Publications by Sandra Freitag-Wolf
Müller R, Freitag-Wolf S, Weiner J, Chopra A, Top T, Dommisch H, Schaefer AS.
Case-only design identifies interactions of genetic risk variants at SIGLEC5 and PLG with the lncRNA CTD-2353F22.1 implying the importance of periodontal wound healing for disease aetiology.J Clin Periodontol,
50 (2023), 90-101.
[abstract]
Abstract:
CTD-2353F22.1 mediates interaction of SIGLEC5 and PLG, together with genes that function in periodontal wound healing.
Sharma A, Szymczak S, Rühlemann M, Freitag-Wolf S, Knecht C, Enderle J, Schreiber S, Franke A, Lieb W, Krawczak M, Dempfle A.
Linkage analysis identifies novel genetic modifiers of microbiome traits in families with inflammatory bowel disease.Gut Microbes,
14 (2022 Jan-Dec), 2024415.
[abstract]
Abstract:
Odoribacter (chr22, three regions spanning 0.89, 5.57 and 1.71 cM, respectively), as well as the Shannon index of α diversity (chr3, 1.47 cM). Our study thus shows that, in families of IBD patients, pairwise genetic similarity for at least one IBD risk locus is associated with overall microbiome dissimilarity among discordant pairs of relatives, and that hitherto unknown genetic modifiers of microbiome traits are located in at least 12 human genomic regions.
Soeth E, Hilbert C, Scharffenberg S, Wehkamp K, Rogge A, Kahla-Witzsch H, Freitag-Wolf S, Scholz J, Petzina R.
[Further Development of Maturity Levels of Quality and Risk Management System at the University Hospital Schleswig-Holstein].Gesundheitswesen,
(2022).
[abstract]
Abstract:
Das integrierte QRM ist seit Jahren fester Bestandteil am UKSH. Die Wirksamkeitsüberprüfungen der initiierten zielgerichteten Maßnahmen stellen jedoch eine Herausforderung dar. Aus diesem Grund erscheint es notwendig, wirkungsvolle und ressourcenschonende Ansätze für eine Evaluation von Maßnahmen und für die Identifikation von Verbesserungspotentialen zu entwickeln. Die erkannten Verbesserungspotentiale sollen risikopriorisiert und mit umsetzbaren Maßnahmen ausgeschöpft werden. Diesen Grundsätzen folgend konzipierten wir 2016 ein qualitatives Reifegradmodell zur Evaluation des QRM-Systems am UKSH, dessen Weiterentwicklung wir hier aufzeigen.
Dawid A, Borzikowsky C, Freitag-Wolf S, Herlitzius S, Wenz HJ, Wiltfang J, Hertrampf K.
Evaluation of prevention behaviour and its influencing factors with respect to cancer screening.J Cancer Res Clin Oncol,
(2022).
[abstract]
Abstract:
The results showed interesting trends in the different barriers and how they are influenced by socioeconomic factors and the stages of change. Especially the stages require different gender-specific approaches to mobilisation for cancer screening.
Passia N, Chaar MS, Krummel A, Nagy A, Freitag-Wolf S, Ali S, Kern M.
Influence of the number of implants in the edentulous mandible on chewing efficacy and oral health-related quality of life-A within-subject design study.Clin Oral Implants Res,
(2022).
[abstract]
Abstract:
Within the limitations of the present clinical trial regarding the number of patients, chewing efficacy as well OHRQoL of edentulous patients improve after implant placement in the mandible, irrespective of the number of implants. The best chewing efficacy was achieved with two implants.
Schwefer N, Freitag-Wolf S, Meyer G, Kern M.
Investigation of the esthetic perception of different canine parameters.Clin Oral Investig,
(2022).
[abstract]
Abstract:
The aim of this study is to give clear definitions of esthetically favored shades, incisal edge shapes, and lengths of the canines, as the esthetics of the smile line play a critical role for patients, dentists, dental technicians, and their supplying industry (e.g., denture tooth manufacturers). Precise knowledge of esthetic preferences is important in clinical practice for both dentists and dental technicians, for example, in order to adequately advise patients regarding esthetic corrections. Also, in the case of missing teeth, this knowledge is essential for optimal and satisfactory restorations. Thus, this study can contribute to the satisfaction of general practitioners and patients.
Yengo L, Vedantam S, Marouli E, Sidorenko J, Bartell E, Sakaue S, Graff M, Eliasen AU, Jiang Y, Raghavan S, Miao J, Arias JD, Graham SE, Mukamel RE, Spracklen CN, Yin X, Chen SH, Ferreira T, Highland HH, Ji Y, Karaderi T, Lin K, Lüll K, Malden DE, Medina-Gomez C, Machado M, Moore A, Rüeger S, Sim X, Vrieze S, Ahluwalia TS, Akiyama M, Allison MA, Alvarez M, Andersen MK, Ani A, Appadurai V, Arbeeva L, Bhaskar S, Bielak LF, Bollepalli S, Bonnycastle LL, Bork-Jensen J, Bradfield JP, Bradford Y, Braund PS, Brody JA, Burgdorf KS, Cade BE, Cai H, Cai Q, Campbell A, Cañadas-Garre M, Catamo E, Chai JF, Chai X, Chang LC, Chang YC, Chen CH, Chesi A, Choi SH, Chung RH, Cocca M, Concas MP, Couture C, Cuellar-Partida G, Danning R, Daw EW, Degenhard F, Delgado GE, Delitala A, Demirkan A, Deng X, Devineni P, Dietl A, Dimitriou M, Dimitrov L, Dorajoo R, Ekici AB, Engmann JE, Fairhurst-Hunter Z, Farmaki AE, Faul JD, Fernandez-Lopez JC, Forer L, Francescatto M, Freitag-Wolf S, Fuchsberger C, Galesloot TE, Gao Y, Gao Z, Geller F, Giannakopoulou O, Giulianini F, Gjesing AP, Goel A, Gordon SD, Gorski M, Grove J, Guo X, Gustafsson S, Haessler J, Hansen TF, Havulinna AS, Haworth SJ, He J, Heard-Costa N, Hebbar P, Hindy G, Ho YA, Hofer E, Holliday E, Horn K, Hornsby WE, Hottenga JJ, Huang H, Huang J, Huerta-Chagoya A, Huffman JE, Hung YJ, Huo S, Hwang MY, Iha H, Ikeda DD, Isono M, Jackson AU, Jäger S, Jansen IE, Johansson I, Jonas JB, Jonsson A, Jørgensen T, Kalafati IP, Kanai M, Kanoni S, Kårhus LL, Kasturiratne A, Katsuya T, Kawaguchi T, Kember RL, Kentistou KA, Kim HN, Kim YJ, Kleber ME, Knol MJ, Kurbasic A, Lauzon M, Le P, Lea R, Lee JY, Leonard HL, Li SA, Li X, Li X, Liang J, Lin H, Lin SY, Liu J, Liu X, Lo KS, Long J, Lores-Motta L, Lyssenko V, Lyytikäinen LP, Mahajan A, Mamakou V, Mangino M, Manichaikul A, Marten J, Mattheisen M, Mavarani L, McDaid AF, Meidtner K, Melendez TL, Mercader JM, Milaneschi Y, Miller JE, Millwood IY, Mishra PP, Mitchell RE, Møllehave LT, Morgan A, Mucha S, Munz M, Nakatochi M, Nelson CP, Nethander M, Nho CW, Nielsen AA, Nolte IM, Nongmaithem SS, Noordam R, Ntalla I, Nutile T, Pandit A, Christofidou P, Pärna K, Pauper M, Petersen ERB, Petersen LV, Pitkänen N, Polašek O, Poveda A, Preuss MH, Pyarajan S, Raffield LM, Rakugi H, Ramirez J, Rasheed A, Raven D, Rayner NW, Riveros C, Rohde R, Ruggiero D, Ruotsalainen SE, Ryan KA, Sabater-Lleal M, Saxena R, Scholz M, Sendamarai A, Shen B, Shi J, Shin JH, Sidore C, Sitlani CM, Slieker RC, Smit RAJ, Smith AV, Smith JA, Smyth LJ, Southam L, Steinthorsdottir V, Sun L, Takeuchi F, Tallapragada DSP, Taylor KD, Tayo BO, Tcheandjieu C, Terzikhan N, Tesolin P, Teumer A, Theusch E, Thompson DJ, Thorleifsson G, Timmers PRHJ, Trompet S, Turman C, Vaccargiu S, van der Laan SW, van der Most PJ, van Klinken JB, van Setten J, Verma SS, Verweij N, Veturi Y, Wang CA, Wang C, Wang L, Wang Z, Warren HR, Bin Wei W, Wickremasinghe AR, Wielscher M, Wiggins KL, Winsvold BS, Wong A, Wu Y, Wuttke M, Xia R, Xie T, Yamamoto K, Yang J, Yao J, Young H, Yousri NA, Yu L, Zeng L, Zhang W, Zhang X, Zhao JH, Zhao W, Zhou W, Zimmermann ME, Zoledziewska M, Adair LS, Adams HHH, Aguilar-Salinas CA, Al-Mulla F, Arnett DK, Asselbergs FW, Åsvold BO, Attia J, Banas B, Bandinelli S, Bennett DA, Bergler T, Bharadwaj D, Biino G, Bisgaard H, Boerwinkle E, Böger CA, Bønnelykke K, Boomsma DI, Børglum AD, Borja JB, Bouchard C, Bowden DW, Brandslund I, Brumpton B, Buring JE, Caulfield MJ, Chambers JC, Chandak GR, Chanock SJ, Chaturvedi N, Chen YI, Chen Z, Cheng CY, Christophersen IE, Ciullo M, Cole JW, Collins FS, Cooper RS, Cruz M, Cucca F, Cupples LA, Cutler MJ, Damrauer SM, Dantoft TM, de Borst GJ, de Groot LCPGM, De Jager PL, de Kleijn DPV, Janaka de Silva H, Dedoussis GV, den Hollander AI, Du S, Easton DF, Elders PJM, Eliassen AH, Ellinor PT, Elmståhl S, Erdmann J, Evans MK, Fatkin D, Feenstra B, Feitosa MF, Ferrucci L, Ford I, Fornage M, Franke A, Franks PW, Freedman BI, Gasparini P, Gieger C, Girotto G, Goddard ME, Golightly YM, Gonzalez-Villalpando C, Gordon-Larsen P, Grallert H, Grant SFA, Grarup N, Griffiths L, Gudnason V, Haiman C, Hakonarson H, Hansen T, Hartman CA, Hattersley AT, Hayward C, Heckbert SR, Heng CK, Hengstenberg C, Hewitt AW, Hishigaki H, Hoyng CB, Huang PL, Huang W, Hunt SC, Hveem K, Hyppönen E, Iacono WG, Ichihara S, Ikram MA, Isasi CR, Jackson RD, Jarvelin MR, Jin ZB, Jöckel KH, Joshi PK, Jousilahti P, Jukema JW, Kähönen M, Kamatani Y, Kang KD, Kaprio J, Kardia SLR, Karpe F, Kato N, Kee F, Kessler T, Khera AV, Khor CC, Kiemeney LALM, Kim BJ, Kim EK, Kim HL, Kirchhof P, Kivimaki M, Koh WP, Koistinen HA, Kolovou GD, Kooner JS, Kooperberg C, Köttgen A, Kovacs P, Kraaijeveld A, Kraft P, Krauss RM, Kumari M, Kutalik Z, Laakso M, Lange LA, Langenberg C, Launer LJ, Le Marchand L, Lee H, Lee NR, Lehtimäki T, Li H, Li L, Lieb W, Lin X, Lind L, Linneberg A, Liu CT, Liu J, Loeffler M, London B, Lubitz SA, Lye SJ, Mackey DA, Mägi R, Magnusson PKE, Marcus GM, Vidal PM, Martin NG, März W, Matsuda F, McGarrah RW, McGue M, McKnight AJ, Medland SE, Mellström D, Metspalu A, Mitchell BD, Mitchell P, Mook-Kanamori DO, Morris AD, Mucci LA, Munroe PB, Nalls MA, Nazarian S, Nelson AE, Neville MJ, Newton-Cheh C, Nielsen CS, Nöthen MM, Ohlsson C, Oldehinkel AJ, Orozco L, Pahkala K, Pajukanta P, Palmer CNA, Parra EJ, Pattaro C, Pedersen O, Pennell CE, Penninx BWJH, Perusse L, Peters A, Peyser PA, Porteous DJ, Posthuma D, Power C, Pramstaller PP, Province MA, Qi Q, Qu J, Rader DJ, Raitakari OT, Ralhan S, Rallidis LS, Rao DC, Redline S, Reilly DF, Reiner AP, Rhee SY, Ridker PM, Rienstra M, Ripatti S, Ritchie MD, Roden DM, Rosendaal FR, Rotter JI, Rudan I, Rutters F, Sabanayagam C, Saleheen D, Salomaa V, Samani NJ, Sanghera DK, Sattar N, Schmidt B, Schmidt H, Schmidt R, Schulze MB, Schunkert H, Scott LJ, Scott RJ, Sever P, Shiroma EJ, Shoemaker MB, Shu XO, Simonsick EM, Sims M, Singh JR, Singleton AB, Sinner MF, Smith JG, Snieder H, Spector TD, Stampfer MJ, Stark KJ, Strachan DP, Tabara Y, Tang H, Tardif JC, Thanaraj TA, Timpson NJ, Tönjes A, Tremblay A, Tuomi T, Tuomilehto J, Tusié-Luna MT, Uitterlinden AG, van Dam RM, van der Harst P, Van der Velde N, van Duijn CM, van Schoor NM, Vitart V, Völker U, Vollenweider P, Völzke H, Wacher-Rodarte NH, Walker M, Wang YX, Wareham NJ, Watanabe RM, Watkins H, Weir DR, Werge TM, Widen E, Wilkens LR, Willemsen G, Willett WC, Wilson JF, Wong TY, Woo JT, Wright AF, Wu JY, Xu H, Yajnik CS, Yokota M, Yuan JM, Zeggini E, Zemel BS, Zheng W, Zhu X, Zmuda JM, Zonderman AB, Zwart JA, , , , , , , , Chasman DI, Cho YS, Heid IM, McCarthy MI, Ng MCY, Rivadeneira F, Thorsteinsdottir U, Sun YV, Tai ES, Boehnke M, Deloukas P, Justice AE, Lindgren CM, Loos RJF, Mohlke KL, North KE, Stefansson K, Walters RG, Winkler TW, Young KL, Loh PR, Yang J, Esko T, Assimes TL, Auton A, Abecasis GR, Willer CJ, Locke AE, Berndt SI, Lettre G, Frayling TM, Okada Y, Wood AR, Visscher PM, Hirschhorn JN.
A saturated map of common genetic variants associated with human height.Nature,
610 (2022), 704-712.
[abstract]
Abstract:
2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.
Fabian A, Domschikowski J, Letsch A, Schmalz C, Freitag-Wolf S, Dunst J, Krug D.
Use and Reporting of Patient-Reported Outcomes in Trials of Palliative Radiotherapy: A Systematic Review.JAMA Netw Open,
5 (2022), e2231930.
[abstract]
Abstract:
In this systematic review of palliative radiotherapy trials, the use and reporting of PROs had room for improvement for future trials, preferably with PROs as a primary end point.
Harder S, Freitag-Wolf S, Quabius ES, Becker M, Kern M.
Sealing Behavior of a New Material Combination in Two-Part Dental Implant Systems: An In Vitro Examination.Int J Prosthodont,
(2022).
[abstract]
Abstract:
The internal hexalobe IAI of two-piece dental implants fabricated from Y-TZP and PEKK do not prevent LPS molecular microleakage.
Kanngiesser LM, Freitag-Wolf S, Boroni Grazioli S, Gabbert DD, Hansen JH, Uebing AS, Voges I.
Serial Assessment of Right Ventricular Deformation in Patients With Hypoplastic Left Heart Syndrome: A Cardiovascular Magnetic Resonance Feature Tracking Study.J Am Heart Assoc,
11 (2022), e025332.
[abstract]
Abstract:
P<0.0002). Conclusions Serial assessment of cardiovascular magnetic resonance studies in patients with hypoplastic left heart syndrome after Fontan completion demonstrates a significant reduction in global strain values and right ventricular ejection fraction at follow-up. The significant reduction in global longitudinal strain between the first 2 examinations with non-significant changes in right ventricular ejection fraction suggest that global longitudinal strain measured by 2-dimensional cardiovascular magnetic resonance feature tracking might be a superior technique for the detection of changes in myocardial function.
Winkler TW, Rasheed H, Teumer A, Gorski M, Rowan BX, Stanzick KJ, Thomas LF, Tin A, Hoppmann A, Chu AY, Tayo B, Thio CHL, Cusi D, Chai JF, Sieber KB, Horn K, Li M, Scholz M, Cocca M, Wuttke M, van der Most PJ, Yang Q, Ghasemi S, Nutile T, Li Y, Pontali G, Günther F, Dehghan A, Correa A, Parsa A, Feresin A, de Vries APJ, Zonderman AB, Smith AV, Oldehinkel AJ, De Grandi A, Rosenkranz AR, Franke A, Teren A, Metspalu A, Hicks AA, Morris AP, Tönjes A, Morgan A, Podgornaia AI, Peters A, Körner A, Mahajan A, Campbell A, Freedman BI, Spedicati B, Ponte B, Schöttker B, Brumpton B, Banas B, Krämer BK, Jung B, Åsvold BO, Smith BH, Ning B, Penninx BWJH, Vanderwerff BR, Psaty BM, Kammerer CM, Langefeld CD, Hayward C, Spracklen CN, Robinson-Cohen C, Hartman CA, Lindgren CM, Wang C, Sabanayagam C, Heng CK, Lanzani C, Khor CC, Cheng CY, Fuchsberger C, Gieger C, Shaffer CM, Schulz CA, Willer CJ, Chasman DI, Gudbjartsson DF, Ruggiero D, Toniolo D, Czamara D, Porteous DJ, Waterworth DM, Mascalzoni D, Mook-Kanamori DO, Reilly DF, Daw EW, Hofer E, Boerwinkle E, Salvi E, Bottinger EP, Tai ES, Catamo E, Rizzi F, Guo F, Rivadeneira F, Guilianini F, Sveinbjornsson G, Ehret G, Waeber G, Biino G, Girotto G, Pistis G, Nadkarni GN, Delgado GE, Montgomery GW, Snieder H, Campbell H, White HD, Gao H, Stringham HM, Schmidt H, Li H, Brenner H, Holm H, Kirsten H, Kramer H, Rudan I, Nolte IM, Tzoulaki I, Olafsson I, Martins J, Cook JP, Wilson JF, Halbritter J, Felix JF, Divers J, Kooner JS, Lee JJ, Rotter JI, Liu J, Xu J, Thiery J, Ärnlöv J, Kuusisto J, Jakobsdottir J, Tremblay J, Chambers JC, Whitfield JB, Gaziano JM, Marten J, Coresh J, Jonas JB, Mychaleckyj JC, Christensen K, Eckardt KU, Mohlke KL, Endlich K, Dittrich K, Ryan KA, Rice KM, Taylor KD, Ho K, Nikus K, Matsuda K, Strauch K, Miliku K, Hveem K, Lind L, Wallentin L, Yerges-Armstrong LM, Raffield LM, Phillips LS, Launer LJ, Lyytikäinen LP, Lange LA, Citterio L, Klaric L, Ikram MA, Ising M, Kleber ME, Francescatto M, Concas MP, Ciullo M, Piratsu M, Orho-Melander M, Laakso M, Loeffler M, Perola M, de Borst MH, Gögele M, Bianca M, Lukas MA, Feitosa MF, Biggs ML, Wojczynski MK, Kavousi M, Kanai M, Akiyama M, Yasuda M, Nauck M, Waldenberger M, Chee ML, Chee ML, Boehnke M, Preuss MH, Stumvoll M, Province MA, Evans MK, Kubo M, Kähönen M, Kastarinen M, Nalls MA, Kuokkanen M, Ghanbari M, Bochud M, Josyula NS, Martin NG, Tan NYQ, Palmer ND, Pirastu N, Schupf N, Verweij N, Hutri-Kähönen N, Mononen N, Bansal N, Devuyst O, Melander O, Raitakari OT, Polasek O, Manunta P, Gasparini P, Mishra PP, Sulem P, Magnusson PKE, Elliott P, Ridker PM, Hamet P, Svensson PO, Joshi PK, Kovacs P, Pramstaller PP, Rossing P, Vollenweider P, van der Harst P, Dorajoo R, Sim RZH, Burkhardt R, Tao R, Noordam R, Mägi R, Schmidt R, de Mutsert R, Rueedi R, van Dam RM, Carroll RJ, Gansevoort RT, Loos RJF, Felicita SC, Sedaghat S, Padmanabhan S, Freitag-Wolf S, Pendergrass SA, Graham SE, Gordon SD, Hwang SJ, Kerr SM, Vaccargiu S, Patil SB, Hallan S, Bakker SJL, Lim SC, Lucae S, Vogelezang S, Bergmann S, Corre T, Ahluwalia TS, Lehtimäki T, Boutin TS, Meitinger T, Wong TY, Bergler T, Rabelink TJ, Esko T, Haller T, Thorsteinsdottir U, Völker U, Foo VHX, Salomaa V, Vitart V, Giedraitis V, Gudnason V, Jaddoe VWV, Huang W, Zhang W, Wei WB, Kiess W, März W, Koenig W, Lieb W, Gao X, Sim X, Wang YX, Friedlander Y, Tham YC, Kamatani Y, Okada Y, Milaneschi Y, Yu Z, , , , Stark KJ, Stefansson K, Böger CA, Hung AM, Kronenberg F, Köttgen A, Pattaro C, Heid IM.
Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals.Commun Biol,
5 (2022), 580.
[abstract]
Abstract:
noDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.
Ramdas S, Judd J, Graham SE, Kanoni S, Wang Y, Surakka I, Wenz B, Clarke SL, Chesi A, Wells A, Bhatti KF, Vedantam S, Winkler TW, Locke AE, Marouli E, Zajac GJM, Wu KH, Ntalla I, Hui Q, Klarin D, Hilliard AT, Wang Z, Xue C, Thorleifsson G, Helgadottir A, Gudbjartsson DF, Holm H, Olafsson I, Hwang MY, Han S, Akiyama M, Sakaue S, Terao C, Kanai M, Zhou W, Brumpton BM, Rasheed H, Havulinna AS, Veturi Y, Pacheco JA, Rosenthal EA, Lingren T, Feng Q, Kullo IJ, Narita A, Takayama J, Martin HC, Hunt KA, Trivedi B, Haessler J, Giulianini F, Bradford Y, Miller JE, Campbell A, Lin K, Millwood IY, Rasheed A, Hindy G, Faul JD, Zhao W, Weir DR, Turman C, Huang H, Graff M, Choudhury A, Sengupta D, Mahajan A, Brown MR, Zhang W, Yu K, Schmidt EM, Pandit A, Gustafsson S, Yin X, Zhao JH, Matsuda F, Jang HM, Yoon K, Medina-Gomez C, Pitsillides A, Hottenga JJ, Wood AR, Ji Y, Gao Z, Haworth S, Mitchell RE, Chai JF, Aadahl M, Bjerregaard AA, Yao J, Manichaikul A, Lee WJ, Hsiung CA, Warren HR, Ramirez J, Bork-Jensen J, Kårhus LL, Goel A, Sabater-Lleal M, Noordam R, Mauro P, Matteo F, McDaid AF, Marques-Vidal P, Wielscher M, Trompet S, Sattar N, Møllehave LT, Munz M, Zeng L, Huang J, Yang B, Poveda A, Kurbasic A, Schönherr S, Forer L, Scholz M, Galesloot TE, Bradfield JP, Ruotsalainen SE, Daw EW, Zmuda JM, Mitchell JS, Fuchsberger C, Christensen H, Brody JA, Le P, Feitosa MF, Wojczynski MK, Hemerich D, Preuss M, Mangino M, Christofidou P, Verweij N, Benjamins JW, Engmann J, Noah TL, Verma A, Slieker RC, Lo KS, Zilhao NR, Kleber ME, Delgado GE, Huo S, Ikeda DD, Iha H, Yang J, Liu J, Demirkan A, Leonard HL, Marten J, Emmel C, Schmidt B, Smyth LJ, Cañadas-Garre M, Wang C, Nakatochi M, Wong A, Hutri-Kähönen N, Sim X, Xia R, Huerta-Chagoya A, Fernandez-Lopez JC, Lyssenko V, Nongmaithem SS, Sankareswaran A, Irvin MR, Oldmeadow C, Kim HN, Ryu S, Timmers PRHJ, Arbeeva L, Dorajoo R, Lange LA, Prasad G, Lorés-Motta L, Pauper M, Long J, Li X, Theusch E, Takeuchi F, Spracklen CN, Loukola A, Bollepalli S, Warner SC, Wang YX, Wei WB, Nutile T, Ruggiero D, Sung YJ, Chen S, Liu F, Yang J, Kentistou KA, Banas B, Morgan A, Meidtner K, Bielak LF, Smith JA, Hebbar P, Farmaki AE, Hofer E, Lin M, Concas MP, Vaccargiu S, van der Most PJ, Pitkänen N, Cade BE, van der Laan SW, Chitrala KN, Weiss S, Bentley AR, Doumatey AP, Adeyemo AA, Lee JY, Petersen ERB, Nielsen AA, Choi HS, Nethander M, Freitag-Wolf S, Southam L, Rayner NW, Wang CA, Lin SY, Wang JS, Couture C, Lyytikäinen LP, Nikus K, Cuellar-Partida G, Vestergaard H, Hidalgo B, Giannakopoulou O, Cai Q, Obura MO, van Setten J, He KY, Tang H, Terzikhan N, Shin JH, Jackson RD, Reiner AP, Martin LW, Chen Z, Li L, Kawaguchi T, Thiery J, Bis JC, Launer LJ, Li H, Nalls MA, Raitakari OT, Ichihara S, Wild SH, Nelson CP, Campbell H, Jäger S, Nabika T, Al-Mulla F, Niinikoski H, Braund PS, Kolcic I, Kovacs P, Giardoglou T, Katsuya T, de Kleijn D, de Borst GJ, Kim EK, Adams HHH, Ikram MA, Zhu X, Asselbergs FW, Kraaijeveld AO, Beulens JWJ, Shu XO, Rallidis LS, Pedersen O, Hansen T, Mitchell P, Hewitt AW, Kähönen M, Pérusse L, Bouchard C, Tönjes A, Ida Chen YD, Pennell CE, Mori TA, Lieb W, Franke A, Ohlsson C, Mellström D, Cho YS, Lee H, Yuan JM, Koh WP, Rhee SY, Woo JT, Heid IM, Stark KJ, Zimmermann ME, Völzke H, Homuth G, Evans MK, Zonderman AB, Polasek O, Pasterkamp G, Hoefer IE, Redline S, Pahkala K, Oldehinkel AJ, Snieder H, Biino G, Schmidt R, Schmidt H, Bandinelli S, Dedoussis G, Thanaraj TA, Peyser PA, Kato N, Schulze MB, Girotto G, Böger CA, Jung B, Joshi PK, Bennett DA, De Jager PL, Lu X, Mamakou V, Brown M, Caulfield MJ, Munroe PB, Guo X, Ciullo M, Jonas JB, Samani NJ, Kaprio J, Pajukanta P, Tusié-Luna T, Aguilar-Salinas CA, Adair LS, Bechayda SA, de Silva HJ, Wickremasinghe AR, Krauss RM, Wu JY, Zheng W, den Hollander AI, Bharadwaj D, Correa A, Wilson JG, Lind L, Heng CK, Nelson AE, Golightly YM, Wilson JF, Penninx B, Kim HL, Attia J, Scott RJ, Rao DC, Arnett DK, Walker M, Scott LJ, Koistinen HA, Chandak GR, Mercader JM, Villalpando CG, Orozco L, Fornage M, Tai ES, van Dam RM, Lehtimäki T, Chaturvedi N, Yokota M, Liu J, Reilly DF, McKnight AJ, Kee F, Jöckel KH, McCarthy MI, Palmer CNA, Vitart V, Hayward C, Simonsick E, van Duijn CM, Jin ZB, Lu F, Hishigaki H, Lin X, März W, Gudnason V, Tardif JC, Lettre G, T Hart LM, Elders PJM, Rader DJ, Damrauer SM, Kumari M, Kivimaki M, van der Harst P, Spector TD, Loos RJF, Province MA, Parra EJ, Cruz M, Psaty BM, Brandslund I, Pramstaller PP, Rotimi CN, Christensen K, Ripatti S, Widén E, Hakonarson H, Grant SFA, Kiemeney L, de Graaf J, Loeffler M, Kronenberg F, Gu D, Erdmann J, Schunkert H, Franks PW, Linneberg A, Jukema JW, Khera AV, Männikkö M, Jarvelin MR, Kutalik Z, Francesco C, Mook-Kanamori DO, Willems van Dijk K, Watkins H, Strachan DP, Grarup N, Sever P, Poulter N, Huey-Herng Sheu W, Rotter JI, Dantoft TM, Karpe F, Neville MJ, Timpson NJ, Cheng CY, Wong TY, Khor CC, Li H, Sabanayagam C, Peters A, Gieger C, Hattersley AT, Pedersen NL, Magnusson PKE, Boomsma DI, de Geus EJC, Cupples LA, van Meurs JBJ, Ikram A, Ghanbari M, Gordon-Larsen P, Huang W, Kim YJ, Tabara Y, Wareham NJ, Langenberg C, Zeggini E, Tuomilehto J, Kuusisto J, Laakso M, Ingelsson E, Abecasis G, Chambers JC, Kooner JS, de Vries PS, Morrison AC, Hazelhurst S, Ramsay M, North KE, Daviglus M, Kraft P, Martin NG, Whitfield JB, Abbas S, Saleheen D, Walters RG, Holmes MV, Black C, Smith BH, Baras A, Justice AE, Buring JE, Ridker PM, Chasman DI, Kooperberg C, Tamiya G, Yamamoto M, van Heel DA, Trembath RC, Wei WQ, Jarvik GP, Namjou B, Hayes MG, Ritchie MD, Jousilahti P, Salomaa V, Hveem K, Åsvold BO, Kubo M, Kamatani Y, Okada Y, Murakami Y, Kim BJ, Thorsteinsdottir U, Stefansson K, Zhang J, Chen YE, Ho YL, Lynch JA, Tsao PS, Chang KM, Cho K, Gaziano JM, Wilson P, Mohlke KL, Frayling TM, Hirschhorn JN, Kathiresan S, Boehnke M, , , Struan Grant , Natarajan P, Sun YV, Morris AP, Deloukas P, Peloso G, Assimes TL, Willer CJ, Zhu X, Brown CD.
