitive CFAE sites were located predominately in the septum, posterior wall, and PV ostia. Patients with persistent AF had a different anatomical distribution pattern of highly repetitive CFAE sites from those with paroxysmal AF, with a greater prevalence of highly repetitive CFAEs located on the posterior wall. Further studies are warranted to determine the clinical significance of these findings.\n\nScherr, Daniel\n\n\n"
},
{
"text": "\n140546\nGenome-wide association study of kidney function decline in individuals of European descent.\n\nGorski, M\n\nTin, A\n\nGarnaas, M\n\nMcMahon, GM\n\nChu, AY\n\nTayo, BO\n\nPattaro, C\n\nTeumer, A\n\nChasman, DI\n\nChalmers, J\n\nHamet, P\n\nTremblay, J\n\nWoodward, M\n\nAspelund, T\n\nEiriksdottir, G\n\nGudnason, V\n\nHarris, TB\n\nLauner, LJ\n\nSmith, AV\n\nMitchell, BD\n\nO'Connell, JR\n\nShuldiner, AR\n\nCoresh, J\n\nLi, M\n\nFreudenberger, P\n\nHofer, E\n\nSchmidt, H\n\nSchmidt, R\n\nHolliday, EG\n\nMitchell, P\n\nWang, JJ\n\nde Boer, IH\n\nLi, G\n\nSiscovick, DS\n\nKutalik, Z\n\nCorre, T\n\nVollenweider, P\n\nWaeber, G\n\nGupta, J\n\nKanetsky, PA\n\nHwang, SJ\n\nOlden, M\n\nYang, Q\n\nde Andrade, M\n\nAtkinson, EJ\n\nKardia, SL\n\nTurner, ST\n\nStafford, JM\n\nDing, J\n\nLiu, Y\n\nBarlassina, C\n\nCusi, D\n\nSalvi, E\n\nStaessen, JA\n\nRidker, PM\n\nGrallert, H\n\nMeisinger, C\n\nMüller-Nurasyid, M\n\nKrämer, BK\n\nKramer, H\n\nRosas, SE\n\nNolte, IM\n\nPenninx, BW\n\nSnieder, H\n\nFabiola Del Greco, M\n\nFranke, A\n\nNöthlings, U\n\nLieb, W\n\nBakker, SJ\n\nGansevoort, RT\n\nvan der Harst, P\n\nDehghan, A\n\nFranco, OH\n\nHofman, A\n\nRivadeneira, F\n\nSedaghat, S\n\nUitterlinden, AG\n\nCoassin, S\n\nHaun, M\n\nKollerits, B\n\nKronenberg, F\n\nPaulweber, B\n\nAumann, N\n\nEndlich, K\n\nPietzner, M\n\nVölker, U\n\nRettig, R\n\nChouraki, V\n\nHelmer, C\n\nLambert, JC\n\nMetzger, M\n\nStengel, B\n\nLehtimäki, T\n\nLyytikäinen, LP\n\nRaitakari, O\n\nJohnson, A\n\nParsa, A\n\nBochud, M\n\nHeid, IM\n\nGoessling, W\n\nKöttgen, A\n\nKao, WH\n\nFox, CS\n\nBöger, CA\n\nBeiträge in Fachzeitschriften\nISI:000354066900019\n25493955.0\n10.1038/ki.2014.361\nPMC4425568\nGenome-wide association studies (GWASs) have identified multiple loci associated with cross-sectional eGFR, but a systematic genetic analysis of kidney function decline over time is missing. Here we conducted a GWAS meta-analysis among 63, 58 participants of European descent, initially from 16 cohorts with serial kidney function measurements within the CKDGen Consortium, followed by independent replication among additional participants from 13 cohorts. In stage 1 GWAS meta-analysis, single-nucleotide polymorphisms (SNPs) at MEOX2, GALNT11, IL1RAP, NPPA, HPCAL1, and CDH23 showed the strongest associations for at least one trait, in addition to the known UMOD locus, which showed genome-wide significance with an annual change in eGFR. In stage 2 meta-analysis, the significant association at UMOD was replicated. Associations at GALNT11 with Rapid Decline (annual eGFR decline of 3 ml/min per 1.73 m(2) or more), and CDH23 with eGFR change among those with CKD showed significant suggestive evidence of replication. Combined stage 1 and 2 meta-analyses showed significance for UMOD, GALNT11, and CDH23. Morpholino knockdowns of galnt11 and cdh23 in zebrafish embryos each had signs of severe edema 72 h after gentamicin treatment compared with controls, but no gross morphological renal abnormalities before gentamicin administration. Thus, our results suggest a role in the deterioration of kidney function for the loci GALNT11 and CDH23, and show that the UMOD locus is significantly associated with kidney function decline.\n\nHofer, Edith\n\nSchmidt, Helena\n\nSchmidt, Reinhold\n\n\n"
},
{
