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5. Cellular and molecular characterisation of familial haemophagocytic lymphohistiocytosis type 1

Author

Chakravorty, Subarna, Layton, Mark, and Karadimitris, Anastasios

Subjects
616.042
Abstract

Haemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory condition in which absent or markedly reduced T cell and natural killer (NK) cell cytotoxicity results in uncontrolled proliferation of T cells, activation of macrophages, hypercytokinaemia, pancytopaenia, and hepatosplenomegaly. Familial HLH (FHL), an autosomal recessive disorder affecting young infants and children, is fatal unless treated with chemotherapy and allogeneic haemopoietic stem cell transplantation. Mutations in the gene encoding perforin, a lytic protein involved in cell cytotoxicity, account for 30% of cases of FHL (FHL II). Mutations in genes encoding hMunc 13-4, syntaxin 11, and syntaxin binding protein 2, all essential for perforin release and T/NK cell cytotoxicity, have also been identified in FHL (FHL III IV and V respectively). A previous report form our group showed that in the UK, in consanguineous families of Pakistani descent, FHL (designated FHL I) maps to 9q21.3-22 in an area spanning 5Mb and containing 14 genes. The aim of my project was to identify the gene responsible for FHL I and to study the function of the corresponding protein. Based on the premise that similar to other types of FHL, the protein product of FHL I candidate gene would function in the perforin-dependent cytotoxic pathway, 4 out of the 14 genes emerged as strong functional candidates: KIF27, RASEF, UBQLN1 and FRMD3. My mutation screening strategy aimed at amplifying and sequencing all exons and intronexon boundaries of the candidate genes, followed by screening the remaining genes of the FHL I locus. The material used was either genomic DNA extracted from 4 parental and 1 patient B cell line, or cDNA from the latter. In 2 newly identified patients, genomic DNA from granulocytes was used. PCR amplification of genomic DNA and direct sequencing or cloning and sequencing of individual clones or in some cases direct sequencing of the full length cDNA from the patient B cell line did not reveal any mutations in any of the known genes in the FHL I locus. For KIF27, mutations were excluded in gene regulatory areas by amplification and direct sequencing of the whole promoter region, up to 1kb upstream of the transcription start site. KIF27 protein expression was also studied by immunoblotting and immunostaining followed by confocal microscopy but no abnormality was identified at protein level. Promoter area mutation was also excluded in UBQLN1, the other strong candidate. The gene responsible for FHL I remains unidentified. Further refinement of the locus with high-density SNP arrays in newly diagnosed patients demonstrating linkage to the FHL I locus might help identify the gene responsible for FHL I.

Published
2011
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9. Contributors