A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids.Am J Hum Genet,
109 (2022), 1366-1387.
[abstract]
Abstract:
A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.
Gorski M, Rasheed H, Teumer A, Thomas LF, Graham SE, Sveinbjornsson G, Winkler TW, Günther F, Stark KJ, Chai JF, Tayo BO, Wuttke M, Li Y, Tin A, Ahluwalia TS, Ärnlöv J, Åsvold BO, Bakker SJL, Banas B, Bansal N, Biggs ML, Biino G, Böhnke M, Boerwinkle E, Bottinger EP, Brenner H, Brumpton B, Carroll RJ, Chaker L, Chalmers J, Chee ML, Chee ML, Cheng CY, Chu AY, Ciullo M, Cocca M, Cook JP, Coresh J, Cusi D, de Borst MH, Degenhardt F, Eckardt KU, Endlich K, Evans MK, Feitosa MF, Franke A, Freitag-Wolf S, Fuchsberger C, Gampawar P, Gansevoort RT, Ghanbari M, Ghasemi S, Giedraitis V, Gieger C, Gudbjartsson DF, Hallan S, Hamet P, Hishida A, Ho K, Hofer E, Holleczek B, Holm H, Hoppmann A, Horn K, Hutri-Kähönen N, Hveem K, Hwang SJ, Ikram MA, Josyula NS, Jung B, Kähönen M, Karabegović I, Khor CC, Koenig W, Kramer H, Krämer BK, Kühnel B, Kuusisto J, Laakso M, Lange LA, Lehtimäki T, Li M, Lieb W, , Lind L, Lindgren CM, Loos RJF, Lukas MA, Lyytikäinen LP, Mahajan A, Matias-Garcia PR, Meisinger C, Meitinger T, Melander O, Milaneschi Y, Mishra PP, Mononen N, Morris AP, Mychaleckyj JC, Nadkarni GN, Naito M, Nakatochi M, Nalls MA, Nauck M, Nikus K, Ning B, Nolte IM, Nutile T, Olafsson I, Orho-Melander M, Parsa A, Pendergrass SA, Penninx BWJH, Pirastu M, Preuss MH, Psaty BM, Raffield LM, Raitakari OT, Rheinberger M, Rice KM, Rizzi F, Rosenkranz AR, Rossing P, Rotter JI, Ruggiero D, Ryan KA, Sabanayagam C, Salvi E, Schmidt H, Schmidt R, Scholz M, Schöttker B, Schulz CA, Sedaghat S, Shaffer CM, Sieber KB, Sim X, Sims M, Snieder H, Stanzick KJ, Thorsteinsdottir U, Stocker H, Strauch K, Stringham HM, Sulem P, Szymczak S, Taylor KD, Thio CHL, Tremblay J, Vaccargiu S, van der Harst P, van der Most PJ, Verweij N, Völker U, Wakai K, Waldenberger M, Wallentin L, Wallner S, Wang J, Waterworth DM, White HD, Willer CJ, Wong TY, Woodward M, Yang Q, Yerges-Armstrong LM, Zimmermann M, Zonderman AB, Bergler T, Stefansson K, Böger CA, Pattaro C, Köttgen A, Kronenberg F, Heid IM.
Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies.Kidney Int,
(2022).
[abstract]
Abstract:
Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.
Kanoni S, Graham SE, Wang Y, Surakka I, Ramdas S, Zhu X, Clarke SL, Bhatti KF, Vedantam S, Winkler TW, Locke AE, Marouli E, Zajac GJM, Wu KH, Ntalla I, Hui Q, Klarin D, Hilliard AT, Wang Z, Xue C, Thorleifsson G, Helgadottir A, Gudbjartsson DF, Holm H, Olafsson I, Hwang MY, Han S, Akiyama M, Sakaue S, Terao C, Kanai M, Zhou W, Brumpton BM, Rasheed H, Havulinna AS, Veturi Y, Pacheco JA, Rosenthal EA, Lingren T, Feng Q, Kullo IJ, Narita A, Takayama J, Martin HC, Hunt KA, Trivedi B, Haessler J, Giulianini F, Bradford Y, Miller JE, Campbell A, Lin K, Millwood IY, Rasheed A, Hindy G, Faul JD, Zhao W, Weir DR, Turman C, Huang H, Graff M, Choudhury A, Sengupta D, Mahajan A, Brown MR, Zhang W, Yu K, Schmidt EM, Pandit A, Gustafsson S, Yin X, Zhao JH, Matsuda F, Jang HM, Yoon K, Medina-Gomez C, Pitsillides A, Hottenga JJ, Wood AR, Ji Y, Gao Z, Haworth S, Yousri NA, Mitchell RE, Chai JF, Aadahl M, Bjerregaard AA, Yao J, Manichaikul A, Hwu CM, Hung YJ, Warren HR, Ramirez J, Bork-Jensen J, Kårhus LL, Goel A, Sabater-Lleal M, Noordam R, Mauro P, Matteo F, McDaid AF, Marques-Vidal P, Wielscher M, Trompet S, Sattar N, Møllehave LT, Munz M, Zeng L, Huang J, Yang B, Poveda A, Kurbasic A, Lamina C, Forer L, Scholz M, Galesloot TE, Bradfield JP, Ruotsalainen SE, Daw E, Zmuda JM, Mitchell JS, Fuchsberger C, Christensen H, Brody JA, Vazquez-Moreno M, Feitosa MF, Wojczynski MK, Wang Z, Preuss MH, Mangino M, Christofidou P, Verweij N, Benjamins JW, Engmann J, Tsao NL, Verma A, Slieker RC, Lo KS, Zilhao NR, Le P, Kleber ME, Delgado GE, Huo S, Ikeda DD, Iha H, Yang J, Liu J, Demirkan A, Leonard HL, Marten J, Frank M, Schmidt B, Smyth LJ, Cañadas-Garre M, Wang C, Nakatochi M, Wong A, Hutri-Kähönen N, Sim X, Xia R, Huerta-Chagoya A, Fernandez-Lopez JC, Lyssenko V, Nongmaithem SS, Bayyana S, Stringham HM, Irvin MR, Oldmeadow C, Kim HN, Ryu S, Timmers PRHJ, Arbeeva L, Dorajoo R, Lange LA, Prasad G, Lorés-Motta L, Pauper M, Long J, Li X, Theusch E, Takeuchi F, Spracklen CN, Loukola A, Bollepalli S, Warner SC, Wang YX, Wei WB, Nutile T, Ruggiero D, Sung YJ, Chen S, Liu F, Yang J, Kentistou KA, Banas B, Nardone GG, Meidtner K, Bielak LF, Smith JA, Hebbar P, Farmaki AE, Hofer E, Lin M, Concas MP, Vaccargiu S, van der Most PJ, Pitkänen N, Cade BE, van der Laan SW, Chitrala KN, Weiss S, Bentley AR, Doumatey AP, Adeyemo AA, Lee JY, Petersen ERB, Nielsen AA, Choi HS, Nethander M, Freitag-Wolf S, Southam L, Rayner NW, Wang CA, Lin SY, Wang JS, Couture C, Lyytikäinen LP, Nikus K, Cuellar-Partida G, Vestergaard H, Hidalgo B, Giannakopoulou O, Cai Q, Obura MO, van Setten J, Li X, Liang J, Tang H, Terzikhan N, Shin JH, Jackson RD, Reiner AP, Martin LW, Chen Z, Li L, Kawaguchi T, Thiery J, Bis JC, Launer LJ, Li H, Nalls MA, Raitakari OT, Ichihara S, Wild SH, Nelson CP, Campbell H, Jäger S, Nabika T, Al-Mulla F, Niinikoski H, Braund PS, Kolcic I, Kovacs P, Giardoglou T, Katsuya T, de Kleijn D, de Borst GJ, Kim EK, Adams HHH, Ikram MA, Zhu X, Asselbergs FW, Kraaijeveld AO, Beulens JWJ, Shu XO, Rallidis LS, Pedersen O, Hansen T, Mitchell P, Hewitt AW, Kähönen M, Pérusse L, Bouchard C, Tönjes A, Chen YI, Pennell CE, Mori TA, Lieb W, Franke A, Ohlsson C, Mellström D, Cho YS, Lee H, Yuan JM, Koh WP, Rhee SY, Woo JT, Heid IM, Stark KJ, Zimmermann ME, Völzke H, Homuth G, Evans MK, Zonderman AB, Polasek O, Pasterkamp G, Hoefer IE, Redline S, Pahkala K, Oldehinkel AJ, Snieder H, Biino G, Schmidt R, Schmidt H, Bandinelli S, Dedoussis G, Thanaraj TA, Kardia SLR, Peyser PA, Kato N, Schulze MB, Girotto G, Böger CA, Jung B, Joshi PK, Bennett DA, De Jager PL, Lu X, Mamakou V, Brown M, Caulfield MJ, Munroe PB, Guo X, Ciullo M, Jonas JB, Samani NJ, Kaprio J, Pajukanta P, Tusié-Luna T, Aguilar-Salinas CA, Adair LS, Bechayda SA, de Silva HJ, Wickremasinghe AR, Krauss RM, Wu JY, Zheng W, Hollander AI, Bharadwaj D, Correa A, Wilson JG, Lind L, Heng CK, Nelson AE, Golightly YM, Wilson JF, Penninx B, Kim HL, Attia J, Scott RJ, Rao DC, Arnett DK, Hunt SC, Walker M, Koistinen HA, Chandak GR, Mercader JM, Costanzo MC, Jang D, Burtt NP, Villalpando CG, Orozco L, Fornage M, Tai E, van Dam RM, Lehtimäki T, Chaturvedi N, Yokota M, Liu J, Reilly DF, McKnight AJ, Kee F, Jöckel KH, McCarthy MI, Palmer CNA, Vitart V, Hayward C, Simonsick E, van Duijn CM, Jin ZB, Qu J, Hishigaki H, Lin X, März W, Gudnason V, Tardif JC, Lettre G, Elders PJM, Damrauer SM, Kumari M, Kivimaki M, van der Harst P, Spector TD, Loos RJF, Province MA, Parra EJ, Cruz M, Psaty BM, Brandslund I, Pramstaller PP, Rotimi CN, Christensen K, Ripatti S, Widén E, Hakonarson H, Grant SFA, Kiemeney LALM, de Graaf J, Loeffler M, Kronenberg F, Gu D, Erdmann J, Schunkert H, Franks PW, Linneberg A, Jukema JW, Khera AV, Männikkö M, Jarvelin MR, Kutalik Z, Francesco C, Mook-Kanamori DO, van Dijk KW, Watkins H, Strachan DP, Grarup N, Sever P, Poulter N, Chuang LM, Rotter JI, Dantoft TM, Karpe F, Neville MJ, Timpson NJ, Cheng CY, Wong TY, Khor CC, Li H, Sabanayagam C, Peters A, Gieger C, Hattersley AT, Pedersen NL, Magnusson PKE, Boomsma DI, Willemsen AHM, Cupples L, van Meurs JBJ, Ghanbari M, Gordon-Larsen P, Huang W, Kim YJ, Tabara Y, Wareham NJ, Langenberg C, Zeggini E, Kuusisto J, Laakso M, Ingelsson E, Abecasis G, Chambers JC, Kooner JS, de Vries PS, Morrison AC, Hazelhurst S, Ramsay M, North KE, Daviglus M, Kraft P, Martin NG, Whitfield JB, Abbas S, Saleheen D, Walters RG, Holmes MV, Black C, Smith BH, Baras A, Justice AE, Buring JE, Ridker PM, Chasman DI, Kooperberg C, Tamiya G, Yamamoto M, van Heel DA, Trembath RC, Wei WQ, Jarvik GP, Namjou B, Hayes MG, Ritchie MD, Jousilahti P, Salomaa V, Hveem K, Åsvold BO, Kubo M, Kamatani Y, Okada Y, Murakami Y, Kim BJ, Thorsteinsdottir U, Stefansson K, Zhang J, Chen Y, Ho YL, Lynch JA, Rader DJ, Tsao PS, Chang KM, Cho K, Gaziano JM, Wilson PWF, Frayling TM, Hirschhorn JN, Kathiresan S, Mohlke KL, Sun YV, Morris AP, Boehnke M, Brown CD, Natarajan P, Deloukas P, Willer CJ, Assimes TL, Peloso GM.
Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.Genome Biol,
23 (2022), 268.
[abstract]
Abstract:
Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
Fabian A, Domschikowski J, Letsch A, Schmalz C, Freitag-Wolf S, Dunst J, Krug D.
Clinical endpoints in trials of palliative radiotherapy: A systematic meta-research analysis.Radiother Oncol,
174 (2022), 123-131.
[abstract]
Abstract:
Although "patient-centered primary endpoints" appear relatively prevalent in published trials of palliative radiotherapy, their use is still suboptimal and appears to be lower in currently ongoing trials.
Wang Y, Polten F, Jäckle F, Korf-Klingebiel M, Kempf T, Bauersachs J, Freitag-Wolf S, Lichtinghagen R, Pich A, Wollert KC.
Corrigendum to: A mouse model of cardiogenic shock.Cardiovasc Res,
118 (2022), 653.
Peña JA, Shaul JL, Müller M, Damm T, Barkmann R, Kurz B, Campbell GM, Freitag-Wolf S, Glüer CC.
Dual-Layer Spectral-Computed Tomography Enhances the Separability of Calcium-Based Implant Material from Bone: An Ex Vivo Quantitative Imaging Study.J Bone Miner Res,
37 (2022), 2472-2482.
[abstract]
Abstract:
3 , 1648 HU, 177 EDW, and 13.06 Zeff and were maintained postoperatively. Zeff showed substantially sharper distributions and significantly greater separability compared to ED, BMD, and HU (all p < 0.002, for both regions) with average AUCs for BMD, HU, ED, and Zeff of 0.670, 0.640, 0.645, and 0.753 for AGN1 versus compact and 0.996, 0.995, 0.994, and 0.998 for AGN1 versus femoral neck cancellous sites, respectively. Spectral-CT permits better discrimination of calcium-based implants like AGN1 from bone ex vivo. Our results warrant application of spectral-CT in patients undergoing procedures with similar implants. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Fölster-Holst R, Naß C, Dähnhardt-Pfeiffer S, Freitag-Wolf S.
Analysis of the structure and function of the epidermal barrier in patients with ichthyoses-clinical and electron microscopical investigations.J Eur Acad Dermatol Venereol,
36 (2022), 726-738.
[abstract]
Abstract:
The results demonstrate the extent of the epidermal barrier disruption in ichthyoses. In combination with the knowledge about pathogenetic causes, individually improved therapeutic options can be derived from our results. In the future, the analyses of the organization of intercellular lipid lamellae and corneocyte membrane undulation will enable improved investigations of the epidermal barrier in ichthyoses and may be used to study and evaluate possible effects of topical skin preparations.
Lutter G, Topal A, Hansen JH, Haneya A, Santhanthan J, Freitag-Wolf S, Frank D, Puehler T.
Transcatheter pulmonary valve replacement: a new polycarbonate urethane valve.Eur J Cardiothorac Surg,
59 (2021), 1048-1056.
[abstract]
Abstract:
This study demonstrates successful transcatheter pulmonary valve replacement with a novel dip-coated valved nitinol stent. The trileaflet PCU prostheses indicated good functional and biocompatible properties after a 6-month observation period.
Fölster-Holst R, Reimer R, Neumann C, Proksch E, Rodriguez E, Weidinger S, Goldust M, Hanisch E, Dähnhardt-Pfeiffer S, Freitag-Wolf S.
Comparison of Epidermal Barrier Integrity in Adults with Classic Atopic Dermatitis, Atopic Prurigo and Non-Atopic Prurigo Nodularis.Biology (Basel),
10 (2021).
[abstract]
Abstract:
A deficient epidermal barrier is a key feature of atopic dermatitis (AD) and comprises altered lipid and protein content and composition of the stratum corneum resulting in disturbed water balance. Clinically, eczematous lesions on dry skin and pruritus develop. Pruritic nodules occur in prurigo nodularis (PN), another chronic skin disease, which can be associated with atopy. We aimed at comparing the three clinical pictures, classic AD, atopic prurigo (AP), and non-atopic PN, to healthy controls regarding the epidermal barrier. We determined clinical parameters and performed biophysical measurements, histology/immunohistochemistry, electron microscopy, and molecular biological analysis. We found distinctively elevated clinical scores, reduced hydration and increased transepidermal water loss, epidermal hyperplasia and inflammation reduced filaggrin and increased loricrin and involucrin expression, as well as reduced intercellular lipid lamellae in all three disease groups. These findings show a severe disruption in epidermal barrier structure and function in all three disorders so that epidermal barrier impairment is now proven not only for AD but also for PN.
Graham SE, Clarke SL, Wu KH, Kanoni S, Zajac GJM, Ramdas S, Surakka I, Ntalla I, Vedantam S, Winkler TW, Locke AE, Marouli E, Hwang MY, Han S, Narita A, Choudhury A, Bentley AR, Ekoru K, Verma A, Trivedi B, Martin HC, Hunt KA, Hui Q, Klarin D, Zhu X, Thorleifsson G, Helgadottir A, Gudbjartsson DF, Holm H, Olafsson I, Akiyama M, Sakaue S, Terao C, Kanai M, Zhou W, Brumpton BM, Rasheed H, Ruotsalainen SE, Havulinna AS, Veturi Y, Feng Q, Rosenthal EA, Lingren T, Pacheco JA, Pendergrass SA, Haessler J, Giulianini F, Bradford Y, Miller JE, Campbell A, Lin K, Millwood IY, Hindy G, Rasheed A, Faul JD, Zhao W, Weir DR, Turman C, Huang H, Graff M, Mahajan A, Brown MR, Zhang W, Yu K, Schmidt EM, Pandit A, Gustafsson S, Yin X, Zhao JH, Matsuda F, Jang HM, Yoon K, Medina-Gomez C, Pitsillides A, Hottenga JJ, Willemsen G, Wood AR, Ji Y, Gao Z, Haworth S, Mitchell RE, Chai JF, Aadahl M, Yao J, Manichaikul A, Warren HR, Ramirez J, Bork-Jensen J, Kårhus LL, Goel A, Sabater-Lleal M, Noordam R, Sidore C, Fiorillo E, McDaid AF, Marques-Vidal P, Wielscher M, Trompet S, Sattar N, Møllehave LT, Thuesen BH, Munz M, Zeng L, Huang J, Yang B, Poveda A, Kurbasic A, Lamina C, Forer L, Scholz M, Galesloot TE, Bradfield JP, Daw EW, Zmuda JM, Mitchell JS, Fuchsberger C, Christensen H, Brody JA, Feitosa MF, Wojczynski MK, Preuss M, Mangino M, Christofidou P, Verweij N, Benjamins JW, Engmann J, Kember RL, Slieker RC, Lo KS, Zilhao NR, Le P, Kleber ME, Delgado GE, Huo S, Ikeda DD, Iha H, Yang J, Liu J, Leonard HL, Marten J, Schmidt B, Arendt M, Smyth LJ, Cañadas-Garre M, Wang C, Nakatochi M, Wong A, Hutri-Kähönen N, Sim X, Xia R, Huerta-Chagoya A, Fernandez-Lopez JC, Lyssenko V, Ahmed M, Jackson AU, Irvin MR, Oldmeadow C, Kim HN, Ryu S, Timmers PRHJ, Arbeeva L, Dorajoo R, Lange LA, Chai X, Prasad G, Lorés-Motta L, Pauper M, Long J, Li X, Theusch E, Takeuchi F, Spracklen CN, Loukola A, Bollepalli S, Warner SC, Wang YX, Wei WB, Nutile T, Ruggiero D, Sung YJ, Hung YJ, Chen S, Liu F, Yang J, Kentistou KA, Gorski M, Brumat M, Meidtner K, Bielak LF, Smith JA, Hebbar P, Farmaki AE, Hofer E, Lin M, Xue C, Zhang J, Concas MP, Vaccargiu S, van der Most PJ, Pitkänen N, Cade BE, Lee J, van der Laan SW, Chitrala KN, Weiss S, Zimmermann ME, Lee JY, Choi HS, Nethander M, Freitag-Wolf S, Southam L, Rayner NW, Wang CA, Lin SY, Wang JS, Couture C, Lyytikäinen LP, Nikus K, Cuellar-Partida G, Vestergaard H, Hildalgo B, Giannakopoulou O, Cai Q, Obura MO, van Setten J, Li X, Schwander K, Terzikhan N, Shin JH, Jackson RD, Reiner AP, Martin LW, Chen Z, Li L, Highland HM, Young KL, Kawaguchi T, Thiery J, Bis JC, Nadkarni GN, Launer LJ, Li H, Nalls MA, Raitakari OT, Ichihara S, Wild SH, Nelson CP, Campbell H, Jäger S, Nabika T, Al-Mulla F, Niinikoski H, Braund PS, Kolcic I, Kovacs P, Giardoglou T, Katsuya T, Bhatti KF, de Kleijn D, de Borst GJ, Kim EK, Adams HHH, Ikram MA, Zhu X, Asselbergs FW, Kraaijeveld AO, Beulens JWJ, Shu XO, Rallidis LS, Pedersen O, Hansen T, Mitchell P, Hewitt AW, Kähönen M, Pérusse L, Bouchard C, Tönjes A, Chen YI, Pennell CE, Mori TA, Lieb W, Franke A, Ohlsson C, Mellström D, Cho YS, Lee H, Yuan JM, Koh WP, Rhee SY, Woo JT, Heid IM, Stark KJ, Völzke H, Homuth G, Evans MK, Zonderman AB, Polasek O, Pasterkamp G, Hoefer IE, Redline S, Pahkala K, Oldehinkel AJ, Snieder H, Biino G, Schmidt R, Schmidt H, Chen YE, Bandinelli S, Dedoussis G, Thanaraj TA, Kardia SLR, Kato N, Schulze MB, Girotto G, Jung B, Böger CA, Joshi PK, Bennett DA, De Jager PL, Lu X, Mamakou V, Brown M, Caulfield MJ, Munroe PB, Guo X, Ciullo M, Jonas JB, Samani NJ, Kaprio J, Pajukanta P, Adair LS, Bechayda SA, de Silva HJ, Wickremasinghe AR, Krauss RM, Wu JY, Zheng W, den Hollander AI, Bharadwaj D, Correa A, Wilson JG, Lind L, Heng CK, Nelson AE, Golightly YM, Wilson JF, Penninx B, Kim HL, Attia J, Scott RJ, Rao DC, Arnett DK, Walker M, Koistinen HA, Chandak GR, Yajnik CS, Mercader JM, Tusié-Luna T, Aguilar-Salinas CA, Villalpando CG, Orozco L, Fornage M, Tai ES, van Dam RM, Lehtimäki T, Chaturvedi N, Yokota M, Liu J, Reilly DF, McKnight AJ, Kee F, Jöckel KH, McCarthy MI, Palmer CNA, Vitart V, Hayward C, Simonsick E, van Duijn CM, Lu F, Qu J, Hishigaki H, Lin X, März W, Parra EJ, Cruz M, Gudnason V, Tardif JC, Lettre G, Elders PJM, Damrauer SM, Kumari M, Kivimaki M, van der Harst P, Spector TD, Loos RJF, Province MA, Psaty BM, Brandslund I, Pramstaller PP, Christensen K, Ripatti S, Widén E, Hakonarson H, Grant SFA, Kiemeney LALM, de Graaf J, Loeffler M, Kronenberg F, Gu D, Erdmann J, Schunkert H, Franks PW, Linneberg A, Jukema JW, Khera AV, Männikkö M, Jarvelin MR, Kutalik Z, Cucca F, Mook-Kanamori DO, van Dijk KW, Watkins H, Strachan DP, Grarup N, Sever P, Poulter N, Rotter JI, Dantoft TM, Karpe F, Neville MJ, Timpson NJ, Cheng CY, Wong TY, Khor CC, Sabanayagam C, Peters A, Gieger C, Hattersley AT, Pedersen NL, Magnusson PKE, Boomsma DI, de Geus EJC, Cupples LA, van Meurs JBJ, Ghanbari M, Gordon-Larsen P, Huang W, Kim YJ, Tabara Y, Wareham NJ, Langenberg C, Zeggini E, Kuusisto J, Laakso M, Ingelsson E, Abecasis G, Chambers JC, Kooner JS, de Vries PS, Morrison AC, North KE, Daviglus M, Kraft P, Martin NG, Whitfield JB, Abbas S, Saleheen D, Walters RG, Holmes MV, Black C, Smith BH, Justice AE, Baras A, Buring JE, Ridker PM, Chasman DI, Kooperberg C, Wei WQ, Jarvik GP, Namjou B, Hayes MG, Ritchie MD, Jousilahti P, Salomaa V, Hveem K, Åsvold BO, Kubo M, Kamatani Y, Okada Y, Murakami Y, Thorsteinsdottir U, Stefansson K, Ho YL, Lynch JA, Rader DJ, Tsao PS, Chang KM, Cho K, Gaziano JM, Wilson P, Rotimi CN, Hazelhurst S, Ramsay M, Trembath RC, van Heel DA, Tamiya G, Yamamoto M, Kim BJ, Mohlke KL, Frayling TM, Hirschhorn JN, Kathiresan S, , , Boehnke M, Natarajan P, Peloso GM, Brown CD, Morris AP, Assimes TL, Deloukas P, Sun YV, Willer CJ.
The power of genetic diversity in genome-wide association studies of lipids.Nature,
600 (2021), 675-679.
[abstract]
Abstract:
26 application of polygenic scores in clinical practice.
Dumke C, Gemoll T, Oberländer M, Freitag-Wolf S, Thorns C, Glaessgen A, Klooster R, van der Maarel SM, Widengren J, Doehn C, Auer G, Habermann JK.
SATB1, genomic instability and Gleason grading constitute a novel risk score for prostate cancer.Sci Rep,
11 (2021), 24446.
[abstract]
Abstract:
Current prostate cancer risk classifications rely on clinicopathological parameters resulting in uncertainties for prognostication. To improve individual risk stratification, we examined the predictive value of selected proteins with respect to tumor heterogeneity and genomic instability. We assessed the degree of genomic instability in 50 radical prostatectomy specimens by DNA-Image-Cytometry and evaluated protein expression in related 199 tissue-microarray (TMA) cores. Immunohistochemical data of SATB1, SPIN1, TPM4, VIME and TBB5 were correlated with the degree of genomic instability, established clinical risk factors and overall survival. Genomic instability was associated with a GS ≥ 7 (p = 0.001) and worse overall survival (p = 0.008). A positive SATB1 expression was associated with a GS ≤ 6 (p = 0.040), genomic stability (p = 0.027), and was a predictor for increased overall survival (p = 0.023). High expression of SPIN1 was also associated with longer overall survival (p = 0.048) and lower preoperative PSA-values (p = 0.047). The combination of SATB1 expression, genomic instability, and GS lead to a novel Prostate Cancer Prediction Score (PCP-Score) which outperforms the current D'Amico et al. stratification for predicting overall survival. Low SATB1 expression, genomic instability and GS ≥ 7 were identified as markers for poor prognosis. Their combination overcomes current clinical risk stratification regimes.
