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4. The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research

Author

McAlpine, JB, Chen, SN, Kutateladze, A, Macmillan, JB, Appendino, G, Barison, A, Beniddir, MA, Biavatti, MW, Bluml, S, Boufridi, A, Butler, MS, Capon, RJ, Choi, YH, Coppage, D, Crews, P, Crimmins, MT, Csete, M, Dewapriya, P, Egan, JM, Garson, MJ, Genta-Jouve, G, Gerwick, WH, Gross, H, Harper, MK, Hermanto, P, Hook, JM ; https://orcid.org/0000-0002-1185-7320, Hunter, L ; https://orcid.org/0000-0002-8678-3602, Jeannerat, D, Ji, NY, Johnson, TA, Kingston, DGI, Koshino, H, Lee, HW, Lewin, G, Li, J, Linington, RG, Liu, M, McPhail, KL, Molinski, TF, Moore, BS, Nam, JW, Neupane, RP, Niemitz, M, Nuzillard, JM, Oberlies, NH, Ocampos, FMM, Pan, G, Quinn, RJ, Reddy, DS, Renault, JH, Rivera-Chávez, J, Robien, W, Saunders, CM, Schmidt, TJ, Seger, C, Shen, B, Steinbeck, C, Stuppner, H, Sturm, S, Taglialatela-Scafati, O, Tantillo, DJ, Verpoorte, R, Wang, BG, Williams, CM, Williams, PG, Wist, J, Yue, JM, Zhang, C, Xu, Z, Simmler, C, Lankin, DC, Bisson, J, Pauli, GF, McAlpine, JB, Chen, SN, Kutateladze, A, Macmillan, JB, Appendino, G, Barison, A, Beniddir, MA, Biavatti, MW, Bluml, S, Boufridi, A, Butler, MS, Capon, RJ, Choi, YH, Coppage, D, Crews, P, Crimmins, MT, Csete, M, Dewapriya, P, Egan, JM, Garson, MJ, Genta-Jouve, G, Gerwick, WH, Gross, H, Harper, MK, Hermanto, P, Hook, JM ; https://orcid.org/0000-0002-1185-7320, Hunter, L ; https://orcid.org/0000-0002-8678-3602, Jeannerat, D, Ji, NY, Johnson, TA, Kingston, DGI, Koshino, H, Lee, HW, Lewin, G, Li, J, Linington, RG, Liu, M, McPhail, KL, Molinski, TF, Moore, BS, Nam, JW, Neupane, RP, Niemitz, M, Nuzillard, JM, Oberlies, NH, Ocampos, FMM, Pan, G, Quinn, RJ, Reddy, DS, Renault, JH, Rivera-Chávez, J, Robien, W, Saunders, CM, Schmidt, TJ, Seger, C, Shen, B, Steinbeck, C, Stuppner, H, Sturm, S, Taglialatela-Scafati, O, Tantillo, DJ, Verpoorte, R, Wang, BG, Williams, CM, Williams, PG, Wist, J, Yue, JM, Zhang, C, Xu, Z, Simmler, C, Lankin, DC, Bisson, J, and Pauli, GF

Abstract

Covering: up to 2018 With contributions from the global natural product (NP) research community, and continuing the Raw Data Initiative, this review collects a comprehensive demonstration of the immense scientific value of disseminating raw nuclear magnetic resonance (NMR) data, independently of, and in parallel with, classical publishing outlets. A comprehensive compilation of historic to present-day cases as well as contemporary and future applications show that addressing the urgent need for a repository of publicly accessible raw NMR data has the potential to transform natural products (NPs) and associated fields of chemical and biomedical research. The call for advancing open sharing mechanisms for raw data is intended to enhance the transparency of experimental protocols, augment the reproducibility of reported outcomes, including biological studies, become a regular component of responsible research, and thereby enrich the integrity of NP research and related fields.

Published
2019

5. Non-classical monocytes as mediators of tissue destruction in arthritis

Author

Puchner, A., Saferding, V., Bonelli, M., Mikami, Y., Hofmann, M., Brunner, J.S., Caldera, M., Goncalves-Alves, E., Binder, N.B., Fischer, A., Simader, E., Steiner, C.W., Leiss, H., Hayer, S., Niederreiter, B., Karonitsch, T., Koenders, M.I., Podesser, B.K., O'Shea, J.J., Menche, J., Smolen, J.S., Redlich, K., Bluml, S., Puchner, A., Saferding, V., Bonelli, M., Mikami, Y., Hofmann, M., Brunner, J.S., Caldera, M., Goncalves-Alves, E., Binder, N.B., Fischer, A., Simader, E., Steiner, C.W., Leiss, H., Hayer, S., Niederreiter, B., Karonitsch, T., Koenders, M.I., Podesser, B.K., O'Shea, J.J., Menche, J., Smolen, J.S., Redlich, K., and Bluml, S.

Abstract

Contains fulltext : 196916.pdf (publisher's version ) (Open Access), OBJECTIVES: Bone destruction in rheumatoid arthritis is mediated by osteoclasts (OC), which are derived from precursor cells of the myeloid lineage. The role of the two monocyte subsets, classical monocytes (expressing CD115, Ly6C and CCR2) and non-classical monocytes (which are CD115 positive, but low in Ly6C and CCR2), in serving as precursors for OC in arthritis is still elusive. METHODS: We investigated CCR2(-/-) mice, which lack circulating classical monocytes, crossed into hTNFtg mice for the extent of joint damage. We analysed monocyte subsets in hTNFtg and K/BxN serum transfer arthritis by flow cytometry. We sorted monocyte subsets and analysed their potential to differentiate into OC and their transcriptional response in response to RANKL by RNA sequencing. With these data, we performed a gene ontology enrichment analysis and gene set enrichment analysis. RESULTS: We show that in hTNFtg arthritis local bone erosion and OC generation are even enhanced in the absence of CCR2. We further show the numbers of non-classical monocytes in blood are elevated and are significantly correlated with histological signs of joint destruction. Sorted non-classical monocytes display an increased capacity to differentiate into OCs. This is associated with an increased expression of signal transduction components of RANK, most importantly TRAF6, leading to an increased responsiveness to RANKL. CONCLUSION: Therefore, non-classical monocytes are pivotal cells in arthritis tissue damage and a possible target for therapeutically intervention for the prevention of inflammatory joint damage.

Published
2018

8. MicroRNA-146a governs fibroblast activation and joint pathology in arthritis

Author

Saferding, V., Puchner, A., Goncalves-Alves, E., Hofmann, M., Bonelli, M., Brunner, J.S., Sahin, E., Niederreiter, B., Hayer, S., Kiener, H.P., Einwallner, E., Nehmar, R., Carapito, R., Georgel, P., Koenders, M.I., Boldin, M., Schabbauer, G., Kurowska-Stolarska, M., Steiner, G., Smolen, J.S., Redlich, K., Bluml, S., Saferding, V., Puchner, A., Goncalves-Alves, E., Hofmann, M., Bonelli, M., Brunner, J.S., Sahin, E., Niederreiter, B., Hayer, S., Kiener, H.P., Einwallner, E., Nehmar, R., Carapito, R., Georgel, P., Koenders, M.I., Boldin, M., Schabbauer, G., Kurowska-Stolarska, M., Steiner, G., Smolen, J.S., Redlich, K., and Bluml, S.

Abstract

Contains fulltext : 177821.pdf (publisher's version ) (Closed access), Synovial fibroblasts are key cells orchestrating the inflammatory response in arthritis. Here we demonstrate that loss of miR-146a, a key epigenetic regulator of the innate immune response, leads to increased joint destruction in a TNF-driven model of arthritis by specifically regulating the behavior of synovial fibroblasts. Absence of miR-146a in synovial fibroblasts display a highly deregulated gene expression pattern and enhanced proliferation in vitro and in vivo. Deficiency of miR-146a induces deregulation of tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6) in synovial fibroblasts, leading to increased proliferation. In addition, loss of miR-146a shifts the metabolic state of fibroblasts towards glycolysis and augments the ability of synovial fibroblasts to support the generation of osteoclasts by controlling the balance of osteoclastogenic regulatory factors receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin (OPG). Bone marrow transplantation experiments confirmed the importance of miR-146a in the radioresistant mesenchymal compartment for the control of arthritis severity, in particular for inflammatory joint destruction. This study therefore identifies microRNA-146a as an important local epigenetic regulator of the inflammatory response in arthritis. It is a central element of an anti-inflammatory feedback loop in resident synovial fibroblasts, who are orchestrating the inflammatory response in chronic arthritis. MiR-146a restricts their activation, thereby preventing excessive tissue damage during arthritis.