Author

Alsousou, Joseph, primary, Angiolillo, Dominick J., additional, Arachiche, Amal, additional, Aster, Richard H., additional, Barbui, Tiziano, additional, Basili, Stefania, additional, Battinelli, Elisabeth M., additional, Bavry, Anthony A., additional, Bergmeier, Wolfgang, additional, Bertrand, Gerald, additional, Bhatt, Deepak L., additional, Blair, Thomas A., additional, Bledzka, Kamila, additional, Borst, Oliver, additional, Bouck, Emma G., additional, Brass, Lawrence F., additional, Bray, Paul F., additional, Briggs, Carol, additional, Brzoska, Tomasz, additional, Bussel, James B., additional, Cattaneo, Marco, additional, Chakravorty, Subarna, additional, Chan, Noel C., additional, Chaturvedi, Shruti, additional, Chong, Beng H., additional, Clemetson, Kenneth J., additional, Clemetson, Jeannine M., additional, Coller, Barry S., additional, del Zoppo, Gregory J., additional, Despotovic, Jenny M., additional, Diamond, Scott L., additional, Easton, J. Donald, additional, Eto, Koji, additional, Falet, Hervé, additional, Ferrer-Marin, Francisca, additional, Finazzi, Guido, additional, Flaumenhaft, Robert, additional, Freedman, Jane E., additional, Frelinger, Andrew L., additional, Freson, Kathleen, additional, Gasecka, Aleksandra, additional, Gawaz, Meinrad, additional, Giannini, Silvia, additional, Greinacher, Andreas, additional, Gremmel, Thomas, additional, Gurbel, Paul A., additional, Haining, Elizabeth J., additional, Han, Xu, additional, Harrison, Paul, additional, Hayward, Catherine P.M., additional, Hoffmeister, Karin, additional, Hvas, Anne-Mette, additional, Israels, Sara J., additional, Italiano, Joseph E., additional, Jeong, Young-Hoon, additional, Johnson, Andrew D., additional, Kaplan, Cecile, additional, Karagiannis, Peter, additional, Kato, Gregory J., additional, Kemble, Samuel, additional, Kolandaivelu, Kumaran, additional, Koupenova, Milka, additional, Kuter, David J., additional, Lambert, Michele P., additional, Lee, Robert H., additional, Levin, Jack, additional, Li, Renhao, additional, Li, Zhenyu, additional, Li, Zihai, additional, Li, Anqi, additional, Liani, Rossella, additional, Lordkipanidzé, Marie, additional, Lorenz, Viola, additional, Machlus, Kellie R., additional, Mahtta, Dhruv, additional, Mannucci, Pier Mannuccio, additional, McCrae, Keith R., additional, Metelli, Alessandra, additional, Michelson, Alan D., additional, Moffat, Karen A., additional, Moon, Jae Youn, additional, Morrissey, James H., additional, Mutch, Nicola J., additional, Nagy, Zoltan, additional, Ni, Heyu, additional, Nicolson, Phillip L.R., additional, Nieman, Marvin T., additional, Nieuwland, Rienk, additional, Onselaer, Marie-Blanche, additional, Patrono, Carlo, additional, Plow, Edward F., additional, Poncz, Mortimer, additional, Poon, Man-Chiu, additional, Poulter, Natalie S., additional, Poventud-Fuentes, Izmarie, additional, Provost, Patrick, additional, Qin, Jun, additional, Rayes, Julie, additional, Reiner, Alexander P., additional, Riesenberg, Brian, additional, Roberts, Irene A.G., additional, Rondina, Matthew T., additional, Rowley, Jesse W., additional, Santilli, Francesca, additional, Scharf, Rüdiger E., additional, Senis, Yotis A., additional, Sharda, Anish, additional, Siddon, Alexa J., additional, Siljander, Pia R.-M., additional, Tricoci, Pierluigi, additional, Simeone, Paola, additional, Smith, Stephanie A., additional, Smyth, Susan S., additional, Snyder, Edward L., additional, Sola-Visner, Martha, additional, Stalker, Timothy J., additional, Stefanini, Lucia, additional, Sugimoto, Naoshi, additional, Sundd, Prithu, additional, Tantry, Udaya S., additional, Tefferi, Ayalew, additional, Thomas, Steven G., additional, Thomas, Mark R., additional, Tomaiuolo, Maurizio, additional, Tormey, Christopher A., additional, Tsai, Han-Mou, additional, Violi, Francesco, additional, Warkentin, Theodore E., additional, Watson, Steve P., additional, Weitz, Jeffrey I., additional, Welsh, John, additional, Weyrich, Andrew S., additional, Wilcox, David A., additional, Wu, Bill X., additional, Yeaman, Michael R., additional, Zhu, Li, additional, Zimmerman, Guy A., additional, and Zunica, Elizabeth R., additional

Published
2019
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12. Structural connectivity mediates the relationship between blood oxygenation and cognitive function in sickle cell anemia

Author

Clayden, Jonathan D, primary, Stotesbury, Hanne, additional, Kawadler, Jamie M, additional, Slee, April, additional, Koelbel, Melanie, additional, Saunders, Dawn E, additional, Hood, Anna M, additional, Wilkey, Olu, additional, Layton, Mark, additional, Inusa, Baba PD, additional, Pelidis, Maria, additional, Chakravorty, Subarna, additional, Rees, David C, additional, Howard, Jo, additional, Awogbade, Moji, additional, Liossi, Christina, additional, Kirkham, Fenella J, additional, and Clark, Chris A, additional