Wang Y, Polten F, Jäckle F, Korf-Klingebiel M, Kempf T, Bauersachs J, Freitag-Wolf S, Lichtinghagen R, Pich A, Wollert KC.
A Mouse model of cardiogenic shock.Cardiovasc Res,
(2021).
Kylies D, Freitag-Wolf S, Fulisch F, Seoudy H, Kuhn C, Kihm LP, Pühler T, Lutter G, Dempfle A, Frey N, Feldkamp T, Frank D.
Improvement of renal function after transcatheter aortic valve replacement and its impact on survival.BMC Nephrol,
22 (2021), 77.
[abstract]
Abstract:
We here describe a propensity score-derived specific subgroup of patients in which RI after TAVR correlated with a significant survival benefit.
Aleknonytė-Resch M, Szymczak S, Freitag-Wolf S, Dempfle A, Krawczak M.
Genotype imputation in case-only studies of gene-environment interaction: validity and power.Hum Genet,
140 (2021), 1217-1228.
[abstract]
Abstract:
Case-only (CO) studies are a powerful means to uncover gene-environment (G × E) interactions for complex human diseases. Moreover, such studies may in principle also draw upon genotype imputation to increase statistical power even further. However, genotype imputation usually employs healthy controls such as the Haplotype Reference Consortium (HRC) data as an imputation base, which may systematically perturb CO studies in genomic regions with main effects upon disease risk. Using genotype data from 719 German Crohn Disease (CD) patients, we investigated the level of imputation accuracy achievable for single nucleotide polymorphisms (SNPs) with or without a genetic main effect, and with varying minor allele frequency (MAF). Genotypes were imputed from neighbouring SNPs at different levels of linkage disequilibrium (LD) to the target SNP using the HRC data as an imputation base. Comparison of the true and imputed genotypes revealed lower imputation accuracy for SNPs with strong main effects. We also simulated different levels of G × E interaction to evaluate the potential loss of statistical validity and power incurred by the use of imputed genotypes. Simulations under the null hypothesis revealed that genotype imputation does not inflate the type I error rate of CO studies of G × E. However, the statistical power was found to be reduced by imputation, particularly for SNPs with low MAF, and a gradual loss of statistical power resulted when the level of LD to the SNPs driving the imputation decreased. Our study thus highlights that genotype imputation should be employed with great care in CO studies of G × E interaction.
Sobh M, Freitag-Wolf S, Scheewe J, Kanngiesser LM, Uebing AS, Gabbert DD, Voges I.
Serial right ventricular assessment in patients with hypoplastic left heart syndrome: a multiparametric cardiovascular magnetic resonance study.Eur J Cardiothorac Surg,
(2021).
[abstract]
Abstract:
Serial assessment of CMR studies in HLHS patients after total cavopulmonary connection completion demonstrate an increase in indexed RV volumes in older HLHS patients but only mild reduction in RVEF and LAS. The correlation of indexed RV volumes with RVEF and LAS together with the significant increase in RV volumes over time suggests that indexed RV volumes might be superior to RV functional markers to monitor the RV in HLHS patients.
Anselmo A, Frank D, Papa L, Viviani Anselmi C, Di Pasquale E, Mazzola M, Panico C, Clemente F, Soldani C, Pagiatakis C, Hinkel R, Thalmann R, Kozlik-Feldmann R, Miragoli M, Carullo P, Vacchiano M, Chaves-Sanjuan A, Santo N, Losi MA, Ferrari MC, Puca AA, Christiansen V, Seoudy H, Freitag-Wolf S, Frey N, Dempfle A, Mercola M, Esposito G, Briguori C, Kupatt C, Condorelli G.
Myocardial hypoxic stress mediates functional cardiac extracellular vesicle release.Eur Heart J,
42 (2021), 2780-2792.
[abstract]
Abstract:
We identified circulating CD172a+ EVs as cardiac derived, showing their release and function and providing evidence for their prognostic potential in aortic stenosis patients.
Schuwerk R, Freitag-Wolf S, Krupickova S, Gabbert DD, Uebing A, Langguth P, Voges I.
Ventricular and atrial function and deformation is largely preserved after arterial switch operation.Heart,
(2021).
[abstract]
Abstract:
Biventricular and biatrial function are largely preserved after ASO for TGA. Using a comprehensive CMR protocol along with statistical machine learning methods and a regression approach, only RV longitudinal function and LA function are significantly impaired.
Freitag-Wolf S, Munz M, Junge O, Graetz C, Jockel-Schneider Y, Staufenbiel I, Bruckmann C, Lieb W, Franke A, Loos BG, Jepsen S, Dommisch H, Schaefer AS.
Sex-specific genetic factors affect the risk of early-onset periodontitis in Europeans.J Clin Periodontol,
(2021).
[abstract]
Abstract:
Our results indicate that natural genetic variation affects the different heritability of periodontitis among sexes and suggest genes that contribute to inter-sex phenotypic variation in early-onset periodontitis.
Lutter G, Bax L, Liu Y, Hansen JH, Frank D, Freitag-Wolf S, Simionescu A, Sathananthan J, Puehler T.
Transcatheter mitral valve replacement: tissue in-growth after 4 weeks.Interact Cardiovasc Thorac Surg,
32 (2021), 1-8.
[abstract]
Abstract:
This is the first report demonstrating good in-growth of transcatheter-delivered anatomically shaped mitral valve stents after at least 4 weeks of follow-up. Histological examination demonstrated progressive healing and neointimalization.
Lischka A, Doberstein N, Freitag-Wolf S, Koçak A, Gemoll T, Heselmeyer-Haddad K, Ried T, Auer G, Habermann JK.
Genome Instability Profiles Predict Disease Outcome in a Cohort of 4,003 Patients with Breast Cancer.Clin Cancer Res,
26 (2020), 4606-4615.
[abstract]
Abstract:
Genome instability profiles predict disease outcome in patients with breast cancer independent of clinicopathologic parameters. This applies especially to premenopausal patients. In patients receiving adjuvant therapy, the profiles improve identification of high-risk patients.
Seoudy H, Lambers M, Winkler V, Dudlik L, Freitag-Wolf S, Frank J, Kuhn C, Rangrez AY, Puehler T, Lutter G, Bramlage P, Frey N, Frank D.
Elevated high-sensitivity troponin T levels at 1-year follow-up are associated with increased long-term mortality after TAVR.Clin Res Cardiol,
(2020).
[abstract]
Abstract:
Elevated hs-TnT concentrations at 1-year after TAVR were associated with a higher long-term mortality.
Becker M, Schmied F, Kadem LF, Freitag-Wolf S, Naujokat H, Mehl C, Kern M, Harder S.
Single-cell adhesion of human osteoblasts on plasma-conditioned titanium implant surfaces in vitro.J Mech Behav Biomed Mater,
109 (2020), 103841.
[abstract]
Abstract:
Conditioning of the titanium surfaces with APP or LPP was not a significant influencing factor in the initial adhesion of the osteoblasts.
Aleknonytė-Resch M, Freitag-Wolf S, , Schreiber S, Krawczak M, Dempfle A.
Case-only analysis of gene-gene interactions in inflammatory bowel disease.Scand J Gastroenterol,
55 (2020), 897-906.
[abstract]
Abstract:
We were able to exemplify the utility of the CO design for analyzing G × G, but had to recognize that such interactions are probably scarce for IBD.
Gorski M, Jung B, Li Y, Matias-Garcia PR, Wuttke M, Coassin S, Thio CHL, Kleber ME, Winkler TW, Wanner V, Chai JF, Chu AY, Cocca M, Feitosa MF, Ghasemi S, Hoppmann A, Horn K, Li M, Nutile T, Scholz M, Sieber KB, Teumer A, Tin A, Wang J, Tayo BO, Ahluwalia TS, Almgren P, Bakker SJL, Banas B, Bansal N, Biggs ML, Boerwinkle E, Bottinger EP, Brenner H, Carroll RJ, Chalmers J, Chee ML, Chee ML, Cheng CY, Coresh J, de Borst MH, Degenhardt F, Eckardt KU, Endlich K, Franke A, Freitag-Wolf S, Gampawar P, Gansevoort RT, Ghanbari M, Gieger C, Hamet P, Ho K, Hofer E, Holleczek B, Xian Foo VH, Hutri-Kähönen N, Hwang SJ, Ikram MA, Josyula NS, Kähönen M, Khor CC, Koenig W, Kramer H, Krämer BK, Kühnel B, Lange LA, Lehtimäki T, Lieb W, , , Loos RJF, Lukas MA, Lyytikäinen LP, Meisinger C, Meitinger T, Melander O, Milaneschi Y, Mishra PP, Mononen N, Mychaleckyj JC, Nadkarni GN, Nauck M, Nikus K, Ning B, Nolte IM, Orho-Melander M, Pendergrass SA, Penninx BWJH, Preuss MH, Psaty BM, Raffield LM, Raitakari OT, Rettig R, Rheinberger M, Rice KM, Rosenkranz AR, Rossing P, Rotter JI, Sabanayagam C, Schmidt H, Schmidt R, Schöttker B, Schulz CA, Sedaghat S, Shaffer CM, Strauch K, Szymczak S, Taylor KD, Tremblay J, Chaker L, van der Harst P, van der Most PJ, Verweij N, Völker U, Waldenberger M, Wallentin L, Waterworth DM, White HD, Wilson JG, Wong TY, Woodward M, Yang Q, Yasuda M, Yerges-Armstrong LM, Zhang Y, Snieder H, Wanner C, Böger CA, Köttgen A, Kronenberg F, Pattaro C, Heid IM.
Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline.Kidney Int,
(2020).
[abstract]
Abstract:
2 or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
Dai H, Lutter G, Frank D, Freitag-Wolf S, Topal A, Haneya A, Sathananthan J, Puehler T.
Transcatheter aortic valve resection: new mechanical devices.J Thorac Dis,
12 (2020), 6586-6597.
[abstract]
Abstract:
Transcatheter aortic valve resection is feasible with variable aortic leaflet resection times and mild risk of lesions of the surrounding tissue.
Koçak A, Heselmeyer-Haddad K, Lischka A, Hirsch D, Fiedler D, Hu Y, Doberstein N, Torres I, Chen WD, Gertz EM, Schäffer AA, Freitag-Wolf S, Kirfel J, Auer G, Habermann JK, Ried T.
High Levels of Chromosomal Copy Number Alterations and TP53 Mutations Correlate with Poor Outcome in Younger Breast Cancer Patients.Am J Pathol,
190 (2020), 1643-1656.
[abstract]
Abstract:
Prognosis in young patients with breast cancer is generally poor, yet considerable differences in clinical outcomes between individual patients exist. To understand the genetic basis of the disparate clinical courses, tumors were collected from 34 younger women, 17 with good and 17 with poor outcomes, as determined by disease-specific survival during a follow-up period of 17 years. The clinicopathologic parameters of the tumors were complemented with DNA image cytometry profiles, enumeration of copy numbers of eight breast cancer genes by multicolor fluorescence in situ hybridization, and targeted sequence analysis of 563 cancer genes. Both groups included diploid and aneuploid tumors. The degree of intratumor heterogeneity was significantly higher in aneuploid versus diploid cases, and so were gains of the oncogenes MYC and ZNF217. Significantly more copy number alterations were observed in the group with poor outcome. Almost all tumors in the group with long survival were classified as luminal A, whereas triple-negative tumors predominantly occurred in the short survival group. Mutations in PIK3CA were more common in the group with good outcome, whereas TP53 mutations were more frequent in patients with poor outcomes. This study shows that TP53 mutations and the extent of genomic imbalances are associated with poor outcome in younger breast cancer patients and thus emphasize the central role of genomic instability vis-a-vis tumor aggressiveness.
Pfeiffer D, Chen B, Schlicht K, Ginsbach P, Abboud S, Bersano A, Bevan S, Brandt T, Caso V, Debette S, Erhart P, Freitag-Wolf S, Giacalone G, Grau AJ, Hayani E, Jern C, Jiménez-Conde J, Kloss M, Krawczak M, Lee JM, Lemmens R, Leys D, Lichy C, Maguire JM, Martin JJ, Metso AJ, Metso TM, Mitchell BD, Pezzini A, Rosand J, Rost NS, Stenman M, Tatlisumak T, Thijs V, Touzé E, Traenka C, Werner I, Woo D, Del Zotto E, Engelter ST, Kittner SJ, Cole JW, Grond-Ginsbach C, Lyrer PA, Lindgren A, .
Genetic Imbalance Is Associated With Functional Outcome After Ischemic Stroke.Stroke,
50 (2019), 298-304.
[abstract]
Abstract:
Background and Purpose- We sought to explore the effect of genetic imbalance on functional outcome after ischemic stroke (IS). Methods- Copy number variation was identified in high-density single-nucleotide polymorphism microarray data of IS patients from the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) and SiGN (Stroke Genetics Network)/GISCOME (Genetics of Ischaemic Stroke Functional Outcome) networks. Genetic imbalance, defined as total number of protein-coding genes affected by copy number variations in an individual, was compared between patients with favorable (modified Rankin Scale score of 0-2) and unfavorable (modified Rankin Scale score of ≥3) outcome after 3 months. Subgroup analyses were confined to patients with imbalance affecting ohnologs-a class of dose-sensitive genes, or to those with imbalance not affecting ohnologs. The association of imbalance with outcome was analyzed by logistic regression analysis, adjusted for age, sex, stroke subtype, stroke severity, and ancestry. Results- The study sample comprised 816 CADISP patients (age 44.2±10.3 years) and 2498 SiGN/GISCOME patients (age 67.7±14.2 years). Outcome was unfavorable in 122 CADISP and 889 SiGN/GISCOME patients. Multivariate logistic regression analysis revealed that increased genetic imbalance was associated with less favorable outcome in both samples (CADISP: P=0.0007; odds ratio=0.89; 95% CI, 0.82-0.95 and SiGN/GISCOME: P=0.0036; odds ratio=0.94; 95% CI, 0.91-0.98). The association was independent of age, sex, stroke severity on admission, stroke subtype, and ancestry. On subgroup analysis, imbalance affecting ohnologs was associated with outcome (CADISP: odds ratio=0.88; 95% CI, 0.80-0.95 and SiGN/GISCOME: odds ratio=0.93; 95% CI, 0.89-0.98) whereas imbalance without ohnologs lacked such an association. Conclusions- Increased genetic imbalance was associated with poorer functional outcome after IS in both study populations. Subgroup analysis revealed that this association was driven by presence of ohnologs in the respective copy number variations, suggesting a causal role of the deleterious effects of genetic imbalance.
Renner J, Tesdorpf A, Freitag-Wolf S, Francksen H, Petzina R, Lutter G, Frey N, Frank D.
A retrospective study of conscious sedation versus general anaesthesia in patients scheduled for transfemoral aortic valve implantation: A single center experience.Health Sci Rep,
2 (2019), e95.
[abstract]
Abstract:
Our single-center data demonstrate that CS is a feasible and safe alternative, especially with respect to a higher degree of intra-procedural haemodynamic stability, and a reduced length of stay in the intensive care unit.
Friedrich C, Berndt R, Haneya A, Rusch R, Petzina R, Freitag-Wolf S, Cremer J, Hoffmann G.
Sex-specific outcome after minimally invasive direct coronary artery bypass for single-vessel disease.Interact Cardiovasc Thorac Surg,
(2019).
[abstract]
Abstract:
Female patients showed no adverse outcomes after MIDCAB, although risk factors were gender-specific. Overall, MIDCAB demonstrated excellent short- and long-term results as a treatment for single-vessel disease in both genders.
Abou-Ayash S, von Maltzahn N, Passia N, Freitag-Wolf S, Reissmann DR, Luthardt RG, Mundt T, Raedel M, Rammelsberg P, Wolfart S, Kern M.
Stabilizing mandibular complete dentures by a single midline implant-influence on quality of life: 2-year results from a randomized clinical trial comparing different loading protocols.Clin Oral Investig,
(2019).
[abstract]
Abstract:
A single midline implant in the edentulous mandible, stabilizing a mandibular complete denture, cannot be recommended for improving HRQoL.
Schlicht K, Nyczka P, Caliebe A, Freitag-Wolf S, Claringbould A, Franke L, Võsa U, , Kardia SLR, Smith JA, Zhao W, Gieger C, Peters A, Prokisch H, Strauch K, , Baurecht H, Weidinger S, Rosenstiel P, Hütt MT, Knecht C, Szymczak S, Krawczak M.
The metabolic network coherence of human transcriptomes is associated with genetic variation at the cadherin 18 locus.Hum Genet,
138 (2019), 375-388.
[abstract]
Abstract:
- 8). Cadherin 18 is a transmembrane protein involved in human neural development and cell-to-cell signaling. Notably, genetic variation at the CDH18 locus has been associated with metabolic syndrome-related traits before. Replication of our genome-wide significant GWAS result was successful in another population study from the Netherlands (BIOS, n = 2661; lead SNP), but failed in two additional studies (KORA, Germany, n = 711; GENOA, USA, n = 411). Besides sample size issues, we surmise that these discrepant findings may be attributable to technical differences. While 1000 Genomes/GEUVADIS and BIOS gene expression profiles were generated by RNA sequencing, the KORA and GENOA data were microarray-based. In addition to providing first evidence for a link between regional genetic variation and a metabolism-related characteristic of human transcriptomes, our findings highlight the benefit of adopting a systems biology-oriented approach to molecular data analysis.
Teumer A, Li Y, Ghasemi S, Prins BP, Wuttke M, Hermle T, Giri A, Sieber KB, Qiu C, Kirsten H, Tin A, Chu AY, Bansal N, Feitosa MF, Wang L, Chai JF, Cocca M, Fuchsberger C, Gorski M, Hoppmann A, Horn K, Li M, Marten J, Noce D, Nutile T, Sedaghat S, Sveinbjornsson G, Tayo BO, van der Most PJ, Xu Y, Yu Z, Gerstner L, Ärnlöv J, Bakker SJL, Baptista D, Biggs ML, Boerwinkle E, Brenner H, Burkhardt R, Carroll RJ, Chee ML, Chee ML, Chen M, Cheng CY, Cook JP, Coresh J, Corre T, Danesh J, de Borst MH, De Grandi A, de Mutsert R, de Vries APJ, Degenhardt F, Dittrich K, Divers J, Eckardt KU, Ehret G, Endlich K, Felix JF, Franco OH, Franke A, Freedman BI, Freitag-Wolf S, Gansevoort RT, Giedraitis V, Gögele M, Grundner-Culemann F, Gudbjartsson DF, Gudnason V, Hamet P, Harris TB, Hicks AA, Holm H, Foo VHX, Hwang SJ, Ikram MA, Ingelsson E, Jaddoe VWV, Jakobsdottir J, Josyula NS, Jung B, Kähönen M, Khor CC, Kiess W, Koenig W, Körner A, Kovacs P, Kramer H, Krämer BK, Kronenberg F, Lange LA, Langefeld CD, Lee JJ, Lehtimäki T, Lieb W, Lim SC, Lind L, Lindgren CM, Liu J, Loeffler M, Lyytikäinen LP, Mahajan A, Maranville JC, Mascalzoni D, McMullen B, Meisinger C, Meitinger T, Miliku K, Mook-Kanamori DO, Müller-Nurasyid M, Mychaleckyj JC, Nauck M, Nikus K, Ning B, Noordam R, Olafsson I, Palmer ND, Peters A, Podgornaia AI, Ponte B, Poulain T, Pramstaller PP, Rabelink TJ, Raffield LM, Reilly DF, Rettig R, Rheinberger M, Rice KM, Rivadeneira F, Runz H, Ryan KA, Sabanayagam C, Saum KU, Schöttker B, Shaffer CM, Shi Y, Smith AV, Strauch K, Stumvoll M, Sun BB, Szymczak S, Tai ES, Tan NYQ, Taylor KD, Teren A, Tham YC, Thiery J, Thio CHL, Thomsen H, Thorsteinsdottir U, Tönjes A, Tremblay J, Uitterlinden AG, van der Harst P, Verweij N, Vogelezang S, Völker U, Waldenberger M, Wang C, Wilson OD, Wong C, Wong TY, Yang Q, Yasuda M, Akilesh S, Bochud M, Böger CA, Devuyst O, Edwards TL, Ho K, Morris AP, Parsa A, Pendergrass SA, Psaty BM, Rotter JI, Stefansson K, Wilson JG, Susztak K, Snieder H, Heid IM, Scholz M, Butterworth AS, Hung AM, Pattaro C, Köttgen A.
Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria.Nat Commun,
10 (2019), 4130.
[abstract]
Abstract:
Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.
Wuttke M, Li Y, Li M, Sieber KB, Feitosa MF, Gorski M, Tin A, Wang L, Chu AY, Hoppmann A, Kirsten H, Giri A, Chai JF, Sveinbjornsson G, Tayo BO, Nutile T, Fuchsberger C, Marten J, Cocca M, Ghasemi S, Xu Y, Horn K, Noce D, van der Most PJ, Sedaghat S, Yu Z, Akiyama M, Afaq S, Ahluwalia TS, Almgren P, Amin N, Ärnlöv J, Bakker SJL, Bansal N, Baptista D, Bergmann S, Biggs ML, Biino G, Boehnke M, Boerwinkle E, Boissel M, Bottinger EP, Boutin TS, Brenner H, Brumat M, Burkhardt R, Butterworth AS, Campana E, Campbell A, Campbell H, Canouil M, Carroll RJ, Catamo E, Chambers JC, Chee ML, Chee ML, Chen X, Cheng CY, Cheng Y, Christensen K, Cifkova R, Ciullo M, Concas MP, Cook JP, Coresh J, Corre T, Sala CF, Cusi D, Danesh J, Daw EW, de Borst MH, De Grandi A, de Mutsert R, de Vries APJ, Degenhardt F, Delgado G, Demirkan A, Di Angelantonio E, Dittrich K, Divers J, Dorajoo R, Eckardt KU, Ehret G, Elliott P, Endlich K, Evans MK, Felix JF, Foo VHX, Franco OH, Franke A, Freedman BI, Freitag-Wolf S, Friedlander Y, Froguel P, Gansevoort RT, Gao H, Gasparini P, Gaziano JM, Giedraitis V, Gieger C, Girotto G, Giulianini F, Gögele M, Gordon SD, Gudbjartsson DF, Gudnason V, Haller T, Hamet P, Harris TB, Hartman CA, Hayward C, Hellwege JN, Heng CK, Hicks AA, Hofer E, Huang W, Hutri-Kähönen N, Hwang SJ, Ikram MA, Indridason OS, Ingelsson E, Ising M, Jaddoe VWV, Jakobsdottir J, Jonas JB, Joshi PK, Josyula NS, Jung B, Kähönen M, Kamatani Y, Kammerer CM, Kanai M, Kastarinen M, Kerr SM, Khor CC, Kiess W, Kleber ME, Koenig W, Kooner JS, Körner A, Kovacs P, Kraja AT, Krajcoviechova A, Kramer H, Krämer BK, Kronenberg F, Kubo M, Kühnel B, Kuokkanen M, Kuusisto J, La Bianca M, Laakso M, Lange LA, Langefeld CD, Lee JJ, Lehne B, Lehtimäki T, Lieb W, , Lim SC, Lind L, Lindgren CM, Liu J, Liu J, Loeffler M, Loos RJF, Lucae S, Lukas MA, Lyytikäinen LP, Mägi R, Magnusson PKE, Mahajan A, Martin NG, Martins J, März W, Mascalzoni D, Matsuda K, Meisinger C, Meitinger T, Melander O, Metspalu A, Mikaelsdottir EK, Milaneschi Y, Miliku K, Mishra PP, , Mohlke KL, Mononen N, Montgomery GW, Mook-Kanamori DO, Mychaleckyj JC, Nadkarni GN, Nalls MA, Nauck M, Nikus K, Ning B, Nolte IM, Noordam R, Olafsson I, Oldehinkel AJ, Orho-Melander M, Ouwehand WH, Padmanabhan S, Palmer ND, Palsson R, Penninx BWJH, Perls T, Perola M, Pirastu M, Pirastu N, Pistis G, Podgornaia AI, Polasek O, Ponte B, Porteous DJ, Poulain T, Pramstaller PP, Preuss MH, Prins BP, Province MA, Rabelink TJ, Raffield LM, Raitakari OT, Reilly DF, Rettig R, Rheinberger M, Rice KM, Ridker PM, Rivadeneira F, Rizzi F, Roberts DJ, Robino A, Rossing P, Rudan I, Rueedi R, Ruggiero D, Ryan KA, Saba Y, Sabanayagam C, Salomaa V, Salvi E, Saum KU, Schmidt H, Schmidt R, Schöttker B, Schulz CA, Schupf N, Shaffer CM, Shi Y, Smith AV, Smith BH, Soranzo N, Spracklen CN, Strauch K, Stringham HM, Stumvoll M, Svensson PO, Szymczak S, Tai ES, Tajuddin SM, Tan NYQ, Taylor KD, Teren A, Tham YC, Thiery J, Thio CHL, Thomsen H, Thorleifsson G, Toniolo D, Tönjes A, Tremblay J, Tzoulaki I, Uitterlinden AG, Vaccargiu S, van Dam RM, van der Harst P, van Duijn CM, Velez Edward DR, Verweij N, Vogelezang S, Völker U, Vollenweider P, Waeber G, Waldenberger M, Wallentin L, Wang YX, Wang C, Waterworth DM, Bin Wei W, White H, Whitfield JB, Wild SH, Wilson JF, Wojczynski MK, Wong C, Wong TY, Xu L, Yang Q, Yasuda M, Yerges-Armstrong LM, Zhang W, Zonderman AB, Rotter JI, Bochud M, Psaty BM, Vitart V, Wilson JG, Dehghan A, Parsa A, Chasman DI, Ho K, Morris AP, Devuyst O, Akilesh S, Pendergrass SA, Sim X, Böger CA, Okada Y, Edwards TL, Snieder H, Stefansson K, Hung AM, Heid IM, Scholz M, Teumer A, Köttgen A, Pattaro C.
A catalog of genetic loci associated with kidney function from analyses of a million individuals.Nat Genet,
51 (2019), 957-972.
[abstract]
Abstract:
Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
Gierthmühlen J, Schneider U, Seemann M, Freitag-Wolf S, Maihöfner C, Enax-Krumova EK, Azad SC, Üçeyler N, Birklein F, Maier C, Tölle T, Treede RD, Baron R.
Can self-reported pain characteristics and bedside test be used for the assessment of pain mechanisms? An analysis of results of neuropathic pain questionnaires and quantitative sensory testing.Pain,
(2019).
[abstract]
Abstract:
Hyperalgesia and allodynia are frequent in neuropathic pain. Some pain questionnaires like the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) and the Neuropathic Pain Scale (NPS) include self-assessment or bedside-testing of hyperalgesia/allodynia. The aim of this study was to determine to what extent LANSS and NPS data are congruent with findings upon quantitative Sensory Testing (QST).Self-reported presence of dynamic mechanical allodynia (DMA) and descriptors of hot, cold or deep ongoing pain (NPS, LANSS) as well as bedside findings of mechanical allodynia (LANSS) were compared to signs of DMA and thermal hyperalgesia upon QST in 617 neuropathic pain patients.Self-reported abnormal skin sensitivity (LANSS) showed a moderate concordance with DMA during bedside test (67.9%, k=0.391) or QST (52.8%, k=0.165). Receiver operating curve analysis for self-reported DMA yielded similar area-under-the-curve values for LANSS (0.65, CI: 0.59-0.97%) and NPS (0.71, CI: 0.66-0.75%) with high sensitivity but low specificity. Self-reported deep pain intensity was higher in patients with blunt pressure hyperalgesia, but not in patients with DMA or thermal hyperalgesia. No correlations were observed between self-reported hot or cold pain quality and thermal hyperalgesia upon QST.Self-reported abnormal skin sensitivity has a high sensitivity to identify patients with DMA, but its low specificity indicates that many patients mean something other than DMA when reporting this symptom. Self-reported deep pain is related to deep-tissue hypersensitivity, but thermal qualities of ongoing pain are not related to thermal hyperalgesia. Questionnaires mostly evaluate the ongoing pain experience while QST mirrors sensory functions. Therefore, both methods are complementary for pain assessment.