"text": "\n171399\nAnnular closure in lumbar microdiscectomy for prevention of reherniation: a randomized clinical trial.\n\nThomé, C\n\nKlassen, PD\n\nBouma, GJ\n\nKuršumović, A\n\nFandino, J\n\nBarth, M\n\nArts, M\n\nvan den Brink, W\n\nBostelmann, R\n\nHegewald, A\n\nHeidecke, V\n\nVajkoczy, P\n\nFröhlich, S\n\nWolfs, J\n\nAssaker, R\n\nVan de Kelft, E\n\nKöhler, HP\n\nJadik, S\n\nEustacchio, S\n\nHes, R\n\nMartens, F\n\nAnnular Closure RCT Study Group\n\nBeiträge in Fachzeitschriften\nISI:000452738800013\n29730458.0\n10.1016/j.spinee.2018.05.003\nNone\nPatients with large annular defects after lumbar discectomy for disc herniation are at high risk of symptomatic recurrence and reoperation.\n The present study aimed to determine whether a bone-anchored annular closure device, in addition to lumbar microdiscectomy, resulted in lower reherniation and reoperation rates plus increased overall success compared with lumbar microdiscectomy alone.\n This is a multicenter, randomized superiority study.\n Patients with symptoms of lumbar disc herniation for at least 6 weeks with a large annular defect (6-10 mm width) after lumbar microdiscectomy were included in the study.\n The co-primary end points determined a priori were recurrent herniation and a composite end point consisting of patient-reported, radiographic, and clinical outcomes. Study success required superiority of annular closure on both end points at 2-year follow-up.\n Patients received lumbar microdiscectomy with additional bone-anchored annular closure device (n=276 participants) or lumbar microdiscectomy only (control; n=278 participants). This research was supported by Intrinsic Therapeutics. Two authors received study-specific support morethan $10, 00 per year, 8 authors received study-specific support less than $10, 00 per year, and 11 authors received no study-specific support.\n Among 554 randomized participants, 550 (annular closure device: n=272; control: n=278) were included in the modified intent-to-treat efficacy analysis and 550 (annular closure device: n=267; control: n=283) were included in the as-treated safety analysis. Both co-primary end points of the study were met, with recurrent herniation (50% vs. 70%, P<.001) and composite end point success (27% vs. 18%, P=.02) favoring annular closure device. The frequency of symptomatic reherniation was lower with annular closure device (12% vs. 25%, P<.001). There were 29 reoperations in 24 patients in the annular closure device group and 61 reoperations in 45 control patients. The frequency of reoperations to address recurrent herniation was 5% with annular closure device and 13% in controls (P=.001). End plate changes were more prevalent in the annular closure device group (84% vs. 30%, P<.001). Scores for back pain, leg pain, Oswestry Disability Index, and health-related quality of life at regular visits were comparable between groups over 2-year follow-up.\n In patients at high risk of herniation recurrence after lumbar microdiscectomy, annular closure with a bone-anchored implant lowers the risk of symptomatic recurrence and reoperation. Additional study to determine outcomes beyond 2 years with a bone-anchored annular closure device is warranted.\n Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.\n\nEustacchio, Sandro\n\n\n"
},
{
"text": "\n120098\nObesity is associated with worse oncological outcomes in patients treated with radical cystectomy.\n\nChromecki, TF\n\nCha, EK\n\nFajkovic, H\n\nRink, M\n\nEhdaie, B\n\nSvatek, RS\n\nKarakiewicz, PI\n\nLotan, Y\n\nTilki, D\n\nBastian, PJ\n\nDaneshmand, S\n\nKassouf, W\n\nDurand, M\n\nNovara, G\n\nFritsche, HM\n\nBurger, M\n\nIzawa, JI\n\nBrisuda, A\n\nBabjuk, M\n\nPummer, K\n\nShariat, SF\n\nBeiträge in Fachzeitschriften\nISI:000315030200013\n22727036.0\n10.1111/j.1464-410X.2012.11322.x\nNone\nWhat's known on the subject? and What does the study add? Little is known on the association between obesity and urothelial carcinoma of the bladder (UCB). Most studies have shown that higher body mass index (BMI) is associated with higher rates of perioperative complications. Only one study specifically investigated obesity and bladder cancer-specific outcomes and reported no significant association between higher BMI and disease-specific survival in patients with UCB treated with radical cystectomy. However, that study was limited by its small sample size and a high rate of preoperative therapies. In contrast to the only previous study evaluating the association of BMI with oncological outcomes in UCB, we found that obesity (BMI 30kg/m2) was associated with features of biologically aggressive UCB and clinical outcomes after radical cystectomy and, even when adjusting for the effects of standard clinicopathological features, obesity remained an independent predictor of cancer recurrence, cancer-specific mortality and overall mortality. Objective To investigate the association between body mass index (BMI) and oncological outcomes in patients after radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB) in a large multi-institutional series. Patients and Methods Data were collected from 4118 patients treated with RC and pelvic lymphadenectomy for UCB. Patients receiving preoperative chemotherapy or radiotherapy were excluded. Univariable and multivariable models tested the effect of BMI on disease recurrence, cancer-specific mortality and overall mortality. BMI was analysed as a continuous and categorical variable (<25 vs 2529 vs 30kg/m2). Results Median BMI was 28.8kg/m2 (interquartile range 7.9); 25.3% had a BMI <25kg/m2, 32.5% had a BMI between 25 and 29.9kg/m2, and 42.2% had a BMI 30kg/m2. Patients with a higher BMI were older (P < 0.001), had higher tumour grade (P < 0.001), and were more likely to have positive soft tissue surgical margins (P = 0.006) compared with patients with lower BMI. In multivariable analyses that adjusted for the effects of standard clinicopathological features, BMI >30 was associated with higher risk of disease recurrence (hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.461.91, P < 0.001), cancer-specific mortality (HR 1.43, 95% CI 1.241.66, P < 0.001), and overall mortality (HR 1.81, CI 1.602.05, P < 0.001). Themain limitation is the retrospective design of the study. Conclusions Obesity is associated with worse cancer-specific outcomes in patients treated with RC for UCB. Focusing on patient-modifiable factors such as BMI may have significant individual and public health implications in patients with invasive UCB.\n\nPummer, Karl\n\n\n"
},
{
"text": "\n109713\nThe clinical and molecular genetic features of idiopathic infantile periodic alternating nystagmus.\n\nThomas, MG\n\nCrosier, M\n\nLindsay, S\n\nKumar, A\n\nThomas, S\n\nAraki, M\n\nTalbot, CJ\n\nMcLean, RJ\n\nSurendran, M\n\nTaylor, K\n\nLeroy, BP\n\nMoore, AT\n\nHunter, DG\n\nHertle, RW\n\nTarpey, P\n\nLangmann, A\n\nLindner, S\n\nBrandner, M\n\nGottlob, I\n\nBeiträge in Fachzeitschriften\nISI:000287745100023\n21303855.0\n10.1093/brain/awq373\nNone\nPeriodic alternating nystagmus consists of involuntary oscillations of the eyes with cyclical changes of nystagmus direction. It can occur during infancy (e.g. idiopathic infantile periodic alternating nystagmus) or later in life. Acquired forms are often associated with cerebellar dysfunction arising due to instability of the optokinetic-vestibular systems. Idiopathic infantile periodic alternating nystagmus can be familial or occur in isolation; however, very little is known about the clinical characteristics, genetic aetiology and neural substrates involved. Five loci (NYS1-5) have been identified for idiopathic infantile nystagmus; three are autosomal (NYS2, NYS3 and NYS4) and two are X-chromosomal (NYS1 and NYS5). We previously identified the FRMD7 gene on chromosome Xq26 (NYS1 locus); mutations of FRMD7 are causative of idiopathic infantile nystagmus influencing neuronal outgrowth and development. It is unclear whether the periodic alternating nystagmus phenotype is linked to NYS1, NYS5 (Xp11.4-p11.3) or a separate locus. From a cohort of 31 X-linked families and 14 singletons (70 patients) with idiopathic infantile nystagmus we identified 10 families and one singleton (21 patients) with periodic alternating nystagmus of which we describe clinical phenotype, genetic aetiology and neural substrates involved. Periodic alternating nystagmus was not detected clinically but only on eye movement recordings. The cycle duration varied from 90 to 280 s. Optokinetic reflex was not detectable horizontally. Mutations of the FRMD7 gene were found in all 10 families and the singleton (including three novel mutations). Periodic alternating nystagmus was predominantly