Published
2017

9. Phosphatase and tensin homolog (PTEN) in antigen-presenting cells controls Th17-mediated autoimmune arthritis

Author

Bluml, S., Sahin, E., Saferding, V., Goncalves-Alves, E., Hainzl, E., Niederreiter, B., Hladik, A., Lohmeyer, T., Brunner, J.S., Bonelli, M., Koenders, M.I., Berg, W.B. van den, Superti-Furga, G., Smolen, J.S., Schabbauer, G., Redlich, K., Bluml, S., Sahin, E., Saferding, V., Goncalves-Alves, E., Hainzl, E., Niederreiter, B., Hladik, A., Lohmeyer, T., Brunner, J.S., Bonelli, M., Koenders, M.I., Berg, W.B. van den, Superti-Furga, G., Smolen, J.S., Schabbauer, G., and Redlich, K.

Abstract

Contains fulltext : 153653.pdf (publisher's version ) (Open Access), INTRODUCTION: Autoreactive T cells are a central element in many systemic autoimmune diseases. The generation of these pathogenic T cells is instructed by antigen-presenting cells (APCs). However, signaling pathways in APCs that drive autoimmune diseases, such as rheumatoid arthritis, are not understood. METHODS: We measured phenotypic maturation, cytokine production and induction of T cell proliferation of APCs derived from wt mice and mice with a myeloid-specific deletion of PTEN (myeloid PTEN(-/-)) in vitro and in vivo. We induced collagen-induced arthritis (CIA) and K/BxN serum transfer arthritis in wt and myeloid-specific PTEN(-/-) mice. We measured the cellular composition of lymph nodes by flow cytometry and cytokines in serum and after ex vivo stimulation of T cells. RESULTS: We show that myeloid-specific PTEN(-/-) mice are almost protected from CIA. Myeloid-specific deletion of PTEN leads to a significant reduction of cytokine expression pivotal for the induction of systemic autoimmunity such as interleukin (IL)-23 and IL-6, leading to a significant reduction of a Th17 type of immune response characterized by reduced production of IL-17 and IL-22. In contrast, myeloid-specific PTEN deficiency did not affect K/BxN serum transfer arthritis, which is independent of the adaptive immune system and solely depends on innate effector functions. CONCLUSIONS: These data demonstrate that the presence of PTEN in myeloid cells is required for the development of CIA. Deletion of PTEN in myeloid cells inhibits the development of autoimmune arthritis by preventing the generation of a pathogenic Th17 type of immune response.

Published
2015

11. MB-34 * MOLECULAR SUBGROUPS OF MEDULLOBLASTOMA IDENTIFICATION USING NON-INVASIVE MAGNETIC RESONANCE SPECTROSCOPY

Author

Margol, A., primary, Bluml, S., additional, Sposto, R., additional, Kennedy, R., additional, Robison, N., additional, Vali, M., additional, Hung, L., additional, Muthugounder, S., additional, Finlay, J., additional, Erdreich-Epstein, A., additional, Gilles, F., additional, Judkins, A., additional, Krieger, M., additional, Dhall, G., additional, Nelson, M., additional, and Asgharzadeh, S., additional

Published
2015
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15. Essential role of microRNA-155 in the pathogenesis of autoimmune arthritis in mice

Author

Bluml, S., Bonelli, M., Niederreiter, B., Puchner, A., Mayr, G., Hayer, S, Koenders, M.I., Berg, W.B. van den, Smolen, J., Redlich, K., Bluml, S., Bonelli, M., Niederreiter, B., Puchner, A., Mayr, G., Hayer, S, Koenders, M.I., Berg, W.B. van den, Smolen, J., and Redlich, K.

Abstract

Contains fulltext : 96882.pdf (publisher's version ) (Closed access), OBJECTIVE: MicroRNAs (miRNA) are a new class of regulatory elements. Altered expression of miRNA has been demonstrated in the inflamed joints of patients with rheumatoid arthritis (RA). The aim of this study was to examine the role of miRNA in the pathogenesis of autoimmune arthritis, using 2 murine models. METHODS: Collagen-induced arthritis (CIA) and K/BxN serum-transfer arthritis were induced in wild-type (WT) and miR-155-deficient (miR-155(-/-) ) mice. The severity of arthritis was determined clinically and histologically. Anticollagen antibodies and cytokines were measured by enzyme-linked immunosorbent assay. The cellular composition of the draining lymph nodes after induction of CIA was measured by flow cytometry. RESULTS: The miR-155(-/-) mice did not develop CIA. Deficiency in miR-155 prevented the generation of pathogenic autoreactive B and T cells, since anticollagen antibodies and the expression levels of antigen-specific T cells were strongly reduced in miR-155(-/-) mice. Moreover, Th17 polarization of miR-155(-/-) mouse T cells was impaired, as shown by a significant decrease in the levels of interleukin-17 (IL-17) and IL-22. In the K/BxN serum-transfer arthritis model, which only depends on innate effector mechanisms, miR-155(-/-) mice showed significantly reduced local bone destruction, attributed to reduced generation of osteoclasts, although the severity of joint inflammation was similar to that in WT mice. CONCLUSION: These results demonstrate that miR-155 is essentially involved in the adaptive and innate immune reactions leading to autoimmune arthritis, and therefore miR-155 might provide a novel target for the treatment of patients with RA.

Published
2011

16. LAB-RADIOBIOLOGY

Author

Floyd, S. R., primary, Pacold, M. E., additional, Clarke, S. M., additional, Blake, E., additional, Fydrych, A., additional, Ho, R., additional, Lee, M. J., additional, Root, D. E., additional, Carpenter, A. E., additional, Sabatini, D. M., additional, French, C. A., additional, Bradner, J. E., additional, Chen, C. C., additional, Yaffe, M. B., additional, Le Rhun, E., additional, Massin, F., additional, Lefevre, A., additional, Bonneterre, J., additional, Bittencourt, M. d. C., additional, Faure, G., additional, Hiramatsu, R., additional, Kawabata, S., additional, Yamada, Y., additional, Miyatake, S.-I., additional, Kuroiwa, T., additional, Li, S., additional, Chou, A. P., additional, Chen, W., additional, Chen, R., additional, Deng, Y., additional, Phillips, H. S., additional, Faull, K. F., additional, Cloughesy, T., additional, Liau, L. M., additional, Lai, A., additional, Mori, K., additional, Ishikura, R., additional, Tomogane, Y., additional, Izumoto, S., additional, Arita, N., additional, Piao, J., additional, Auyeung, G., additional, Policarpio, E., additional, Tabar, V., additional, Yeung, T. P. C., additional, Morrison, L., additional, Hoffman, L., additional, Lee, T.-Y., additional, Bauman, G., additional, Yartsev, S., additional, Ryu, S., additional, Kolozsvary, A., additional, Lapanowski, M., additional, Jenrow, K., additional, Brown, S., additional, Kim, J. H., additional, Brown, R. J., additional, Love, J., additional, Warburton, D., additional, McBride, W., additional, Bluml, S., additional, Ren, X., additional, Vanderwaal, B., additional, Jaboin, J., additional, Baldock, A. L., additional, Anh, S., additional, Rockne, R., additional, Neal, M., additional, Clark-Swanson, K., additional, Sterin, G., additional, Trister, A. D., additional, Malone, H., additional, Ebiana, V., additional, Sonabend, A. M., additional, Mrugala, M., additional, Rockhill, J. K., additional, Silbergeld, D. L., additional, McKhann, G. M., additional, Bruce, J. N., additional, Rostomily, R., additional, Canoll, P., additional, Swanson, K. R., additional, Hawkins-Daarud, A., additional, Baldock, A., additional, Bridge, C., additional, Corwin, D., additional, Mrugala, M. M., additional, Yagle, K., additional, Born, D., additional, and Swanson, P., additional

Published
2012
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18. QUALITY OF LIFE/AFTERCARE