Freitag-Wolf S, Munz M, Wiehe R, Junge O, Graetz C, Jockel-Schneider Y, Staufenbiel I, Bruckmann C, Lieb W, Franke A, Loos BG, Jepsen S, Dommisch H, Schaefer AS.
Smoking Modifies the Genetic Risk for Early-Onset Periodontitis.J Dent Res,
(2019), 22034519875443.
[abstract]
Abstract:
P = 0.0048). We conclude that the genetic predisposition to early-onset periodontitis is in part triggered by smoking and that tobacco smoke directly affects the expression of genes involved in bone homeostasis, tissue repair, and immune response.
Seoudy H, Frank J, Neu M, Güßefeld N, Klaus Y, Freitag-Wolf S, Lambers M, Lutter G, Dempfle A, Rangrez AY, Kuhn C, Frey N, Frank D.
Periprocedural Changes of NT-proBNP Are Associated With Survival After Transcatheter Aortic Valve Implantation.J Am Heart Assoc,
8 (2019), e010876.
[abstract]
Abstract:
2, P<0.001), and higher mean pressure gradient (41 versus 35 mm Hg, P<0.001). Median follow-up was 22.6 months. Kaplan-Meier analysis showed a highly significant survival benefit for the responder group compared with the nonresponder group (log-rank test, P<0.001). Conclusions A ratio based on periprocedural changes of NT-proBNP is a simple tool for better risk stratification and is associated with survival in patients after transcatheter aortic valve implantation.
Puehler T, Freitag-Wolf S, Friedrich C, Salem M, Renner J, Cremer J, Haneya A.
Outcomes of Patients after Implantation of the Pericardial All-Biological Valve No-React Aortic Conduit (BioIntegral) for Root Replacement in Complex Surgical Procedures.Thorac Cardiovasc Surg,
(2019).
[abstract]
Abstract:
Aortic root replacement for complex pathologies is associated with substantial 30-day mortality, but survival of patients after discharge from hospital was stable. Early functional status of the BioIntegral valve was good. Though freedom from re-operation was low, long-term outcome and long-term functional status have to be further evaluated.
Schlicht K, Nyczka P, Caliebe A, Freitag-Wolf S, Claringbould A, Franke L, Võsa U, , Kardia SLR, Smith JA, Zhao W, Gieger C, Peters A, Prokisch H, Strauch K, , Baurecht H, Weidinger S, Rosenstiel P, Hütt MT, Knecht C, Szymczak S, Krawczak M.
The metabolic network coherence of human transcriptomes is associated with genetic variation at the cadherin 18 locus.Hum Genet,
138 (2019), 375-388.
[abstract]
Abstract:
- 8). Cadherin 18 is a transmembrane protein involved in human neural development and cell-to-cell signaling. Notably, genetic variation at the CDH18 locus has been associated with metabolic syndrome-related traits before. Replication of our genome-wide significant GWAS result was successful in another population study from the Netherlands (BIOS, n = 2661; lead SNP), but failed in two additional studies (KORA, Germany, n = 711; GENOA, USA, n = 411). Besides sample size issues, we surmise that these discrepant findings may be attributable to technical differences. While 1000 Genomes/GEUVADIS and BIOS gene expression profiles were generated by RNA sequencing, the KORA and GENOA data were microarray-based. In addition to providing first evidence for a link between regional genetic variation and a metabolism-related characteristic of human transcriptomes, our findings highlight the benefit of adopting a systems biology-oriented approach to molecular data analysis.
Harder S, Egert C, Freitag-Wolf S, Mehl C, Kern M.
Intraosseous Temperature Changes During Implant Site Preparation: In Vitro Comparison of Thermocouples and Infrared Thermography.Int J Oral Maxillofac Implants,
33 (2018 Jan/Feb), 72-78.
[abstract]
Abstract:
These results suggest that thermography more accurately reflects intraosseous temperature changes during implant site preparation than thermocouples.
Seoudy H, Güßefeld N, Frank J, Freitag-Wolf S, Lutter G, Eden M, Rangrez AY, Kuhn C, Frey N, Frank D.
Incidence and impact of prosthesis-patient mismatch following transcatheter aortic valve implantation.Clin Res Cardiol,
(2018).
[abstract]
Abstract:
The incidence of PPM after TAVI seems to be substantially lower than after SAVR. PPM was less common using self-expandable valves. In our analysis, patients with PPM following TAVI did not have higher rates of all-cause mortality.
Schwindling FS, Raedel M, Passia N, Freitag-Wolf S, Wolfart S, Att W, Mundt T, Reissmann D, Ismail F, von Königsmark V, Kern M.
The single mandibular implant study - Short-term effects of the loading protocol on Oral Health-related Quality of Life.J Prosthodont Res,
62 (2018), 313-316.
[abstract]
Abstract:
The single mandibular implant concept was associated with a positive impact on quality of life. However, no statistically significant influence of implant loading on quality of life was found.
Jagodin S, Sasse M, Freitag-Wolf S, Kern M.
Influence of attachment design and material on the retention of resin-bonded attachments.Clin Oral Investig,
(2018).
[abstract]
Abstract:
Clinical data on the long-term potential of zirconia RBAs is required before these restorations can be recommended for general use.
Jussli-Melchers J, Hilbert C, Jahnke I, Wehkamp K, Rogge A, Freitag-Wolf S, Kahla-Witzsch HA, Scholz J, Petzina R.
[Maturity Levels of Quality and Risk Management at the University Hospital Schleswig-Holstein].Gesundheitswesen,
80 (2018), 648-655.
[abstract]
Abstract:
Durch das strukturierte Analysetool sind sowohl die Gesamtreifegrade des QRM-Systems an 46 Kliniken des UKSH als auch detailliert die Reifegrade 4 wesentlicher Qualitätskriterien (QS, CIRS, BM, PM) erhoben worden. In der Konsequenz wurde ein umfangreiches Maßnahmenpaket zur Verbesserung des QRM-Systems eingeleitet. Zukünftig werden die Reifegrade im 2 Jahresrhythmus re-evaluiert. Dieses qualitative Reifegradmodell ermöglicht auf einfache und effiziente Weise, präzise Aussagen bezüglich des Vorhandenseins, der Ausprägung und der Weiterentwicklung des Qualitäts- und Risikomanagements zu generieren.
Schupp JC, Freitag-Wolf S, Bargagli E, Mihailović-Vučinić V, Rottoli P, Grubanovic A, Müller A, Jochens A, Tittmann L, Schnerch J, Olivieri C, Fischer A, Jovanovic D, Filipovic S, Videnovic-Ivanovic J, Bresser P, Jonkers R, Ho LP, Gaede KI, Zabel P, Dubaniewicz A, Marshall B, Kieszko R, Milanowski J, Günther A, Weihrich A, Petrek M, Kolek V, Keane MP, Donnelly S, Haraldsdottir SO, Jorundsdottir KB, Costabel U, Bonella F, Wallaert B, Grah C, Peroš-Golubičić T, Luisetti M, Kadija Z, Pabst S, Grohé C, Strausz J, Vašáková M, Sterclova M, Millar A, Homolka J, Slováková A, Kendrick Y, Crawshaw A, Wuyts W, Spencer L, Pfeifer M, Valeyre D, Poletti V, Wirtz H, Prasse A, Schreiber S, Krawczak M, Müller-Quernheim J.
Phenotypes of organ involvement in sarcoidosis.Eur Respir J,
51 (2018).
[abstract]
Abstract:
Sarcoidosis is a highly variable, systemic granulomatous disease of hitherto unknown aetiology. The GenPhenReSa (Genotype-Phenotype Relationship in Sarcoidosis) project represents a European multicentre study to investigate the influence of genotype on disease phenotypes in sarcoidosis.The baseline phenotype module of GenPhenReSa comprised 2163 Caucasian patients with sarcoidosis who were phenotyped at 31 study centres according to a standardised protocol.From this module, we found that patients with acute onset were mainly female, young and of Scadding type I or II. Female patients showed a significantly higher frequency of eye and skin involvement, and complained more of fatigue. Based on multidimensional correspondence analysis and subsequent cluster analysis, patients could be clearly stratified into five distinct, yet undescribed, subgroups according to predominant organ involvement: 1) abdominal organ involvement, 2) ocular-cardiac-cutaneous-central nervous system disease involvement, 3) musculoskeletal-cutaneous involvement, 4) pulmonary and intrathoracic lymph node involvement, and 5) extrapulmonary involvement.These five new clinical phenotypes will be useful to recruit homogenous cohorts in future biomedical studies.
Schulte DM, Paulsen K, Türk K, Brandt B, Freitag-Wolf S, Hagen I, Zeuner R, Schröder JO, Lieb W, Franke A, Nikolaus S, Mrowietz U, Gerdes S, Schreiber S, Laudes M.
Small dense LDL cholesterol in human subjects with different chronic inflammatory diseases.Nutr Metab Cardiovasc Dis,
28 (2018), 1100-1105.
[abstract]
Abstract:
Registration at German Clinical Trial Register (DRKS): DRKS00005285.
Yadav P, Ellinghaus D, Rémy G, Freitag-Wolf S, Cesaro A, Degenhardt F, Boucher G, Delacre M, , Peyrin-Biroulet L, Pichavant M, Rioux JD, Gosset P, Franke A, Schumm LP, Krawczak M, Chamaillard M, Dempfle A, Andersen V.
Genetic Factors Interact With Tobacco Smoke to Modify Risk for Inflammatory Bowel Disease in Humans and Mice.Gastroenterology,
153 (2017), 550-565.
[abstract]
Abstract:
In an analysis of 55 Immunochip-wide datasets, we identified 64 SNPs whose association with risk for IBD is modified by tobacco smoking. Gene-smoking interactions were confirmed in mice with disruption of Il10 and Nod2-variants of these genes have been associated with risk for IBD. Our findings from mice and humans revealed that the effects of smoking on risk for IBD depend on genetic variants.
Strohkamp S, Gemoll T, Humborg S, Hartwig S, Lehr S, Freitag-Wolf S, Becker S, Franzén B, Pries R, Wollenberg B, Roblick UJ, Bruch HP, Keck T, Auer G, Habermann JK.
Protein levels of clusterin and glutathione synthetase in platelets allow for early detection of colorectal cancer.Cell Mol Life Sci,
(2017).
[abstract]
Abstract:
Colorectal cancer (CRC) is one of the most frequent malignancies in the Western world. Early tumor detection and intervention are important determinants on CRC patient survival. During early tumor proliferation, dissemination and angiogenesis, platelets store and segregate proteins actively and selectively. Hence, the platelet proteome is a potential source of biomarkers denoting early malignancy. By comparing protein profiles of platelets between healthy volunteers (n = 12) and patients with early- (n = 7) and late-stage (n = 5) CRCs using multiplex fluorescence two-dimensional gel electrophoresis (2D-DIGE), we aimed at identifying differentially regulated proteins within platelets. By inter-group comparisons, 94 differentially expressed protein spots were detected (p < 0.05) between healthy controls and patients with early- and late-stage CRCs and revealed distinct separations between all three groups in principal component analyses. 54 proteins of interest were identified by mass spectrometry and resulted in high-ranked Ingenuity Pathway Analysis networks associated with Cellular function and maintenance, Cellular assembly and organization, Developmental disorder and Organismal injury and abnormalities (p < 0.0001 to p = 0.0495). Target proteins were validated by multiplex fluorescence-based Western blot analyses using an additional, independent cohort of platelet protein samples [healthy controls (n = 15), early-stage CRCs (n = 15), late-stage CRCs (n = 15)]. Two proteins-clusterin and glutathione synthetase (GSH-S)-featured high impact and were subsequently validated in this independent clinical cohort distinguishing healthy controls from patients with early- and late-stage CRCs. Thus, the potential of clusterin and GSH-S as platelet biomarkers for early detection of CRC could improve existing screening modalities in clinical application and should be confirmed in a prospective multicenter trial.
Feldkamp T, Luedemann M, Spehlmann ME, Freitag-Wolf S, Gaensbacher J, Schulte K, Bajrovic A, Hinzmann D, Hippe HJ, Kunzendorf U, Frey N, Luedde M.
Radial access protects from contrast media induced nephropathy after cardiac catheterization procedures.Clin Res Cardiol,
(2017).
[abstract]
Abstract:
Our study shows that cardiac catheterization using radial access bears significantly lower risk of AKI than cardiac catheterization via femoral access. The advantage of radial access in acute coronary syndrome regarding morbidity and mortality could partly be explained by the here demonstrated reduced risk for AKI. Thus, radial access should be preferred in patients at risk for AKI.
Grothusen C, Friedrich C, Loehr J, Meinert J, Ohnewald E, Ulbricht U, Attmann T, Haneya A, Huenges K, Freitag-Wolf S, Schoettler J, Cremer J.
Outcome of Stable Patients With Acute Myocardial Infarction and Coronary Artery Bypass Surgery Within 48 Hours: A Single-Center, Retrospective Experience.J Am Heart Assoc,
6 (2017).
[abstract]
Abstract:
Stable STEMI patients showed a lower rate of perioperative complications and better survival compared with non-STEMI patients when CABG was performed within 48 hours.
Chitadze G, Flüh C, Quabius ES, Freitag-Wolf S, Peters C, Lettau M, Bhat J, Wesch D, Oberg HH, Luecke S, Janssen O, Synowitz M, Held-Feindt J, Kabelitz D.
In-depth immunophenotyping of patients with glioblastoma multiforme: Impact of steroid treatment.Oncoimmunology,
6 (2017), e1358839.
[abstract]
Abstract:
Despite aggressive treatment regimens based on surgery and radiochemotherapy, the prognosis of patients with grade IV glioblastoma multiforme (GBM) remains extremely poor, calling for alternative options such as immunotherapy. Immunological mechanisms including the Natural Killer Group 2 member D (NKG2D) receptor-ligand system play an important role in tumor immune surveillance and targeting the NKG2D system might be beneficial. However, before considering any kind of immunotherapy, a precise characterization of the immune system is important, particularly in GBM patients where conventional therapies with impact on the immune system are frequently co-administered. Here we performed an in-depth immunophenotyping of GBM patients and age-matched healthy controls and analyzed NKG2D ligand expression on primary GBM cells ex vivo. We report that GBM patients have a compromised innate immune system irrespective of steroid (dexamethasone) medication. However, dexamethasone drastically reduced the number of immune cells in the blood of GBM patients. Moreover, higher counts of immune cells influenced by dexamethasone like CD45+ lymphocytes and non-Vδ2 γδ T cells were associated with better overall survival. Higher levels of NKG2D ligands on primary GBM tumor cells were observed in patients who received radiochemotherapy, pointing towards increased immunogenic potential of GBM cells following standard radiochemotherapy. This study sheds light on how steroids and radiochemotherapy affect immune cell parameters of GBM patients, a pre-requisite for the development of new therapeutic strategies targeting the immune system in these patients.
Passia N, Att W, Freitag-Wolf S, Heydecke G, von Königsmark V, Freifrau von Maltzahn N, Mundt T, Rädel M, Schwindling FS, Wolfart S, Kern M.
Single mandibular implant study - denture satisfaction in the elderly.J Oral Rehabil,
44 (2017), 213-219.
[abstract]
Abstract:
To investigate whether there are differences in patients' denture satisfaction when an implant placed in the midline of the edentulous mandible is loaded either immediately or three months later, after second-stage surgery. One hundred and fifty-eight edentulous patients received a single implant in the midline of the mandible. After randomisation, it was loaded either immediately after implant placement (N = 81, group A) or three months later, after a submerged healing phase and a second-stage surgery (N = 77, group B). Patients' denture satisfaction aspects were assessed, using visual analogue scales (VAS), before treatment, one month after implant placement during the submerged healing phase (only group B) and one and four months after implant loading. The statistical analysis was performed using the Wilcoxon signed-rank and rank-sum tests. One month after loading, a significant improvement in comfort, function and stability of the mandibular denture could be observed in both groups (P ≤ 0·05). A slight but not significant improvement was found between one and four months after loading. Patients with second-stage surgery and delayed loading rated the stability and fit of the mandibular denture as significantly better than patients who had immediate loading. A single implant in the edentulous mandible significantly increased patients' denture satisfaction. After four months, stability and fit of the mandibular denture were considered better when a delayed loading protocol had been followed. A single mandibular implant in the edentulous mandible significantly increases patients' denture satisfaction, regardless of the loading protocol.
Koch M, Freitag-Wolf S, Schlesinger S, Borggrefe J, Hov JR, Jensen MK, Pick J, Markus MRP, Höpfner T, Jacobs G, Siegert S, Artati A, Kastenmüller G, Römisch-Margl W, Adamski J, Illig T, Nothnagel M, Karlsen TH, Schreiber S, Franke A, Krawczak M, Nöthlings U, Lieb W.
Serum metabolomic profiling highlights pathways associated with liver fat content in a general population sample.Eur J Clin Nutr,
71 (2017), 995-1001.
[abstract]
Abstract:
A serum metabolomic profile was associated with FLD and liver fat content. We identified a simplified metabolomics score, which should be evaluated in prospective studies.
Fangmann D, Theismann EM, Türk K, Schulte DM, Relling I, Hartmann K, Keppler JK, Knipp JR, Rehman A, Heinsen FA, Franke A, Lenk L, Freitag-Wolf S, Appel E, Gorb S, Brenner C, Seegert D, Waetzig GH, Rosenstiel P, Schreiber S, Schwarz K, Laudes M.
Targeted Microbiome Intervention by Microencapsulated Delayed-Release Niacin Beneficially Affects Insulin Sensitivity in Humans.Diabetes Care,
(2017).
[abstract]
Abstract:
Targeted microbiome intervention by delayed-release NA might represent a future therapeutic option for prediabetes and type 2 diabetes.
Kreutzer C, Peters S, Schulte DM, Fangmann D, Türk K, Wolff S, van Eimeren T, Ahrens M, Beckmann J, Schafmayer C, Becker T, Kerby T, Rohr A, Riedel C, Heinsen FA, Degenhardt F, Franke A, Rosenstiel P, Zubek N, Henning C, Freitag-Wolf S, Dempfle A, Psilopanagioti A, Petrou-Papadaki H, Lenk L, Jansen O, Schreiber S, Laudes M.
Hypothalamic Inflammation in Human Obesity Is Mediated by Environmental and Genetic Factors.Diabetes,
66 (2017), 2407-2415.
[abstract]
Abstract:
Obesity is associated with hypothalamic inflammation (HI) in animal models. In the current study, we examined the mediobasal hypothalamus (MBH) of 57 obese human subjects and 54 age- and sex- matched nonobese control subjects by MRI and analyzed the T2 hyperintensity as a measure of HI. Obese subjects exhibited T2 hyperintensity in the left but not the right MBH, which was strongly associated with systemic low-grade inflammation. MRS revealed the number of neurons in the left hypothalamic region to be similar in obese versus control subjects, suggesting functional but not structural impairment due to the inflammatory process. To gain mechanistic insights, we performed nutritional analysis and 16S rDNA microbiome sequencing, which showed that high-fat diet induces reduction of Parasutterella sp. in the gut, which is significantly correlated with MBH T2 hyperintensity. In addition to these environmental factors, we found subjects carrying common polymorphisms in the JNK or the MC4R gene to be more susceptible to HI. Finally, in a subgroup analysis, bariatric surgery had no effect on MBH T2 hyperintensity despite inducing significant weight loss and improvement of peripheral insulin sensitivity. In conclusion, obesity in humans is associated with HI and disturbances in the gut-brain axis, which are influenced by both environmental and genetic factors.
Stundl A, Lünstedt NS, Courtz F, Freitag-Wolf S, Frey N, Holdenrieder S, Zur B, Grube E, Nickenig G, Werner N, Frank D, Sinning JM.
Soluble ST2 for Risk Stratification and the Prediction of Mortality in Patients Undergoing Transcatheter Aortic Valve Implantation.Am J Cardiol,
120 (2017), 986-993.
[abstract]
Abstract:
This study aimed to assess the prognostic value of soluble ST2 (sST2) for risk stratification in patients undergoing transcatheter aortic valve implantation (TAVI). In 461 patients undergoing TAVI, sST2 was determined at baseline and categorized into quartiles. An optimum cutoff of 29 ng/ml was calculated. Primary end point was 1-year all-cause mortality. Results were validated in an independent cohort. Patients with sST2 >29 ng/ml had an increased 30-day (9.7% vs 4.6%, p = 0.043) and 1-year mortality (38.1% vs 21.8%, p = 0.001). In accordance, patients with N-terminal pro-brain natriuretic peptide (NT-proBNP) >8145 pg/ml revealed a comparable 30-day mortality (7.9% vs 4.7%, p = 0.189) and 1-year mortality (39.5% vs 21.0%, p <0.001). In univariate regression analysis, sST2 and NT-proBNP were associated with increased mortality risk. In multivariate regression analysis, independent predictors of mortality were logistic EuroSCORE, chronic renal failure, left ventricular ejection fraction, and sST2. In receiver operating characteristic curve analysis, sST2 did not provide incremental prognostic information beyond that obtained from surgical risk scores such as the STS-PROM or NT-proBNP. Similar findings could be achieved in an independent validation cohort. In conclusion, sST2 is independently associated with adverse outcome after TAVI but was not superior to NT-proBNP or surgical risk scores for the prediction of postprocedural outcomes.
Brasch J, Freitag-Wolf S, Beck-Jendroschek V, Huber M.
Inhibition of dermatophytes by photodynamic treatment with curcumin.Med Mycol,
(2017).
[abstract]
Abstract:
Treatment of dermatophytoses with currently available antimycotic agents is often tedious and sometimes unsatisfactory. A search for better therapeutic methods-ideally with an immediate fungicidal effect-has, among others, lead to photodynamic procedures as a promising alternative, and recently curcumin was found to be a suitable agent for this application. In this study the effect of photodynamic treatment with curcumin on dermatophytes was tested in vitro Wells of microtiter plates were filled with conidia of Trichophyton rubrum, Trichophyton interdigitale, Trichophyton terrestre, Microsporum canis, Microsporum gypseum and Epidermophyton floccosum in buffer. Then curcumin was added to the conidia and after 20 min the assays were irradiated one time only with visible light (peak wave length 367 nm, 5 J/cm(2)). Thereafter the wells were filled up with Sabouraud's glucose broth and in the following fungal growth was measured photometrically. The results showed that all dermatophytes were markedly inhibited depending on the concentration of curcumin. With 5.4 mg/l curcumin plus irradiation fungal growth was significantly suppressed over a period of 96 h (P < .001). Even after 96 h inhibition of T. rubrum was still complete and marked for all other species as well. M. gypseum was least susceptible. Our results are very encouraging to pursue the development of a photodynamic therapy of tinea with curcumin. The outstanding tolerance of curcumin and the innocuousness of the required light are favorable preconditions for this task.
Lutz M, von Ingersleben N, Lambers M, Rosenberg M, Freitag-Wolf S, Dempfle A, Lutter G, Frank J, Bramlage P, Frey N, Frank D.
Osteopontin predicts clinical outcome in patients after treatment of severe aortic stenosis with transcatheter aortic valve implantation (TAVI).Open Heart,
4 (2017), e000633.
[abstract]
Abstract:
OPN levels at baseline are associated with adverse outcomes in patients with severe, symptomatic AS undergoing TAVI.
Petzina R, Lutter G, Wolf C, Kühl C, Freitag-Wolf S, Panholzer B, Bramlage P, Frey N, Cremer J, Frank D.
Transaortic transcatheter aortic valve implantation: experience from the Kiel study.Interact Cardiovasc Thorac Surg,
(2016).
[abstract]
Abstract:
The efficacy and safety of the Edwards SAPIEN-XT or SAPIEN-3 heart valves via TAo access were demonstrated by high procedural success and low complication rates. The data indicate that this approach is a viable alternative to established access routes.
Genrich G, Kruppa M, Lenk L, Helm O, Broich A, Freitag-Wolf S, Röcken C, Sipos B, Schäfer H, Sebens S.
The anti-oxidative transcription factor Nuclear factor E2 related factor-2 (Nrf2) counteracts TGF-β1 mediated growth inhibition of pancreatic ductal epithelial cells -Nrf2 as determinant of pro-tumorigenic functions of TGF-β1.BMC Cancer,
16 (2016), 155.
[abstract]
Abstract:
Overall, our data demonstrate that Nrf2 being elevated in early precursor lesions counteracts the growth inhibiting function of TGF-β1 already in benign and premalignant pancreatic ductal epithelial cells. This could represent one fundamental mechanism underlying the functional switch of both- TGF-β1 and Nrf2 - which may manifest already in early stages of PDAC development.
Mundt T, Passia N, Att W, Heydecke G, Freitag-Wolf S, Luthardt RG, Kappel S, Konstantinidis IK, Stiesch M, Wolfart S, Kern M.
Pain and discomfort following immediate and delayed loading by overdentures in the single mandibular implant study (SMIS).Clin Oral Investig,
(2016).
[abstract]
Abstract:
Immediate loading of a single mandibular midline implant supporting overdentures should be carefully considered.
Libecki W, Elsayed A, Freitag-Wolf S, Kern M.
Reducing the effect of polymerization shrinkage of temporary fixed dental prostheses by using different materials and fabrication techniques.Dent Mater,
(2016).
[abstract]
Abstract:
Relining of directly fabricated temporary FDPs significantly reduces the effect of polymerization shrinkage and thus secures the position of the prepared teeth.
Meyer R, Freitag-Wolf S, Blindow S, Büning J, Habermann JK.
Combining aneuploidy and dysplasia for colitis' cancer risk assessment outperforms current surveillance efficiency: a meta-analysis.Int J Colorectal Dis,
(2016).
[abstract]
Abstract:
This meta-analysis reveals that aneuploidy is an equally effective parameter for individual cancer risk assessment in ulcerative colitis as the detection of dysplasia. More important, the combined assessment of dysplasia and aneuploidy outperforms the use of each parameter alone. We suggest image cytometry for ploidy assessment to become an additional feature of consensus criteria to individually assess cancer risk in UC.
Köhler WM, Freitag-Wolf S, Lambers M, Lutz M, Niemann PM, Petzina R, Lutter G, Bramlage P, Frey N, Frank D.
Preprocedural but not periprocedural high-sensitive Troponin T (hsTNT) levels predict outcome in patients undergoing transcatheter aortic valve implantation (TAVI).Cardiovasc Ther,
(2016).
[abstract]
Abstract:
Elevated preprocedural hsTNT represents an independent risk predictor of all-cause death while periprocedural hsTNT elevation failed to show prognostic relevance. This article is protected by copyright. All rights reserved.
Oberg HH, Grage-Griebenow E, Adam-Klages S, Jerg E, Peipp M, Kellner C, Petrick D, Gonnermann D, Freitag-Wolf S, Röcken C, Sebens T, Vogel I, Becker T, Ebsen M, Kabelitz D, Wesch D, Sebens S.
Monitoring and functional characterization of the lymphocytic compartment in pancreatic ductal adenocarcinoma patients.Pancreatology,
(2016).
[abstract]
Abstract:
Monitoring immune cells along with the determination of their functional capacity provides a comprehensive assessment as a prerequisite for a personalized immunotherapeutic PDAC treatment.
Steinebrunner L, Harder S, Wolfart S, Freitag-Wolf S, Kern M.
The Precision of Mechanical Torque Wrenches Used for Implants in Dental Offices.Int J Prosthodont,
28 (2015 Sep-Oct), 527-30.
[abstract]
Abstract:
Average deviation from intended torque values, and levels of imprecision, are evidently not major problems in implant prosthetics; however, high torque values are a cause for concern.
Mueller N, Schulte DM, Tuerk K, Freitag-Wolf S, Hampe J, Zeuner R, Schroeder JO, Gouni-Berthold I, Berthold HK, Krone W, Rose-John S, Schreiber S, Laudes M.
IL-6 blockade by monoclonal antibodies inhibits apolipoprotein(a) expression and lipoprotein(a) synthesis in humans.J Lipid Res,
(2015).
[abstract]
Abstract:
Lipoprotein(a) [Lp(a)] is a highly atherogenic lipid particle. While earlier reports suggested Lp(a) levels mostly being determined by genetic factors, several recent studies revealed Lp(a) induction also to be caused by chronic inflammation. Therefore, we aimed to examine whether cytokine blockade by monoclonal antibodies may inhibit Lp(a) metabolism. We found that IL-6 blockade by tocilizumab (TCZ) reduced Lp(a) while TNF-α-inhibition by adalimumab in humans had no effect. The specificity of IL-6 in regulating Lp(a) was further demonstrated by serological measurements of n=1153 human subjects revealing that Lp(a) levels are increased in individuals with elevated serum IL-6. Transcriptomic analysis of n=57 human liver biopsies revealed typical IL-6 response genes being correlated with the LPA gene expression in vivo. On a molecular level, we found that TCZ inhibited IL-6-induced LPA mRNA and protein expression in human hepatocytes. Furthermore, examination of IL-6-responsive STAT3-binding sites within the LPA promoter by reporter gene assays, promoter deletion experiments and EMSA analysis showed that the Lp(a) lowering effect of TCZ is specifically mediated via a responsive element at -46 to -40. Therefore, IL-6 blockade might be a potential therapeutic option to treat elevated Lp(a) serum concentrations in humans and therefore might be a non-invasive alternative to lipid apheresis in the future.