associated with missense mutations within the FERM domain. There was significant sibship clustering of the phenotype although in some families not all affected members had periodic alternating nystagmus. In situ hybridization studies during mid-late human embryonic stages in normal tissue showed restricted FRMD7 expression in neuronal tissue with strong hybridization signals within the afferent arms of the vestibulo-ocular reflex consisting of the otic vesicle, cranial nerve VIII and vestibular ganglia. Similarly within the afferent arm of the optokinetic reflex we showed expression in the developing neural retina and ventricular zone of the optic stalk. Strong FRMD7 expression was seen in rhombomeres 1 to 4, which give rise to the cerebellum and the common integrator site for both these reflexes (vestibular nuclei). Based on the expression and phenotypic data, we hypothesize that periodic alternating nystagmus arises from instability of the optokinetic-vestibular systems. This study shows for the first time that mutations in FRMD7 can cause idiopathic infantile periodic alternating nystagmus and may affect neuronal circuits that have been implicated in acquired forms.\n\nBrandner, Martina Christine\n\nLangmann, Andrea\n\n\n"
},
{
"text": "\n172264\nComprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide.\n\nWalpole, S\n\nPritchard, AL\n\nCebulla, CM\n\nPilarski, R\n\nStautberg, M\n\nDavidorf, FH\n\nde la Fouchardière, A\n\nCabaret, O\n\nGolmard, L\n\nStoppa-Lyonnet, D\n\nGarfield, E\n\nNjauw, CN\n\nCheung, M\n\nTurunen, JA\n\nRepo, P\n\nJärvinen, RS\n\nvan Doorn, R\n\nJager, MJ\n\nLuyten, GPM\n\nMarinkovic, M\n\nChau, C\n\nPotrony, M\n\nHöiom, V\n\nHelgadottir, H\n\nPastorino, L\n\nBruno, W\n\nAndreotti, V\n\nDalmasso, B\n\nCiccarese, G\n\nQueirolo, P\n\nMastracci, L\n\nWadt, K\n\nKiilgaard, JF\n\nSpeicher, MR\n\nvan Poppelen, N\n\nKilic, E\n\nAl-Jamal, RT\n\nDianzani, I\n\nBetti, M\n\nBergmann, C\n\nSantagata, S\n\nDahiya, S\n\nTaibjee, S\n\nBurke, J\n\nPoplawski, N\n\nO'Shea, SJ\n\nNewton-Bishop, J\n\nAdlard, J\n\nAdams, DJ\n\nLane, AM\n\nKim, I\n\nKlebe, S\n\nRacher, H\n\nHarbour, JW\n\nNickerson, ML\n\nMurali, R\n\nPalmer, JM\n\nHowlie, M\n\nSymmons, J\n\nHamilton, H\n\nWarrier, S\n\nGlasson, W\n\nJohansson, P\n\nRobles-Espinoza, CD\n\nOssio, R\n\nde Klein, A\n\nPuig, S\n\nGhiorzo, P\n\nNielsen, M\n\nKivelä, TT\n\nTsao, H\n\nTesta, JR\n\nGerami, P\n\nStern, MH\n\nPaillerets, BB\n\nAbdel-Rahman, MH\n\nHayward, NK\n\nBeiträge in Fachzeitschriften\nISI:000455209700007\n30517737.0\n10.1093/jnci/djy171\nPMC6292796\nThe BRCA1-associated protein-1 (BAP1) tumor predisposition syndrome (BAP1-TPDS) is a hereditary tumor syndrome caused by germline pathogenic variants in BAP1 encoding a tumor suppressor associated with uveal melanoma, mesothelioma, cutaneous melanoma, renal cell carcinoma, and cutaneous BAP1-inactivated melanocytic tumors. However, the full spectrum of tumors associated with the syndrome is yet to be determined. Improved understanding of the BAP1-TPDS is crucial for appropriate clinical management of BAP1 germline variant carriers and their families, including genetic counseling and surveillance for new tumors.\n We collated germline variant status, tumor diagnoses, and information on BAP1 immunohistochemistry or loss of somatic heterozygosity on 106 published and 75 unpublished BAP1 germline variant-positive families worldwide to better characterize the genotypes and phenotypes associated with the BAP1-TPDS. Tumor spectrum and ages of onset were compared between missense and null variants. All statistical tests were two-sided.\n The 181 families carried 140 unique BAP1 germline variants. The collated data confirmed the core tumor spectrum associated with the BAP1-TPDS and showed that some families carrying missense variants can exhibit this phenotype. A variety of noncore BAP1-TPDS -associated tumors were found in families of variant carriers. Median ages of onset of core tumor types were lower in null than missense variant carriers for all tumors combined (P < .001), mesothelioma (P < .001), cutaneous melanoma (P < .001), and nonmelanoma skin cancer (P < .001).\n This analysis substantially increases the number of pathogenic BAP1 germline variants and refines the phenotype. It highlights the need for a curated registry of germline variant carriers for proper assessment of the clinical phenotype of the BAP1-TPDS and pathogenicity of new variants, thus guiding management of patients and informing areas requiring further research.\n\nSpeicher, Michael\n\n\n"
