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Gupta P, Kumar R. MicroRNAs in sickle cell disease: A comprehensive review. Gene 2025; 957:149470. [PMID: 40187617 DOI: 10.1016/j.gene.2025.149470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 03/28/2025] [Accepted: 04/01/2025] [Indexed: 04/07/2025]
Abstract
Sickle cell disease (SCD) is a multifactorial disease characterized by a high incidence of morbidity and mortality due to chronic hemolysis, inflammation and oxidative stress. Recent studies have highlighted the crucial role of microRNAs (miRNAs) in regulating key pathophysiological processes in SCD, including high levels of fetal hemoglobin production, and reduction in inflammation and cellular adhesion. This comprehensive review discusses the current understanding of miRNAs in SCD, including their potential as biomarkers and therapeutic targets. Furthermore, despite substantial evidences indicating that malaria exacerbates SCD, the review will explore the complex interplay between miRNAs and SCD, with a focus on the exacerbating effects of malaria on SCD severity. Understanding the complex interplay between miRNAs and SCD may lead to the development of novel therapeutic interventions aimed at ameliorating disease severity and improving patient outcomes. Future prospects, challenges and safety concerns related to miRNA-based therapies, highlighting the need for further research.
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Affiliation(s)
- Parul Gupta
- ICMR-National Institute of Research in Tribal Health, Jabalpur, Madhya Pradesh, India
| | - Ravindra Kumar
- ICMR-National Institute of Research in Tribal Health, Jabalpur, Madhya Pradesh, India; Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, India.
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Ala C, Ramalingam S, Kondapalli Venkata Gowri CS, Sankaranarayanan M. A critique review of fetal hemoglobin modulators through targeting epigenetic regulators for the treatment of sickle cell disease. Life Sci 2025; 369:123536. [PMID: 40057227 DOI: 10.1016/j.lfs.2025.123536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 03/02/2025] [Accepted: 03/03/2025] [Indexed: 03/30/2025]
Abstract
Sickle cell disease (SCD) is one of the most prevalent hereditary blood disorders characterized by aberrant hemoglobin synthesis that causes red blood cells (RBCs) to sickle and result in vaso-occlusion. The complex pathophysiological mechanisms that underlie SCD are explored in this study, including hemoglobin polymerization, the formation of fetal hemoglobin (HbF), and hemoglobin switching regulation. Notably, pharmaceutical approaches like hydroxyurea, l-glutamine, voxelotor, and crizanlizumab, in addition to therapeutic techniques like gene therapies like Casgevy and Lyfgenia, signify noteworthy advancements in the management of issues connected to SCD. Furthermore, the deciphering of the molecular mechanisms that dictate hemoglobin switching has revealed several potentially therapeutic targets, including key transcriptional repressors such as β-cell lymphoma/leukemia 11A (BCL11A), Zinc finger and BTB domain-containing 7A (ZBTB7A), Nuclear Factor IX (NFIX), and Nuclear Factor IA (NFIA), which play crucial roles in γ-globin silencing. Additionally, transcriptional activators such as Nuclear Factor Y (NF-Y), and Hypoxia-inducible factor 1α (HIF1α) have emerged as promising regulators that can disrupt repression and enhance HbF synthesis. Other epigenetic regulators, such as lysine-specific histone demethylase 1 (LSD1), euchromatic histone methyltransferases 1/2 (EHMT1/2), histone deacetylases (HDACs), DNA methyltransferases (DNMTs), and protein arginine methyltransferases (PRMTs). It has been demonstrated that inhibiting these targets can prevent the silencing of the gene encoding for the formation of γ-chains and, in turn, increase the synthesis of HbF, providing a possible treatment option for SCD symptoms. These approaches could pave the way for innovative, mechanism-driven therapies that address the unmet medical needs of SCD patients.