Yadav P, Freitag-Wolf S, Lieb W, Dempfle A, Krawczak M.
Allowing for population stratification in case-only studies of gene-environment interaction, using genomic control.Hum Genet,
134 (2015), 1117-25.
[abstract]
Abstract:
Gene-environment interactions (G × E) have attracted considerable research interest in the past owing to their scientific and public health implications, but powerful statistical methods are required to successfully track down G × E, particularly at a genome-wide level. Previously, a case-only (CO) design has been proposed as a means to identify G × E with greater efficiency than traditional case-control or cohort studies. However, as with genotype-phenotype association studies themselves, hidden population stratification (PS) can impact the validity of G × E studies using a CO design. Since this problem has been subject to little research to date, we used comprehensive simulation to systematically assess the type I error rate, power and effect size bias of CO studies of G × E in the presence of PS. Three types of PS were considered, namely genetic-only (PSG), environment-only (PSE), and joint genetic and environmental stratification (PSGE). Our results reveal that the type I error rate of an unadjusted Wald test, appropriate for the CO design, would be close to its nominal level (0.05 in our study) as long as PS involves only one interaction partner (i.e., either PSG or PSE). In contrast, if the study population is stratified with respect to both G and E (i.e., if there is PSGE), then the type I error rate is seriously inflated and estimates of the underlying G × E interaction are biased. Comparison of CO to a family-based case-parents design confirmed that the latter is more robust against PSGE, as expected. However, case-parent trios may be particularly unsuitable for G × E studies in view of the fact that they require genotype data from parents and that many diseases with an environmental component are likely to be of late onset. An alternative approach to adjusting for PS is principal component analysis (PCA), which has been widely used for this very purpose in past genome-wide association studies (GWAS). However, resolving genetic PS properly by PCA requires genetic data at the population level, the availability of which would conflict with the basic idea of the CO design. Therefore, we explored three modified Wald test statistics, inspired by the genomic control (GC) approach to GWAS, as an alternative means to allow for PSGE. The modified statistics were benchmarked against a stratified Wald test assuming known population affiliation, which should provide maximum power under PS. Our results confirm that GC is capable of successfully and efficiently correcting the PS-induced inflation of the type I error rate in CO studies of G × E.
Krau NC, Lünstedt NS, Freitag-Wolf S, Brehm D, Petzina R, Lutter G, Bramlage P, Dempfle A, Frey N, Frank D.
Elevated growth differentiation factor 15 levels predict outcome in patients undergoing transcatheter aortic valve implantation.Eur J Heart Fail,
17 (2015), 945-55.
[abstract]
Abstract:
Elevated GDF15 levels were superior to NT-proBNP for TAVI risk stratification and provided additional prognostic information. Thus, patient selection for TAVI may benefit from measurement of GDF15.
Krause-Titz UR, Warneke N, Freitag-Wolf S, Barth H, Mehdorn HM.
Factors influencing the outcome (GOS) in reconstructive cranioplasty.Neurosurg Rev,
(2015).
[abstract]
Abstract:
After performing a decompressive craniectomy, a cranioplastic surgery is usually warranted. The complications of this reconstructive procedure may differ from the initial operation. The authors of this study report on their experience to define patient-specific and procedural risk factors for possible complications following cranioplasty influencing the outcome (Glasgow Outcome Scale (GOS)), mobility, shunt dependency, and seizures. A retrospective analysis of 263 patients of all ages and both sexes who had undergone cranioplasty after craniectomy for traumatic brain injury (including chronic subdural hematoma), subarachnoidal hemorrhage (including intracerebral hemorrhage), ischemic stroke, and tumor surgery in one single center in 12 years from January 2000 to March 2012 has been carried out. A multiple logistic regression analysis was performed to identify potential risk factors (age, gender, used cranioplasty material, initial diagnosis, clipped or coil-embolized subarachnoidal hemorrhage (SAH) patients, time interval, complications especially hydrocephalus and seizures, mobility) upon the prognosis described as a dichotomized Glasgow Outcome Scale. Two hundred forty-eight patients met the study criteria. The overall complication rate after cranioplastic surgery was 18.5 % (46 patients). Complications included: surgical site infection, epidural hematoma, hydrocephalus with or without former SAH, and new-onset seizures. Logistic regression analysis identified significant correlation between a low GOS (2 or 3) and postoperative seizures (OR 2.37, CI 1.35-4.18, p < 0.05), shunt-depending hydrocephalus (OR 5.83, CI 3.06-11.11, p < 0.05), and age between 51 and 70 years (OR 2.4, 95 % CI 1.09-5.29, p = 0.029). However, gender, time interval between craniectomy and cranioplasty, initial diagnosis, and used cranioplasty material had no significant influence on post-cranioplasty complications as surgical site infections, hematoma, wound healing disturbance, seizures, or hydrocephalus. Evaluation of treatment modality in aneurysmal SAH clip vs. coil showed no significant relation to postoperative complications either. Complications after cranioplastic surgery are a common problem, as prognostic factors could identify a shunt-depending hydrocephalus and epilepsia to develop a major deficit after cranioplastic surgery (GOS 2 or 3). We detected a significant extra risk of people between the age of 51 and 70 years to end up in GOS level 2 or 3.
Passia N, Lehmann F, Freitag-Wolf S, Kern M.
Tensile bond strength of different universal adhesive systems to lithium disilicate ceramic.J Am Dent Assoc,
146 (2015), 729-34.
[abstract]
Abstract:
Universal adhesive systems that do not contain a silane should be avoided for bonding lithium disilicate ceramic restorations because of their inferior bond strength.
Grassmann F, Friedrich U, Fauser S, Schick T, Milenkovic A, Schulz HL, von Strachwitz CN, Bettecken T, Lichtner P, Meitinger T, Arend N, Wolf A, Haritoglou C, Rudolph G, Chakravarthy U, Silvestri G, McKay GJ, Freitag-Wolf S, Krawczak M, Smith RT, Merriam JC, Merriam JE, Allikmets R, Heid IM, Weber BH.
A Candidate Gene Association Study Identifies DAPL1 as a Female-Specific Susceptibility Locus for Age-Related Macular Degeneration (AMD).Neuromolecular Med,
(2015).
[abstract]
Abstract:
Age-related macular degeneration (AMD) is the leading cause of blindness among white caucasians over the age of 50 years with a prevalence rate expected to increase markedly with an anticipated increase in the life span of the world population. To further expand our knowledge of the genetic architecture of the disease, we pursued a candidate gene approach assessing 25 genes and a total of 109 variants. Of these, synonymous single nucleotide polymorphism (SNP) rs17810398 located in death-associated protein-like 1 (DAPL1) was found to be associated with AMD in a joint analysis of 3,229 cases and 2,835 controls from five studies [combined P ADJ = 1.15 × 10(-6), OR 1.332 (1.187-1.496)]. This association was characterized by a highly significant sex difference (P diff = 0.0032) in that it was clearly confined to females with genome-wide significance [P ADJ = 2.62 × 10(-8), OR 1.541 (1.324-1.796); males: P ADJ = 0.382, OR 1.084 (0.905-1.298)]. By targeted resequencing of risk and non-risk associated haplotypes in the DAPL1 locus, we identified additional potentially functional risk variants, namely a common 897-bp deletion and a SNP predicted to affect a putative binding site of an exonic splicing enhancer. We show that the risk haplotype correlates with a reduced retinal transcript level of two, less frequent, non-canonical DAPL1 isoforms. DAPL1 plays a role in epithelial differentiation and may be involved in apoptotic processes thereby suggesting a possible novel pathway in AMD pathogenesis.
Goebel L, Grage-Griebenow E, Gorys A, Helm O, Genrich G, Lenk L, Wesch D, Ungefroren H, Freitag-Wolf S, Sipos B, Röcken C, Schäfer H, Sebens S.
CD4(+) T cells potently induce epithelial-mesenchymal-transition in premalignant and malignant pancreatic ductal epithelial cells-novel implications of CD4(+) T cells in pancreatic cancer development.Oncoimmunology,
4 (2015), e1000083.
[abstract]
Abstract:
Chronic pancreatitis (CP) is a risk factor of pancreatic ductal adenocarcinoma (PDAC) and characterized by a pronounced desmoplastic reaction with CD4(+) T cells accounting for the majority of the stromal T cell infiltrate. Epithelial-mesenchymal-transition (EMT) is a critical process for metastasis by which epithelial/carcinoma cells become enabled to disseminate probably prior to tumor formation. To investigate whether CD4(+) T cells induce EMT in human pancreatic ductal epithelial cells, premalignant H6c7 cells were mono- or co-cultured with human CD4(+)CD25(+)CD127(-)CD49d(-) regulatory T cells (T-regs) or CD4(+)CD25(-) T-effector cells (T-effs) being isolated by negative magnetic bead separation from blood of healthy donors. Particularly in the presence of activated T-effs, H6c7 cells acquired a spindle-shaped morphology, reduced E-cadherin expression, and elevated expression of the mesenchymal proteins vimentin, L1CAM, and ZEB-1. This was accompanied by an increased invasive behavior. Moreover, activated T-effs exerted similar effects in the PDAC cell line T3M4. Blocking of TNF-α and IL-6 being released at greater amounts into supernatants during co-cultures with activated T-effs attenuated the EMT-associated alterations in H6c7 cells. Supporting these findings, EMT-associated alterations (exemplified by reduced E-cadherin expression and enhanced expression of vimentin and L1CAM) were predominantly detected in ductal epithelium of CP tissues surrounded by a dense stroma enriched with CD4(+) T cells. Overall this study points to a novel role of CD4(+) T cells beyond their immune function in pancreatic tumorigenesis and underscores the view that EMT induction in pancreatic ductal epithelial cells represents an early event in PDAC development being essentially promoted by inflammatory processes.
Laubert T, Freitag-Wolf S, Linnebacher M, König A, Vollmar B, Habermann JK, .
Stage-specific frequency and prognostic significance of aneuploidy in patients with sporadic colorectal cancer-a meta-analysis and current overview.Int J Colorectal Dis,
30 (2015), 1015-28.
[abstract]
Abstract:
A substantial number of studies showed a prognostic importance of aneuploidy in CRC. Furthermore, the higher frequency of aneuploidy in late-stage CRC implies an increase in genomic instability with CRC progression, indicating aneuploidy to be also a stage-specific prognostic marker.
Yadav P, Freitag-Wolf S, Lieb W, Krawczak M.
The role of linkage disequilibrium in case-only studies of gene-environment interactions.Hum Genet,
134 (2015), 89-96.
[abstract]
Abstract:
Gene-environment (G × E) interactions have been invoked to account, at least in part, for the gap between the known heritability of common human diseases and the phenotypic variation hitherto explained by genetic variants. Noteworthy in this context, a case-only (CO) design has been proposed in the past as a means to detect G × E interactions possibly more efficiently than by using classical case-control and cohort designs. So far, however, most CO studies have followed a candidate (or single) gene approach, and the genome-wide utility of the CO design is still more or less unknown. In particular, the way in which linkage disequilibrium (LD) impacts upon the chance to detect G × E interaction through the analysis of proxy markers has not been studied in much detail before. Therefore, we systematically assessed the power to indirectly detect a given G × E interaction through exploiting LD in a CO design. Our simulations revealed a strong relationship between LD and detection power that was subsequently validated in a real colorectal cancer data set.
Madjidyar J, Hermes J, Freitag-Wolf S, Jansen O.
Stent-thrombus interaction and the influence of aspiration on mechanical thrombectomy: evaluation of different stent retrievers in a circulation model.Neuroradiology,
57 (2015), 791-7.
[abstract]
Abstract:
Distal aspiration with intermediate catheters increases the efficacy of mechanical thrombectomy with stent retrievers significantly. In contrary to earlier suggestions, the interaction between the thrombus and the stent retriever is only superficial, rather than an integration of the thrombus into the retriever. No significant differences between the proven devices could be shown in our model.
Schelp V, Freitag-Wolf S, Hinzmann D, Bramlage P, Frey N, Frank D.
Large-scale experience with an anchorless vascular closure device in a real-life clinical setting.Clin Res Cardiol,
(2014).
[abstract]
Abstract:
These results indicate that Exoseal was safe in a broad collective of patients. However, lengthy procedures, PCIs, the use of GP IIb/IIIa inhibitors, and elderly patients require special attention.
Freitag-Wolf S, Dommisch H, Graetz C, Jockel-Schneider Y, Harks I, Staufenbiel I, Meyle J, Eickholz P, Noack B, Bruckmann C, Gieger C, Jepsen S, Lieb W, Schreiber S, König IR, Schaefer AS.
Genome-wide exploration identifies sex-specific genetic effects of alleles upstream NPY to increase the risk of severe periodontitis in men.J Clin Periodontol,
(2014).
[abstract]
Abstract:
The current study is the first to observe a sexually dimorphic role of alleles at NPY in humans and support previous genome-wide findings of a role of NPY in severe PD. This article is protected by copyright. All rights reserved.
Fuhrmann G, Steiner M, Freitag-Wolf S, Kern M.
Resin bonding to three types of polyaryletherketones (PAEKs)-Durability and influence of surface conditioning.Dent Mater,
(2014).
[abstract]
Abstract:
The conditioning method has a significant influence to the bond strength of the bonding to the amorphous and crystalline PEKKs and fiber-reinforced PEEKs.
Grage-Griebenow E, Jerg E, Gorys A, Wicklein D, Wesch D, Freitag-Wolf S, Goebel L, Vogel I, Becker T, Ebsen M, Röcken C, Altevogt P, Schumacher U, Schäfer H, Sebens S.
L1CAM promotes enrichment of immunosuppressive T cells in human pancreatic cancer correlating with malignant progression.Mol Oncol,
(2014).
[abstract]
Abstract:
Regulatory T cell (T-reg) enrichment in the tumor microenvironment is regarded as an important mechanism of tumor immune escape. Hence, the presence of T-regs in highly malignant pancreatic ductal adenocarcinoma (PDAC) is correlated with short survival. Likewise, the adhesion molecule L1CAM is upregulated during PDAC progression in the pancreatic ductal epithelium also being associated with poor prognosis. To investigate whether L1CAM contributes to enrichment of T-regs in PDAC, human CD4(+)CD25(+)CD127(-)CD49d(-) T-regs and CD4(+)CD25(-) T-effector cells (T-effs) were isolated by magnetic bead separation from blood of healthy donors. Their phenotype and functional behavior were analyzed in dependence on human premalignant (H6c7) or malignant (Panc1) pancreatic ductal epithelial cells, either exhibiting or lacking L1CAM expression. T cells derived from blood and tumors of PDAC patients were analyzed by flow cytometry and findings were correlated with clinical parameters. Predominantly T-regs but not T-effs showed an increased migration on L1CAM expressing H6c7 and Panc1 cells. Whereas proliferation of T-regs did not change in the presence of L1CAM, T-effs proliferated less, exhibited a decreased CD25 expression and an increased expression of CD69. Moreover, these T-effs exhibited a regulatory phenotype as they inhibited proliferation of autologous T cells. Accordingly, CD4(+)CD25(-)CD69(+) T cells were highly abundant in PDAC tissues compared to blood being associated with nodal invasion and higher grading in PDAC patients. Overall, these data point to an important role of L1CAM in the enrichment of immunosuppressive T cells in particular of a CD4(+)CD25(-)CD69(+)-phenotype in PDAC providing a novel mechanism of tumor immune escape which contributes to tumor progression.
Helm O, Mennrich R, Petrick D, Goebel L, Freitag-Wolf S, Röder C, Kalthoff H, Röcken C, Sipos B, Kabelitz D, Schäfer H, Oberg HH, Wesch D, Sebens S.
Comparative characterization of stroma cells and ductal epithelium in chronic pancreatitis and pancreatic ductal adenocarcinoma.PLoS One,
9 (2014), e94357.
[abstract]
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive stroma being also present in chronic pancreatitis (CP). Using immunohistochemistry, the stroma of CP and PDAC was comprehensively analyzed and correlated with epithelial/carcinoma-related alterations and clinicopathological patient characteristics. While there were no significant differences between CP and PDAC regarding the distribution of CD3+ T cells and α-SMA+ fibroblasts, proportions of CD4+ and CD8+ T cells were significantly lower and numbers of CD25+(CD4+) and FoxP3+(CD4+) regulatory T cells were greater in PDAC compared with CP. Macrophages were more prevalent in CP, but localized more closely to carcinoma cells in PDAC, as were γδ-T cells. Duct-related FoxP3 and L1CAM expression increased from CP to PDAC, while vimentin expression was similarly abundant in both diseases. Moreover, stromal and epithelial compartments of well-differentiated tumors and CPs shared considerable similarities, while moderately and poorly differentiated tumors significantly differed from CP tissues. Analysis of 27 parameters within each pancreatic disease revealed a significant correlation of i) CD4+ and FoxP3+CD4+ T cells with FoxP3 expression in PDAC cells, ii) α-SMA+ fibroblasts with L1CAM expression and proliferation in PDAC cells, iii) CD3 and CD8 expression with γδ-TCR expression in both pancreatic diseases and iv) CD68+ and CD163+ macrophages with vimentin expression in PDAC cells. High expression of FoxP3, vimentin and L1CAM in PDAC cells as well as a tumor-related localization of macrophages each tended to correlate with higher tumor grade. Multivariate survival analysis revealed a younger age at time of surgery as a positive prognostic marker for PDAC patients with the most frequently operated disease stage T3N1M0. Overall this study identified several interrelationships between stroma and epithelial/carcinoma cells in PDACs but also in CP, which in light of previous experimental data strongly support the view that the inflammatory stroma contributes to malignancy-associated alterations already in precursor cells during CP.
Oberg HH, Peipp M, Kellner C, Sebens S, Krause S, Petrick D, Adam-Klages S, Röcken C, Becker T, Vogel I, Weisner D, Freitag-Wolf S, Gramatzki M, Kabelitz D, Wesch D.
Novel bispecific antibodies increase γδ T-cell cytotoxicity against pancreatic cancer cells.Cancer Res,
(2014).
[abstract]
Abstract:
The ability of human γδ T-cells from healthy donors to kill pancreatic ductal adenocarcinoma (PDAC) in vitro and in vivo in immunocompromised mice requires the addition of γδ T-cell-stimulating antigens. In this study, we demonstrate that γδ T-cells isolated from patients with PDAC tumor infiltrates lyse pancreatic tumor cells after selective stimulation with phosphorylated antigens. We determined the absolute numbers of γδ T-cell subsets in patient whole blood, and applied a Real-Time Cell Analyzer to measure their cytotoxic effector function over prolonged time periods. Since phosphorylated antigens did not optimally enhance γδ T-cell cytotoxicity, we designed bispecific antibodies that bind CD3 or Vγ9 on γδ T-cells and Her2/neu (ERBB2) expressed by pancreatic tumor cells. Both antibodies enhanced γδ T-cell cytotoxicity with the Her2/Vγ9 antibody also selectively enhancing release of granzyme B and perforin. Supporting these observations, adoptive transfer of γδ T-cells with the Her2/Vγ9 antibody reduced growth of pancreatic tumors grafted into SCID-Beige immunocompromised mice. Taken together, our results show how bispecific antibodies that selectively recruit γδ T-cells to tumor antigens expressed by cancer cells illustrate the tractable use of endogenous γδ T-cells for immunotherapy.
Müller N, Döring F, Klapper M, Neumann K, Schulte DM, Türk K, Schröder JO, Zeuner RA, Freitag-Wolf S, Schreiber S, Laudes M.
Interleukin-6 and Tumour Necrosis Factor-α differentially regulate lincRNA transcripts in cells of the innate immune system in vivo in human subjects with rheumatoid arthritis.Cytokine,
(2014).
[abstract]
Abstract:
lincRNAs recently have been discovered as evolutionary conserved transcripts of non-coding DNA sequences and have been implicated in the regulation of cellular differentiation. In humans, molecular studies have suggested a functional role for lincRNAs in cancer development. The aim of the present study was to examine whether these novel molecules are specifically regulated by different cytokines in cells of the innate immune system in humans in vivo and whether lincRNAs thereby might be involved in the pathophysiology of rheumatoid arthritis (RA). Therefore, CD14(+) monocytes were isolated from RA patients before and after anti-IL-6R (tocilizumab) or anti-TNF-α (adalimumab) therapy and lincRNA transcription was analysed by a microarray based experiment. As expected, we found lincRNAs to be present in CD14(+) monocytes of RA patients. However, of the total number of 7.419 lincRNAs examined in this study only a very small number was significantly regulated by either IL-6 or TNF-α (85 lincRNAs, corresponding to 1.1%). The numbers of lincRNAs regulated was higher due to TNF-α compared to IL-6. Interestingly, none of the identified lincRNAs was influenced by both, IL-6 and TNF-α, suggesting the regulation of lincRNA transcription to be highly specific for distinct cytokines. Taken together, our results suggest (1) that lincRNAs are novel intracellular molecular effectors of specific cytokines in cells of the innate immune system in humans in vivo and (2) that lincRNAs might be involved in the molecular pathophysiology of RA.
Schneider BJ, Freitag-Wolf S, Kern M.
Tactile sensitivity of vital and endodontically treated teeth.J Dent,
(2014).
[abstract]
Abstract:
The tactile sensitivity of vital and non vital teeth seems comparable. Clinical significance: The assumption that a lower threshold level for tactile sensitivity in ETT than in vital teeth is responsible for their increased fracture risk could not be confirmed. Therefore other reasons, e.g. loss of hard tissue due to root canal treatment, have to be considered responsible for the increased fracture risk of ETT.
Müller N, Schulte DM, Hillebrand S, Türk K, Hampe J, Schafmayer C, Brosch M, von Schönfels W, Ahrens M, Zeuner R, Schröder JO, Blüher M, Gutschow C, Freitag-Wolf S, Stelmach-Mardas M, Saggau C, Schreiber S, Laudes M.
B Lymphocyte Stimulator (BLyS) Is Expressed in Human Adipocytes In Vivo and Is Related to Obesity but Not to Insulin Resistance.PLoS One,
9 (2014), e94282.
[abstract]
Abstract:
Inflammation and metabolism have been shown to be evolutionary linked and increasing evidence exists that pro-inflammatory factors are involved in the pathogenesis of obesity and type 2 diabetes. Until now, most data suggest that within adipose tissue these factors are secreted by cells of the innate immune system, e. g. macrophages. In the present study we demonstrate that B lymphocyte stimulator (BLyS) is increased in human obesity. In contrast to several pro-inflammatory factors, we found the source of BLyS in human adipose tissue to be the adipocytes rather than immune cells. In grade 3 obese human subjects, expression of BLyS in vivo in adipose tissue is significantly increased (p<0.001). Furthermore, BLyS serum levels are elevated in grade 3 human obesity (862.5+222.0 pg/ml vs. 543.7+60.7 pg/ml in lean controls, p<0.001) and are positively correlated to the BMI (r = 0.43, p<0.0002). In the present study, bariatric surgery significantly altered serum BLyS concentrations. In contrast, weight loss due to a very-low-calorie-formula-diet (800 kcal/d) had no such effect. To examine metabolic activity of BLyS, in a translational research approach, insulin sensitivity was measured in human subjects in vivo before and after treatment with the human recombinant anti-BLyS antibody belimumab. Since BLyS is known to promote B-cell proliferation and immunoglobulin secretion, the present data suggest that adipocytes of grade 3 obese human subjects are able to activate the adaptive immune system, suggesting that in metabolic inflammation in humans both, innate and adaptive immunity, are of pathophysiological relevance.
Poetsch M, Blöhm R, Harder M, Inoue H, von Wurmb-Schwark N, Freitag-Wolf S.
Prediction of people's origin from degraded DNA--presentation of SNP assays and calculation of probability.Int J Legal Med,
127 (2013), 347-57.
[abstract]
Abstract:
The characterization of externally visible traits by DNA analysis is already an important tool when investigating ancient skeletal remains and may gain similar importance in future forensic DNA analysis. This, however, depends on the different legal regulations in the different countries. Besides eye or hair color, the population origin can provide crucial information in criminal prosecution. In this study, we present the analysis of 16 single-nucleotide polymorphisms (SNPs) combined to two robust SNaPshot assays with a detection threshold of 25-pg DNA. This assay was applied to 891 people from seven different populations (West Africa, North Africa, Turkey, Near East, Balkan states, North Europe, and Japan) with a thorough statistical evaluation. The prediction model was validated by an additional 125 individuals predominantly with an ancestry from those same regions. The specificity of these SNPs for the prediction of all population origins is very high (>90 %), but the sensitivity varied greatly (more than 90 % for West Africa, but only 25 % for the Near East). We could identify West Africans with a certainty of 100 %, and people from North Africa, the Balkan states, or North Europe nearly with the same reliability while determination of Turks or people from the Near East was rather difficult. In conclusion, the two SNaPshot assays are a powerful and reliable tool for the identification of people with an ancestry in one of the above listed populations, even from degraded DNA.
Laubert T, Bente V, Freitag-Wolf S, Voulgaris H, Oberländer M, Schillo K, Kleemann M, Bürk C, Bruch HP, Roblick UJ, Habermann JK.
Aneuploidy and elevated CEA indicate an increased risk for metachronous metastasis in colorectal cancer.Int J Colorectal Dis,
(2013).
[abstract]
Abstract:
PURPOSE: Presently, no markers exist to predict metachronous metastasis at the time a primary colorectal cancer is diagnosed. While aneuploidy indicates poor survival prognosis and elevated carcinoembryonic antigen (CEA) levels the presence of recurrent disease, the predictive value of both markers regarding imminent metachronous metastases is unclear. METHODS: Sixty patients with distant recurrence throughout a 5-year follow-up (TM+) were randomly chosen and 60 patients without metastasis matched to this cohort (TM-). In addition, an enlarged collective (n = 217; n (TM+) = 85, n (TM-) = 132) with median follow-up of 79.2 months was assessed by logistic regression regarding metachronous metastases. Univariate and stepwise regression analyses included clinicopathological characteristics, preoperative CEA levels and aneuploidy assessed by DNA image cytometry. RESULTS: The matched-pair collective showed aneuploidy in 71.1 % (TM-) and 85.0 % (TM+; p = 0.076), and elevated CEA in 24.5 % (TM-) and 52.2 % [TM+; odds ratio (OR), 3.414; p = 0.007]. The enlarged collective presented aneuploidy in 71.2 % (TM-) and 83.5 % (TM+; OR 2.050, p = 0.038), and elevated CEA in 28.6 % (TM-) and 48.9 % (TM+; OR 2.391, p = 0.020). Elevated CEA and aneuploidy did not show any association (p = 0.919). In contrast, logistic regression analyses demonstrated that besides increased T category (OR 1.745, p = 0.019), both elevated CEA level (OR 2.633, p = 0.015) and aneuploidy (OR 1.929, p = 0.058) were independent predictive markers for metachronous metastasis. CONCLUSIONS: Our data show that aneuploidy and elevated CEA levels besides increased T category could serve for individual risk assessment to predict metachronous metastases. The fact that still aneuploidy missed the significance level by a small margin emphasizes the need for larger validation studies.
Frank D, Stark S, Lutz M, Weissbrodt A, Freitag-Wolf S, Petzina R, Rosenberg M, Lutter G, Frey N.
Preprocedural high-sensitive troponin predicts survival after transcatheter aortic valve implantation (TAVI).Int J Cardiol,
(2013).
Zick G, Elke G, Becher T, Schädler D, Pulletz S, Freitag-Wolf S, Weiler N, Frerichs I.
Effect of PEEP and tidal volume on ventilation distribution and end-expiratory lung volume: a prospective experimental animal and pilot clinical study.PLoS One,
8 (2013), e72675.
[abstract]
Abstract:
Tidal recruitment and end-inspiratory overinflation can be assessed by EIT-based analysis of regional C(RS).
Grothusen C, Attmann T, Friedrich C, Freitag-Wolf S, Haake N, Cremer J, Schöttler J.
Predictors for long-term outcome and quality of life of patients after cardiac surgery with prolonged intensive care unit stay.Interv Med Appl Sci,
5 (2013), 3-9.
[abstract]
Abstract:
Pre-operative AF proved to be the most important factor determining the 5-year outcome of patients with a prolonged ICU stay after cardiac surgery. Neither physical nor mental health appeared to be impaired in these patients.