},
{
"text": "\n175588\nPublisher Correction: Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.\n\nMalik, R\n\nChauhan, G\n\nTraylor, M\n\nSargurupremraj, M\n\nOkada, Y\n\nMishra, A\n\nRutten-Jacobs, L\n\nGiese, AK\n\nvan der Laan, SW\n\nGretarsdottir, S\n\nAnderson, CD\n\nChong, M\n\nAdams, HHH\n\nAgo, T\n\nAlmgren, P\n\nAmouyel, P\n\nAy, H\n\nBartz, TM\n\nBenavente, OR\n\nBevan, S\n\nBoncoraglio, GB\n\nBrown, RD\n\nButterworth, AS\n\nCarrera, C\n\nCarty, CL\n\nChasman, DI\n\nChen, WM\n\nCole, JW\n\nCorrea, A\n\nCotlarciuc, I\n\nCruchaga, C\n\nDanesh, J\n\nde Bakker, PIW\n\nDeStefano, AL\n\nden Hoed, M\n\nDuan, Q\n\nEngelter, ST\n\nFalcone, GJ\n\nGottesman, RF\n\nGrewal, RP\n\nGudnason, V\n\nGustafsson, S\n\nHaessler, J\n\nHarris, TB\n\nHassan, A\n\nHavulinna, AS\n\nHeckbert, SR\n\nHolliday, EG\n\nHoward, G\n\nHsu, FC\n\nHyacinth, HI\n\nIkram, MA\n\nIngelsson, E\n\nIrvin, MR\n\nJian, X\n\nJiménez-Conde, J\n\nJohnson, JA\n\nJukema, JW\n\nKanai, M\n\nKeene, KL\n\nKissela, BM\n\nKleindorfer, DO\n\nKooperberg, C\n\nKubo, M\n\nLange, LA\n\nLangefeld, CD\n\nLangenberg, C\n\nLauner, LJ\n\nLee, JM\n\nLemmens, R\n\nLeys, D\n\nLewis, CM\n\nLin, WY\n\nLindgren, AG\n\nLorentzen, E\n\nMagnusson, PK\n\nMaguire, J\n\nManichaikul, A\n\nMcArdle, PF\n\nMeschia, JF\n\nMitchell, BD\n\nMosley, TH\n\nNalls, MA\n\nNinomiya, T\n\nO'Donnell, MJ\n\nPsaty, BM\n\nPulit, SL\n\nRannikmäe, K\n\nReiner, AP\n\nRexrode, KM\n\nRice, K\n\nRich, SS\n\nRidker, PM\n\nRost, NS\n\nRothwell, PM\n\nRotter, JI\n\nRundek, T\n\nSacco, RL\n\nSakaue, S\n\nSale, MM\n\nSalomaa, V\n\nSapkota, BR\n\nSchmidt, R\n\nSchmidt, CO\n\nSchminke, U\n\nSharma, P\n\nSlowik, A\n\nSudlow, CLM\n\nTanislav, C\n\nTatlisumak, T\n\nTaylor, KD\n\nThijs, VNS\n\nThorleifsson, G\n\nThorsteinsdottir, U\n\nTiedt, S\n\nTrompet, S\n\nTzourio, C\n\nvan Duijn, CM\n\nWalters, M\n\nWareham, NJ\n\nWassertheil-Smoller, S\n\nWilson, JG\n\nWiggins, KL\n\nYang, Q\n\nYusuf, S\n\nAFGen Consortium\n\nCohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium\n\nInternational Genomics of Blood Pressure (iGEN-BP) Consortium\n\nINVENT Consortium\n\nSTARNET\n\nBis, JC\n\nPastinen, T\n\nRuusalepp, A\n\nSchadt, EE\n\nKoplev, S\n\nBjörkegren, JLM\n\nCodoni, V\n\nCivelek, M\n\nSmith, NL\n\nTrégouët, DA\n\nChristophersen, IE\n\nRoselli, C\n\nLubitz, SA\n\nEllinor, PT\n\nTai, ES\n\nKooner, JS\n\nKato, N\n\nHe, J\n\nvan der Harst, P\n\nElliott, P\n\nChambers, JC\n\nTakeuchi, F\n\nJohnson, AD\n\nBioBank Japan Cooperative Hospital Group\n\nCOMPASS Consortium\n\nEPIC-CVD Consortium\n\nEPIC-InterAct Consortium\n\nInternational Stroke Genetics Consortium (ISGC)\n\nMETASTROKE Consortium\n\nNeurology Working Group of the CHARGE Consortium\n\nNINDS Stroke Genetics Network (SiGN)\n\nUK Young Lacunar DNA Study\n\nMEGASTROKE Consortium\n\nSanghera, DK\n\nMelander, O\n\nJern, C\n\nStrbian, D\n\nFernandez-Cadenas, I\n\nLongstreth, WT\n\nRolfs, A\n\nHata, J\n\nWoo, D\n\nRosand, J\n\nPare, G\n\nHopewell, JC\n\nSaleheen, D\n\nStefansson, K\n\nWorrall, BB\n\nKittner, SJ\n\nSeshadri, S\n\nFornage, M\n\nMarkus, HS\n\nHowson, JMM\n\nKamatani, Y\n\nDebette, S\n\nDichgans, M\n\nBeiträge in Fachzeitschriften\nISI:000473491900024\n31160810.0\n10.1038/s41588-019-0449-0\nNone\nAn amendment to this paper has been published and can be accessed via a link at the top of the paper.\n\nSchmidt, Reinhold\n\n\n"
},
{