Published
2022
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14. White matter integrity and processing speed in sickle cell anemia

Author

Stotesbury, Hanne, Kirkham, Fenella J., Kölbel, Melanie, Balfour, Philippa, Clayden, Jonathan D., Sahota, Sati, Sakaria, Simrat, Saunders, Dawn E., Howard, Jo, Kesse-Adu, Rachel, Inusa, Baba, Pelidis, Maria, Chakravorty, Subarna, Rees, David C., Awogbade, Moji, Wilkey, Olu, Layton, Mark, Clark, Christopher A., and Kawadler, Jamie M.

Published
2018
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18. Quantification of Silent Cerebral Infarction on High-Resolution FLAIR and Cognition in Sickle Cell Anemia

Author

Stotesbury, Hanne, primary, Kawadler, Jamie M., additional, Clayden, Jonathan D., additional, Saunders, Dawn E., additional, Hood, Anna M., additional, Koelbel, Melanie, additional, Sahota, Sati, additional, Rees, David C., additional, Wilkey, Olu, additional, Layton, Mark, additional, Pelidis, Maria, additional, Inusa, Baba P. D., additional, Howard, Jo, additional, Chakravorty, Subarna, additional, Clark, Chris A., additional, and Kirkham, Fenella J., additional

Published
2022
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19. Individual Watershed Areas in Sickle Cell Anemia: An Arterial Spin Labeling Study

Author

Stotesbury, Hanne, primary, Hales, Patrick W., additional, Hood, Anna M., additional, Koelbel, Melanie, additional, Kawadler, Jamie M., additional, Saunders, Dawn E., additional, Sahota, Sati, additional, Rees, David C., additional, Wilkey, Olu, additional, Layton, Mark, additional, Pelidis, Maria, additional, Inusa, Baba P. D., additional, Howard, Jo, additional, Chakravorty, Subarna, additional, Clark, Chris A., additional, and Kirkham, Fenella J., additional

Published
2022
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20. The risk of hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type 2

Author

Jessen, Birthe, Bode, Sebastian F.N., Ammann, Sandra, Chakravorty, Subarna, Davies, Graham, Diestelhorst, Jana, Frei-Jones, Melissa, Gahl, William A., Gochuico, Bernadette R., Griese, Matthias, Griffiths, Gillian, Janka, Gritta, Klein, Christoph, Kögl, Tamara, Kurnik, Karin, Lehmberg, Kai, Maul-Pavicic, Andrea, Mumford, Andrew D., Pace, David, Parvaneh, Nima, Rezaei, Nima, de Saint Basile, Geneviève, Schmitt-Graeff, Annette, Schwarz, Klaus, Karasu, Gulsun T., Zieger, Barbara, zur Stadt, Udo, Aichele, Peter, and Ehl, Stephan

Published
2013
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21. sj-pdf-1-jcb-10.1177_0271678X211072391 - Supplemental material for Venous cerebral blood flow quantification and cognition in patients with sickle cell anemia

Author

Stotesbury, Hanne, Hales, Patrick W, Koelbel, Melanie, Hood, Anna M, Kawadler, Jamie M, Saunders, Dawn E, Sahota, Sati, Rees, David C, Wilkey, Olu, Layton, Mark, Pelidis, Maria, Inusa, Baba PD, Howard, Jo, Chakravorty, Subarna, Clark, Chris A, and Kirkham, Fenella J

Subjects
110320 Radiology and Organ Imaging, FOS: Clinical medicine, FOS: Biological sciences, Medicine, Cell Biology, 110305 Emergency Medicine, 110306 Endocrinology, Biochemistry, 69999 Biological Sciences not elsewhere classified, 110904 Neurology and Neuromuscular Diseases, Neuroscience
Abstract

Supplemental material, sj-pdf-1-jcb-10.1177_0271678X211072391 for Venous cerebral blood flow quantification and cognition in patients with sickle cell anemia by Hanne Stotesbury, Patrick W Hales, Melanie Koelbel, Anna M Hood, Jamie M Kawadler, Dawn E Saunders, Sati Sahota, David C Rees, Olu Wilkey, Mark Layton, Maria Pelidis, Baba PD Inusa, Jo Howard, Subarna Chakravorty, Chris A Clark and Fenella J Kirkham in Journal of Cerebral Blood Flow & Metabolism

Published
2022
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26. Average Lifetime Hemoglobin Concentration Improves Prediction of Cognitive Outcomes in Pediatric Patients with Sickle Cell Anemia

Author

Hood, Anna M, primary, Stotesbury, Hanne, additional, Fadahunsi-Oduyemi, Simisola, additional, Kawadler, Jamie M, additional, Koelbel, Melanie, additional, Sahota, Satwinder, additional, Chakravorty, Subarna, additional, Wilkey, Olu, additional, Kirkham, Fenella Jane, additional, Howard, Joanna, additional, and Inusa, Baba PD, additional

Published
2021
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28. Study of montelukast in children with sickle cell disease (SMILES): a study protocol for a randomised controlled trial

Author

Hood, Anna M., primary, Stotesbury, Hanne, additional, Kölbel, Melanie, additional, DeHaan, Michelle, additional, Downes, Michelle, additional, Kawadler, Jamie M., additional, Sahota, Satwinder, additional, Dimitriou, Dagmara, additional, Inusa, Baba, additional, Wilkey, Olu, additional, Pelidis, Maria, additional, Trompeter, Sara, additional, Leigh, Andrea, additional, Younis, Janine, additional, Drasar, Emma, additional, Chakravorty, Subarna, additional, Rees, David C., additional, Height, Sue, additional, Lawson, Sarah, additional, Gavlak, Johanna, additional, Gupta, Atul, additional, Ridout, Deborah, additional, Clark, Christopher A., additional, and Kirkham, Fenella J., additional

Published
2021
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31. Bridging the Gap 2021- Report

Author

Chakravorty, Indranil, primary, Daga, Sunil, additional, Sharma, Shivani, additional, Chakravorty, Subarna, additional, Fischer, Martin, additional, and Mehta, Ramesh, additional

Published
2021
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33. Bridging the Gap 2021- Summary Report

Author

Chakravorty, Indranil, primary, Daga, Sunil, additional, Sharma, Shivani, additional, Fischer, Martin, additional, Chakravorty, Subarna, additional, and Mehta, Ramesh, additional

Published
2021
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34. Biopsychosocial Predictors of Quality of Life in Paediatric Patients With Sickle Cell Disease

Author

Hood, Anna M., primary, Kölbel, Melanie, additional, Stotesbury, Hanne, additional, Kawadler, Jamie, additional, Slee, April, additional, Inusa, Baba, additional, Pelidis, Maria, additional, Howard, Jo, additional, Chakravorty, Subarna, additional, Height, Sue, additional, Awogbade, Moji, additional, Kirkham, Fenella J., additional, and Liossi, Christina, additional

Published
2021
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43. List of Contributors

Author

Andrews, Robert K., primary, Aster, Richard H., additional, Atkinson, Ben T, additional, Barnard, Marc R., additional, Bavry, Anthony A., additional, Bayer, Arnold S., additional, Beaulieu, Lea M., additional, Berndt, Michael C., additional, Berny-Lang, Michelle A., additional, Bhatt, Deepak L., additional, Bizzaro, Nicola, additional, Bledzka, Kamila, additional, Bouchard, Beth A., additional, Brass, Lawrence F., additional, Bray, Paul F., additional, Briggs, Carol, additional, Bussel, James B., additional, Cattaneo, Marco, additional, Chakravorty, Subarna, additional, Chong, Beng H., additional, Clemetson, Jeannine, additional, Clemetson, Kenneth J., additional, Coller, Barry S., additional, Covic, Lidija, additional, Davì, Giovanni, additional, del Zoppo, Gregory J., additional, Dowling, Mark R., additional, Dubois, Christophe, additional, Eisert, Wolfgang G., additional, Evangelista, Virgilio, additional, Flaumenhaft, Robert, additional, Freedman, Jane E., additional, Freedman, John, additional, Frelinger, Andrew L., additional, Furie, Barbara C., additional, Furie, Bruce, additional, Gardiner, Chris, additional, Gawaz, Meinrad, additional, Geisler, Tobias, additional, Greinacher, Andreas, additional, Gurbel, Paul A., additional, Harrison, Paul, additional, Hartwig, John H., additional, Hayward, Catherine P.M., additional, Hughes, Craig E., additional, Ikeda, Yasuo, additional, Israels, Sara J., additional, Italiano, Joseph E., additional, Jackson, Shaun, additional, Jain, Shashank, additional, Jones, Chris I., additional, Josefsson, Emma C., additional, Kaplan, Cécile, additional, Kile, Benjamin T., additional, Kimura, Yukio, additional, Klement, Giannoula Lakka, additional, Kolandaivelu, Kumaran, additional, Kuliopulos, Athan, additional, Kuter, David J., additional, Lambert, Michelle P., additional, Langer, Harald F., additional, Lebois, Marion, additional, Levin, Jack, additional, Lordkipanidzé, Marie, additional, Ma, Yan-Qing, additional, Mannucci, Pier Mannuccio, additional, McCrae, Keith R., additional, Merrill-Skoloff, Glenn, additional, Michelson, Alan D., additional, Moffat, Karen A., additional, Mutch, Nicola J., additional, Newman, Debra K., additional, Newman, Peter E., additional, Ni, Heyu, additional, Nieuwland, Rienk, additional, Ouwehand, Willem H., additional, Parsons, Jeremy, additional, Patrono, Carlo, additional, Perrotta, Peter L., additional, Pesho, Michelle M., additional, Plow, Edward F., additional, Politt, Alice Y., additional, Poncz, Mortimer, additional, Poon, Man-Chiu, additional, Provost, Patrick, additional, Psaila, Bethan, additional, Rao, A. Koneti, additional, Rinder, Henry M., additional, Roberts, Irene A.G., additional, Rondina, Matthew T., additional, Ruggeri, Zaverio M., additional, Santilli, Francesca, additional, Schwertz, Hansjörg, additional, Shai, Ela, additional, Silveira, Jay R., additional, Smith, Brian R., additional, Smith, Matthew C., additional, Smyth, Susan S., additional, Snyder, Edward L., additional, Sobel, Michael, additional, Soranzo, Nicole, additional, Stalker, Timothy J., additional, Sturk, Auguste, additional, Sudo, Toshiki, additional, Sullivan, Spencer, additional, Tantry, Udaya S., additional, Tefferi, Ayalew, additional, Tracy, Paul B., additional, Tsai, Han-Mou, additional, van der Pol, Edwin, additional, Varon, David, additional, Vazzana, Natale, additional, Vieira-de-Abreu, Adriana, additional, Wannemacher, Kenneth, additional, Ware, Jerry, additional, Warkentin, Theodore E., additional, Watson, Steve P., additional, Weyrich, Andrew S., additional, White, James G., additional, Wilcox, David A., additional, Yeaman, Michael R., additional, Zhang, Ping, additional, Zhu, Li, additional, and Zimmerman, Guy A., additional

Published
2013
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46. Clinical management of sickle cell liver disease in children and young adults

Author

Kyrana, Eirini, primary, Rees, David, additional, Lacaille, Florence, additional, Fitzpatrick, Emer, additional, Davenport, Mark, additional, Heaton, Nigel, additional, Height, Sue, additional, Samyn, Marianne, additional, Mavilio, Fulvio, additional, Brousse, Valentine, additional, Suddle, Abid, additional, Chakravorty, Subarna, additional, Verma, Anita, additional, Gupte, Girish, additional, Velangi, Marki, additional, Inusa, Baba, additional, Drasar, Emma, additional, Hadzic, Nedim, additional, Grammatikopoulos, Tassos, additional, Hind, Jonathan, additional, Deheragoda, Maesha, additional, Sellars, Maria, additional, and Dhawan, Anil, additional

Published
2020
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49. Contributors

Author

Abhyankar, Aruna, primary, Agrawal, Shruti, additional, Allen, Stephen J, additional, Ani, Cornelius, additional, Bishop, Jonathan, additional, Booth, Ian, additional, Boyle, Robert J, additional, Brodlie, Malcolm, additional, Chakravorty, Subarna, additional, Clarke, Angus John, additional, Clayden, Graham, additional, Dimitri, Paul, additional, Dommett, Rachel, additional, Foster, Helen E, additional, Hodges, Stephen, additional, Jaques, Siobhan, additional, Jandial, Sharmila, additional, Kerecuk, Larissa, additional, Lagunju, Ike, additional, Lander, Anthony, additional, Lissauer, Tom, additional, McDonagh, Janet E, additional, McKean, Michael C, additional, Newton, Richard W, additional, Pard´ñaz-Sol´s, Raúl, additional, Patel, Sanjay, additional, Prendergast, Andrew, additional, Roberts, Irene AG, additional, Salter, Rebecca C, additional, Sidebotham, Peter, additional, Sim, Kathleen, additional, Siou, Gerard P S, additional, Smyth, Diane P L, additional, Stevens, Michael, additional, Mark, Professor, additional, Taylor, Sharon E, additional, David, Professor, additional, Tudor-Williams, Gareth, additional, Tulloh, Robert M R, additional, Verbov, Julian L, additional, Wales, Jerry K H, additional, Wilkinson, Andrew R, additional, and Wimalasundera, Neil, additional

Published
2012
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50. What is the role of chest X‐ray imaging in the acute management of children with sickle cell disease?

Author

Griffin, Ryan, Panayiotou, Andreas, Allen, Pamela, Height, Sue, Chakravorty, Subarna, and Rees, David C.

Subjects
SICKLE cell anemia, COUGH, X-ray imaging, CHEST X rays, ELECTRONIC records, HOSPITAL records
Abstract

Summary: Children with sickle cell disease (SCD) frequently present to hospital acutely unwell and are often exposed to diagnostic chest X‐rays (CXRs). Little evidence exists to determine when CXRs are clinically useful. Using electronic hospital records, we audited CXR use in children aged 0–18 who presented to hospital over the past 10 years in both an inpatient and emergency department setting. From a total of 915 first CXRs, only 28·2% of CXRs (n = 258) had clinically significant findings that altered management or final diagnosis. Of these abnormalities, consolidation represented 52·3%, effusion 8·9%, cardiomegaly 8·4% and sickle cell‐related bone changes 6·3%. Indications for CXR of respiratory distress (OR = 3·74, 95% CI 2·28–6·13), hypoxia (OR = 1·86, 95% CI 1·50–2·31) and cough (OR = 1·64, 95% CI 1·33–2·02), were more likely to have significant CXR findings. Patients who had higher peak fever (38·4°C vs. 37·4°C, P = 0·001), higher peak CRP (156·4 vs. 46·1, P < 0·001) and higher WCC (20·2 vs. 13·6, P < 0·001) were more likely to have clinically significant abnormalities on CXR. We found a decision tool using either hypoxia, cough, respiratory distress, T > 38°C, CRP > 50 or WCC > 15 × 109/l as indications for CXR, to have a sensitivity of 88% (with 95% CI 0·78–0·95) and specificity of 46% (95% CI 0·43–0·50) for clinically significant findings. [ABSTRACT FROM AUTHOR]

Published
2022
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