Poetsch M, Wiegand A, Harder M, Blöhm R, Rakotomavo N, Freitag-Wolf S, von Wurmb-Schwark N.
Determination of population origin: a comparison of autosomal SNPs, Y-chromosomal and mtDNA haplogroups using a Malagasy population as example.Eur J Hum Genet,
(2013).
[abstract]
Abstract:
Y-chromosomal and mitochondrial DNA (mtDNA) polymorphisms have been used for population studies for a long time. However, there is another possibility to define the origin of a population: autosomal single-nucleotide polymorphisms (SNPs) whose allele frequencies differ considerably in different populations. In an attempt to compare the usefulness of these approaches we studied a population from Madagascar using all the three mentioned approaches. Former investigations of Malagasy maternal (mtDNA) and paternal (Y chromosome) lineages have led to the assumption that the Malagasy are an admixed population with an African and Asian-Indonesian heritage. Our additional study demonstrated that more than two-third of the Malagasy investigated showed clearly a West African genotype regarding only the autosomal SNPs despite the fact that 64% had an Asian mtDNA and more than 70% demonstrated an Asian-Indonesian heritage in either mtDNA or Y-chromosomal haplogroup or both. Nonetheless, the admixture of the Malagasy could be confirmed. A clear African or Asian-Indonesian heritage according to all the three DNA approaches investigated was only found in 14% and 1% of male samples, respectively. Not even the European or Northern African influences, detected in 9% of males (Y-chromosomal analysis) and 11% of samples (autosomal SNPs) were consistent. No Malagasy in our samples showed a European or Northern African origin in both categories. So, the analysis of autosomal SNPs could confirm the admixed character of the Malagasy population, even if it pointed to a greater African influence as detectable by Y-chromosomal or mtDNA analysis.European Journal of Human Genetics advance online publication, 24 April 2013; doi:10.1038/ejhg.2013.51.
El Bahra S, Ludwig K, Samran A, Freitag-Wolf S, Kern M.
Linear and volumetric dimensional changes of injection-molded PMMA denture base resins.Dent Mater,
29 (2013), 1091-7.
[abstract]
Abstract:
Denture base resins (IvoBase Hybrid and IvoBase Hi Impact) processed by the new injection-molding system (IvoBase), revealed superior dimensional precision.
Meyer KF, Nause SL, Freitag-Wolf S, Krüger S, Bruch HP, Roblick UJ, Habermann JK.
Aneuploidy characterizes adjacent non-malignant mucosa of ulcerative colitis-associated but not sporadic colorectal carcinomas: a matched-pair analysis.Scand J Gastroenterol,
(2013).
[abstract]
Abstract:
Abstract Introduction. Aneuploidy has been suggested as independent prognostic marker in ulcerative colitis (UC) patients for developing UC-associated colorectal carcinomas (UCCs). UCCs are associated with a poorer prognosis and more frequently present with synchronous carcinomas when compared with sporadic colorectal carcinomas (SCCs). The authors therefore investigated if the adjacent non-malignant mucosa of aneuploid UCCs and aneuploid SCCs shows differences regarding the frequency of aneuploidy and if this aneuploidy is associated with histomorphological alterations. Methods. Primary tumors of 25 UCCs and 20 SCCs were selected showing exclusively aneuploid DNA patterns and matching DNA stemlines. The UCCs' (n = 82) and SCCs' (n = 40) adjacent non-malignant mucosa were evaluated for histopathology and assessed for DNA ploidy status by image cytometry. Results. UCCs' non-malignant mucosa showed dysplasia in 31.7% and aneuploidy in 89%. In contrast, SCCs' non-malignant mucosa revealed no dysplasia and aneuploidy in only 5%. Irrespective of dysplastic lesions, aneuploidy was observed more frequently in adjacent non-malignant mucosa of UCCs than of SCCs (p < 0.001). Neither a correlation between aneuploidy and inflammation (p = 0.916) nor between aneuploidy and dysplastic lesions (p = 0.159) could be observed. Conclusion. Aneuploidy is more frequent in adjacent non-malignant mucosa of aneuploid UCCs than in adjacent non-malignant mucosa of aneuploid SCCs. Furthermore, aneuploidy seems to be irrespective of inflammation or dysplasia. The results therefore emphasize the importance of aneuploidy for UC-associated carcinogenesis and its potential as new diagnostic target.
Wulff AM, Fabel M, Freitag-Wolf S, Tepper M, Knabe HM, Schäfer JP, Jansen O, Bolte H.
Volumetric response classification in metastatic solid tumors on MSCT: Initial results in a whole-body setting.Eur J Radiol,
(2013).
[abstract]
Abstract:
Under standard RECIST thresholds there was no advantage of volumetric compared to manual response evaluation. However volumetric assessment yielded significantly lower interobserver variability. This may allow narrower thresholds for volumetric response classification in the future.
Rubin D, Helwig U, Pfeuffer M, Auinger A, Ruether A, Matusch D, Darabaneanu S, Freitag-Wolf S, Nothnagel M, Schreiber S, Schrezenmeir J.
The effect of FABP2 promoter haplotype on response to a diet with medium-chain triacylglycerols.Genes Nutr,
(2012).
[abstract]
Abstract:
The fatty-acid-binding protein-2 (FABP2) gene has been proposed as a candidate gene for diabetes because the encoded protein is involved in fatty acid absorption and therefore may affect insulin sensitivity and glucose metabolism. The rare haplotype (B) of its promoter was shown to be associated with a lower risk for type 2 diabetes. The aim of this study was to investigate whether a polymorphism in the FABP2 promoter does affect the metabolic response to either an medium-chain triacylglycerol (MCT) or an long-chain triacylglycerol (LCT) diet, which were suggested to differ in transport mechanisms, in affinity to FABP2, in activating transcription factors binding to the FABP2 promoter and in their effects on insulin sensitivity. We studied 82 healthy male subjects varying in the FABP2 promoter (42 homozygous for common haplotype (A), 40 homozygous for the rare haplotype (B)) in an interventional study with either an MCT or LCT diet over 2 weeks to examine gene-nutrient interaction. The saturation grade of MCT was adjusted to that of the LCT fat. We determined glucose, insulin, triacylglycerols (TGs), chylomicron triacylglycerols and cholesterol before and after a standardised mixed meal before and after the intervention. HDL cholesterol increased in all groups, which was most pronounced in subjects homozygous for the common promoter haplotype A who received MCT diet (P = 0.001), but not significant in homozygous rare haplotype B subjects who received MCT fat. Subjects homozygous for FABP2 haplotype A showed a significant decrease in fasting and postprandial glucose (P = 0.01, 0.04, respectively) and a decrease in insulin resistance (HOMA-IR, P = 0.04) during LCT diet. After correction for multiple testing, those effects did not remain significant. Fasting and postprandial triacylglycerols, LDL cholesterol, chylomicron TGs and cholesterol were not affected by genotype or diet. MCT diet increased HDL cholesterol dependent on the FABP2 promoter haplotype. The effects of the promoter haplotype B could be mediated by PPARγ, which is upregulated by medium-chain fatty acids.
Bünger S, Barow M, Thorns C, Freitag-Wolf S, Danner S, Tiede S, Pries R, Görg S, Bruch HP, Roblick UJ, Kruse C, Habermann JK.
Pancreatic Carcinoma Cell Lines Reflect Frequency and Variability of Cancer Stem Cell Markers in Clinical Tissue.Eur Surg Res,
49 (2012), 88-98.
[abstract]
Abstract:
Background: Pancreatic cancer is one of the most deadly malignancies with insufficient therapeutic options and poor outcome. Cancer stem cells (CSCs) are thought to be responsible for progression and therapy resistance. We investigated the potential of pancreatic cell lines for CSC research by analyzing to what extent they contain CSC populations and how representative these are compared to clinical tissue. Methods: Six pancreatic cancer cell lines were analyzed by flow cytometry for CD326, CD133, CD44, CD24, CXCR4 and ABCG2. Subsequently, 70 primary pancreatic tissues were evaluated for CD326, CD133 and CD44 by immunohistochemistry. Results: All the cell lines but one showed a stable expression pattern throughout biological replicates. Marker expression in clinical tissue of CD44 distinguished normal patients from pancreatic carcinoma patients with a sensitivity of 50% at 80% specificity and metastasized from nonmetastasized carcinomas with 69% sensitivity at 100% specificity. Conclusions: Our results indicate a link between elevated CD44 expression, malignancy and metastasis of pancreatic tissue. Furthermore, individual pancreatic cell lines show a substantial amount of cells with CSC properties which is comparable with interpatient variability detected in primary tissue. These pancreatic cancer cell lines could thus serve for urgently needed pharmacological CSC in vitro research.
Fabel M, Wulff A, Heckel F, Bornemann L, Freitag-Wolf S, Heller M, Biederer J, Bolte H.
Clinical lymph node staging-Influence of slice thickness and reconstruction kernel on volumetry and RECIST measurements.Eur J Radiol,
(2012).
[abstract]
Abstract:
PURPOSE: Therapy response evaluation in oncological patient care requires reproducible and accurate image evaluation. Today, common standard in measurement of tumour growth or shrinkage is one-dimensional RECIST 1.1. A proposed alternative method for therapy monitoring is computer aided volumetric analysis. In lung metastases volumetry proved high reliability and accuracy in experimental studies. High reliability and accuracy of volumetry in lung metastases has been proven. However, other metastatic lesions such as enlarged lymph nodes are far more challenging. The aim of this study was to investigate the reproducibility of semi-automated volumetric analysis of lymph node metastases as a function of both slice thickness and reconstruction kernel. In addition, manual long axis diameters (LAD) as well as short axis diameters (SAD) were compared to automated RECIST measurements. MATERIALS AND METHODS: Multislice-CT of the chest, abdomen and pelvis of 15 patients with lymph node metastases of malignant melanoma were included. Raw data were reconstructed using different slice thicknesses (1-5mm) and varying reconstruction kernels (B20f, B40f, B60f). Volume and RECIST measurements were performed for 85 lymph nodes between 10 and 60mm using Oncology Prototype Software (Fraunhofer MEVIS, Siemens, Germany) and were compared to a defined reference volume and diameter by calculating absolute percentage errors (APE). Variability of the lymph node sizes was computed as relative measurement differences, precision of measurements was computed as relative measurement deviation. RESULTS: Mean absolute percentage error (APE) for volumetric analysis varied between 3.95% and 13.8% and increased significantly with slice thickness. Differences between reconstruction kernels were not significant, however, a trend towards middle soft tissue kernel could be observed.. Between automated and manual short axis diameter (SAD, RECIST 1.1) and long axis diameter (LAD, RECIST 1.0) no significant differences were found. The most unsatisfactory segmentation results occurred in higher slice thickness (3 and 5mm) and sharp tissue kernel. CONCLUSION: Volumetric analysis of lymph nodes works satisfying in a clinical setting. Thin slice reconstructions (≤3mm) and a middle soft tissue reconstruction kernel are recommended. LAD and SAD did not show significant differences regarding APE. Automated RECIST measurement showed lower APE than manual measurement in trend.
Wulff AM, Bolte H, Fischer S, Freitag-Wolf S, Soza G, Tietjen C, Biederer J, Heller M, Fabel M.
Lung, Liver and Lymph Node Metastases in Follow-Up MSCT: Comprehensive Volumetric Assessment of Lesion Size Changes.Rofo,
(2012).
[abstract]
Abstract:
Purpose: To investigate measurement accuracy in terms of precision and inter-rater variability in the simultaneous volumetric assessment of lung, liver and lymph node metastasis size change over time in comparison to RECIST 1.1. Materials and Methods: Three independent readers evaluated multislice CT data from clinical follow-up studies (chest/abdomen) in 50 patients with metastases. A total of 117 lung, 77 liver and 97 lymph node metastases were assessed manually (RECIST 1.1) and by volumetry with semi-automated software. The quality of segmentation and need for manual adjustments were recorded. Volumes were converted to effective diameters to allow comparison to RECIST. For statistical assessment of precision and interobserver agreement, the Wilcoxon-signed rank test and Bland-Altman plots were utilized. Results: The quality of segmentation after manual correction was acceptable to excellent in 95 % of lesions and manual corrections were applied in 21 - 36 % of all lesions, most predominantly in lymph nodes. Mean precision was 2.6 - 6.3 % (manual) with 0.2 - 1.5 % (effective) relative measurement deviation (p <.001). Inter-reader median variation coefficients ranged from 9.4 - 12.8 % (manual) and 2.9 - 8.2 % (volumetric) for different lesion types (p < .001). The limits of agreement were ± 9.8 to ± 11.2 % for volumetric assessment. Conclusion: Superior precision and inter-rater variability of volumetric over manual measurement of lesion change over time was demonstrated in a whole body setting.
Habermann JK, Brucker CA, Freitag-Wolf S, Heselmeyer-Haddad K, Krüger S, Barenboim L, Downing T, Bruch HP, Auer G, Roblick UJ, Ried T.
Genomic instability and oncogene amplifications in colorectal adenomas predict recurrence and synchronous carcinoma.Mod Pathol,
24 (2011), 542-55.
[abstract]
Abstract:
Individual colorectal adenomas have different propensities to progress to invasive disease. In this study, we explored whether these differences could be explained by gene copy number alterations. We evaluated 18 adenomas of patients without synchronous or subsequent carcinoma (6.5 years follow-up), 23 adenomas of carcinoma patients, and 6 related carcinomas. All samples were measured for their DNA ploidy status. Centromere probes for chromosomes 17 and 18, as well as gene-specific probes for SMAD7, EGFR, NCOA3, TP53, MYC, and RAB20 were assessed by multicolor fluorescence in situ hybridization. An increased genomic instability index of CEP17, SMAD7, and EGFR, as well as TP53 deletions and MYC amplifications defined adenomas of patients with synchronous carcinoma (P<0.05). Diploid NCOA3 signal counts were associated with longer adenoma recurrence-free surveillance (P=0.042). In addition, NCOA3, MYC, EGFR, and RAB20 amplifications, as well as TP53 deletions correlated with increased DNA stem line values and/or aneuploidy in adenomas (P<0.05). Furthermore, aberrations of NCOA3, MYC, and RAB20 were associated with histopathologically defined high-risk adenomas (P<0.05). RAB20 amplifications were also correlated with high-grade dysplastic adenomas (P=0.002). We conclude that genomic instability in colorectal adenomas is reflected by EGFR, MYC, NCOA3, and RAB20 amplifications that do correlate with histomorphological features and are indicative for adenoma recurrence and the presence of synchronous carcinomas.
Wruck CJ, Fragoulis A, Gurzynski A, Brandenburg LO, Kan YW, Chan K, Hassenpflug J, Freitag-Wolf S, Varoga D, Lippross S, Pufe T.
Role of oxidative stress in rheumatoid arthritis: insights from the Nrf2-knockout mice.Ann Rheum Dis,
70 (2011), 844-50.
[abstract]
Abstract:
These results provide strong evidence that oxidative stress is significantly involved in cartilage degradation in experimental arthritis, and indicate that the presence of a functional Nrf2 gene is a major requirement for limiting cartilage destruction.
Harder S, Dimaczek B, Açil Y, Terheyden H, Freitag-Wolf S, Kern M.
Molecular leakage at implant-abutment connection--in vitro investigation of tightness of internal conical implant-abutment connections against endotoxin penetration.Clin Oral Investig,
14 (2010), 427-32.
[abstract]
Abstract:
Microleakage has been discussed as a major contributing factor for inflammatory reactions at the implant-abutment connection. In previous studies, the tightness against corpuscular bodies (viable bacteria) has been successfully investigated under static and dynamic conditions. The aim of this study was to investigate the tightness against endotoxins of two implant systems (AstraTech and Ankylos) with conical internal connections under static conditions. The inner parts of eight implants of each system were inoculated with endotoxin. Implants were screwed together with the respective abutments and stored under isostatic conditions in a supernatant of pyrogen-free water for 168 h. Supernatant samples were taken after 5 min, 24 h, 72 h, and 168 h, and endotoxin contamination was determined by the amebocyte-lysate test. Only one implant in the AstraTech group showed no sign of endotoxin contamination after 168 h, while the other implants showed contamination after varying storage times, respectively. The implants in the Ankylos group showed endotoxin contamination after only 5 min of storage in the supernatant solution. The tested internal conical implant-abutment connections appear to be unable to prevent endotoxin leakage. In average, Astra implants showed a higher tightness than Ankylos implants.
Biederer J, Bolte H, Schmidt T, Charalambous N, Both M, Kopp U, Hoffmann B, Freitag-Wolf S, Van Metter R, Heller M.
Detection of Artificial Air Space Opacities with Digital Radiography: Ex Vivo Study on Enhanced Latitude Post-Processing.Rofo,
(2010).
[abstract]
Abstract:
PURPOSE: To evaluate in a.-p. digital chest radiograms of an ex vivo system if increased latitude and enhanced image detail contrast (EVP) improve the accuracy of detecting artificial air space opacities in parts of the lung that are superimposed by the diaphragm. MATERIALS AND METHODS: 19 porcine lungs were inflated inside a chest phantom, prepared with 20 - 50 ml gelatin-stabilized liquid to generate alveolar air space opacities, and examined with direct radiography (3.0 x 2.5 k detector/ 125 kVp/ 4 mAs). 276 a.-p. images with and without EVP of 1.0 - 3.0 were presented to 6 observers. 8 regions were read for opacities, the reference was defined by CT. Statistics included sensitivity/specificity, interobserver variability, and calculation of Az (area under ROC curve). RESULTS: Behind the diaphragm (opacities in 32 / 92 regions), the median sensitivity increased from 0.35 without EVP to 0.53 - 0.56 at EVP 1.5 - 3.0 (significant in 5 / 6 observers). The specificity decreased from 0.96 to 0.90 (significant in 6 / 6), and the Az value and interobserver correlation increased from 0.66 to 0.74 and 0.39 to 0.48, respectively. Above the diaphragm, the median sensitivity for artificial opacities (136 / 276 regions) increased from 0.71 to 0.77 - 0.82 with EVP (significant in 4 / 6 observers). The specificity and Az value decreased from 0.76 to 0.62 and 0.74 to 0.70, respectively, (significant in 3 / 6). CONCLUSION: In this ex vivo experiment, EVP improved the diagnostic accuracy for artificial air space opacities in the superimposed parts of the lung (area under the ROC curve). Above the diaphragm, the accuracy was not affected due to a tradeoff in sensitivity/specificity.
Mehl C, Kern M, Freitag-Wolf S, Wolfart M, Brunzel S, Wolfart S.
Does the oral health impact profile questionnaire measure dental appearance?.Int J Prosthodont,
22 (2009 Jan-Feb), 87-93.
[abstract]
Abstract:
PURPOSE: The aim of this study was to evaluate whether there is a need to develop a new questionnaire measuring dental appearance or if this is already covered by the Oral Health Impact Profile (OHIP-49). MATERIALS AND METHODS: Based on internationally accepted guidelines about dental esthetics, a questionnaire was developed to measure dental appearance (QDA). Eleven items defined a QDA sum score (0 = absolutely satisfied, 44 = absolutely dissatisfied). Furthermore, oral health-related quality of life was evaluated using the German version of the OHIP-49 and the OHIP-esthetic. Thirty patients (14 women, 16 men; mean age 59 +/- 10 years) were included in the study. All patients received a complete oral rehabilitation including the anterior teeth of the maxilla. Questionnaires were completed before and after treatment. RESULTS: The median values were 16 and 1.5 for the QDA sum score, 46 and 16 for the OHIP sum score, and 14.5 and 2 for the OHIP-esthetic before and after rehabilitation, respectively. The improvement after treatment was significant for all questionnaires (P < or = .0001). Between the QDA sum score and the OHIP sum score or any of the OHIP subscales (the only exception being "psychological discomfort"), no significant correlation could be found (P > .05). Between the QDA sum score and the OHIP-esthetic, a significant correlation could be found before treatment (r = 0.505, P = .004) but not after treatment (P > .05). CONCLUSIONS: If the OHIP-49 is used in clinical studies and a profound evaluation of dental appearance is desired, it is reasonable to use an additional esthetic modulus.
Lu TT, Lao O, Nothnagel M, Junge O, Freitag-Wolf S, Caliebe A, Balascakova M, Bertranpetit J, Bindoff LA, Comas D, Holmlund G, Kouvatsi A, Macek M, Mollet I, Nielsen F, Parson W, Palo J, Ploski R, Sajantila A, Tagliabracci A, Gether U, Werge T, Rivadeneira F, Hofman A, Uitterlinden AG, Gieger C, Wichmann HE, Ruether A, Schreiber S, Becker C, Nürnberg P, Nelson MR, Kayser M, Krawczak M.
An evaluation of the genetic-matched pair study design using genome-wide SNP data from the European population.Eur J Hum Genet,
17 (2009), 967-75.
[abstract]
Abstract:
Genetic matching potentially provides a means to alleviate the effects of incomplete Mendelian randomization in population-based gene-disease association studies. We therefore evaluated the genetic-matched pair study design on the basis of genome-wide SNP data (309 790 markers; Affymetrix GeneChip Human Mapping 500K Array) from 2457 individuals, sampled at 23 different recruitment sites across Europe. Using pair-wise identity-by-state (IBS) as a matching criterion, we tried to derive a subset of markers that would allow identification of the best overall matching (BOM) partner for a given individual, based on the IBS status for the subset alone. However, our results suggest that, by following this approach, the prediction accuracy is only notably improved by the first 20 markers selected, and increases proportionally to the marker number thereafter. Furthermore, in a considerable proportion of cases (76.0%), the BOM of a given individual, based on the complete marker set, came from a different recruitment site than the individual itself. A second marker set, specifically selected for ancestry sensitivity using singular value decomposition, performed even more poorly and was no more capable of predicting the BOM than randomly chosen subsets. This leads us to conclude that, at least in Europe, the utility of the genetic-matched pair study design depends critically on the availability of comprehensive genotype information for both cases and controls.European Journal of Human Genetics advance online publication, 21 January 2009; doi:10.1038/ejhg.2008.266.
Fritsche LG, Freitag-Wolf S, Bettecken T, Meitinger T, Keilhauer CN, Krawczak M, Weber BH.
Age-related macular degeneration and functional promoter and coding variants of the apolipoprotein E gene.Hum Mutat,
30 (2009), 1048-53.
[abstract]
Abstract:
Age-related macular degeneration (AMD) is a frequent, multifactorial disease of the central retina and a major cause of irreversible vision loss in industrialized countries. Apolipoprotein E (APOE) has been consistently associated with AMD, particularly its two functional isoforms E2 (predisposing) and E4 (protective). The biological correlate of this association, however, is still unclear. In this study, we have defined an extended haplotype block encompassing the entire APOE gene locus, including known coding as well as cis-regulatory promoter variants. Of the five extended APOE haplotypes common in the general population, two were found to be significantly associated with AMD, namely G-G-G-G-epsilon2 (odds ratio [OR], 1.59; 95% confidence interval [CI], 1.19-2.12) and T-G-A-G-epsilon4 (OR, 0.76; 95% CI, 0.58-0.99). When analyzing common extended haplotype combinations, T-C-G-G-epsilon3/T-G-A-G-epsilon4 exhibited the most prominent effect (OR, 0.32; 95% CI, 0.20-0.51). Intriguingly, we also found one extended epsilon3-haplotype, G-G-G-A-epsilon3, to be protective in the homozygous state (OR, 0.65; 95% CI, 0.49-0.87). Since single nucleotide polymorphism (SNP) rs405509:G>T is a constituent of the extended epsilon-haplotype block and is known to significantly influence APOE promoter activity, we hypothesize that both the relative rate of APOE isoform expression in conjunction with established functional differences of the respective isoforms may be crucial in mediating AMD pathology. This would also imply that genotyping of the core epsilon-haplotypes alone is not sufficient to estimate AMD risk, but that determination of extended haplotype combinations, including the functional promoter SNP rs405509, is required instead.
Häsler R, Begun A, Freitag-Wolf S, Kerick M, Mah N, Zvirbliene A, Spehlmann ME, von Wurmb-Schwark N, Kupcinskas L, Rosenstiel P, Schreiber S.
Genetic control of global gene expression levels in the intestinal mucosa - a human twin study.Physiol Genomics,
(2009).
[abstract]
Abstract:
Phenotypic variation between individuals, such as different mRNA expression levels, is influenced by genetic and non-genetic factors. Although several studies have addressed the interplay between genotypes and expression profiles in various model organisms in the recent years, the detailed and relative contributions of genetic and non-genetic factors in regulating plasticity of gene expression in barrier organs (e.g. skin, gut) which are exposed to continuous environmental challenge, are still poorly understood. Here we systematically monitor the level of genetic control over genome-wide mRNA expression profiles in the healthy intestinal mucosa of 10 monozygotic and 10 dizygotic human twin pairs using microarray analyses. Our results, which are supported by real time PCR verification and the analysis of molecular phylogenetic conservation, indicate that genes associated with energy metabolism and cell and tissue regeneration pathways are under strong genetic control. Conversely, genes associated with immune response seem to be mainly controlled by exogenous factors. Further insights into the relative extent of genetic and non-genetic determinants of transcriptomal profiles and their influence on physiological and pathophysiological mechanisms are crucial to understanding the key-role played by gene-environmentinteractions in health and disease. Key words: Gene Expression Profiling, Genome, Primary Tissue, Twins.
Hübner RH, Gitter W, El Mokhtari NE, Mathiak M, Both M, Bolte H, Freitag-Wolf S, Bewig B.
Standardized quantification of pulmonary fibrosis in histological samples.Biotechniques,
44 (2008), 507-11, 514-7.
[abstract]
Abstract:
The Ashcroft scale for the evaluation of bleomycin-induced lung fibrosis is the analysis of stained histological samples by visual assessment. Based on the knowledge that this procedure is not standardized in animals and results are highly variable, we hypothesized that modification of this method may improve quantification of lung fibrosis in small animals. To prove our hypothesis, we evaluated pulmonary fibrosis in Lewis rats induced by a single intratracheal injection of 0.3 mg/kg body weight bleomycin (n = 13) compared with the same amount of saline in a control group (n = 4). We modified the Ashcroft scale by precisely defining the assignment of grades from 0 to 8 for the increasing extent of fibrosis in lung histological samples. Thirty-two observers were randomly assigned to evaluate 108 photographs of slides using either the Ashcroft scale or the modified scale. Consistent with our hypothesis, there was a significant reduction in the variability of standard deviations with the modified scale compared with the Ashcroft scale (mean of variability 0.25 versus 0.62, P < 0.0001). Applying the kappa index, the Ashcroft scale showed only a fair to moderate agreement (0.23-0.59) between the observers and a low intra-observer agreement (0.51-0.74) in contrast to the modified scale, which demonstrated a moderate to good agreement between the observers (0.65-0.93, P < 0.0001) and a high intra-observer agreement (0.87-0.91, P < 0.05). To test the modified scale in vivo, we compared both scales with the results of computed tomography (CT) of the lungs obtained from the same mice. In agreement, the modified scale demonstrated a better correlation to CT scans (R = 0.58) compared with the Ashcroft scale (R = 0.33). In summary, quantification of lung fibrosis in histological lung sections using the modified scale is reliable and reproducible.
Schafmayer C, Freitag-Wolf S, Wolken H, Buch S, Brosch M, Egberts JH, Shekarriz H, Fölsch UR, Fändrich F, Krawczak M, Schreiber S, Tepel J, Hampe J.
Increased heritability of gallstone disease in early onset cases.Liver Int,
28 (2008), 895-7.
Lao O, Lu TT, Nothnagel M, Junge O, Freitag-Wolf S, Caliebe A, Balascakova M, Bertranpetit J, Bindoff LA, Comas D, Holmlund G, Kouvatsi A, Macek M, Mollet I, Parson W, Palo J, Ploski R, Sajantila A, Tagliabracci A, Gether U, Werge T, Rivadeneira F, Hofman A, Uitterlinden AG, Gieger C, Wichmann HE, Rüther A, Schreiber S, Becker C, Nürnberg P, Nelson MR, Krawczak M, Kayser M.
Correlation between genetic and geographic structure in Europe.Curr Biol,
18 (2008), 1241-8.