Author

Rednam, S., primary, Scheurer, M., additional, Adesina, A., additional, Lau, C., additional, Okcu, M., additional, Deatrick, J., additional, Ogle, S., additional, Fisher, M., additional, Barakat, L., additional, Hardie, T., additional, Li, Y., additional, Ginsberg, J., additional, Ben-Arush, M., additional, Krivoy, E., additional, Rosenkranz, R., additional, Peretz-Nahum, M., additional, Brown, R. J., additional, Love, J., additional, Warburton, D., additional, McBride, W. H., additional, Bluml, S., additional, Mueller, S., additional, Sear, K., additional, Hills, N., additional, Chettout, N., additional, Afghani, S., additional, Lew, L., additional, Tolentino, E., additional, Haas-Kogan, D., additional, Fullerton, H., additional, Reddick, W., additional, Palmer, S., additional, Glass, J., additional, Ogg, R., additional, Gajjar, A., additional, Omar, A., additional, Perkins, S., additional, Shinohara, E., additional, Spoljaric, D., additional, Isenberg, J., additional, Whittington, M., additional, Hauff, M., additional, King, A., additional, Litzelman, K., additional, Barker, E., additional, Catrine, K., additional, Puccetti, D., additional, Possin, P., additional, Witt, W., additional, Mallucci, C., additional, Kumar, R., additional, Pizer, B., additional, Williams, D., additional, Pettorini, B., additional, Piscione, J., additional, Bouffet, E., additional, Shams, I., additional, Kulkarni, A., additional, Remes, T., additional, Harila-Saari, A., additional, Suo-Palosaari, M., additional, Arikoski, P., additional, Riikonen, P., additional, Sutela, A., additional, Koskenkorva, P., additional, Ojaniemi, M., additional, Rantala, H., additional, Campen, C. J., additional, Ashby, D., additional, Fisher, P. G., additional, Monje, M., additional, Kulkarni, A. V., additional, Nakamura, H., additional, Makino, K., additional, Yano, S., additional, Kuratsu, J.-i., additional, Jadrijevic-Cvrlje, F., additional, Batinica, M., additional, Toledano, H., additional, Hoffman, T., additional, Ezer-Cohen, Y., additional, Michowiz, S., additional, Yaniv, I., additional, Cohen, I. J., additional, Adler, I., additional, Mindel, S., additional, Gopalakrishnamoorthy, M., additional, Saunders, D., additional, Gaze, M., additional, Spoudeas, H., additional, Kieffer, V., additional, Dellatolas, G., additional, Chevignard, M., additional, Puget, S., additional, Dhermain, F., additional, Grill, J., additional, Dufour, C., additional, Muir, R., additional, Hunter, A., additional, Latchman, A., additional, de Camargo, O., additional, Scheinemann, K., additional, Dhir, N., additional, Zaky, W., additional, Zomorodian, T., additional, Wong, K., additional, Dhall, G., additional, Macy, M., additional, Lauro, C., additional, Zeitler, P., additional, Foreman, N., additional, Liu, A., additional, Chocholous, M., additional, Dodier, P., additional, Peyrl, A., additional, Dieckmann, K., additional, Hausler, G., additional, Slavc, I., additional, Avula, S., additional, Garlick, D., additional, Armstrong, G., additional, Kawashima, T., additional, Leisenring, W., additional, Stovall, M., additional, Sklar, C., additional, Robison, L., additional, Samaan, C., additional, Duckworth, J., additional, Greenberg-Kushnir, N., additional, Freedman, S., additional, Eshel, R., additional, Zverling, N., additional, Elhasid, R., additional, Dvir, R., additional, Yalon, M., additional, Constantini, S., additional, Wilne, S., additional, Liu, J.-F., additional, Trusler, J., additional, Lundsell, S., additional, Kennedy, C., additional, Clough, L., additional, Dickson, N., additional, Lakhanpaul, M., additional, Baker, M., additional, Dudley, J., additional, Grundy, R., additional, Walker, D., additional, von Hoff, K., additional, Herzog, N., additional, Ottensmeier, H., additional, Grabow, D., additional, Gerber, N. U., additional, Friedrich, C., additional, von Bueren, A. O., additional, Resch, A., additional, Kortmann, R. D., additional, Kaatsch, P., additional, Doerr, H. G., additional, Rutkowski, S., additional, del Bufalo, F., additional, Mastronuzzi, A., additional, Serra, A., additional, de Sio, L., additional, Locatelli, F., additional, Biassoni, V., additional, Leonardi, M., additional, Ajovalasit, D., additional, Riva, D., additional, Vago, C., additional, Usilla, A., additional, Fidani, P., additional, Schiavello, E., additional, Gariboldi, F., additional, Massimino, M., additional, Lober, R., additional, Perrault, S., additional, Partap, S., additional, Edwards, M., additional, Fisher, P., additional, Yeom, K., additional, Salgado, D., additional, Nunes, S., additional, Vinhais, S., additional, Wells, E. M., additional, Seidel, K., additional, Ullrich, N. J., additional, Diller, L., additional, Krull, K. R., additional, Neglia, J., additional, Robison, L. L., additional, Whelan, K., additional, Russell, C. E., additional, Brownstone, D., additional, Kaise, C., additional, Bull, K., additional, Culliford, D., additional, Calaminus, G., additional, Bertin, D., additional, Vallero, S., additional, Romano, E., additional, Basso, M. E., additional, Biasin, E., additional, Fagioli, F., additional, Ziara, K., additional, L'Hotta, A., additional, Williams, A., additional, Thede, R., additional, Moore, K., additional, James, A., additional, Bjorn, E., additional, Franzen, P., additional, Haag, A., additional, Lax, A.-K., additional, Moreno, I., additional, Obeid, J., additional, Timmons, B. W., additional, Iwata, W., additional, Wagner, S., additional, Lai, J.-S., additional, Waddell, K., additional, VanLeeuwen, S., additional, Newmark, M., additional, Noonan, J., additional, O'Connell, K., additional, Urban, M., additional, Yount, S., additional, Goldman, S., additional, Igoe, D., additional, Cunningham, T., additional, Orfus, M., additional, Mabbott, D., additional, Liptak, C., additional, Manley, P., additional, Recklitis, C., additional, Zhang, P., additional, Shaikh, F., additional, Narang, I., additional, Matsumoto, K., additional, Yamasaki, K., additional, Okada, K., additional, Fujisaki, H., additional, Osugi, Y., additional, Hara, J., additional, Phipps, K., additional, Gumley, D., additional, Jacques, T., additional, Hargrave, D., additional, Michalski, A., additional, Chordas, C., additional, Chi, S., additional, Robison, N., additional, Bandopadhayay, P., additional, Marcus, K., additional, Zimmerman, M. A., additional, Goumnerova, L., additional, Kieran, M., additional, Brand, S., additional, Brinkman, T., additional, Delaney, B., additional, Diver, T., additional, Rey, C., additional, Madden, J. R., additional, Hemenway, M. S., additional, Dorneman, L., additional, Stiller, D., additional, Liu, A. K., additional, Foreman, N. K., additional, Vibhakar, R., additional, Mitchell, M., additional, Hemenway, M., additional, Madden, J., additional, Ryan, M., additional, O'Kane, R., additional, Picton, S., additional, Kenny, T., additional, Stiller, C., additional, Chumas, P., additional, Bendel, A., additional, Patterson, R., additional, Barrera, M., additional, Schulte, F., additional, Bartels, U., additional, Janzen, L., additional, Johnston, D., additional, Cataudella, D., additional, Chung, J., additional, Sung, L., additional, Hancock, K., additional, Hukin, J., additional, Zelcer, S., additional, Brandon, S., additional, Montour-Proulx, I., additional, Strother, D., additional, Cooksey, R., additional, Bowers, D., additional, Gargan, L., additional, Gode, A., additional, Klesse, L., additional, Oden, J., additional, Vega, G., additional, Sala, F., additional, Nuzzi, D., additional, Mulino, M., additional, Masotto, B., additional, Mazza, C., additional, Bricolo, A., additional, Gerosa, M., additional, Tong, M., additional, Laughlin, S., additional, Mackie, S., additional, Taylor, L., additional, Sharpe, G., additional, Al-Salihi, O., additional, and Nicolin, G., additional

Published
2012
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19. DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