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Affiliation(s)
- Chandu Ala
- Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Pilani 333031, Rajasthan, India.
| | - Sivaprakash Ramalingam
- Department of Biological Sciences and Bioengineering, Mehta Family Centre for Engineering in Medicine, Indian Institute of Technology, Kanpur, Uttar Pradesh, India.
| | - Chandra Sekhar Kondapalli Venkata Gowri
- Department of Chemistry, Birla Institute of Technology and Science Pilani, Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Hyderabad 500078, Telangana, India.
| | - Murugesan Sankaranarayanan
- Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Pilani 333031, Rajasthan, India.
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Butt H, Sathish S, London E, Lee Johnson T, Essawi K, Leonard A, Tisdale JF, Demirci S. Genome editing strategies for targeted correction of β-globin mutation in sickle cell disease: From bench to bedside. Mol Ther 2025; 33:2154-2171. [PMID: 40165374 DOI: 10.1016/j.ymthe.2025.03.047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2025] [Revised: 03/22/2025] [Accepted: 03/26/2025] [Indexed: 04/02/2025] Open
Abstract
Sickle cell disease (SCD) includes a range of genotypes that result in a clinical syndrome, where abnormal red blood cell (RBC) physiology leads to widespread complications affecting nearly every organ system. Treatment strategies for SCD can be broadly categorized into disease-modifying therapies and those aimed toward a cure. Although several disease-modifying drugs have been approved, they do not fully address the complexity and severity of SCD. Recent advances in allogeneic transplantation and autologous gene therapy show promising outcomes in terms of efficacy and safety. While these approaches have improved the lives of many patients, achieving a durable and comprehensive cure for all remains challenging. To address this, gene-editing technologies, including zinc-finger nucleases, TALENs, CRISPR-Cas, base editing, and prime editing, have been explored both ex vivo and in vivo for targeted correction of the β-globin gene (HBB) in SCD. However, direct correction of HBB and its translation from the laboratory to the clinic presents ongoing limitations, with challenges involved in achieving robust mutation-correction efficiency, off-target effects, and high costs of therapies. The optimal strategy for curing SCD remains uncertain, but several promising approaches are emerging. This review touches on past, present, and future developments in HBB correction.
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Affiliation(s)
- Henna Butt
- Cellular and Molecular Therapeutics Branch (CMTB), National Heart Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20814, USA
| | - Shruti Sathish
- Cellular and Molecular Therapeutics Branch (CMTB), National Heart Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20814, USA
| | - Evan London
- Cellular and Molecular Therapeutics Branch (CMTB), National Heart Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20814, USA
| | - Taylor Lee Johnson
- Cellular and Molecular Therapeutics Branch (CMTB), National Heart Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20814, USA
| | - Khaled Essawi
- Department of Medical Laboratory Technology, College of Applied Medical Sciences, Jazan University, Gizan 45142, Saudi Arabia
| | - Alexis Leonard
- Cellular and Molecular Therapeutics Branch (CMTB), National Heart Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20814, USA; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - John F Tisdale
- Cellular and Molecular Therapeutics Branch (CMTB), National Heart Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20814, USA.
| | - Selami Demirci
- Cellular and Molecular Therapeutics Branch (CMTB), National Heart Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20814, USA.