"text": "\n88217\nConcept and treatment of hydrocephalus in the Greco-Roman and early Arabic medicine.\n\nGrunert, P\n\nCharalampaki, P\n\nAyyad, A\n\nBeiträge in Fachzeitschriften\nISI:000251980800001\n18058640.0\n10.1055/s-2007-991178\nNone\nIn the ancient medical literature hydrocephalus was not often described although its existence and symptomatology were well known. Most detailed descriptions of hydrocephalus including the surgical treatment are extant in the encyclopaedic works on medicine of the physicians Oreibasios and Aetios from Amida from the 4th and 6th centuries AD, respectively. Because of their broad scientific interests, this type of physicians, typical for the late Roman empire, were known as philosophy-physicians (iota alpha tau rho o sigma o phi iota sigma tau alpha iota). They defined hydrocephalus in contrast to our present understanding as a fluid collection excluding abscesses visible as a bulging tumour localised either outside or inside the skull of an infant. They classified the hydrocephalus similar as stated first by Galen in the 2nd century AD in four types corresponding to the assumed anatomic localisation of the fluid collection: 1st Type between the skin and the pericranium corresponding to the subgaleal haematoma or caput succedaneum of the newborn in our terminology, 2nd Type between the pericranium and the skull corresponding to the cephal haematoma after delivery, 3rd Type between skull and the meninges with increased head circumference, bone sutures being increasingly driven apart corresponding most likely to the hydrocephalus in our understanding, and 4th Type between the menings and the brain characterised by severe neurological deficit with lethal prognosis corresponding probably to all pathologies which were accompanied by an excessive increase of the intracranial pressure with a bulging fontanel. Due to the lack of autopsies in ancient times, the hydrocephalus was never linked to the pathology of the ventricles. All forms of hydrocephalus were believed to be caused by improper handling of the head by the midwife during delivery. Only the extracranial fluid collections, but not hydrocephalus in our sense, were considered to be suitable for surgical treatment. The surgery consisted in one or more incisions and evacuation of the fluid. The wound was not closed but let open for three days. Thereafter plasters or sutures closed the incisions. The surgical technique goes back probably to Antyllos a surgeon from the 3rd century AD whose considerations were cited in the work of Oreibasios. The early Arabic physicians took over the surgical indications, the operative technique and modified the Greek concept of hydrocephalus. Avicenna separated the traumatic haematomas outside the skull from the term hydrocephalus. However Avicenna, as all previous authors, had not linked hydrocephalus with the ventricular system. The autopsy of a child with an exorbitant hydrocephalus performed by the anatomist Vesalius in the 16th century revealed as a single pathology an extremely dilative ventricular system filled with water-like fluid which made it necessary to change completely the ancient concept of hydrocephalus.\n\n\n"
},
{
"text": "\n124184\nCancer classification using the Immunoscore: a worldwide task force.\n\nGalon, J\n\nPagès, F\n\nMarincola, FM\n\nAngell, HK\n\nThurin, M\n\nLugli, A\n\nZlobec, I\n\nBerger, A\n\nBifulco, C\n\nBotti, G\n\nTatangelo, F\n\nBritten, CM\n\nKreiter, S\n\nChouchane, L\n\nDelrio, P\n\nArndt, H\n\nAsslaber, M\n\nMaio, M\n\nMasucci, GV\n\nMihm, M\n\nVidal-Vanaclocha, F\n\nAllison, JP\n\nGnjatic, S\n\nHakansson, L\n\nHuber, C\n\nSingh-Jasuja, H\n\nOttensmeier, C\n\nZwierzina, H\n\nLaghi, L\n\nGrizzi, F\n\nOhashi, PS\n\nShaw, PA\n\nClarke, BA\n\nWouters, BG\n\nKawakami, Y\n\nHazama, S\n\nOkuno, K\n\nWang, E\n\nO'Donnell-Tormey, J\n\nLagorce, C\n\nPawelec, G\n\nNishimura, MI\n\nHawkins, R\n\nLapointe, R\n\nLundqvist, A\n\nKhleif, SN\n\nOgino, S\n\nGibbs, P\n\nWaring, P\n\nSato, N\n\nTorigoe, T\n\nItoh, K\n\nPatel, PS\n\nShukla, SN\n\nPalmqvist, R\n\nNagtegaal, ID\n\nWang, Y\n\nD'Arrigo, C\n\nKopetz, S\n\nSinicrope, FA\n\nTrinchieri, G\n\nGajewski, TF\n\nAscierto, PA\n\nFox, BA\n\nBeiträge in Fachzeitschriften\nISI:000315104900001\n23034130.0\n10.1186/1479-5876-10-205\nPMC3554496\nPrediction of clinical outcome in cancer is usually achieved by histopathological evaluation of tissue samples obtained during surgical resection of the primary tumor. Traditional tumor staging (AJCC/UICC-TNM classification) summarizes data on tumor burden (T), presence of cancer cells in draining and regional lymph nodes (N) and evidence for metastases (M). However, it is now recognized that clinical outcome can significantly vary among patients within the same stage. The current classification provides limited prognostic information, and does not predict response to therapy. Recent literature has alluded to the importance of the host immune system in controlling tumor progression. Thus, evidence supports the notion to include immunological biomarkers, implemented as a tool for the prediction of prognosis and response to therapy. Accumulating data, collected from large cohorts of human cancers, has demonstrated the impact of immune-classification, which has a prognostic value that may add to the significance of the AJCC/UICC TNM-classification. It is therefore imperative to begin to incorporate the 'Immunoscore' into traditional classification, thus providing an essential prognostic and potentially predictive tool. Introduction of this parameter as a biomarker to classify cancers, as part of routine diagnostic and prognostic assessment of tumors, will facilitate clinical decision-making including rational stratification of patient treatment. Equally, the inherent complexity of quantitative immunohistochemistry, in conjunction with protocol variation across laboratories, analysis of different immune cell types, inconsistent region selection criteria, and variable ways to quantify immune infiltration, all underline the urgent requirement to reach assay harmonization. In an effort to promote the Immunoscore in routine clinical settings, an international task force was initiated. This review represents a follow-up of the announcement of this initiative, and of the J Transl Med. editorial from January 2012. Immunophenotyping of tumors may provide crucial novel prognostic information. The results of this international validation may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune).\n\nAsslaber, Martin\n\n\n"
},
{
"text": "\n169462\nAllergic Rhinitis and its Impact on Asthma (ARIA) Phase 4 (2018): Change management in allergic rhinitis and asthma multimorbidity using mobile technology.\n\nBousquet, J\n\nHellings, PW\n\nAgache, I\n\nAmat, F\n\nAnnesi-Maesano, I\n\nAnsotegui, IJ\n\nAnto, JM\n\nBachert, C\n\nBateman, ED\n\nBedbrook, A\n\nBennoor, K\n\nBewick, M\n\nBindslev-Jensen, C\n\nBosnic-Anticevich, S\n\nBosse, I\n\nBrozek, J\n\nBrussino, L\n\nCanonica, GW\n\nCardona, V\n\nCasale, T\n\nCepeda Sarabia, AM\n\nChavannes, NH\n\nCecchi, L\n\nCorreia de Sousa, J\n\nCosta, E\n\nCruz, AA\n\nCzarlewski, W\n\nDe Carlo, G\n\nDe Feo, G\n\nDemoly, P\n\nDevillier, P\n\nDykewicz, MS\n\nEl-Gamal, Y\n\nEller, EE\n\nFonseca, JA\n\nFontaine, JF\n\nFokkens, WJ\n\nGuzmán, MA\n\nHaahtela, T\n\nIllario, M\n\nIvancevich, JC\n\nJust, J\n\nKaidashev, I\n\nKhaitov, M\n\nKalayci, O\n\nKeil, T\n\nKlimek, L\n\nKowalski, ML\n\nKuna, P\n\nKvedariene, V\n\nLarenas-Linnemann, D\n\nLaune, D\n\nLe, LTT\n\nCarlsen, KL\n\nLourenço, O\n\nMahboub, B\n\nMair, A\n\nMenditto, E\n\nMilenkovic, B\n\nMorais-Almeida, M\n\nMösges, R\n\nMullol, J\n\nMurray, R\n\nNaclerio, R\n\nNamazova-Baranova, L\n\nNovellino, E\n\nO'Hehir, RE\n\nOhta, K\n\nOkamoto, Y\n\nOkubo, K\n\nOnorato, GL\n\nPalkonen, S\n\nPanzner, P\n\nPapadopoulos, NG\n\nPark, HS\n\nPaulino, E\n\nPawankar, R\n\nPfaar, O\n\nPlavec, D\n\nPopov, TA\n\nPotter, P\n\nProkopakis, EP\n\nRottem, M\n\nRyan, D\n\nSalimäki, J\n\nSamolinski, B\n\nSanchez-Borges, M\n\nSchunemann, HJ\n\nSheikh, A\n\nSisul, JC\n\nRajabian-Söderlund, R\n\nSooronbaev, T\n\nStellato, C\n\nTo, T\n\nTodo-Bom, AM\n\nTomazic, PV\n\nToppila-Salmi, S\n\nValero, A\n\nValiulis, A\n\nValovirta, E\n\nVentura, MT\n\nWagenmann, M\n\nWang, Y\n\nWallace, D\n\nWaserman, S\n\nWickman, M\n\nYorgancioglu, A\n\nZhang, L\n\nZhong, N\n\nZidarn, M\n\nZuberbier, T\n\nMobile Airways Sentinel Network (MASK) Study Group\n\nBeiträge in Fachzeitschriften\nISI:000460272900005\n30273709.0\n10.1016/j.jaci.2018.08.049\nNone\nAllergic Rhinitis and its Impact on Asthma (ARIA) has evolved from a guideline by using the best approach to integrated care pathways using mobile technology in patients with allergic rhinitis (AR) and asthma multimorbidity. The proposed next phase of ARIA is change management, with the aim of providing an active and healthy life to patients with rhinitis and to those with asthma multimorbidity across the lifecycle irrespective of their sex or socioeconomic status to reduce health and social inequities incurred by the disease. ARIA has followed the 8-step model of Kotter to assess and implement the effect of rhinitis on asthma multimorbidity and to propose multimorbid guidelines. A second change management strategy is proposed by ARIA Phase 4 to increase self-medication and shared decision making in rhinitis and asthma multimorbidity. An innovation of ARIA has been the development and validation of information technology evidence-based tools (Mobile Airways Sentinel Network [MASK]) that can inform patient decisions on the basis of a self-care plan proposed by the health care professional.\n Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.\n\nTomazic, Peter Valentin\n\n\n"
},
{
"text": "\n187424\nReal-world data on metabolic effects of PCSK9 inhibitors in a tertiary care center in patients with and without diabetes mellitus.\n\nFischer, LT\n\nHochfellner, DA\n\nKnoll, L\n\nPöttler, T\n\nMader, JK\n\nAberer, F\n\nBeiträge in Fachzeitschriften\nISI:000643237000003\n33894772.0\n10.1186/s12933-021-01283-w\nPMC8070307\nThe lipid-lowering and positive cardiovascular effect of proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors was shown in several studies, hence, they are more widely used in the lipid-lowering management of individuals with high cardiovascular risk. As real-world data are still scarce, specifically in patients with type 2 diabetes (T2D), the aim of this retrospective analysis was to investigate the efficacy of PCSK9 inhibitors in lowering low-density lipoprotein cholesterol (LDL-C) in an outpatient clinic of a tertiary care center in routine care.\n A retrospective analysis of data extracted from the electronic patient record was performed. Patients who were routinely prescribed with PCSK9 inhibitor therapy (alirocumab or evolocumab) during the years 2016 and 2019 were included in the analysis. Characteristics of the patient population, the effects on LDL-C and HbA1c levels as well as subsequent cardiovascular events were assessed over an observation period of 18 months.\n We identified 237 patients treated with PCSK9 inhibitors between January 2016 and September 2019. Almost all patients (97.5%) received PCSK9 inhibitors for secondary prevention. 26.2% of the population had a concomitant diabetes diagnosis. Intolerance to statins (83.1%), ezetimibe (44.7%) or both agents (42.6%) was reported frequently. Three months after initiation of PCSK9 inhibitor therapy, 61.2% of the patients achieved LDL-C levels < 70 mg/dl, and 44.1% LDL-C levels < 55 mg/dl. The median LDL-C was lowered from 141 mg/dl at baseline, to 60 mg/dl after 3 months and 66 mg/dl after 12 months indicating a reduction of LDL-C as follows: 57.5% after 3 months and 53.6% after 12 months. After 3 months of observation, target achievement of LDL-C was higher in patients with T2D compared to non-diabetes patients; < 55 mg/dl: 51% vs. 41.5%; < 70 mg/dl 69.4 vs. 58.5%. After 12 months even more pronounced target LDL achievement in T2D was demonstrated < 55 mg/dl: 58.8% vs. 30.1%; < 70 mg/dl 70.6 vs. 49.6%. Patients with insufficiently controlled T2D (HbA1c > 54 mmol/mol) had a higher reduction in LDL-C but still were more likely to subsequent cardiovascular events.\n Significant reductions in LDL-C and a high percentage of patients achieving recommended treatment targets were observed. The percentage of patients with T2D meeting recommended LDL-C targets was higher than in those without T2D. Still some patients did not achieve LDL-C levels as recommended in current guidelines. Special attention to the characteristics of these patients is required in the future to enable achievement of treatment goals and avoid adverse cardiovascular outcomes.\n\nAberer, Felix\n\nHochfellner, Daniel\n\nKnoll, Lisa\n\nMader, Julia\n\nPöttler, Tina\n\n\n"
}
]
}