Author

Zaghloul, M., primary, Ahmed, S., additional, Eldebaway, E., additional, Mousa, A., additional, Amin, A., additional, Elkhateeb, N., additional, Sabry, M., additional, Ogiwara, H., additional, Morota, N., additional, Sufit, A., additional, Donson, A., additional, Birks, D., additional, Patel, P., additional, Foreman, N., additional, Handler, M., additional, Massimino, M., additional, Biassoni, V., additional, Gandola, L., additional, Schiavello, E., additional, Pecori, E., additional, Potepan, P., additional, Bach, F., additional, Janssens, G. O., additional, Jansen, M. H., additional, Lauwers, S. J., additional, Nowak, P. J., additional, Oldenburger, F. R., additional, Bouffet, E., additional, Saran, F., additional, van Ulzen, K. K., additional, van Lindert, E. J., additional, Schieving, J. H., additional, Boterberg, T., additional, Kaspers, G. J., additional, Span, P. N., additional, Kaanders, J. H., additional, Gidding, C. E., additional, Hargrave, D., additional, Bailey, S., additional, Howman, A., additional, Pizer, B., additional, Harris, D., additional, Jones, D., additional, Kearns, P., additional, Picton, S., additional, Wheatley, K., additional, Gibson, M., additional, Glaser, A., additional, Connolly, D., additional, Kawamura, A., additional, Nagashima, T., additional, Yamamoto, K., additional, Sakata, J., additional, Lober, R., additional, Freret, M., additional, Fisher, P., additional, Edwards, M., additional, Yeom, K., additional, Monje, M., additional, Jansen, M., additional, Aliaga, E. S., additional, Van Der Hoeven, E., additional, Van Vuurden, D., additional, Heymans, M., additional, Gidding, C., additional, De Bont, E., additional, Reddingius, R., additional, Peeters-Scholte, C., additional, van Meeteren, A. S., additional, Gooskens, R., additional, Granzen, B., additional, Paardekoper, G., additional, Janssens, G., additional, Noske, D., additional, Barkhof, F., additional, Vandertop, W. P., additional, Kaspers, G., additional, Saratsis, A., additional, Yadavilli, S., additional, Nazarian, J., additional, Mitra, S., additional, Mallick, S., additional, Kim, J., additional, Beachy, P., additional, Nobre, L., additional, Vasconcelos, F., additional, Lima, F., additional, Mattos, D., additional, Kuiven, N., additional, Lima, G., additional, Silveira, J., additional, Sevilha, M., additional, Lima, M. A., additional, Ferman, S., additional, Leblond, P., additional, Lansiaux, A., additional, Rialland, X., additional, Gentet, J.-C., additional, Geoerger, B., additional, Frappaz, D., additional, Aerts, I., additional, Bernier-Chastagner, V., additional, Shah, R., additional, Zaky, W., additional, Grimm, J., additional, Bluml, S., additional, Wong, K., additional, Dhall, G., additional, Caretti, V., additional, Schellen, P., additional, Lagerweij, T., additional, Bugiani, M., additional, Navis, A., additional, Wesseling, P., additional, Noske, D. P., additional, Wurdinger, T., additional, Lee, H., additional, Ziegler, D., additional, Schroeder, K., additional, Huang, E., additional, Berlow, N., additional, Patel, R., additional, Becher, O., additional, Taylor, I., additional, Mao, X.-g., additional, Hutt, M., additional, Weingart, M., additional, Kahlert, U., additional, Maciacyk, J., additional, Nikkhah, G., additional, Eberhart, C., additional, Raabe, E., additional, Barton, K., additional, Misuraca, K., additional, Zhou, Z., additional, Rotman, L., additional, Ho, S., additional, Souweidane, M., additional, Lim, K. J., additional, Warren, K., additional, Chang, H., additional, Lightner, D., additional, Haque, S., additional, Khakoo, Y., additional, Dunkel, I., additional, Gilheeney, S., additional, Kramer, K., additional, Lyden, D., additional, Wolden, S., additional, Greenfield, J., additional, De Braganca, K., additional, Ting-Rong, H., additional, Muh-Li, L., additional, Kai-Ping, C., additional, Tai-Tong, W., additional, Hsin-Hung, C., additional, Kebudi, R., additional, Cakir, F. B., additional, Agaoglu, F. Y., additional, Gorgun, O., additional, Dizdar, Y., additional, Ayan, I., additional, Darendeliler, E., additional, Zapotocky, M., additional, Churackova, M., additional, Malinova, B., additional, Kodet, R., additional, Kyncl, M., additional, Tichy, M., additional, Stary, J., additional, Sumerauer, D., additional, Minturn, J., additional, Shu, H.-K., additional, Fisher, M., additional, Patti, R., additional, Janss, A., additional, Allen, J., additional, Phillips, P., additional, Belasco, J., additional, Taylor, K., additional, Baudis, M., additional, von Beuren, A., additional, Fouladi, M., additional, and Jones, C., additional

Published
2012
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21. RADIOLOGY

Author

Bluml, S., primary, Panigrahy, A., additional, Laskov, M., additional, Dhall, G., additional, Nelson, M. D., additional, Finlay, J. L., additional, Gilles, F. H., additional, Arita, H., additional, Kinoshita, M., additional, Kagawa, N., additional, Fujimoto, Y., additional, Hashimoto, N., additional, Yoshimine, T., additional, Hamilton, J. D., additional, Wang, J., additional, Levin, V. A., additional, Hou, P., additional, Loghin, M. E., additional, Gilbert, M. R., additional, Leeds, N. E., additional, deGroot, J. F., additional, Puduvalli, V., additional, Jackson, E. F., additional, Yung, W. K. A., additional, Kumar, A. J., additional, Ellingson, B. M., additional, Cloughesy, T. F., additional, Pope, W. B., additional, Zaw, T., additional, Phillips, H., additional, Lalezari, S., additional, Nghiemphu, P. L., additional, Ibrahim, H., additional, Motevalibashinaeini, K., additional, Lai, A., additional, Harris, R., additional, Douw, L., additional, Van de Nieuwenhuijzen, M. E., additional, Heimans, J. J., additional, Baayen, J. C., additional, Stam, C. J., additional, Reijneveld, J. C., additional, Juhasz, C., additional, Mittal, S., additional, Altinok, D., additional, Robinette, N. L., additional, Muzik, O., additional, Chakraborty, P. K., additional, Barger, G. R., additional, Zaw, T. M., additional, Goldin, J., additional, Chen, W., additional, Ahlman, M. A., additional, Giglio, P., additional, Kaufmann, T. J., additional, Anderson, S. K., additional, Jaeckle, K. A., additional, Uhm, J. H., additional, Northfelt, D. W., additional, Flynn, P. J., additional, Buckner, J. C., additional, Galanis, E., additional, Zalatimo, O., additional, Weston, C., additional, Allison, D., additional, Bota, D., additional, Kesari, S., additional, Glantz, M., additional, Sheehan, J., additional, Harbaugh, R. E., additional, Chiba, Y., additional, Tsuboi, A., additional, Hatazawa, J., additional, Sugiyama, H., additional, Nariai, T., additional, Toyohara, J., additional, Tanaka, Y., additional, Inaji, M., additional, Aoyagi, M., additional, Yamamoto, M., additional, Ishiwara, K., additional, Ohno, K., additional, Jalilian, L., additional, Essock-Burns, E., additional, Cha, S., additional, Chang, S., additional, Prados, M., additional, Butowski, N., additional, Nelson, S., additional, Kawahara, Y., additional, Nakada, M., additional, Hayashi, Y., additional, Kai, Y., additional, Uchiyama, N., additional, Kuratsu, J.-i., additional, Hamada, J.-i., additional, Yeom, K., additional, Rosenberg, J., additional, Andre, J. B., additional, Fisher, P. G., additional, Edwards, M. S., additional, Barnes, P. D., additional, Partap, S., additional, Lupo, J. M., additional, Crane, J. C., additional, Chang, S. M., additional, Nelson, S. J., additional, Romanowski, C. A., additional, Hoggard, N., additional, Jellinek, D. A., additional, Clenton, S., additional, McKevitt, F., additional, Wharton, S., additional, Craven, I., additional, Buller, A., additional, Waddle, C., additional, Bigley, J., additional, Wilkinson, I. D., additional, Metherall, P., additional, Eckel, L. J., additional, Keating, G. F., additional, Wetjen, N. M., additional, Giannini, C., additional, Wetmore, C., additional, Jain, R., additional, Narang, J., additional, Arbab, A. S., additional, Schultz, L., additional, Scarpace, L., additional, Mikkelsen, T., additional, Babajni-Feremi, A., additional, Poisson, L., additional, Gutman, D., additional, Jaffe, C., additional, Saltz, J., additional, Flanders, A., additional, Daniel, B., additional, Zach, L., additional, Guez, D., additional, Last, D., additional, Daniels, D., additional, Hoffman, C., additional, Mardor, Y., additional, Guha-Thakurta, N., additional, Debnam, J. M., additional, Kotsarini, C., additional, Jellinek, D., additional, Griffiths, P. D., additional, Khandanpour, N., additional, Bambrough, P., additional, Prabhu, S., additional, Bassett, R. L., additional, Yung, W. A., additional, Campen, C. J., additional, Soman, S., additional, Yeom, K. W., additional, Vos, M. J., additional, Berkhof, J., additional, Postma, T. J., additional, Sanchez, E., additional, Sizoo, E. M., additional, Lagerwaard, F. J., additional, Buter, J., additional, Noske, D. P., additional, Colen, R. R., additional, Mahajan, B., additional, Jolesz, F. A., additional, Zinn, P. O., additional, Molinaro, A., additional, Lawton, K., additional, Alexandru, D., additional, Linskey, M. E., additional, Chaumeil, M. M., additional, Gini, B., additional, Yang, H., additional, Iwanami, A., additional, Subramanian, S., additional, Ozawa, T., additional, Read, E. J., additional, Pieper, R. O., additional, Mischel, P., additional, James, C. D., additional, Ronen, S. M., additional, LaViolette, P. S., additional, Cochran, E., additional, Al-Gizawiy, M., additional, Connelly, J. M., additional, Malkin, M. G., additional, Rand, S. D., additional, Mueller, W. M., additional, Schmainda, K. M., additional, Cohen, A. D., additional, Prah, M., additional, Hartman, C. J., additional, Qiao, X. J., additional, He, R., additional, Brown, M., additional, and Cloughesy, T., additional