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Viggiano D, Iulianiello P, Mancini A, Iacuzzo C, Apicella L, Di Pietro RA, Hamzeh S, Cacciola G, Lippiello E, Gigliotti A, Secondulfo C, Bilancio G, Gigliotti G. Immunological Avalanches in Renal Immune Diseases. Biomedicines 2025; 13:1003. [PMID: 40299571 PMCID: PMC12024534 DOI: 10.3390/biomedicines13041003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2025] [Revised: 04/04/2025] [Accepted: 04/09/2025] [Indexed: 05/01/2025] Open
Abstract
The complex nature of immune system behavior in both autoimmune diseases and transplant rejection can be understood through the lens of avalanche dynamics in critical-point systems. This paper introduces the concept of the "immunological avalanche" as a framework for understanding unpredictable patterns of immune activity in both contexts. Just as avalanches represent sudden releases of accumulated potential energy, immune responses exhibit periods of apparent stability followed by explosive flares triggered by seemingly minor stimuli. The model presented here draws parallels between immune system behavior and other complex systems such as earthquakes, forest fires, and neuronal activity, where localized events can propagate into large-scale disruptions. In autoimmune conditions like systemic lupus erythematosus (SLE), which affects multiple organ systems including the kidneys in approximately 50% of patients, these dynamics manifest as alternating periods of remission and flares. Similarly, in transplant recipients, the immune system exhibits metastable behavior under constant allograft stimulation. This critical-point dynamics framework is characterized by threshold-dependent activation, positive feedback loops, and dynamic non-linearity. In autoimmune diseases, triggers such as UV light exposure, infections, or stress can initiate cascading immune responses. In transplant patients, longitudinal analysis reveals how monitoring oscillatory patterns in blood parameters and biological age markers can predict rejection risk. In a preliminary study on kidney transplant, all measured variables showed temporal instability. Proteinuria exhibited precise log-log linearity in power law analysis, confirming near-critical-point system behavior. Two distinct dynamic patterns emerged: large oscillations in eGFR, proteinuria, or biological age predicted declining function, while small oscillations indicated stability. During avalanche events, biological age increased dramatically, with partial reversal leaving persistent elevation after acute episodes. Understanding these dynamics has important implications for therapeutic approaches in both contexts. Key findings suggest that monitoring parameter oscillations, rather than absolute values, better indicates system instability and potential avalanche events. Additionally, biological age calculations provide valuable prognostic information, while proteinuria measurements offer efficient sampling for system dynamics assessment. This conceptual model provides a unifying framework for understanding the pathogenesis of both autoimmune and transplant-related immune responses, potentially leading to new perspectives in disease management and rejection prediction.
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Affiliation(s)
- Davide Viggiano
- Department Translational Medical Sciences, University of Campania, 80131 Naples, Italy; (P.I.); (G.C.)
| | - Pietro Iulianiello
- Department Translational Medical Sciences, University of Campania, 80131 Naples, Italy; (P.I.); (G.C.)
| | - Antonio Mancini
- Department of Nephrology and Dialysis, Eboli Hospital, 84025 Eboli, Italy; (A.M.); (A.G.); (G.G.)
| | - Candida Iacuzzo
- Unit of Nephrology, Dialysis and Transplantation, Salerno University Hospital, 84131 Salerno, Italy; (C.I.); (L.A.); (R.A.D.P.)
| | - Luca Apicella
- Unit of Nephrology, Dialysis and Transplantation, Salerno University Hospital, 84131 Salerno, Italy; (C.I.); (L.A.); (R.A.D.P.)
| | - Renata Angela Di Pietro
- Unit of Nephrology, Dialysis and Transplantation, Salerno University Hospital, 84131 Salerno, Italy; (C.I.); (L.A.); (R.A.D.P.)
| | - Sarah Hamzeh
- Department of Public Health, Federico II University of Naples, 80131 Naples, Italy;
| | - Giovanna Cacciola
- Department Translational Medical Sciences, University of Campania, 80131 Naples, Italy; (P.I.); (G.C.)
| | - Eugenio Lippiello
- Department Mathematics and Physics, University of Campania, 81100 Caserta, Italy;
| | - Andrea Gigliotti
- Department of Nephrology and Dialysis, Eboli Hospital, 84025 Eboli, Italy; (A.M.); (A.G.); (G.G.)
| | - Carmine Secondulfo
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (C.S.)
| | - Giancarlo Bilancio
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (C.S.)
| | - Giuseppe Gigliotti
- Department of Nephrology and Dialysis, Eboli Hospital, 84025 Eboli, Italy; (A.M.); (A.G.); (G.G.)