[abstract]
Abstract:
Understanding the genetic structure of the European population is important, not only from a historical perspective, but also for the appropriate design and interpretation of genetic epidemiological studies. Previous population genetic analyses with autosomal markers in Europe either had a wide geographic but narrow genomic coverage [1, 2], or vice versa [3-6]. We therefore investigated Affymetrix GeneChip 500K genotype data from 2,514 individuals belonging to 23 different subpopulations, widely spread over Europe. Although we found only a low level of genetic differentiation between subpopulations, the existing differences were characterized by a strong continent-wide correlation between geographic and genetic distance. Furthermore, mean heterozygosity was larger, and mean linkage disequilibrium smaller, in southern as compared to northern Europe. Both parameters clearly showed a clinal distribution that provided evidence for a spatial continuity of genetic diversity in Europe. Our comprehensive genetic data are thus compatible with expectations based upon European population history, including the hypotheses of a south-north expansion and/or a larger effective population size in southern than in northern Europe. By including the widely used CEPH from Utah (CEU) samples into our analysis, we could show that these individuals represent northern and western Europeans reasonably well, thereby confirming their assumed regional ancestry.
Herber-Jonat S, von Bismarck P, Freitag-Wolf S, Nikischin W.
Limitation of measurements of expiratory tidal volume and expiratory compliance under conditions of endotracheal tube leaks.Pediatr Crit Care Med,
9 (2008), 69-75.
[abstract]
Abstract:
OBJECTIVE: Endotracheal tube leaks (ETTLs) occur in neonates ventilated with uncuffed tubes. Assuming that the influence of ETTLs might be neglected during expiration, only expiratory tidal volume is measured for calculation of expiratory compliance in cases of large ETTLs. However, expiratory ETTL might be substantial. Therefore, we evaluated the effect of ETTL size on expiratory tidal volume and compliance. DESIGN: Prospective laboratory study and retrospective clinical study. SETTING: University research laboratory and neonatal intensive care unit. PATIENTS: Sixty ventilated neonates (weight 640-2160 g, gestational age 25-33 wks) were investigated. INTERVENTIONS: The impact of increasing ETTLs on inspiratory and expiratory measured tidal volume (Vm), corrected tidal volume (Vc), and leak volume (Vl) was investigated in a ventilated neonatal lung model. The range of ETTLs (1% to 95%) was subdivided into five groups of 12 infants each. Furthermore, the relationships between standard ETTL size and inspiratory and expiratory ETTLs were evaluated using nonlinear regression. Standard ETTL size was defined as the difference between measured inspiratory and expiratory tidal volume (Vm) related to inspiratory Vm. MEASUREMENTS AND MAIN RESULTS: The size of a standard ETTL was 40% when expiratory ETTL reached 10% and was 12% when the inspiratory ETTL reached 10%. In infants, the differences between Vm and Vc were statistically significant during inspiration in the group beginning at a standard ETTL of 41% and during expiration in the group beginning at a standard ETTL of 69% (p < .05). Results of nonlinear regression showed that the standard ETTL was 33% (95% confidence interval, 28% to 36%) when expiratory ETTL reached 10% and was 13% (95% confidence interval, 12% to 15%) when inspiratory ETTL reached 10%. CONCLUSIONS: Expiratory Vl has a relevant impact if a certain ETTL size is reached.
Hübner RH, El Mokhtari NE, Freitag S, Rausche T, Göder R, Tiroke A, Lins M, Simon R, Bewig B.
NT-proBNP is not elevated in patients with obstructive sleep apnoea.Respir Med,
102 (2008), 134-42.
[abstract]
Abstract:
BACKGROUND: N-terminal pro-brain natriuretic peptide (NT-ProBNP) has emerged as an important marker of cardiac stress and may reflect the severity of underlying cardiac dysfunction, which is thought to be associated with obstructive sleep apnoea syndrome (OSAS). METHODS: This study evaluated the plasma concentration of NT-ProBNP in 60 consecutive patients (median age 55.7 years, median body mass index (BMI) 31.8) who were referred to a sleep laboratory with a suspicion of OSAS. Each subject underwent measurement of morning NT-ProBNP plasma levels, polysomnography and echocardiography. Patients were treated with nasal continuous or bilevel positive airway pressure ventilation (nCPAP/BIPAP) or without mechanical respiratory support, depending on clinical symptoms and results of polysomnography. Three months after treatment of OSAS 28 of the patients were reassessed for re-evaluation of NT-ProBNP and polysomnography. RESULTS: Low or high levels of NT-proBNP were not associated with AHI and other sleep related indices (p>0.3). There was no correlation between NT-proBNP and AHI or other sleep related indices. In multiple regression analysis, NT-proBNP was significantly correlated with left ventricular ejection fraction, creatinine clearance and the presence of systemic arterial hypertension but not with AHI. CONCLUSIONS: Our results show by a robust multiple regression analysis, that NT-pro BNP is not associated with OSAS and NT-pro BNP cannot be used as a sensitive marker for underlying cardiovascular abnormalities in patients with OSAS.
Biederer J, Gottwald T, Bolte H, Riedel C, Freitag S, Van Metter R, Heller M.
Pulmonary nodule detection with digital projection radiography: an ex-vivo study on increased latitude post-processing.Eur Radiol,
17 (2007), 1089-100.
[abstract]
Abstract:
To evaluate increased image latitude post-processing of digital projection radiograms for the detection of pulmonary nodules. 20 porcine lungs were inflated inside a chest phantom, prepared with 280 solid nodules of 4-8 mm in diameter and examined with direct radiography (3.0x2.5 k detector, 125 kVp, 4 mAs). Nodule position and size were documented by CT controls and dissection. Four intact lungs served as negative controls. Image post-processing included standard tone scales and increased latitude with detail contrast enhancement (log-factors 1.0, 1.5 and 2.0). 1280 sub-images (512x512 pixel) were centred on nodules or controls, behind the diaphragm and over free parenchyma, randomized and presented to six readers. Confidence in the decision was recorded with a scale of 0-100%. Sensitivity and specificity for nodules behind the diaphragm were 0.87/0.97 at standard tone scale and 0.92/0.92 with increased latitude (log factor 2.0). The fraction of "not diagnostic" readings was reduced (from 208/1920 to 52/1920). As an indicator of increased detection confidence, the median of the ratings behind the diaphragm approached 100 and 0, respectively, and the inter-quartile width decreased (controls: p<0.001, nodules: p=0.239) at higher image latitude. Above the diaphragm, accuracy and detection confidence remained unchanged. Here, the sensitivity for nodules was 0.94 with a specificity from 0.96 to 0.97 (all p>0.05). Increased latitude post-processing has minimal effects on the overall accuracy, but improves the detection confidence for sub-centimeter nodules in the posterior recesses of the lung.
Bolte H, Jahnke T, Schäfer FK, Wenke R, Hoffmann B, Freitag-Wolf S, Dicken V, Kuhnigk JM, Lohmann J, Voß S, Knöß N, Heller M, Biederer J.
Interobserver-variability of lung nodule volumetry considering different segmentation algorithms and observer training levels.Eur J Radiol,
64 (2007), 285-295.
[abstract]
Abstract:
OBJECTIVE: The aim of this study was to investigate the interobserver variability of CT based diameter and volumetric measurements of artificial pulmonary nodules. A special interest was the consideration of different measurement methods, observer experience and training levels. MATERIALS AND METHODS: For this purpose 46 artificial small solid nodules were examined in a dedicated ex-vivo chest phantom with multislice-spiral CT (20mAs, 120kV, collimation 16mmx0.75mm, table feed 15mm, reconstructed slice thickness 1mm, reconstruction increment 0.7mm, intermediate reconstruction kernel). Two observer groups of different radiologic experience (0 and more than 5 years of training, 3 observers each) analysed all lesions with digital callipers and 2 volumetry software packages (click-point depending and robust volumetry) in a semi-automatic and manually corrected mode. For data analysis the variation coefficient (VC) was calculated in per cent for each group and a Wilcoxon test was used for analytic statistics. RESULTS: Click-point robust volumetry showed with a VC of <0.01% in both groups the smallest interobserver variability. Between experienced and un-experienced observers interobserver variability was significantly different for diameter measurements (p=0.023) but not for semi-automatic and manual corrected volumetry. A significant training effect was revealed for diameter measurements (p=0.003) and semi-automatic measurements of click-point depending volumetry (p=0.007) in the un-experienced observer group. CONCLUSIONS: Compared to diameter measurements volumetry achieves a significantly smaller interobserver variance and advanced volumetry algorithms are independent of observer experience.
Bolte H, Riedel C, Knöss N, Freitag S, Hoffmann B, Heller M, Biederer J.
Computed tomography-based lung nodule volumetry--do optimized reconstructions of routine protocols achieve similar accuracy, reproducibility and interobserver variability to that of special volumetry protocols?.Rofo,
179 (2007), 276-81.
[abstract]
Abstract:
PURPOSE: The aim of this in vitro and ex vivo CT study was to investigate whether the use of a routine thorax protocol (RTP) with optimized reconstruction parameters can provide comparable accuracy, reproducibility and interobserver variability of volumetric analyses to that of a special volumetry protocol (SVP). MATERIALS AND METHODS: To assess accuracy, 3 polyurethane (PU) spheres (35 HU; diameters: 4, 6 and 10 mm) were examined with a recommended SVP using a multislice CT (collimation 16 x 0.75 mm, pitch 1.25, 20 mAs, slice thickness 1 mm, increment 0.7 mm, medium kernel) and an optimized RTP (collimation 16 x 1.5 mm, pitch 1.25, 100 mAs, reconstructed slice thickness 2 mm, increment 0.4 mm, sharp kernel). For the assessment of intrascan and interscan reproducibility and interobserver variability, 20 artificial small pulmonary nodules were placed in a dedicated ex vivo chest phantom and examined with identical scan protocols. The artificial lesions consisted of a fat-wax-Lipiodol mixture. Phantoms and ex vivo lesions were examined afterwards using commercial volumetry software. To describe accuracy the relative deviations from the true volumes of the PU phantoms were calculated. For intrascan and interscan reproducibility and interobserver variability, the 95 % normal range (95 % NR) of relative deviations between two measurements was calculated. RESULTS: For the SVP the achieved relative deviations for the 4, 6 and 10 mm PU phantoms were - 14.3 %, - 12.7 % and - 6.8 % and were 4.5 %, - 0.6 % and - 2.6 %, respectively, for the optimized RTP. SVP showed a 95 % NR of 0 - 1.5 % for intrascan and a 95 % NR of - 10.8 - 2.9 % for interscan reproducibility. The 95 % NR for interobserver variability was - 4.3 - 3.3 %. The optimized RTP achieved a 95 % NR of - 3.1 - 4.3 % for intrascan reproducibility and a 95 % NR of - 7.0 - 3.5 % for interscan reproducibility. The 95 % NR for interobserver variability was - 0.4 - 6.8 %. CONCLUSION: For datasets achieved with an SVP and an optimized RTP, this experimental approach showed comparable accuracy, reproducibility, and interobserver variability to allow for sufficient volumetric analysis of pulmonary lesions.
Bolte H, Riedel C, Müller-Hülsbeck S, Freitag-Wolf S, Kohl G, Drews T, Heller M, Biederer J.
Precision of computer-aided volumetry of artificial small solid pulmonary nodules in ex vivo porcine lungs.Br J Radiol,
80 (2007), 414-21.
[abstract]
Abstract:
The purpose of this study was to investigate the precision of CT-based volumetric measurements of artificial small pulmonary nodules under ex vivo conditions. We implanted 322 artificial nodules in 23 inflated ex vivo porcine lungs in a dedicated chest phantom. The lungs were examined with a multislice spiral CT (20 mAs, collimation 16x0.75 mm, 1 mm slice thickness, 0.7 mm increment). A commercial volumetry software package (LungCARE VA70C-W; Siemens, Erlangen, Germany) was used for volume analysis in a semi-automatic and a manual corrected mode. After imaging, the lungs were dissected to harvest the nodules for gold standard determination. The volumes of 202 solitary, solid and well-defined lesions without contact with the pleura, greater bronchi or vessels were compared with the results of volumetry. A mean nodule diameter of 8.3 mm (+/-2.1 mm) was achieved. The mean relative deviation from the true lesion volume was -9.2% (+/-10.6%) for semi-automatic and -0.3% (+/-6.5%) for manual corrected volumetry. The subgroup of lesions from 5 mm to <10 mm in diameter showed a mean relative deviation of -8.7% (+/-10.9%) for semi-automatic volumetry and -0.3% (+/-6.9%) for manually corrected volumetry. We conclude that the presented software allowed for precise volumetry of artificial nodules in ex vivo lung tissue. This result is comparable to the findings of previous in vitro studies.
Wolfart S, Quaas AC, Freitag S, Kropp P, Gerber WD, Kern M.
General well-being as an important co-factor of self-assessment of dental appearance.Int J Prosthodont,
19 (2006 Sep-Oct), 449-54.
[abstract]
Abstract:
PURPOSE: This study aimed to correlate the general well-being of patients and their judgment about their dental appearance. MATERIALS AND METHODS: Based on internationally accepted guidelines regarding dental esthetics, a questionnaire was developed to measure subjective assessments of dental appearance. Fourteen items defined an esthetic sum score (0 = satisfied; 56 = dissatisfied). Further, general well-being was evaluated with a long-established and highly reliable test. Eighty participants were included (47 women, 33 men). Participants were.drawn from 4 different groups (n = 20): natural dentition (group N), fixed partial dentures (group F), removable partial dentures (group R), and patients who had an esthetic problem with their teeth (group P). RESULTS: Seventy-five participants showed a normal well-being. Five participants showed a depressive state and formed a new group (group D). The medians of the sum scores (25th, 75th percentile) were: group N: 12 (10, 14); group F: 14 (8, 29); group R: 14 (9, 27); group P: 23 (18, 35); group D: 30 (26, 35). Significant differences were found between groups N and P, as well as between group D and groups N, F, and R. CONCLUSION: Because of the significant difference between groups N and P, basis validation of the sum score was achieved. Further, self-assessments of dental appearance appeared to be more negative for participants with a depressive state compared with the other groups. In clinical studies, selection bias can be prevented by using a test that measures well-being to verify if a study sample includes a normal number of depressive subjects and therefore represents the general population.
Dümbgen L, Freitag-Wolf S, Jongbloed G.
Estimating a Unimodal Distribution from Interval-Censored Data..Journal of the American Statistical Association,
101 (2006), 1094-1106.
[abstract]
Abstract:
In this paper we consider three nonparametric maximum likelihood estimators based on mixed case interval-censored data. Apart from the unrestricted estimator, we consider estimators under the assumption that the underlying distribution function of event times is concave or unimodal. Characterizations of the estimates are derived, and algorithms are proposed for their computation. The estimators are shown to be asymptotically consistent, and the additional constraints' benefits are illustrated via simulations. Finally, the estimators are used as an ingredient for a nonparametric comparison of two samples.
Ott SJ, El Mokhtari NE, Musfeldt M, Hellmig S, Freitag S, Rehman A, Kühbacher T, Nikolaus S, Namsolleck P, Blaut M, Hampe J, Sahly H, Reinecke A, Haake N, Günther R, Krüger D, Lins M, Herrmann G, Fölsch UR, Simon R, Schreiber S.
Detection of diverse bacterial signatures in atherosclerotic lesions of patients with coronary heart disease.Circulation,
113 (2006), 929-37.
[abstract]
Abstract:
Detection of a broad variety of molecular signatures in all CHD specimens suggests that diverse bacterial colonization may be more important than a single pathogen. Our observation does not allow us to conclude that bacteria are the causative agent in the etiopathogenesis of CHD. However, bacterial agents could have secondarily colonized atheromatous lesions and could act as an additional factor accelerating disease progression.
Bolte H, Riedel C, Jahnke T, Inan N, Freitag S, Kohl G, Heller M, Biederer J.
Reproducibility of computer-aided volumetry of artificial small pulmonary nodules in ex vivo porcine lungs.Invest Radiol,
41 (2006), 28-35.
[abstract]
Abstract:
OBJECTIVE: The main purpose of this study was to investigate the reproducibility of computed tomography (CT)-based volumetric measurements of small pulmonary nodules. METHODS: We implanted 70 artificial pulmonary nodules in 5 ex vivo porcine lungs in a dedicated chest phantom. The lungs were scanned 5 times consecutively with multislice-CT (collimation 16 x 0.75 mm, slice thickness 1 mm, reconstruction increment 0.7 mm). A commercial software package was used for lesion volumetry. The authors differentiated between intrascan reproducibility, interscan reproducibility, and results from semiautomatic and postprocessed volumetry. RESULTS: Analysis of intrascan reproducibility revealed a mean variation coefficient of 6.2% for semiautomatic volumetry and of 0.7% for human adapted volumetry. For interscan reproducibility a mean variation coefficient of 9.2% and for human adapted volumetry a mean of 3.7% was detected. CONCLUSION: The presented volumetry software showed a high reproducibility that can be expected to detect nodule growth with a high degree of certainty.
Attia A, Abdelaziz KM, Freitag S, Kern M.
Fracture load of composite resin and feldspathic all-ceramic CAD/CAM crowns.J Prosthet Dent,
95 (2006), 117-23.
[abstract]
Abstract:
STATEMENT OF PROBLEM: Various machinable materials are currently used with computer-aided design/computer-assisted manufacturing (CAD/CAM) technologies for the chairside fabrication of restorations. However, properties of these new machinable materials, such as fracture load, wear, marginal deterioration, and color stability, should be investigated in vitro under replicated clinical conditions prior to time-consuming clinical studies. PURPOSE: This study investigated the effect of cyclic loading fatigue and different luting agents under wet conditions on the fracture load of CAD/CAM machined composite resin and all-ceramic crowns. MATERIALS AND METHODS: Ninety-six intact human maxillary premolars were prepared for composite resin and all-ceramic crowns with the following preparation criteria: 6-degree axial taper, 1.5-mm shoulder finish line placed 0.5 mm occlusal to the cemento-enamel junction, 1.5-mm axial reduction, 2-mm occlusal reduction, and 5-mm occluso-gingival height. Sixteen unprepared premolars served as controls. Forty-eight all-ceramic crowns (Vita Mark II) and 48 millable composite resin crowns (MZ100 Block) were fabricated using a CAD/CAM system (Cerec 3). Three luting agents-RelyX ARC (RX), GC Fuji CEM (FC), and zinc phosphate cement (ZP)-were used for cementation (n = 16). After 1-week storage in water, half of the specimens (n=8) in each subgroup were cyclically loaded and thermal cycled under wet conditions for 600,000 masticatory cycles and 3500 thermal cycles (58 degrees C/4 degrees C; dwell time, 60 seconds) in a masticatory simulator; the other half (n = 8) were fractured without cyclic loading. All specimens were loaded in a universal testing machine with a compressive load (N) applied along the long axis of the specimen at a crosshead speed of 1 mm/min until fracture. Fracture loads (N) were recorded for each specimen. Three-way analysis of variance was used to detect the effects of the experimental factors (crown material, luting agent, and loading conditions) on the fracture load. The comparison with the unprepared natural teeth as controls was done by means of t tests (alpha=.05). RESULTS: Analysis of variance revealed a statistically significant influence of the luting agent and the cyclic loading (P < .001), whereas the crown material had no significant influence. Cyclic loading fatigue significantly decreased the mean fracture load of test groups independent of the 3 luting agents used: MZ100/ZP, 827.1 to 552.5 N; MZ100/FC, 914.7 to 706.2 N; MZ100/RX, 955.9 to 724.4 N; Vita/ZP, 772.3 to 571.5 N; Vita/FC, 923.6 to 721.1 N; and Vita/RX, 929.1 to 752.7 N. However, there was no significant difference in the mean fracture load of control specimens before and after cyclic loading (1140.1 N and 1066.2 N, respectively). Adhesive luting agents RelyX ARC and GC Fuji CEM increased fracture load significantly compared to zinc phosphate cement. CONCLUSIONS: Cyclic loading fatigue significantly reduced the fracture loads of composite resin and all-ceramic crowns, whereas adhesive cementation significantly increased the fracture loads.
Ott SJ, El Mokhtari NE, Musfeldt M, Hellmig S, Freitag S, Rehman A, Kühbacher T, Nikolaus S, Namsolleck P, Blaut M, Hampe J, Sahly H, Reinecke A, Haake N, Günther R, Krüger D, Lins M, Herrmann G, Fölsch UR, Simon R, Schreiber S.
Detection of diverse bacterial signatures in atherosclerotic lesions of patients with coronary heart disease.Circulation,
113 (2006), 929-37.
[abstract]
Abstract:
BACKGROUND: Bacterial infection has been discussed as a potential etiologic factor in the pathophysiology of coronary heart disease (CHD). This study analyzes molecular phylogenies to systematically explore the presence, frequency, and diversity of bacteria in atherosclerotic lesions in patients with CHD. METHODS AND RESULTS: We investigated 16S rDNA signatures in atherosclerotic tissue obtained through catheter-based atherectomy of 38 patients with CHD, control material from postmortem patients (n=15), and heart-beating organ donors (n=11) using clone libraries, denaturating gradient gel analysis, and fluorescence in situ hybridization. Bacterial DNA was found in all CHD patients by conserved PCR but not in control material or in any of the normal/unaffected coronary arteries. Presence of bacteria in atherosclerotic lesions was confirmed by fluorescence in situ hybridization. A high overall bacterial diversity of >50 different species, among them Staphylococcus species, Proteus vulgaris, Klebsiella pneumoniae, and Streptococcus species, was demonstrated in >1500 clones from a combined library and confirmed by denaturating gradient gel analysis. Mean bacterial diversity in atheromas was high, with a score of 12.33+/-3.81 (range, 5 to 22). A specific PCR detected Chlamydia species in 51.5% of CHD patients. CONCLUSIONS: Detection of a broad variety of molecular signatures in all CHD specimens suggests that diverse bacterial colonization may be more important than a single pathogen. Our observation does not allow us to conclude that bacteria are the causative agent in the etiopathogenesis of CHD. However, bacterial agents could have secondarily colonized atheromatous lesions and could act as an additional factor accelerating disease progression.
Brunzel S, Kern M, Freitag S, Wolfart S.
Aesthetic effect of minor changes in incisor angulation: an internet evaluation.J Oral Rehabil,
33 (2006), 430-5.
[abstract]
Abstract:
The aim of this study was to evaluate the aesthetic assessment of different tiltings of the upper incisors with surrounding tissues. A picture of a smiling mouth revealing the upper anterior teeth from 15 to 25 was digitally transformed producing different tiltings of the incisors. These seven versions presented in a web-based survey were evaluated concerning their attractiveness. Overall 439 judges joined the evaluation. However, 249 judges were included in analysis, because only judges with normal wellbeings and completed questionnaires were accepted. These judges consisted of 38 dentists, 26 dental and 24 other students, 45 academics and 89 non-academics, while 27 gave no data about their profession. The results [median (first; third quartile)] showed significant that symmetrical incisors [67.5 (47.5; 85.0)] and minor changes in the angulation of one [65.0 (42.5; 80.0)] or both lateral incisors [65.0 (42.5; 80.0)], respectively, are aesthetically more attractive than the angulation of one [45.0 (27.5; 62.5)] or both central incisors [27.5 (16.3; 45.0)], or the combination of one tilted lateral and central incisor [37.5 (25.0; 60.0)]. These results confirm the results of a previous study where similar image versions without surrounding tissues were assessed concerning their attractiveness on printed photos.
Stock UA, Degenkolbe I, Attmann T, Schenke-Layland K, Freitag S, Lutter G.
Prevention of device-related tissue damage during percutaneous deployment of tissue-engineered heart valves.J Thorac Cardiovasc Surg,
131 (2006), 1323-30.
[abstract]
Abstract:
BACKGROUND: Endovascular application of pulmonary heart valves has been recently introduced clinically. A tissue-engineering approach was pursued to overcome the current limitations of bovine jugular vein valves (degeneration and limited longevity). However, deployment of the delicate tissue-engineered valves resulted in severe tissue damage. Therefore the objective of this study was to prevent tissue damage during the folding and deployment maneuver. MATERIAL AND METHODS: Porcine pulmonary heart valves, small intestinal submucosa, and ovine carotid arteries were obtained from a slaughterhouse. After dissection and antimicrobial incubation, the valves were trimmed (removal of sinus and most of the muscular ring) to fit into the deployment catheter. The inside (in-stent group, n = 6) or outside (out-stent group, n = 6) of a nitinol stent was covered by an acellular small intestinal submucosa, and the valves were sutured into the stent. The valves were folded, tested for placement in the deployment catheter, and decellularized enzymatically. Myofibroblasts were obtained from carotid artery segments and seeded onto the scaffolds. The seeded constructs were placed in a dynamic bioreactor system and cultured for 16 consecutive days. After endothelial cell seeding, the constructs were folded, deployed, and processed for histology and surface electron microscopy. RESULTS: The valves opened and closed competently throughout the entire dynamic culture. Surface electron microscopy revealed an almost completely preserved tissue in the in-stent group. Stents covered with small intestinal submucosa on the outside, however, showed severe damage. CONCLUSION: This study demonstrates that small intestinal submucosa covering of the inside of a pulmonary valved stent can prevent stent strut-related tissue damage.
Wolfart S, Quaas AC, Freitag S, Kropp P, Gerber WD, Kern M.
Subjective and objective perception of upper incisors.J Oral Rehabil,
33 (2006), 489-95.
[abstract]
Abstract:
The purpose of this study was to evaluate the subjective judgment (SJ) of patients on their own dental appearance and to correlate the results with objective measurements (OM) of their dentition concerning the appearance of the upper incisors. Seventy-five participants (30 men and 45 women) with normal well-being were included in the study. In a questionnaire they judged the appearance of their upper incisors. Furthermore, OM were evaluated by the investigator with regard to the following points: (i) absolute length of the upper central incisors, (ii) their length exposed during laughing, (iii) width-to-length ratio of central incisors and (iv) the proportion between the width of the lateral and central incisors. The subjective results were registered on visual-analogue scales. For the objective results standardized photographs were taken. No gender dependent differences could be found for the objectively measured parameters (median): OM1, 10.7 mm; OM2, 8.1 mm; OM3, 0.81; OM4, 0.79. However, significant correlations between subjective and objective results (SJ1/OM1, SJ2/OM2, SJ3/OM3) could be shown for men, but not for women. The maximum of the calculated regression-curves for men reflect 'golden standard values' well known from the literature. The degree of satisfaction concerning appearance of anterior incisors in accordance with golden standard values is higher for men than for women.
Schafmayer C, Hartleb J, Tepel J, Albers S, Freitag S, Völzke H, Buch S, Seeger M, Timm B, Kremer B, Fölsch UR, Fändrich F, Krawczak M, Schreiber S, Hampe J.
Predictors of gallstone composition in 1025 symptomatic gallstones from Northern Germany.BMC Gastroenterol,
6 (2006), 36.
[abstract]
Abstract:
BACKGROUND: Gallstones represent a prevalent and costly health problem. The changing epidemiology and the emerging non-surgical interventions for gallstone disease necessitate the definition of target populations for future therapies. This study aimed to define patterns of gallstone composition and identify demographic predictors of gallstone composition in a large sample of symptomatic gallstones from Northern Germany. METHODS: One thousand and seventy-four post-cholecystectomy gallstone specimens were obtained. Demographic and clinical information was provided by questionnaire (N = 1025 independent individuals with complete information). Two samples from each gallstone were analyzed using Fourier transformed infrared spectrometry. RESULTS: The most prevalent substance was cholesterol, which was detected in 95.0% of gallstone specimens. Bilirubin and bilirubinate were present in 30.0% and calcium was detected in 10.0% of the spectra. Ninety-two percent of measurements from the same stone yielded the same "main" substances, indicating a homogenous stone composition in most cases. Female sex and higher body mass index (BMI) were associated with the presence of cholesterol as a main substance in the gallstones (p < 0.001). CONCLUSION: The changing epidemiology of gallstone disease is reflected by a marked shift in stone composition: Only two percent of stones in this study were pigment stones as compared to 91% percent of stones containing cholesterol as a main substance. Obese individuals from Germany with a BMI > 30 kg/m2 have in 95% cholesterol-dominant gallstones and represent a potential target population for non-surgical interventions for the prevention or treatment of cholesterol stones.
Wegner PK, Freitag S, Kern M.
Survival rate of endodontically treated teeth with posts after prosthetic restoration.J Endod,
32 (2006), 928-31.
[abstract]
Abstract:
The purpose of this retrospective clinical study was to evaluate the survival rate of teeth that were endodontically treated and restored with endodontic posts and prosthodontic restorations. A total of 864 teeth in 360 patients were included in the study. Dental records and radiographs of the patients were evaluated and four parameters were documented. The parameters were type of post, type of prosthodontic restoration, observation time, and, in cases of failure, failure mode. Statistical survival analyses were performed according to Kaplan-Meier. The mean observation time was 22.5 +/- 14.9 months. The calculated survival rates of the abutments were statistically significant different for fixed partial dentures (FPDs) and for removable partial dentures (RPDs) with survival rates of 92.7% and 51.0% after 60 months, respectively. Most of the presumed factors influencing the survival rate of endodontically treated abutment teeth only affected the outcome in the RPD group. Teeth restored with post and cores present a high risk for failure when used as abutments for conical-double-crown-retained RPDs.
Rubin D, Helwig U, Pfeuffer M, Schreiber S, Boeing H, Fisher E, Pfeiffer A, Freitag-Wolf S, Foelsch UR, Doering F, Schrezenmeir J.
A common functional exon polymorphism in the microsomal triglyceride transfer protein gene is associated with type 2 diabetes, impaired glucose metabolism and insulin levels.J Hum Genet,
51 (2006), 567-74.
[abstract]
Abstract:
The microsomal triglyceride transfer protein (MTP) is required for the assembly and secretion of apolipoprotein B-containing lipoproteins. Emerging evidence has indicated that the functional MTP exon polymorphism I128T is associated with dyslipidemia and other traits of the insulin-resistance syndrome, and the T128 variant seems to confer a reduced stability of MTP, resulting in reduced binding of LDL particles. The aim of the study was to elucidate the association of this MTP polymorphism with parameters of postprandial metabolism. A total of 716 male subjects from a postprandially characterized cohort (MICK) and a nested case-control study (EPIC) of 190 incident type 2 diabetes cases and 380 sex- or age-matched controls were genotyped for the I128T exon polymorphism. In comparison to homozygote subjects of the wild allele, carriers of the less common allele of the MTP T128 genotype showed significantly lower postprandial insulin levels (P=0.017), lower diastolic blood pressure (P=0.049) and had a lower prevalence of impaired glucose metabolism and diabetes type 2 (P=0.03) in the MICK. Consistent with this, we found a lower incidence of type 2 diabetes in male subjects of the nested case-control study in the T128 genotype (P=0.007). These results suggest that the rare allele of the MTP I128T polymorphism may be protective against impaired glucose tolerance, type 2 diabetes and other parameters of the metabolic syndrome.
Bartsch T, Alfke K, Stingele R, Rohr A, Freitag-Wolf S, Jansen O, Deuschl G.
Selective affection of hippocampal CA-1 neurons in patients with transient global amnesia without long-term sequelae.Brain,
129 (2006), 2874-84.
[abstract]
Abstract:
The aetiology, pathomechanisms and anatomical correlates of transient global amnesia (TGA) still remain obscure. Recently, focal MR-signal diffusion-weighted imaging (DWI) changes in the hippocampus have been described in patients with TGA, but the exact localization, long term outcome and pathophysiological nature of these lesions still remain unknown. The topography and time course of hippocampal DWI lesions in 41 TGA patients was studied using serial 3 T high-resolution MR-imaging and correlated to clinical and neuropsychometric results. Of these, 29 patients showed 36 DWI lesions with corresponding T(2) lesions in the hippocampus within a time window of 48 h after onset. Almost all lesions (94%; 34/36) were selectively found in the CA-1 sector (Sommer sector) of the hippocampal cornu ammonis. Most DWI lesions (8/10) were already detectable in the peri-acute phase <6 h after onset of symptoms. A follow-up study 4-6 months after the episode did not show evidence for residual structural sequelae of these lesions (n = 20/20). A venous MR angiography of the intracranial dural sinus showed an asymmetric venous drainage in 21/24 (88%) patients. In 11/16 (69%) patients with unilateral lesions, the asymmetry corresponded to the side of the DWI lesion. Significant episodic verbal memory deficits in the acute phase (n = 14/18) were associated with lesions of the dominant hemisphere while impairment of visuospatial memory was associated with lesions of the non-dominant hemisphere. Persistent neuropsychological sequelae were not detected 4-6 months after the episode (n = 16). This is the first prospective study combining high-resolution imaging and neuropsychometry analysing the detailed functional anatomy and outcome of hippocampal DWI/T(2) lesions in TGA supporting the view the TGA being a benign transient disorder. The TGA can be considered a model for a focal transient perturbation of memory circuits in the temporo-mesial region.
Hübner RH, Meffert S, Mundt U, Böttcher H, Freitag S, El Mokhtari NE, Pufe T, Hirt S, Fölsch UR, Bewig B.
Matrix metalloproteinase-9 in bronchiolitis obliterans syndrome after lung transplantation.Eur Respir J,
25 (2005), 494-501.
[abstract]
Abstract:
Bronchiolitis obliterans syndrome (BOS) is a severe complication after lung transplantation (LTX). In a retrospective cohort study 12 stable healthy recipients (non-BOS) and eight patients with BOS were enrolled after LTX and matrix metalloproteinases (MMP)-9, TIMP-1 and cell characteristics in bronchoalveolar lavage (BAL) samples (n = 145) were analysed. BALs from patients with BOS were further divided according to whether they were obtained before (pre-BOS) or after manifestation of BOS (BOS group). The MMP-9/TIMP-1 ratio was significantly increased in the BOS group compared with non-BOS or pre-BOS; furthermore, the ratio was negatively correlated with forced expiratory volume in one second. In zymography, the active form of MMP-9 was detected predominantly in the BOS group. In addition, zymography showed the banding pattern of neutrophil-derived MMP-9, indicating that polymorphonuclear neutrophils (PMNs) were the main source of MMP-9. According to that, MMP-9 was significantly correlated with the number of PMN. In immunocytochemistry, MMP-9 was also associated predominantly with PMN. This is the first study to evaluate the expression of matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases-1 over time during manifestation of a fibroproliferative lung disease in patients. It demonstrates development of bronchiolitis obliterans syndrome after lung transplantation is associated with an imbalance of matrix metalloproteinases-9/tissue inhibitors of metalloproteinase-1 ratio.
Quaas AC, Heide S, Freitag S, Kern M.
Influence of metal cleaning methods on the resin bond strength to NiCr alloy.Dent Mater,
21 (2005), 192-200.
[abstract]
Abstract:
OBJECTIVES: The purpose of this laboratory study was to evaluate the influence of different metal cleaning methods on the bond strength of various resin bonding systems and its durability to a NiCr alloy. The hypothesis was that the resin bond strength and its durability is related to the cleaning method and to the bonding system used. METHODS: Plexiglas tubes filled with composite resin were bonded to NiCr disks using three different bonding systems: tribochemical silica-coating and silanization of the alloy, acrylization of the alloy, or bonding with a phosphate monomer containing composite resin. For each bonding system, three cleaning methods were used after the last air abrasion step: cleaning with a stiff brush, ultrasonic cleaning in alcohol or in a neutral detergent. For each combination 20 samples were bonded. Subgroups of 10 bonded samples were tested for tensile strength following storage for either 3 or 150 days. In addition, the 150-day samples were thermal cycled 37,500 times. The statistical analyses were made by ANOVA, followed by multiple pair-wise comparison of the groups using Scheffe and t-tests with Bonferroni-Holm correction. RESULTS: The mean tensile bond strengths ranged from 34.8 to 49.2 MPa after 3 days and from 2.1 to 43.1 MPa after 150 days. Acrylization of the alloy did not provide durable bond strength to NiCr alloy over storage time. Cleaning the alloy surface with alcohol provided statistically significant higher bond strength than the other cleaning methods after 3 days. SIGNIFICANCE: Alloy cleaning methods after air abrasion have a significant influence on the resin bond strength.
Caliebe A, Freitag S, Krawczak M.
Stochastische Modelle für Interaktion und Effektmodifikation.Medizinische genetik,
17 (2005), 14-9.
Wolfart S, Thormann H, Freitag S, Kern M.
Assessment of dental appearance following changes in incisor proportions.Eur J Oral Sci,
113 (2005), 159-65.
[abstract]
Abstract:
This study aimed to evaluate the assessment of attractiveness of standardized changes in incisor proportions. Two original photographs, showing the maxillary anterior teeth in the frame of a smile, were computer-manipulated. From the so-produced symmetrical 'golden standard' images, two sets were constructed. Each set contained one golden standard image and seven images with different standardized changes concerning (i) width-to-length ratios of the central incisors (60-96%) and (ii) tooth-to-tooth proportions between the widths of lateral and central incisors (43-87%). The judges, consisting of three groups of individuals (24 dentists, 24 medical students, and 179 patients), ranked each photo set for attractiveness on a visual analogue scale. The width-to-length ratios were assessed as most attractive within a range of 75-85% (medical students, patients) or 75-80% (dentists), respectively. The tooth-to-tooth proportions showed the best results concerning attractive appearance within a range of 50-74% (medical students, patients) or 56-68% (dentists), respectively. No significant differences between the participant groups were found except for some extreme variations. It was concluded that a most attractive 'golden range' could be identified for both the width-to-length ratios and the tooth-to-tooth proportions of the maxillary incisors.
Eberhard J, Reimers N, Dommisch H, Hacker J, Freitag S, Acil Y, Albers HK, Jepsen S.
The effect of the topical administration of bioactive glass on inflammatory markers of human experimental gingivitis.Biomaterials,
26 (2005), 1545-51.
[abstract]
Abstract:
Recent studies demonstrated that bioactive glass attenuated inflammatory reactions and bacterial growth in vitro. The aim of the present clinical study was to evaluate the effects of local bioactive glass-administration in vivo in subjects with experimental gingivitis. In each individual, contralateral teeth served as test and control over a 21-day non-hygiene (preventive phase) and a 7-day therapeutic phase. A 45S5 bioactive glass (10% solution) was applied daily (2 x 1 h) on the test teeth during the preventive and therapeutic phase of the study. Inflammation assessment was based on the plaque index record (PI), on the bleeding frequency (BOP) and the gingival crevicular fluid volume (GCF). Interleukin-1beta levels (IL-1beta) in the GCF were measured by ELISA. Bacterial deposits on teeth increased during the 21-days non-brushing period, with no difference in plaque accumulation between test and control sides. BOP levels were significantly reduced during the therapeutic phase by the application of bioactive glass. GCF-values showed a significant reduction on the test compared to control side during the preventive and therapeutic phase. IL-1beta counts decreased during the last 7 days of the study on the test side, but no significance was given. The topical application of 45S5 bioactive glass in humans with experimental gingivitis attenuated the clinical signs of inflammation, although the bacterial accumulation was not inhibited in this clinical trial.
Domm C, Schünke M, Steinhagen J, Freitag S, Kurz B.
Influence of various alginate brands on the redifferentiation of dedifferentiated bovine articular chondrocytes in alginate bead culture under high and low oxygen tension.Tissue Eng,
10 (2004 Nov-Dec), 1796-805.
[abstract]
Abstract:
We examined the influence of various alginates on the redifferentiation of dedifferentiated articular chondrocytes in alginate bead culture under low (5%) and (21%) high oxygen supply. Isolated bovine articular chondrocytes were dedifferentiated and multiplied by 2-week monolayer culture under 21% oxygen. They were subcultured at a density of 10(7) cells/mL in six different commercially available sodium alginates (1.2%, w/v) and held under 21 or 5% oxygen for 3 weeks. Proliferation (DNA measurement on days 0 and 21 of culture), collagen type II production (immunocytochemistry and Western blotting), and [(3)H]proline and [(35)S]sulfate incorporation were monitored. Collagen type II production was significantly stronger under 5% oxygen compared with 21% oxygen in two alginates (three other alginates nearly reached the significance level). However, alginate-based differences proved not to be significant. [(3)H]Proline incorporation was not influenced by alginate but showed strong oxygen dependency (up to 3-fold higher under 5% oxygen). For [(35)S]sulfate incorporation oxygen dependency was even stronger (up to 8-fold higher under 5% oxygen) and significant alginate-dependent differences were found for several alginates. The effects of the different alginates did not correlate with their pH, viscosity, or guluronic:mannuronic acid ratio. Thus, the type of alginate and even more, the oxygen supply, influence the redifferentiation and matrix production of dedifferentiated bovine articular chondrocytes.
Wolfart S, Brunzel S, Freitag S, Kern M.
Assessment of dental appearance following changes in incisor angulation.Int J Prosthodont,
17 (2004 Mar-Apr), 150-4.
[abstract]
Abstract:
PURPOSE: This study evaluated the assessment of attractiveness of standardized changes in incisor angulation of different tooth arrangements. MATERIALS AND METHODS: Four sets of images showing the maxillary anterior teeth without lips against a black background were used for evaluation. Each set contained the original photograph, one computer-manipulated symmetric image, and four images with different standardized changes in incisor angulation (10 degrees). The judges, consisting of three groups (30 dental students, 30 medical students, 30 art students), ranked each photo set for attractiveness from 1 (most attractive) to 6 (most unattractive). RESULTS: The mean ranking (in parentheses) showed that symmetric teeth with ideal axes (2.5) and changes in the angulation of one (2.8) or both (2.5) lateral incisors were significantly more attractive than the angulation of one (4.2) or both (4.6) central incisors. There were no differences between the groups of participants. All findings were reproducible. CONCLUSION: Tooth arrangements showing central incisors with ideal axes were more attractive. Slight changes in the angulation of one or both lateral incisors did not influence attractiveness negatively.
Habermann JK, Hellman K, Freitag S, Heselmeyer-Haddad K, Hellström AC, Shah K, Auer G, Ried T.
A recurrent gain of chromosome arm 3q in primary squamous carcinoma of the vagina.Cancer Genet Cytogenet,
148 (2004), 7-13.
[abstract]
Abstract:
Primary carcinomas of the vagina are rare tumors, accounting for 2%-3% of all gynecologic malignancies. Only a few karyotypes based on chromosome banding techniques have been reported. We have, therefore, used comparative genomic hybridization to establish a pattern of genomic imbalances in vaginal squamous cell carcinomas. Analysis of 16 formalin-fixed and paraffin-embedded tumors revealed that 70% of vaginal carcinomas carry relative copy number increases that map to chromosome arm 3q. Other recurring gains were observed on chromosome arms 5p and 19p. Chromosomal losses were infrequent. Most tumors were aneuploid, as measured by image cytometry on Feulgen-stained tissue sections. The cytogenetic data were related to the presence of human papillomavirus genomes, expression of laminin-5 as a marker for invasiveness, and expression levels of markers for proliferative activity and mutated TP53. All relevant clinical data were recorded. The results suggest that vaginal carcinomas are defined by a specific distribution of chromosomal aneuploidies and that the pattern of genomic imbalances is strikingly similar to that observed in squamous cell carcinomas of the uterine cervix. Age at diagnosis (P=0.031), tumor size (P=0.025), and increased laminin-5 expression (P=0.006) have a significant influence on the survival time.
Böning A, Scheewe J, Ivers T, Friedrich C, Stieh J, Freitag S, Cremer JT.
Phosphorylcholine or heparin coating for pediatric extracorporeal circulation causes similar biologic effects in neonates and infants.J Thorac Cardiovasc Surg,
127 (2004), 1458-65.
[abstract]
Abstract:
OBJECTIVE: Cardiac surgery for complex congenital malformations with use of extracorporeal circulation predisposes to an excessive systemic inflammatory response and a consecutive capillary leak syndrome. In a prospective randomized study the influence of 2 oxygenators especially designed for pediatric use on inflammatory markers and clinical outcome was investigated. METHODS: Forty neonates and infants (body surface area, <0.36 m(2)) undergoing cardiac surgery with extracorporeal circulation were randomized into one of 3 groups: in the first group (n = 14) the Medtronic Minimax Oxygenator and in the second group (n = 12) the Dideco Lilliput 1 Oxygenator, both with a 750-mL priming volume, were used. In the third group the Dideco Lilliput 1 Oxygenator was filled with a reduced priming volume of 450 mL. Parameters of interest for evaluation of a systemic inflammatory response after extracorporeal circulation were interleukin 6, tumor necrosis factor alpha, neutrophil elastase, complement C3, and free hemoglobin. In addition, erythrocyte, leukocyte, and thrombocyte counts and hemoglobin and C-reactive protein values were determined at different measurement points before, during, and after the operation. RESULTS: In all 3 groups peak values for tumor necrosis factor alpha were observed during the operation, whereas interleukin 6, elastase, and free hemoglobin values peaked in the first 4 hours. The highest values for leukocytes and C-reactive protein were obtained between 24 and 72 hours after the operation. Erythrocyte and thrombocyte counts, as well as hemoglobin values, were lowest at extracorporeal circulation onset, normalizing under substitution in the first 4 hours after the operation. By using the Lilliput/750 oxygenator, higher interleukin 6 values 1 and 4 hours after the operation and higher tumor necrosis factor alpha values during and 1 hour after the operation could be observed compared with results with the Minimax and Lilliput/450 oxygenators. In spite of our randomization protocol, patients in the Lilliput/750 group were significantly smaller and younger than those in the Minimax group. However, the statistical analysis showed no correlation between age and interleukin 6 or tumor necrosis factor alpha values, but it did show a correlation between younger age and the occurrence of capillary leak syndrome. Accordingly, the number of children with clinically complicated course (capillary leak, longer duration of catecholamine therapy, and ventilation) was higher in the Lilliput/750 group than in the Minimax group. CONCLUSION: By using an adequate priming volume, the systemic inflammatory response is similar after use of the Dideco Lilliput 1 Oxygenator and the Medtronic Minimax Oxygenator. Tip-to-tip surface coating of the extracorporeal circulation with either heparin or phosphorylcholine seems to have similar biologic effects in neonates and infants undergoing cardiac surgery.
Roldán JC, Jepsen S, Miller J, Freitag S, Rueger DC, Açil Y, Terheyden H.
Bone formation in the presence of platelet-rich plasma vs. bone morphogenetic protein-7.Bone,
34 (2004), 80-90.
[abstract]
Abstract:
Growth factors contained in platelet-rich plasma (PRP) have recently been proposed to enhance maturation of bone grafts and, in combination with anorganic bovine bone, to support repair in the treatment of small bone defects in maxillofacial surgery. Bone morphogenetic proteins (BMP) carried in a matrix may be able to replace the autologous bone graft in the treatment of critical size defects. However, no studies have compared the bone stimulating capacity of PRP and BMP. Likewise there is no data comparing the effects of PRP in either an autologous bone graft or in anorganic bovine bone. We augmented the mandible of Wistar rats (n = 28) on both sides with either anorganic bovine bone (Bio-Oss) or autologous rib bone. On the test side we applied either 20 microl of autologous PRP or 10 microl of rhBMP-7 (4 groups, n = 7). In addition, bone induction was evaluated in an extraskeletal site (n = 14). A polychrome sequential labeling was performed. The animals were sacrificed by intra-vital perfusion on day 50. Undecalcified ground sections were evaluated by microradiography, digitized histomorphometry and under fluorescent light. The qualitative analysis of fluorochrome labels suggested that PRP and rhBMP-7 accelerated bone growth. However, histomorphometric analysis revealed no significant differences in the area of newly mineralized bone under either the influence of PRP or rhBMP-7 on autologous bone graft. Likewise, the addition of PRP to anorganic bovine bone showed no statistical difference to the control group. The strongest bone stimulating effect was seen for the combination of rhBMP-7 with anorganic bovine bone (p = 0.028). In the extraskeletal model, newly formed bone was evident in the presence of rhBMP-7, but not of PRP. In conclusion, according to the histomorphometry, the addition of platelet-rich plasma failed to enhance bone formation on anorganic bovine bone and on autologous bone grafts.
Eberhard J, Damm S, Freitag S, Albers HK, Jepsen S.
Plaque removing capacity of a novel high pressure water irrigator.Am J Dent,
17 (2004), 199-202.
[abstract]
Abstract:
PURPOSE: To evaluate the capacity of a novel oral water irrigator to remove established plaque deposits. METHODS: The study was designed as a randomized two-treatment, crossover, examiner-blinded clinical trial. The plaque removing capability of a prototype oral irrigator was compared to a conventional electric toothbrush. After 48 hours of plaque accumulation the 35 subjects were randomly assigned to professional plaque removal by either oral irrigation or by electric toothbrushing for a timed 2-minute total cleaning. Pre- and post cleaning plaque was disclosed and gingival abrasions were identified. Plaque was assessed on gingival and approximal surfaces of the oral and buccal sites according to the Rustogi et al modification of the Modified Navy Plaque Index. The assessment of gingival abrasions was performed according to the method introduced by Danser et al. RESULTS: The overall plaque removing capacity of the oral irrigator reached approximately 40.7 +/- 16.7% as compared to 71.6 +/- 11.5% by the electric toothbrush. Similar effects were observed for the gingival and approximal areas. The electric toothbrush caused significantly more gingival abrasions than the oral irrigator.
Dümbgen L, Freitag S, Jongbloed G.
Consistency of Concave Regression with an Application to Current-Status Data.Mathematical Methods of Statistics,
(2004), 69-81.
[abstract]
Abstract:
We consider the problem of nonparametric estimation of a concave regression function F. We show that the supremum distance between the least squares estimator and F on a compact interval is typically of order (log(n)/n)2/5. This entails rates of convergence for the estimator's derivative. Moreover, we discuss the impact of additional constraints on F such as monotonicity and pointwise bounds. Then we apply these results to the analysis of current status data, where the distribution function of the event times is assumed to be concave.
Habermann JK, Upender MB, Roblick UJ, Krüger S, Freitag S, Blegen H, Bruch HP, Schimmelpenning H, Auer G, Ried T.
Pronounced chromosomal instability and multiple gene amplifications characterize ulcerative colitis-associated colorectal carcinomas.Cancer Genet Cytogenet,
147 (2003), 9-17.
[abstract]
Abstract:
Patients with ulcerative colitis have a significantly increased lifetime risk for the development of colorectal carcinomas. While genetic and genomic changes during carcinogenesis have been thoroughly studied in sporadic colorectal cancers, less is known about ulcerative colitis-associated colorectal carcinomas. The aim of this study was to extend the identification of specific genomic imbalances to ulcerative colitis-associated colorectal carcinomas and to establish a comprehensive map of DNA gains and losses by investigating 23 tumor specimens from 23 patients. The molecular cytogenetic characterization was performed using comparative genomic hybridization; immunohistochemistry was used to measure proliferative activity and laminin-5 expression as a marker for invasiveness. The results indicate that these tumors are invariably aneuploid, with a high proliferative activity and increased invasive potential. The average number of copy alterations correlates with increased cyclin A levels (P=0.044), which is an independent predictor of risk of carcinoma development in ulcerative colitis. Despite severe genetic instability, the general pattern of specific chromosomal aberrations that defines sporadic colorectal carcinomas is maintained in ulcerative colitis-associated malignancies. High-level copy number increases (amplifications) are dispersed throughout the genome. Strikingly, these amplifications are much more frequent than in sporadic carcinomas and map to chromosomal regions that have not been described before.
Biederer J, Schoene A, Freitag S, Reuter M, Heller M.
Simulated pulmonary nodules implanted in a dedicated porcine chest phantom: sensitivity of MR imaging for detection.Radiology,
227 (2003), 475-83.
[abstract]
Abstract:
PURPOSE: To evaluate the diagnostic accuracy of common magnetic resonance (MR) imaging sequences for detection of small pulmonary nodules by using a chest phantom and porcine lungs containing simulated lesions. MATERIALS AND METHODS: Fourteen porcine lungs containing 366 porcine myocardial tissue implants were inflated inside a phantom. Two-dimensional (2D) and three-dimensional (3D) gradient-echo (GRE), T2-weighted turbo spin-echo (SE), and T2-weighted single-shot SE train MR sequences were performed. Spiral computed tomography (CT) was performed for comparison. Blinded observers read the images and recorded the sizes and locations of visible nodules by consensus. The sensitivity of each imaging method for depicting single nodules of given sizes was calculated. Specificities, positive predictive values (PPVs), and negative predictive values (NPVs) for detection of one or more nodules of various sizes were calculated. RESULTS: Sensitivities of 3D GRE, 2D GRE, T2-weighted turbo SE, and T2-weighted single-shot SE train MR imaging and of CT were 0.50, 0.40, 0.12, 0.00, and 0.55, respectively, for detection of 1.4-mm nodules and 0.88, 0.84, 0.69, 0.06, and 0.96, respectively, for detection of 4.2-mm nodules. The 95% CIs for CT and GRE MR imaging overlapped, but those for turbo SE and single-shot SE train MR imaging differed significantly (P <.05). For detection of nodules larger than 5 mm, all examinations except single-shot SE train MR imaging yielded a specificity, PPV, and NPV of 1.00 each. For detection of nodules smaller than 5 mm, diagnostic accuracy of 3D GRE MR imaging was high: Specificity, PPV, and NPV all were approximately 0.90. Two-dimensional GRE MR imaging results were influenced by false-positive findings: Specificity was 0.64; PPV, 0.74; and NPV, 1.00. CONCLUSION: Common MR imaging sequences such as 3D GRE have high diagnostic accuracy in depicting small pulmonary nodules when artifacts from cardiac and respiratory motion are absent.
Biederer J, Busse I, Grimm J, Reuter M, Muhle C, Freitag S, Heller M.
[Sensitivity of MRI in detecting alveolar Infiltrates: Experimental studies].Rofo,
174 (2002), 1033-9.
[abstract]
Abstract:
PURPOSE: An experimental study using porcine lung explants and a dedicated chest phantom to evaluate the signal intensity of artificial alveolar infiltrates with T 1 - and T 2 -weighted MRI sequences. MATERIAL AND METHODS: 10 porcine lung explants were intubated, transferred into the cavity of a MRI-compatible chest phantom and inflated by continuous evacuation of the artificial pleural space. All lungs were examined with MRI at 1.5 T before and after intra-tracheal instillation of either 100 or 200 ml gelatine-stabilised liquid to simulate alveolar infiltrates. MR-examination comprised gradient echo (2D- and 3D-GRE) and fast spin echo sequences (T 2 -TSE and T 2 -HASTE). The signal intensity of lung parenchyma was evaluated at representative cross sections using a standardised scheme. Control studies were acquired with helical CT. RESULTS: The instilled liquid caused patchy confluent alveolar infiltrates resembling the findings in patients with pneumonia or ARDS. CT revealed typical ground-glass opacities. Before the application of the liquid, only T 2 -HASTE and T 2 -TSE displayed lung parenchyma signals with a signal/noise ratio of 3.62 and 1.39, respectively. After application of the liquid, both T 2 -weighted sequences showed clearly visible infiltrates with an increase in signal intensity of approx. 30 % at 100 ml (p < 0.01) and 60 % at 200 ml (p < 0.01). With 2D- and 3D-GRE the infiltrates were not visible, although the lung parenchyma signal increase was statistically significant. On 2D-GRE the increase in signal intensity reached 0.74 % (p = 0.32) after 100 ml and 5.6 % (p < 0.01) after 200 ml (for 3D-GRE: 2.2 % [p = 0.02] at 100 ml and 4.4 % at 200 ml [p < 0.01]). The CT controls revealed a significant increase of lung density of 17 H.E. at 100 ml (p = 0.02) and 75 H.E. at 200 ml (p < 0.01). CONCLUSIONS: MRI with T 2 -weighted sequences detects artificial alveolar infiltrates with high signal intensity and may be a highly sensitive tool to detect pneumonia in patients.
Habermann J, Lenander C, Roblick UJ, Krüger S, Ludwig D, Alaiya A, Freitag S, Dümbgen L, Bruch HP, Stange E, Salo S, Tryggvason K, Auer G, Schimmelpenning H.
Ulcerative colitis and colorectal carcinoma: DNA-profile, laminin-5 gamma2 chain and cyclin A expression as early markers for risk assessment.Scand J Gastroenterol,
36 (2001), 751-8.
[abstract]
Abstract:
BACKGROUND: Ulcerative colitis patients are at increased risk for developing colorectal carcinomas. Despite expensive surveillance programmes, clinical practice reflects an uncertainty in individual risk assessment. The aim of the study was to evaluate independent cellular features with possible predictive value. METHODS: Two patient groups were selected: group A comprised 8 patients with ulcerative colitis-associated colorectal carcinomas, group B comprised 16 ulcerative colitis patients with risk factors (duration of disease, extent of inflammation, epithelial dysplasias). A total of 683 paraffin-embedded mucosal biopsies were retrospectively evaluated for inflammatory activity, grade of dysplasia, ploidy status, laminin-5 gamma2 chain and cyclin A expression. RESULTS: Mild or moderate inflammatory activity was present in 78% of all biopsies, low- or high-grade dysplasia in 5.5%. There was no difference in inflammatory activity and dysplasia between patient groups. In group A, 75% of the biopsies exhibited aneuploid DNA distribution patterns. Group B showed mainly proliferative-diploid cell populations (85% / P = 0.006). Laminin-5 gamma2 chain was expressed in 13% of all biopsies, with a higher frequency in group A (P = 0.002). Cyclin A expression was found in 98% of all biopsies, with a higher number of immunopositive cells in group A biopsies (P = 0.014). CONCLUSIONS: Combined nuclear DNA assessment, laminin-5 gamma2 chain and cyclin A expression may help to identify ulcerative colitis patients with an increased risk for cancer development.