Published
2011
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22. PEDIATRICS CLINICAL RESEARCH

Author

Murray, J. C., primary, Rainusso, N., additional, Roberts, R. A., additional, Gomez, A. M., additional, Egler, R., additional, Russell, H., additional, Okcu, M. F., additional, Gururangan, S., additional, Fangusaro, J., additional, Young-Poussaint, T., additional, Lesh, S., additional, Onar, A., additional, Gilbertson, R., additional, Packer, R., additional, McLendon, R., additional, Friedman, H. S., additional, Boyett, J., additional, Kun, L. E., additional, Venkatramani, R., additional, Haley, K., additional, Gilles, F., additional, Sposto, R., additional, Ji, L., additional, Olshefski, R., additional, Garvin, J., additional, Tekautz, T., additional, Kennedy, G., additional, Rassekh, R., additional, Moore, T., additional, Gardner, S., additional, Allen, J., additional, Shore, R., additional, Moertel, C., additional, Atlas, M., additional, Lasky, J., additional, Finlay, J., additional, Valera, E. T., additional, Brassesco, M. S., additional, Scrideli, C. A., additional, Oliveira, R. S., additional, Machado, H. R., additional, Tone, L. G., additional, Finlay, J. L., additional, Kreimer, S., additional, Dagri, J., additional, Grimm, J., additional, Bluml, S., additional, Britt, B., additional, Dhall, G., additional, Brown, R. J., additional, Shah, A., additional, Kapoor, N., additional, Abdel-Azim, H., additional, Rao, A. A. N., additional, Wallace, D., additional, Gajjar, A., additional, Packer, R. J., additional, Pearlman, M. L., additional, Sadighi, Z., additional, Bingham, R., additional, Vats, T., additional, Khatua, S., additional, Ko, R. H., additional, O'Neil, S., additional, Lavey, R. S., additional, Davidson, T. B., additional, Tovar, J., additional, Wong, K., additional, Olch, A., additional, Murray, J. C., additional, Honeycutt, J. H., additional, Donahue, D. J., additional, Head, H. W., additional, Alles, A. J., additional, Ray, A., additional, Pearlman, M., additional, Baskin, J., additional, Qaddoumi, I., additional, Ahchu, M. S., additional, Alabi, S. F., additional, Arambu, I. C., additional, Castellanos, M., additional, Gamboa, Y., additional, Martinez, R., additional, Montero, M., additional, Ocampo, E., additional, Howard, S. C., additional, Broniscer, A., additional, Baker, S. D., additional, Baker, J. N., additional, Panandiker, A. P., additional, Onar-Thomas, A., additional, Chin, T. K., additional, Merchant, T. E., additional, Davidoff, A., additional, Kaste, S. C., additional, Stewart, C. F., additional, Espinoza, J., additional, Patel, N., additional, Jeffrey, A., additional, Torkildson, J., additional, Cornelius, A., additional, Bedros, A., additional, Etzl, M., additional, Pradhan, K., additional, Corbett, R., additional, Sullivan, M., additional, McGowage, G., additional, Puccetti, D., additional, Stein, D., additional, Jasty, R., additional, Antony, R., additional, Patel, M., additional, Wong, K. E., additional, Krieger, M., additional, McComb, G., additional, Sanchez-Lara, P. A., additional, Randolph, L. M., additional, Krieger, M. D., additional, Wu, S., additional, Panigrahy, A., additional, Shimada, H., additional, Erdreich-Epstein, A., additional, Puccetti, D. M., additional, Kennedy, T., additional, Salamat, S., additional, Bradfield, Y., additional, Park, H. J., additional, Yoon, J. H., additional, Ahn, H. S., additional, Shin, H. Y., additional, Kim, S. K., additional, Im, H. J., additional, Ra, Y. S., additional, Won, S. C., additional, Baek, H. J., additional, Sung, K. W., additional, Hah, J. O., additional, Lim, Y. T., additional, Lee, G. S., additional, Lee, Y. H., additional, Kim, H. S., additional, Park, J. K., additional, Kim, M. K., additional, Park, J. E., additional, Chung, N. G., additional, Choi, H. S., additional, Campen, C. J., additional, Fisher, P. G., additional, Ruge, M. I., additional, Simon, T., additional, Suchorska, B., additional, Lehrke, R., additional, Hamisch, C., additional, Koerber, F., additional, Treuer, H., additional, Berthold, F., additional, Sturm, V., additional, Voges, J., additional, Kirsch, M., additional, Lindner, C., additional, and Schackert, G., additional

Published
2011
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34. Brain Injury Outcomes after Adjuvant Erythropoietin Neuroprotection for Moderate or Severe Neonatal Hypoxic-Ischemic Encephalopathy: A Report from the HEAL Trial.

Author

Wisnowski JL, Monsell SE, Bluml S, Goodman AM, Li Y, Comstock BA, Heagerty PJ, Juul SE, Wu YW, McKinstry RC, and Mathur AM

Subjects
Humans, Infant, Newborn, Female, Male, Erythropoietin therapeutic use, Magnetic Resonance Imaging, Treatment Outcome, Neuroprotection drug effects, Hypothermia, Induced methods, Brain Injuries drug therapy, Epoetin Alfa, Hypoxia-Ischemia, Brain drug therapy, Neuroprotective Agents therapeutic use
Abstract

Introduction: Erythropoietin (Epo) is a putative neuroprotective therapy that did not improve overall outcomes in a phase 3 randomized controlled trial for neonates with moderate or severe hypoxic-ischemic encephalopathy (HIE). However, HIE is a heterogeneous disorder, and it remains to be determined whether Epo had beneficial effects on a subset of perinatal brain injuries., Methods: This study was a secondary analysis of neuroimaging data from the High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial, which was conducted from 2016 to 2021 at 17 sites involving 23 US academic medical centers. Participants were neonates >36 weeks' gestation undergoing therapeutic hypothermia for moderate or severe HIE who received 5 doses of study drug (Epoetin alpha 1,000 U/kg/dose) or placebo in the first week of life. Treatment assignment was stratified by trial site and severity of encephalopathy. The primary outcome was the locus, pattern, and acuity of brain injury as determined by three independent readers using a validated HIE Magnetic Resonance Imaging (MRI) scoring system., Results: Of the 500 infants enrolled in HEAL, 470 (94%) had high quality MRI data obtained at a median of 4.9 days of age (IQR: 4.5-5.8). The incidence of injury to the deep gray nuclei, cortex, white matter, brainstem and cerebellum was similar between Epo and placebo groups. Likewise, the distribution of injury patterns was similar between groups. Among infants imaged at less than 8 days (n = 414), 94 (23%) evidenced only acute, 93 (22%) only subacute and 89 (21%) both acute and subacute injuries, with similar distribution across treatment groups., Conclusion: Adjuvant erythropoietin did not reduce the incidence of regional brain injury. Subacute brain injury was more common than previously reported, which has key implications for the development of adjuvant neuroprotective therapies for this population., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Published
2024
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36. How well does neonatal neuroimaging correlate with neurodevelopmental outcomes in infants with hypoxic-ischemic encephalopathy?

Author

Wu YW, Monsell SE, Glass HC, Wisnowski JL, Mathur AM, McKinstry RC, Bluml S, Gonzalez FF, Comstock BA, Heagerty PJ, and Juul SE

Subjects
Humans, Infant, Newborn, Infant, Child, Preschool, Magnetic Resonance Imaging methods, Neuroimaging, Magnetic Resonance Spectroscopy, Hypoxia-Ischemia, Brain diagnostic imaging, Hypoxia-Ischemia, Brain therapy, Hypoxia-Ischemia, Brain complications, Hypothermia, Induced methods, Brain Injuries complications, Brain Injuries diagnostic imaging, Brain Injuries therapy
Abstract

Background: In newborns with hypoxic-ischemic encephalopathy (HIE), the correlation between neonatal neuroimaging and the degree of neurodevelopmental impairment (NDI) is unclear., Methods: Infants with HIE enrolled in a randomized controlled trial underwent neonatal MRI/MR spectroscopy (MRS) using a harmonized protocol at 4-6 days of age. The severity of brain injury was measured with a validated scoring system. Using proportional odds regression, we calculated adjusted odds ratios (aOR) for the associations between MRI/MRS measures of injury and primary ordinal outcome (i.e., normal, mild NDI, moderate NDI, severe NDI, or death) at age 2 years., Results: Of 451 infants with MRI/MRS at a median age of 5 days (IQR 4.5-5.8), outcomes were normal (51%); mild (12%), moderate (14%), severe NDI (13%); or death (9%). MRI injury score (aOR 1.06, 95% CI 1.05, 1.07), severe brain injury (aOR 39.6, 95% CI 16.4, 95.6), and MRS lactate/n-acetylaspartate (NAA) ratio (aOR 1.6, 95% CI 1.4,1.8) were associated with worse primary outcomes. Infants with mild/moderate MRI brain injury had similar BSID-III cognitive, language, and motor scores as infants with no injury., Conclusion: In the absence of severe injury, brain MRI/MRS does not accurately discriminate the degree of NDI. Given diagnostic uncertainty, families need to be counseled regarding a range of possible neurodevelopmental outcomes., Impact: Half of all infants with hypoxic-ischemic encephalopathy (HIE) enrolled in a large clinical trial either died or had neurodevelopmental impairment at age 2 years despite receiving therapeutic hypothermia. Severe brain injury and a global pattern of brain injury on MRI were both strongly associated with death or neurodevelopmental impairment. Infants with mild or moderate brain injury had similar mean BSID-III cognitive, language, and motor scores as infants with no brain injury on MRI. Given the prognostic uncertainty of brain MRI among infants with less severe degrees of brain injury, families should be counseled regarding a range of possible neurodevelopmental outcomes., (© 2023. The Author(s).)

Published
2023
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37. Neuroimaging of complications arising after CD19 chimeric antigen receptor T-cell therapy: A review.

Author

Pinto SN, Liu CJ, Nelson MD Jr, Bluml S, Livingston D, and Tamrazi B

Subjects
Humans, Immunotherapy, Adoptive adverse effects, Immunotherapy, Adoptive methods, Neuroimaging, Antigens, CD19 adverse effects, Cell- and Tissue-Based Therapy, Receptors, Chimeric Antigen, Posterior Leukoencephalopathy Syndrome
Abstract

Chimeric antigen receptor (CAR) T cells targeting the CD19 (cluster of differentiation 19) cell surface glycoprotein have emerged as a highly effective immunologic therapy in patients with relapsed or refractory B-cell malignancies. The engagement of CAR T cells with CD19 on the surface of neoplastic B cells causes a systemic cytokine release, which can compromise the blood-brain barrier and cause an immune effector cell-associated neurotoxicity syndrome (ICANS). In a small proportion of ICANS patients who demonstrate neuroimaging abnormalities, certain distinct patterns have been recognized, including signal changes in the thalami, external capsule, and brainstem, the subcortical and/or periventricular white matter, the splenium of the corpus callosum, and the cerebellum. On careful review of the underlying pathophysiology of ICANS, we noticed that these changes closely mirror the underlying blood-brain barrier disruption and neuroinflammatory and excitotoxic effects of the offending cytokines released during ICANS. Furthermore, other uncommon complications of CD19 CAR T-cell therapy such as posterior reversible encephalopathy syndrome, ocular complications, and opportunistic fungal infections can be catastrophic if not diagnosed in a timely manner, with neuroimaging playing a significant role in management. In this narrative review, we will summarize the current literature on the spectrum of neuroimaging findings in ICANS, list appropriate differential diagnoses, and explore the imaging features of other uncommon central nervous system complications of CD19 CAR T-cell therapy using illustrative cases from two tertiary care institutions., (© 2023 American Society of Neuroimaging.)

Published
2023
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38. Brain Glutathione Increase and Seizure Burden Decrease in Patients with Intractable Epilepsy on Ketogenic Diet.

Author

Hazany S, DeClouette B, Lowe J, Hwang DH, Kim PE, Bluml S, and Partikian A

Abstract

Background and Purpose: Ketogenic diet (KD) improves seizure control in patients with drug-resistant epilepsy. As increased mitochondrial levels of glutathione (GSH) might contribute to a change in seizure susceptibility, we quantified changes of absolute GSH levels in the brain by in vivo 1H magnetic resonance spectroscopy (1H MRS) and correlate that with degree of seizure control in patients on KD., Methods: Five cognitively normal adult patients with drug-resistant epilepsy were initially included and 2 completed the study. Each patient was evaluated by a neurologist and registered dietitian at baseline, 1, 3, and 6 months for seizure status and diet adherence after initiation of a modified atkins diet. Multiple metabolites including GSH were quantified using LCModel (version 6.3-1P; Stephen Provencher, Oakville, ON, CA) on a short echo time single-voxel 1H MRS in parieto/occipital grey matter and parietal white matter on a 3 Tesla General Electric magnet prior to starting the ketogenic diet and at 6 months., Results: Both patients (42-years-old male and 35-years-old female) demonstrated marked increases in absolute GSH level in both gray matter (0.12 to 1.40 and 0.10 to 0.70 international unit [IU]) and white matter (0.65 to 1.50 and 0.80 to 2.00 IU), as well as 50% improvements in seizure duration and frequency. Other metabolites including ketone bodies did not demonstrate consistent changes., Conclusions: Markedly increased levels of GSH (7-fold and 14-fold) were observed in longitudinal prospective study of two adult patients with intractable epilepsy with 50% seizure improvement after initiation of ketogenic diets. This pilot study supports the possible anticonvulsant role of GSH in the brain., Competing Interests: None., (Copyright © 2023 Korean Epilepsy Society.)

Published
2023
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39. Magnetic Resonance Spectroscopy Metabolites as Biomarkers of Disease Status in Pediatric Diffuse Intrinsic Pontine Gliomas (DIPG) Treated with Glioma-Associated Antigen Peptide Vaccines.

Author

Panigrahy A, Jakacki RI, Pollack IF, Ceschin R, Okada H, Nelson MD, Kohanbash G, Dhall G, and Bluml S

Abstract

Purpose: Diffuse intrinsic pontine gliomas (DIPG) are highly aggressive tumors with no currently available curative therapy. This study evaluated whether measurements of in vivo cell metabolites using magnetic resonance spectroscopy (MRS) may serve as biomarkers of response to therapy, including progression., Methods: Single-voxel MR spectra were serially acquired in two cohorts of patients with DIPG treated with radiation therapy (RT) with or without concurrent chemotherapy and prior to progression: 14 participants were enrolled in a clinical trial of adjuvant glioma-associated antigen peptide vaccines and 32 patients were enrolled who did not receive adjuvant vaccine therapy. Spearman correlations measured overall survival associations with absolute metabolite concentrations of myo-inositol (mI), creatine (Cr), and n -acetyl-aspartate (NAA) and their ratios relative to choline (Cho) during three specified time periods following completion of RT. Linear mixed-effects regression models evaluated the longitudinal associations between metabolite ratios and time from death (terminal decline)., Results: Overall survival was not associated with metabolite ratios obtained shortly after RT (1.9-3.8 months post-diagnosis) in either cohort. In the vaccine cohort, an elevated mI/Cho ratio after 2-3 doses (3.9-5.2 months post-diagnosis) was associated with longer survival (rho = 0.92, 95% CI 0.67-0.98). Scans performed up to 6 months before death showed a terminal decline in the mI/Cho ratio, with an average of 0.37 ratio/month in vaccine patients (95% CI 0.11-0.63) and 0.26 (0.04-0.48) in the non-vaccine cohort., Conclusion: Higher mI/Cho ratios following RT, consistent with less proliferate tumors and decreased cell turnover, were associated with longer survival, suggesting that this ratio can serve as a biomarker of prognosis following RT. This finding was seen in both cohorts, although the association with OS was detected earlier in the vaccine cohort. Increased mI/Cho (possibly reflecting immune-effector cell influx into the tumor as a mechanism of tumor response) requires further study.

Published
2022
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40. Trial of Erythropoietin for Hypoxic-Ischemic Encephalopathy in Newborns.

Author

Wu YW, Comstock BA, Gonzalez FF, Mayock DE, Goodman AM, Maitre NL, Chang T, Van Meurs KP, Lampland AL, Bendel-Stenzel E, Mathur AM, Wu TW, Riley D, Mietzsch U, Chalak L, Flibotte J, Weitkamp JH, Ahmad KA, Yanowitz TD, Baserga M, Poindexter BB, Rogers EE, Lowe JR, Kuban KCK, O'Shea TM, Wisnowski JL, McKinstry RC, Bluml S, Bonifacio S, Benninger KL, Rao R, Smyser CD, Sokol GM, Merhar S, Schreiber MD, Glass HC, Heagerty PJ, and Juul SE

Subjects
Administration, Intravenous, Cerebral Palsy etiology, Double-Blind Method, Humans, Infant, Infant, Newborn, Erythropoietin administration & dosage, Erythropoietin adverse effects, Erythropoietin therapeutic use, Hypothermia, Induced methods, Hypoxia-Ischemia, Brain complications, Hypoxia-Ischemia, Brain drug therapy, Hypoxia-Ischemia, Brain therapy, Neuroprotective Agents administration & dosage, Neuroprotective Agents adverse effects, Neuroprotective Agents therapeutic use
Abstract

Background: Neonatal hypoxic-ischemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesized to have neuroprotective effects in infants with hypoxic-ischemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown., Methods: In a multicenter, double-blind, randomized, placebo-controlled trial, we assigned 501 infants born at 36 weeks or more of gestation with moderate or severe hypoxic-ischemic encephalopathy to receive erythropoietin or placebo, in conjunction with standard therapeutic hypothermia. Erythropoietin (1000 U per kilogram of body weight) or saline placebo was administered intravenously within 26 hours after birth, as well as at 2, 3, 4, and 7 days of age. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months of age. Neurodevelopmental impairment was defined as cerebral palsy, a Gross Motor Function Classification System level of at least 1 (on a scale of 0 [normal] to 5 [most impaired]), or a cognitive score of less than 90 (which corresponds to 0.67 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition., Results: Of 500 infants in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received placebo. The incidence of death or neurodevelopmental impairment was 52.5% in the erythropoietin group and 49.5% in the placebo group (relative risk, 1.03; 95% confidence interval [CI], 0.86 to 1.24; P = 0.74). The mean number of serious adverse events per child was higher in the erythropoietin group than in the placebo group (0.86 vs. 0.67; relative risk, 1.26; 95% CI, 1.01 to 1.57)., Conclusions: The administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment than placebo and was associated with a higher rate of serious adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT02811263.)., (Copyright © 2022 Massachusetts Medical Society.)

Published
2022
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41. Proton and Multinuclear Spectroscopy of the Pediatric Brain.

Author

Whitehead MT and Bluml S

Subjects
Brain diagnostic imaging, Child, Humans, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Brain Diseases diagnostic imaging, Protons
Abstract

Magnetic resonance spectroscopy (MRS) is a valuable adjunct to structural brain imaging. State-of-the-art MRS has benefited greatly from recent technical advancements. Neurometabolic alterations in pediatric brain diseases have implications for diagnosis, prognosis, and therapy. Herein, the authors discuss MRS technical considerations and applications in the setting of various pediatric disease processes including tumors, metabolic diseases, hypoxic/ischemic encephalopathy/stroke, epilepsy, demyelinating disease, and infection., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Published
2021
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42. Integrating neuroimaging biomarkers into the multicentre, high-dose erythropoietin for asphyxia and encephalopathy (HEAL) trial: rationale, protocol and harmonisation.

Author

Wisnowski JL, Bluml S, Panigrahy A, Mathur AM, Berman J, Chen PK, Dix J, Flynn T, Fricke S, Friedman SD, Head HW, Ho CY, Kline-Fath B, Oveson M, Patterson R, Pruthi S, Rollins N, Ramos YM, Rampton J, Rusin J, Shaw DW, Smith M, Tkach J, Vasanawala S, Vossough A, Whitehead MT, Xu D, Yeom K, Comstock B, Heagerty PJ, Juul SE, Wu YW, and McKinstry RC

Subjects
Asphyxia, Biomarkers, Clinical Trial Protocols as Topic, Humans, Infant, Newborn, Multicenter Studies as Topic, Neuroimaging, Erythropoietin, Hypoxia-Ischemia, Brain diagnostic imaging, Hypoxia-Ischemia, Brain drug therapy
Abstract

Introduction: MRI and MR spectroscopy (MRS) provide early biomarkers of brain injury and treatment response in neonates with hypoxic-ischaemic encephalopathy). Still, there are challenges to incorporating neuroimaging biomarkers into multisite randomised controlled trials. In this paper, we provide the rationale for incorporating MRI and MRS biomarkers into the multisite, phase III high-dose erythropoietin for asphyxia and encephalopathy (HEAL) Trial, the MRI/S protocol and describe the strategies used for harmonisation across multiple MRI platforms., Methods and Analysis: Neonates with moderate or severe encephalopathy enrolled in the multisite HEAL trial undergo MRI and MRS between 96 and 144 hours of age using standardised neuroimaging protocols. MRI and MRS data are processed centrally and used to determine a brain injury score and quantitative measures of lactate and n-acetylaspartate. Harmonisation is achieved through standardisation-thereby reducing intrasite and intersite variance, real-time quality assurance monitoring and phantom scans., Ethics and Dissemination: IRB approval was obtained at each participating site and written consent obtained from parents prior to participation in HEAL. Additional oversight is provided by an National Institutes of Health-appointed data safety monitoring board and medical monitor., Trial Registration Number: NCT02811263; Pre-result., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2021
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43. Fetal neurodevelopmental recovery in donors after laser surgery for twin-twin transfusion syndrome.

Author

Rajagopalan V, Ashouri K, Llanes A, Vanderbilt DL, Lepore N, Bluml S, Lai HA, Wisnowski J, Chon AH, and Chmait RH

Subjects
Adult, Brain embryology, Brain metabolism, Female, Fetofetal Transfusion diagnostic imaging, Fetofetal Transfusion metabolism, Humans, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Organ Size, Pregnancy, Recovery of Function, Treatment Outcome, Young Adult, Brain diagnostic imaging, Fetal Therapies, Fetofetal Transfusion surgery, Laser Coagulation
Abstract

Background: Fetal magnetic resonance imaging (MRI) and spectroscopy (MRS) provide a unique opportunity to non-invasively measure markers of neurodevelopment in survivors of twin-twin transfusion syndrome (TTTS)., Objective: To characterize fetal brain maturation after laser surgery for TTTS by measuring brain volumes and cerebral metabolite concentrations using fetal MRI + MRS., Study Design: Prospective study of dual surviving fetuses treated with laser surgery for TTTS. At 4-5 postoperative weeks, fetal MRI was used together with novel image analysis to automatically extract major brain tissue volumes. Fetal MRS was used to measure major metabolite concentrations in the fetal brain., Results: Twenty-one twin pairs were studied. The average (±SD) gestational age at MRI was 25.89 (±2.37) weeks. Total brain volume (TBV) was lower in the donors, although cerebral volumes were not different between twin pairs. Recipients showed lower proportions of cortical and cerebellar volumes, normalized to TBV and cerebral volumes. MRS data showed that biochemical differences between twin brains were related to discrepancy in their brain volumes., Conclusion: Although donors have a smaller TBV compared to recipients, proportionality of brain tissue volumes are preserved in donors. MRS maturational markers of fetal brain development show that recovery in donors persists 4 weeks after surgery., (© 2020 John Wiley & Sons, Ltd.)

Published
2021
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44. Brain MR imaging and spectroscopy for outcome prognostication after pediatric cardiac arrest.

Author

Fink EL, Wisnowski J, Clark R, Berger RP, Fabio A, Furtado A, Narayan S, Angus DC, Watson RS, Wang C, Callaway CW, Bell MJ, Kochanek PM, Bluml S, and Panigrahy A

Subjects
Brain diagnostic imaging, Child, Child, Preschool, Humans, Infant, Magnetic Resonance Imaging, Spectrum Analysis, Heart Arrest therapy, Hypoxia-Ischemia, Brain
Abstract

Aim: Children surviving cardiac arrest are at high risk of neurological morbidity and mortality; however, there is a lack of validated prognostic biomarkers. We aimed to evaluate brain magnetic resonance imaging (MRI) and spectroscopy (MRS) as predictors of death and disability. Secondly, we evaluated whether MRI/S by randomized group., Methods: This single center study analyzed clinically indicated brain MRI/S data from children enrolled in a randomized controlled trial of 24 vs. 72 h of hypothermia following cardiac arrest. Two pediatric radiologists scored conventional MRIs. Lactate and N-acetyl-aspartate (NAA) concentrations (mmol/kg) were determined from spectra acquired from the basal ganglia, thalamus, parietal white matter and parietooccipital gray matter. Mortality and neurological outcomes (favorable = Pediatric Cerebral Performance Category [PCPC] 1, 2, 3 or increase < 2) were assessed at hospital discharge. Non-parametric tests were used to test for associations between MRI/S biomarkers and outcome and randomized group., Results: 23 children with (median [interquartile range]) age of 1.5 (0.3-4.0) years. Ten (44%) had favorable outcome. There were more T2 brain lesions in the lentiform nuclei in children with unfavorable 12 (92%) vs. favorable 3 (33%) outcome, p = 0.007. Increased lactate and decreased NAA concentrations in the parietooccipital gray matter and decreased NAA in the parietal white matter were associated with unfavorable outcome (p's < 0.05). There were no differences for any biomarker by randomized group., Conclusion: Regional cerebral and metabolic MRI/S biomarkers are predictive of neurological outcomes at hospital discharge in pediatric cardiac arrest and should undergo validation testing in a large sample., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Published
2020
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45. Personalising Outcomes after Child Cardiac Arrest (POCCA): design and recruitment challenges of a multicentre, observational study.

Author

Fink EL, Clark RSB, Panigrahy A, Berger R, Wisnowski J, Bluml S, Maloney D, Rubin P, Haller T, Bayir H, Beers SR, Kochanek PM, and Fabio A

Subjects
Aftercare, Child, Humans, Patient Discharge, Quality of Life, SARS-CoV-2, Wisconsin, COVID-19, Heart Arrest therapy
Abstract

Introduction: Blood and imaging biomarkers show promise in prognosticating outcomes after paediatric cardiac arrest in pilot studies. We describe the methods and early recruitment challenges and solutions for an ongoing multicentre (n=14) observational trial, Personalising Outcomes following Child Cardiac Arrest to validate clinical, blood and imaging biomarkers individually and together in a clinically relevant panel., Methods and Analysis: Children (n=164) between 48 hours and 17 years of age who receive chest compressions irrespective of provider, duration, or event location and are admitted to an intensive care unit are eligible. Blood samples will be taken on days 1-3 for the measurement of brain-focused biomarkers analysed to predict the outcome. Clinically indicated and timed brain MRI and spectroscopy biomarkers will be analysed to predict the outcome. The primary outcome for the trial is survival with favourable (Vineland Adaptive Behavioural Scale score >70) outcome at 1 year. Secondary outcomes include mortality and pre-event and postdischarge measures of emotional, cognitive, physical and family functioning and health-related quality of life. Early enrollment targets were not met due to prolonged regulatory and subcontract processes. Multiple, simultaneous interventions including modification to inclusion criteria, additional sites and site visits were implemented with successful improvement in recruitment. Study procedures including outcomes and biomarker analysis are ongoing., Ethics and Dissemination: Twelve of 14 sites will use the centralised Institutional Review Board (IRB) at the University of Pittsburgh (PRO14030712). Two sites will use individual IRBs: Children's Healthcare of Atlanta Institutional Review Board and Children's Hospital of Wisconsin IRB. Parents and/or guardians are consented and children assented (when possible) by the site Primary investigator (PI) or research coordinator for enrollment. Study findings will be disseminated through scientific conferences, peer-reviewed journal publications, public study website materials and invited lectures., Trial Registration Number: NCT02769026., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2020
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47. Correction: The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research.

Author

McAlpine JB, Chen SN, Kutateladze A, MacMillan JB, Appendino G, Barison A, Beniddir MA, Biavatti MW, Bluml S, Boufridi A, Butler MS, Capon RJ, Choi YH, Coppage D, Crews P, Crimmins MT, Csete M, Dewapriya P, Egan JM, Garson MJ, Genta-Jouve G, Gerwick WH, Gross H, Harper MK, Hermanto P, Hook JM, Hunter L, Jeannerat D, Ji NY, Johnson TA, Kingston DGI, Koshino H, Lee HW, Lewin G, Li J, Linington RG, Liu M, McPhail KL, Molinski TF, Moore BS, Nam JW, Neupane RP, Niemitz M, Nuzillard JM, Oberlies NH, Ocampos FMM, Pan G, Quinn RJ, Reddy DS, Renault JH, Rivera-Chávez J, Robien W, Saunders CM, Schmidt TJ, Seger C, Shen B, Steinbeck C, Stuppner H, Sturm S, Taglialatela-Scafati O, Tantillo DJ, Verpoorte R, Wang BG, Williams CM, Williams PG, Wist J, Yue JM, Zhang C, Xu Z, Simmler C, Lankin DC, Bisson J, and Pauli GF

Abstract

Correction for 'The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research' by James B. McAlpine et al., Nat. Prod. Rep., 2018, DOI: .

Published
2019
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48. The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research.

Author

McAlpine JB, Chen SN, Kutateladze A, MacMillan JB, Appendino G, Barison A, Beniddir MA, Biavatti MW, Bluml S, Boufridi A, Butler MS, Capon RJ, Choi YH, Coppage D, Crews P, Crimmins MT, Csete M, Dewapriya P, Egan JM, Garson MJ, Genta-Jouve G, Gerwick WH, Gross H, Harper MK, Hermanto P, Hook JM, Hunter L, Jeannerat D, Ji NY, Johnson TA, Kingston DGI, Koshino H, Lee HW, Lewin G, Li J, Linington RG, Liu M, McPhail KL, Molinski TF, Moore BS, Nam JW, Neupane RP, Niemitz M, Nuzillard JM, Oberlies NH, Ocampos FMM, Pan G, Quinn RJ, Reddy DS, Renault JH, Rivera-Chávez J, Robien W, Saunders CM, Schmidt TJ, Seger C, Shen B, Steinbeck C, Stuppner H, Sturm S, Taglialatela-Scafati O, Tantillo DJ, Verpoorte R, Wang BG, Williams CM, Williams PG, Wist J, Yue JM, Zhang C, Xu Z, Simmler C, Lankin DC, Bisson J, and Pauli GF

Subjects
Molecular Conformation, Reproducibility of Results, Biological Products chemistry, Magnetic Resonance Spectroscopy methods
Abstract

Covering: up to 2018With contributions from the global natural product (NP) research community, and continuing the Raw Data Initiative, this review collects a comprehensive demonstration of the immense scientific value of disseminating raw nuclear magnetic resonance (NMR) data, independently of, and in parallel with, classical publishing outlets. A comprehensive compilation of historic to present-day cases as well as contemporary and future applications show that addressing the urgent need for a repository of publicly accessible raw NMR data has the potential to transform natural products (NPs) and associated fields of chemical and biomedical research. The call for advancing open sharing mechanisms for raw data is intended to enhance the transparency of experimental protocols, augment the reproducibility of reported outcomes, including biological studies, become a regular component of responsible research, and thereby enrich the integrity of NP research and related fields.

Published
2019
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49. Association between Subcortical Morphology and Cerebral White Matter Energy Metabolism in Neonates with Congenital Heart Disease.

Author

Gertsvolf N, Votava-Smith JK, Ceschin R, Del Castillo S, Lee V, Lai HA, Bluml S, Paquette L, and Panigrahy A

Subjects
Cerebral Cortex metabolism, Energy Metabolism, Female, Gestational Age, Heart Defects, Congenital metabolism, Humans, Infant, Newborn, Infant, Premature, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Male, Multivariate Analysis, White Matter diagnostic imaging, Cerebral Cortex diagnostic imaging, Heart Defects, Congenital diagnostic imaging, Metabolomics methods, White Matter metabolism
Abstract

Complex congenital heart disease (CHD) is associated with neurodevelopmental impairment, the mechanism of which is unknown. Cerebral cortical dysmaturation in CHD is linked to white matter abnormalities, including developmental vulnerability of the subplate, in relation to oxygen delivery and metabolism deficits. In this study, we report associations between subcortical morphology and white matter metabolism in neonates with CHD using quantitative magnetic resonance imaging (MRI) and spectroscopy (MRS). Multi-modal brain imaging was performed in three groups of neonates close to term-equivalent age: (1) term CHD (n = 56); (2) preterm CHD (n = 37) and (3) preterm control group (n = 22). Thalamic volume and cerebellar transverse diameter were obtained in relation to cerebral metrics and white matter metabolism. Short echo single-voxel MRS of parietal and frontal white matter was used to quantitate metabolites related to brain maturation (n-acetyl aspartate [NAA], choline, myo-inositol), neurotransmitter (glutamate), and energy metabolism (glutamine, citrate, creatine and lactate). Multi-variate regression was performed to delineate associations between subcortical morphological measurements and white matter metabolism controlling for age and white matter injury. Reduced thalamic volume, most pronounced in the preterm control group, was associated with increased citrate levels in all three group in the parietal white matter. In contrast, reduced cerebellar volume, most pronounced in the preterm CHD group, was associated with reduced glutamine in parietal grey matter in both CHD groups. Single ventricle anatomy, aortic arch obstruction, and cyanotic lesion were predictive of the relationship between reduced subcortical morphometry and reduced GLX (particularly glutamine) in both CHD cohorts (frontal white matter and parietal grey matter). Subcortical morphological associations with brain metabolism were also distinct within each of the three groups, suggesting these relationships in the CHD groups were not directly related to prematurity or white matter injury alone. Taken together, these findings suggest that subplate vulnerability in CHD is likely relevant to understanding the mechanism of both cortical and subcortical dysmaturation in CHD infants. Future work is needed to link this potential pattern of encephalopathy of CHD (including the constellation of grey matter, white matter and brain metabolism deficits) to not only abnormal fetal substrate delivery and oxygen conformance, but also regional deficits in cerebral energy metabolism.

Published
2018
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