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Magalhães NNS, Mathiasi LB, Werneck Rodrigues DDO. Importance of neonatal screening: A case study of sickle cell disease and cystic fibrosis coexistence. World J Clin Pediatr 2025; 14:97537. [DOI: 10.5409/wjcp.v14.i1.97537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 09/10/2024] [Accepted: 09/30/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Neonatal screening (NS) is a public health policy to identify genetic pathologies such as cystic fibrosis (CF), sickle cell disease, and other diseases. Sickle cell disease is the comprehensive term for a group of hemoglobinopathies characterized by the presence of hemoglobin S. CF is an autosomal recessive multisystemic disease with pathophysiology involving deleterious mutations in the transmembrane regulatory gene that encodes a protein that regulates the activity of chloride and sodium channels in the cell surface epithelium. NS is crucial for early diagnosis and management, which ensures a better quality of life.
AIM To report a case of the coexistence of sickle cell anemia (SCA) and CF and perform an integrative literature review.
METHODS This is an observational study and a review of the literature focusing on two rare genetic pathologies identified simultaneously in NS from the perspective of a clinical case. The authors identified only 5 cases of SCA associated with CF. No clinical trials or review articles were identified considering the rarity of the coexistence of these two pathologies.
RESULTS Herein, the authors reported the case of a girl who after undergoing NS on day 8 of life was diagnosed with SCA with an alteration in the dosage of immunoreactive trypsin. The diagnosis of CF was confirmed by the Coulometry Sweat Test. The rarity of the co-occurrence of these two severe genetic pathologies (CF and SCA) is a challenge for medical science.
CONCLUSION This study adds to the few case reports present in the literature that highlight the identification of two severe diseases via NS.
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Affiliation(s)
| | - Lucas Barra Mathiasi
- Department of Internal Medicine, Rede D'Or Rio de Janeiro, Rio de Janeiro 22270-010, Brazil
| | - Daniela de Oliveira Werneck Rodrigues
- Department of Hematology, Fundação Hemominas, Juiz de Fora 36010-560, MG, Brazil
- Department of Internal Medicine, Universidade Presidente Antônio Carlos - Faculdade de Medicina Juiz de Fora, Juiz de Fora 36010-560, Minas Gerais, Brazil
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Illa AC, Hvid H, Elm T, Frederiksen CA, Bangshof LF, Danielsen DF, Skov S, Dan Ley C. From early development to maturity: a phenotypic analysis of the Townes sickle cell disease mice. Biol Open 2025; 14:bio061828. [PMID: 39912492 PMCID: PMC11832121 DOI: 10.1242/bio.061828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 01/07/2025] [Indexed: 02/07/2025] Open
Abstract
Well-characterised mouse models of disease may provide valuable insights into pathophysiology. This study characterises the Townes mouse model of sickle cell disease (SCD) and establishes a time window in which the disease is present but does not progress significantly in terms of severity. We examined Townes mice with the HbAA, HbAS, and HbSS genotypes from young (4 weeks) to mature (5 months) stages of life to assess the disease state at different ages and any progression. We conducted blood tests, histological organ damage evaluations, and metabolic assessments to identify a suitable time frame for study based on welfare considerations. Townes HbSS mice displayed key SCD features such as anaemia, haemolysis, thromboinflammation and organ pathology. Notably, these manifestations remained relatively stable over the study period, indicating a stable phase suitable for conducting intervention studies. Mice with HbAS and HbAA genotypes served as comparative controls, showing minimal to no pathology throughout. These findings are valuable for future research on SCD and may ultimately lead to the development of more effective treatments for this debilitating disease.
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Affiliation(s)
- Ariadna Carol Illa
- Rare Disease Research, Global Drug Discovery, Novo Nordisk A/S, 2760 Måløv, Denmark
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg C, Denmark
| | - Henning Hvid
- Global Discovery & Development Sciences, Global Drug Discovery, Novo Nordisk A/S, 2760 Måløv, Denmark
| | - Torben Elm
- Rare Disease Research, Global Drug Discovery, Novo Nordisk A/S, 2760 Måløv, Denmark
| | | | | | | | - Søren Skov
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg C, Denmark
| | - Carsten Dan Ley
- Rare Disease Research, Global Drug Discovery, Novo Nordisk A/S, 2760 Måløv, Denmark
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Ogunde G, Shabi A, Akinyemi JO. Statistical exploration of factors associated with birth of children having sickle cell traits among reproductive-age women in Nigeria. BMC Public Health 2025; 25:419. [PMID: 39894815 PMCID: PMC11789406 DOI: 10.1186/s12889-025-21559-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 01/20/2025] [Indexed: 02/04/2025] Open
Abstract
BACKGROUND Despite the relatively high prevalence of Sickle cell trait (SCT) in Nigeria, there has been little research into the correlates of having children with SCT among Nigerian mothers, particularly in terms of socio-demographic differentials. This study aims to investigate the maternal socio-demographic correlates of having under-five children with SCT in Nigeria. METHOD Data from the 2018 Nigeria Demographic and Health Survey (Household Person Recode and Children Recode) were merged. Mothers with at least one under-five child whose genotype was known (n = 7,493) served as the unit of analysis. Three forms of outcome variable were explored. First was the number of children with SCT by each mother. Second, the number of children with SCT was categorized as zero, one, two or more. Lastly, each mother was categorized as either having no child(ren) with SCT or having at least one child with SCT. Subsequently, we assessed multilevel Poisson, ordinal and binary logit models to identify the best fitting model using Akaike and Bayesian Information Criterion. Multilevel binary logistic regression model was identified as best fit used to identify factors associated with having children with SCT. Adjusted Odds Ratio with 95% Confidence Interval (CI) were reported as measures of association. RESULT Nearly 62% of the mothers lived in rural areas, 38.2% had no formal education and 37.4% had ever given birth to at least five children. About 26.1% (95% CI = 25.2-26.9) of the mothers had children with SCT. By geographical variation, the Northwest region had the highest proportion of mothers of under-five children with SCT. Results from the multilevel binary logistic regression revealed that women who were traditionalists (AOR = 1.77; 95% CI = 1.04-3.02) were more likely of having children with SCT. CONCLUSION Though SCT is a genetic outcome, findings from this study suggest that important socio-demographic factors such as religion, and region of residence are significantly associated with having children with SCT in Nigeria. Sustained efforts on awareness campaigns on SCT are recommended.
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Affiliation(s)
- Gabriel Ogunde
- Department of Epidemiology and Medical Statistics, Faculty of Public Health, College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria.
| | - Ayodele Shabi
- Department of Epidemiology and Medical Statistics, Faculty of Public Health, College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria
| | - Joshua O Akinyemi
- Department of Epidemiology and Medical Statistics, Faculty of Public Health, College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria
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Reddy SP, Jondhale SN, Rathia SK, Yusuf S, Shah S, Goel AK. Ketorolac vs Morphine for Severe Vaso-Occlusive Crisis in Sickle Cell Disease: An Open-Label Randomized Controlled Trial (KISS Study). Indian Pediatr 2025; 62:15-19. [PMID: 39754425 DOI: 10.1007/s13312-025-3351-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 10/13/2024] [Indexed: 01/06/2025]
Abstract
OBJECTIVES To compare the efficacy and safety of intravenous (IV) ketorolac and IV morphine in the management of severe vaso-occlusive crisis (VOC) in children with sickle cell disease (SCD). METHOD An open-label, randomized controlled trial was conducted from January 2021 to July 2022 wherein children with SCD aged 3 to 15 years, presenting with severe VOC (score > 6 on the Wong-Baker Faces Pain scale) were included. Block randomization with minimization was done and participants received either IV ketorolac (intervention) or IV morphine infusion (standard). The pain score was reassessed three hourly and if the pain score exceeded 6, the drug dose was escalated every 3 hours, upto a maximum of three escalating doses. A pain score of ≤ 6 were regarded as response. RESULTS The mean (SD) pain scores at admission in the ketorolac and morphine groups were 9.28 (0.89) and 9.12 (1.01), respectively (P = 0.636). At 3, 6, 9, and 12 hours of infusion, the mean pain scores in the ketorolac and morphine groups were 8.04 (1.24) vs 8.28 (1.24), P = 0.313; 7.04 (1.210) vs 7.28 (1.28), P = 0.331; 6.40 (1.26) vs 6.28 (1.17), P = 0.860; and 5.56 (1.00) vs 5.60 (1.04), P = 0.817, respectively. Five and eleven children developed minor side effects in the ketorolac and morphine groups, respectively (P = 0.069). Overall, one child in the ketorolac group and two in the morphine persisted to have severe pain even after 12 hours of therapy (P = 0.55). CONCLUSION Intravenous ketorolac may be considered as a good alternative to IV morphine in the management of severe VOC in SCD.
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Affiliation(s)
- Sai Pratap Reddy
- Department of Pediatrics, All India Institute of Medical Sciences, Raipur, Chhattisgarh, India
| | - Sunil Natha Jondhale
- Department of Pediatrics, All India Institute of Medical Sciences, Raipur, Chhattisgarh, India
| | - Santosh Kumar Rathia
- Department of Pediatrics, All India Institute of Medical Sciences, Raipur, Chhattisgarh, India
| | - Samreen Yusuf
- Department of Pediatrics, All India Institute of Medical Sciences, Raipur, Chhattisgarh, India
| | - Seema Shah
- Department of Pediatrics, All India Institute of Medical Sciences, Raipur, Chhattisgarh, India
| | - Anil Kumar Goel
- Department of Pediatrics, All India Institute of Medical Sciences, Raipur, Chhattisgarh, India. Correspondence to: Dr Anil Kumar Goel, Department of Pediatrics, All India Institute of Medical Sciences, Raipur, Chhattisgarh, India.
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Adesina OO, Jenkins IC, Galvão F, de Moura AC, Fertrin KY, Zemel BS, Saad STO. Alendronate preserves bone mineral density in adults with sickle cell disease and osteoporosis. Osteoporos Int 2025; 36:93-102. [PMID: 39433652 PMCID: PMC11706892 DOI: 10.1007/s00198-024-07268-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 09/23/2024] [Indexed: 10/23/2024]
Abstract
Low bone mineral density is highly prevalent in sickle cell disease (SCD); whether bisphosphonates can safely preserve or increase bone mass in SCD adults remains unknown. In this study, lumbar spine bone density remained stable with alendronate use, and treatment-related side effects were mostly mild and self-limited. PURPOSE To describe the effects of alendronate in adults with sickle cell disease (SCD) and osteoporosis. METHODS We reviewed retrospective clinical data from adults with SCD and osteoporosis treated with alendronate at a single center in Brazil (2009-2019). Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA) of the lumbar spine, femoral neck, and total hip. We analyzed BMD changes by alendronate treatment duration (months), stratified by sex, skeletal site, and SCD genotype. RESULTS Sixty-four SCD adults with osteoporosis (69% females, 73% HbSS, mean age ± standard deviation 42.4 ± 10.9 years) received alendronate for a median (interquartile range) of 48 (29, 73) months. Compared with males, females had significantly lower baseline BMD (g/cm2) at the femoral neck (0.72 vs 0.85, p = < 0.001) and total hip (0.79 vs 0.88, p = 0.009). The between-sex differences in BMD changes were insignificant. Mean lumbar spine BMD significantly changed by 0.0357 g/cm2 (p = 0.028) in those on alendronate for > 5 years. Four adults (6.3%) reported mild therapy-related side effects. An atypical femoral diaphysis fracture, attributed to alendronate, was incidentally noted in a 37-year-old man on treatment for 4 years. CONCLUSION In this retrospective cohort of adults with SCD and osteoporosis on alendronate for a median of 48 months, we found no significant interactions between sex and changes in lumbar spine, femoral neck, or total hip BMD with alendronate. Lumbar spine BMD was stable in those on alendronate for < 5 years. Side effects of alendronate were mild, though one patient developed an atypical femoral fracture.
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Affiliation(s)
- Oyebimpe O Adesina
- Division of Hematology and Oncology, University of California, Davis School of Medicine, 4501 X Street, Suite 3016, Sacramento, CA, 95817, USA.
| | - Isaac C Jenkins
- Department of Clinical Biostatistics, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Fábio Galvão
- Hematology and Transfusion Medicine Center, University of Campinas - UNICAMP, Campinas, SP, Brazil
| | - Ana C de Moura
- Hematology and Transfusion Medicine Center, University of Campinas - UNICAMP, Campinas, SP, Brazil
| | - Kleber Y Fertrin
- Division of Hematology and Oncology, University of Washington School of Medicine, Seattle, WA, USA
| | - Babette S Zemel
- Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Sara T Olalla Saad
- Hematology and Transfusion Medicine Center, University of Campinas - UNICAMP, Campinas, SP, Brazil
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10
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Gollamudi J, Adesina O. Should we use bisphosphonates to treat bone complications in sickle cell disease? HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2024; 2024:623-626. [PMID: 39644017 DOI: 10.1182/hematology.2024000671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/09/2024]
Affiliation(s)
- Jahnavi Gollamudi
- Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Oyebimpe Adesina
- Division of Hematology and Oncology, University of California Davis School of Medicine, Sacramento, CA
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Laredo J, Torres-Small S, Wu L, Makishima T, Richard C. Vestibular Dysfunction in Patients With Sickle Cell Disease: A Systematic Review. Otol Neurotol 2024; 45:1098-1107. [PMID: 39379006 DOI: 10.1097/mao.0000000000004327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/10/2024]
Abstract
INTRODUCTION Sickle cell disease (SCD) often leads to sensorineural hearing loss due to vaso-occlusive events in the cochlear vasculature. Although the vestibule and cochlea share a blood supply, information on vestibulopathy in SCD is limited. This systematic review aims to consolidate current knowledge on vestibular dysfunction in SCD patients. METHODS This study, registered on PROSPERO, involved a thorough electronic search using MEDLINE-Ovid, Embase, Google Scholar, The Cochrane Library, and Scopus databases from inception to December 2023. Data extraction adhered to PRISMA guidelines. Authors independently assessed bias and evidence quality using NIH Study Quality Assessment tools. Inclusion criteria covered articles mentioning vestibular symptoms in SCD patients, whereas exclusion criteria comprised non-English articles and vestibular symptoms limited to treatment side effects. RESULTS Out of 2,495 studies, only 12 met the criteria. Among SCD patients undergoing head imaging, 19% reported inner ear complaints, and 70% experienced dizziness/imbalance. In a group of SCD children, there was a significant relationship between endothelial dysfunction and vertigo duration. The recommended imaging sequence was T1-weighted thin-section temporal bone MRIs, which revealed abnormal findings even without clinical symptoms. Imaging showed labyrinthine hemorrhage and labyrinthitis ossificans, mostly unilateral. Vestibular symptoms emerged with older age, suggesting cortical compensation kept most subjects asymptomatic. In asymptomatic adult SCD patients, there was no significant difference compared with controls in tracking test batteries and positional tests; however, saccadic latency was longer in SCD patients. CONCLUSION The existing data on vestibulopathy in SCD were limited and often of poor quality. Although a connection between SCD and vestibular symptoms was noted, information on treatment approaches was scant. Further research in this area could contribute to the early diagnosis of vestibular dysfunction, potentially enhancing outcomes for SCD patients.
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Affiliation(s)
- Jonathan Laredo
- University of Tennessee Health Science Center, Memphis, Tennessee
| | | | - Lin Wu
- Research and Learning Services, University of Tennessee Health Science Center Library, Memphis, Tennessee
| | - Tomoko Makishima
- Department of Otolaryngology-Head and Neck Surgery, University of Texas Medical Branch, Galveston, Texas
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12
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Islam MR, Rauf A, Akash S, Sharker M, Mahreen M, