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Warren A Zuckerman, Adriana Zeevi, Kristen L Mason, Brian Feingold, Carol Bentlejewski, Linda J Addonizio, Elizabeth D Blume, Charles E Canter, Anne I Dipchand, Daphne T Hsu, Robert E Shaddy, William T Mahle, Anthony J Demetris, David M Briscoe, Thalachallour Mohanakumar, Joseph M Ahearn, David N Iklé, Brian D Armstrong, Yvonne Morrison, Helena Diop, Jonah Odim, Steven A Webber
Anti-HLA donor-specific antibodies are associated with worse outcomes after organ transplantation. Among sensitized pediatric heart candidates, requirement for negative donor-specific cytotoxicity crossmatch increases wait times and mortality. However, transplantation with positive crossmatch may increase posttransplantation morbidity and mortality. We address this clinical challenge in a prospective, multicenter, observational cohort study of children listed for heart transplantation (Clinical Trials in Organ Transplantation in Children-04 [CTOTC-04])...
February 15, 2018: American Journal of Transplantation
Monal Sharma, Wei Liu, Sudhir Perincheri, Muthukumar Gunasekaran, T Mohanakumar
Long-term success of heart transplantation is hindered by humoral and cell-mediated immune responses. We studied preexisting antibodies to cardiac self-antigens, myosin and vimentin, and exosomes induced by antibodies to self-antigens in eliciting immune responses to cardiac grafts. After syngeneic heterotopic murine heart transplantation, rabbit anti-myosin or normal rabbit immunoglobulin was administered at day 0 or 7. Sera were collected after heartbeat cessation, cellular infiltration was analyzed, and exosomes were isolated from sera...
January 9, 2018: American Journal of Transplantation
P R Aguilar, D Carpenter, J Ritter, R D Yusen, C A Witt, D E Byers, T Mohanakumar, D Kreisel, E P Trulock, R R Hachem
Antibody-mediated rejection (AMR) is an increasingly recognized form of lung rejection. C4d deposition has been an inconsistent finding in previous reports and its role in the diagnosis has been controversial. We conducted a retrospective single-center study to characterize cases of C4d-negative probable AMR and to compare these to cases of definite (C4d-positive) AMR. We identified 73 cases of AMR: 28 (38%) were C4d-positive and 45 (62%) were C4d-negative. The two groups had a similar clinical presentation, and although more patients in the C4d-positive group had neutrophilic capillaritis (54% vs...
April 2018: American Journal of Transplantation
Muthukumar Gunasekaran, Thin Thin Maw, Rowena Delos Santos, Surendra Shenoy, Jason Wellen, T Mohanakumar
BACKGROUND: Immune responses to tissue-restricted self-antigens are thought to play a role in chronic rejection after solid organ transplantation. De novo development of antibodies (Abs) to vimentin have been reported to be associated with interstitial fibrosis/tubular atrophy after kidney transplant, and it has been suggested that immunoglobulin isotype switching of Abs to vimentin may occur during this process. We aimed to determine the correlation between immunoglobulin isotype switching of Abs to vimentin and development of transplant glomerulopathy (TG) after kidney transplant, and to determine whether citrullinated modification of vimentin is required for de novo anti-vimentin development...
September 11, 2017: Transplant Immunology
Deepak K Nayak, Fangyu Zhou, Min Xu, Jing Huang, Moriya Tsuji, Jinsheng Yu, Ramsey Hachem, Andrew E Gelman, Ross M Bremner, Michael A Smith, Thalachallour Mohanakumar
Chronic rejection significantly limits long-term success of solid organ transplantation. De novo donor-specific antibodies (DSAs) to mismatched donor human leukocyte antigen after human lung transplantation predispose lung grafts to chronic rejection. We sought to delineate mediators and mechanisms of DSA pathogenesis and to define early inflammatory events that trigger chronic rejection in lung transplant recipients and obliterative airway disease, a correlate of human chronic rejection, in mouse. Induction of transcription factor zinc finger and BTB domain containing protein 7a (Zbtb7a) was an early response critical in the DSA-induced chronic rejection...
July 12, 2017: Science Translational Medicine
Jun Zou, Brian Duffy, Michael Slade, Andrew Lee Young, Nancy Steward, Ramsey Hachem, T Mohanakumar
Fiberoptic bronchoscopy and transbronchial lung biopsy are currently the gold standard for detection of acute rejection following human lung transplantation (LTx). However, these surveillance procedures are expensive and invasive. Up to now, there are few new methods that have demonstrated clinical utility for detecting early stages of rejection following human lung transplantation. We optimized and technically validated a novel method to quantify donor-derived circulating cell free DNA (DcfDNA) that can be used as an early biomarker for lung allograft rejection...
April 2017: Human Immunology
J Zou, R Romee, M Slade, D Phelan, J Keller, T Mohanakumar, B J Grossman
No abstract text is available yet for this article.
June 2017: Bone Marrow Transplantation
Ankit Bharat, T Mohanakumar
Chronic diseases that result in end-stage organ damage cause inflammation, which can reveal sequestered self-antigens (SAgs) in that organ and trigger autoimmunity. The thymus gland deletes self-reactive T-cells against ubiquitously expressed SAgs, while regulatory mechanisms in the periphery control immune responses to tissue-restricted SAgs. It is now established that T-cells reactive to SAgs present in certain organs (e.g., lungs, pancreas, and intestine) are incompletely eliminated, and the dysregulation of peripheral immuneregulation can generate immune responses to SAgs...
2017: Journal of Immunology Research
Zhongping Xu, Wei Yang, Nancy Steward, Stuart C Sweet, Lara Danziger-Isakov, Peter S Heeger, Thalachallour Mohanakumar
BACKGROUND: Acute rejection (AR) and development of chronic rejection, bronchiolitis obliterans syndrome (BOS) remain major limiting factors for lung transplantation (LTx). This retrospective study is to identify differentially expressed circulating microRNAs (miRNAs) that associate with development of AR and BOS in pediatric lung transplant recipients (LTxR). METHODS: We determined the circulating levels of 7 selected candidate miRNAs in 14 LTxR with AR, 7 with BOS, and compared them against 13 stable pediatric LTxR at 1, 6, and 12 months after LTx...
October 2017: Transplantation
T Sengupta, J Vinayagam, R Singh, P Jaisankar, K P Mohanakumar
Plant-derived natural products have made their own niche in the treatment of neurological diseases since time immemorial. Parkinson's disease (PD), the second most prevalent neurodegenerative disorder, has no cure and the treatment available currently is symptomatic. This chapter thoughtfully and objectively assesses the scientific basis that supports the increasing use of these plant-derived natural products for the treatment of this chronic and progressive disorder. Proper considerations are made on the chemical nature, sources, preclinical tests and their validity, and mechanisms of behavioural or biochemical recovery observed following treatment with various plants derived natural products relevant to PD therapy...
2016: Advances in Neurobiology
Ramiro Fernandez, Stephen Chiu, Kirtee Raparia, Puneet Garcha, Carol Farver, Marie Budev, Anat R Tambur, Malcolm M DeCamp, Scott Budinger, Harris Perlman, T Mohanakumar, Ankit Bharat
A third of lung recipients have preexisting antibodies against nonhuman leukocyte self-antigens (nHAbs) present in the lung tissue. These nHAbs also form de novo in about 70% of patients within 3 years after transplantation. Both preexisting and de novo nHAbs can cause murine lung allograft dysfunction. However, their role in human transplantation remains unclear. We report hyperacute rejection after right lung transplant in a recipient with preexisting nHAbs. The recipient of the left lung from the same donor had an uneventful initial course, but de novo nHAbs developed at 3 weeks, leading to acute humoral rejection...
October 2016: Annals of Thoracic Surgery
Zhenyu Xiao, Babak Banan, Min Xu, Jianluo Jia, Pamela T Manning, Ronald R Hiebsch, Muthukumar Gunasekaran, Gundumi A Upadhya, William A Frazier, Thalachallour Mohanakumar, Yiing Lin, William C Chapman
BACKGROUND: Despite the efficacy of orthotopic liver transplantation in the treatment of end-stage liver diseases, its therapeutic utility is severely limited by the availability of donor organs. The ability to rehabilitate marginal organs, such as steatotic allografts, has the potential to address some of the supply limitations of available organs for transplantation. Steatotic livers are more susceptible to ischemia-reperfusion injury (IRI), which is exacerbated by the thrombospondin-1/CD47 pathway through inhibition of nitric oxide signaling...
July 2016: Transplantation
M Gunasekaran, Z Xu, D K Nayak, M Sharma, R Hachem, R Walia, R M Bremner, M A Smith, T Mohanakumar
The immunological role of exosomes in allograft rejection remains unknown. We sought to determine whether exosomes are induced during lung allograft rejection and to define the antigenic compositions of HLA, lung-associated self-antigens (SAgs) and microRNAs (miRNAs). Exosomes were isolated from sera and bronchoalveolar lavage fluid from 30 lung transplant recipients (LTxRs) who were stable or who had acute rejection (AR) or bronchiolitis obliterans syndrome (BOS). Exosomes were defined by flow cytometry for CD63 and western blotting for annexin V SAgs, collagen V (Col-V) and Kα1 tubulin were examined by electron microscopy; miRNAs were profiled by a miRNA array...
February 2017: American Journal of Transplantation
A J Demetris, C Bellamy, S G Hübscher, J O'Leary, P S Randhawa, S Feng, D Neil, R B Colvin, G McCaughan, J J Fung, A Del Bello, F P Reinholt, H Haga, O Adeyi, A J Czaja, T Schiano, M I Fiel, M L Smith, M Sebagh, R Y Tanigawa, F Yilmaz, G Alexander, L Baiocchi, M Balasubramanian, I Batal, A K Bhan, J Bucuvalas, C T S Cerski, F Charlotte, M E de Vera, M ElMonayeri, P Fontes, E E Furth, A S H Gouw, S Hafezi-Bakhtiari, J Hart, E Honsova, W Ismail, T Itoh, N C Jhala, U Khettry, G B Klintmalm, S Knechtle, T Koshiba, T Kozlowski, C R Lassman, J Lerut, J Levitsky, L Licini, R Liotta, G Mazariegos, M I Minervini, J Misdraji, T Mohanakumar, J Mölne, I Nasser, J Neuberger, M O'Neil, O Pappo, L Petrovic, P Ruiz, Ö Sağol, A Sanchez Fueyo, E Sasatomi, A Shaked, M Shiller, T Shimizu, B Sis, A Sonzogni, H L Stevenson, S N Thung, G Tisone, A C Tsamandas, A Wernerson, T Wu, A Zeevi, Y Zen
The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations...
October 2016: American Journal of Transplantation
Stephen Chiu, Ramiro Fernandez, Vijay Subramanian, Haiying Sun, Malcolm M DeCamp, Daniel Kreisel, Harris Perlman, G R Scott Budinger, Thalachallour Mohanakumar, Ankit Bharat
More than one third of patients with chronic lung disease undergoing lung transplantation have pre-existing Abs against lung-restricted self-Ags, collagen type V (ColV), and k-α1 tubulin (KAT). These Abs can also develop de novo after lung transplantation and mediate allograft rejection. However, the mechanisms leading to lung-restricted autoimmunity remain unknown. Because these self-Ags are normally sequestered, tissue injury is required to expose them to the immune system. We previously showed that respiratory viruses can induce apoptosis in CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs), the key mediators of self-tolerance...
July 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Ankit Bharat, Stephen Chiu, Zhikun Zheng, Haiying Sun, Anjana Yeldandi, Malcolm M DeCamp, Harris Perlman, G R Scott Budinger, Thalachallour Mohanakumar
Over one-third of lung recipients have preexisting antibodies against lung-restricted antigens: collagen (Col) type V and K-α1 tubulin (KAT). Although clinical studies have shown association of these antibodies with primary graft dysfunction (PGD), their biological significance remains unclear. We tested whether preexisting lung-restricted antibodies can mediate PGD and prevent allotolerance. A murine syngeneic (C57BL/6) or allogeneic (C57BL/6 to BALB/c) left lung transplantation model was used. Rabbit polyclonal antibodies were produced against KAT and Col-V and injected pretransplantation...
October 2016: American Journal of Respiratory Cell and Molecular Biology
D K Nayak, F Zhou, M Xu, J Huang, M Tsuji, R Hachem, T Mohanakumar
Steady-state alveolar macrophages (AMs) are long-lived lung-resident macrophages with sentinel function. Evidence suggests that AM precursors originate during embryogenesis and populate lungs without replenishment by circulating leukocytes. However, their presence and persistence are unclear following human lung transplantation (LTx). Our goal was to examine donor AM longevity and evaluate whether AMs of recipient origin seed the transplanted lungs. Origin of AMs was accessed using donor-recipient HLA mismatches...
August 2016: American Journal of Transplantation
William H Hoffman, Monal Sharma, Daniela Cihakova, Monica V Talor, Noel R Rose, T Mohanakumar, Gregory G Passmore
Diabetic cardiomyopathy (DC) is an independent phenotype of diabetic cardiovascular disease. The understanding of the pathogenesis of DC in young patients with type 1 diabetes (T1D) is limited. The cardiac insults of diabetic ketoacidosis (DKA) and progression of DC could include development of antibodies (Abs) to cardiac self-antigens (SAgs) such as: myosin (M), vimentin (V) and k-alpha 1 tubulin (Kα1T). The goal of this study is to determine if the insults of severe DKA and its inflammatory cascade are associated with immune responses to SAgs...
2016: Autoimmunity
Z Xu, S Ramachandran, M Gunasekaran, D Nayak, N Benshoff, R Hachem, A Gelman, T Mohanakumar
Antibodies (Abs) against major histocompatibility complex (MHC) results in T helper-17 (Th17)-mediated immunity against lung self-antigens (SAgs), K-α1 tubulin and collagen V and obliterative airway disease (OAD). Because B cell-activating transcription factor (BATF) controls Th17 and autoimmunity, we proposed that BATF may play a critical role in OAD. Anti-H2K(b) was administered intrabronchially into Batf (-/-) and C57BL/6 mice. Histopathology of the lungs on days 30 and 45 after Ab administration to Batf (-/-) mice resulted in decreased cellular infiltration, epithelial metaplasia, fibrosis, and obstruction...
April 2016: American Journal of Transplantation
Chang Liu, Brian Duffy, Jeffrey J Bednarski, Cecelia Calhoun, Lindsay Lay, Barrett Rundblad, Jacqueline E Payton, Thalachallour Mohanakumar
OBJECTIVES: To report the laboratory investigation of a case of severe combined immunodeficiency (SCID) with maternal T-cell engraftment, focusing on the interference of human leukocyte antigen (HLA) typing by blood chimerism. METHODS: HLA typing was performed with three different methods, including sequence-specific primer (SSP), sequence-specific oligonucleotide, and Sanger sequencing on peripheral blood leukocytes and buccal cells, from a 3-month-old boy and peripheral blood leukocytes from his parents...
February 2016: American Journal of Clinical Pathology
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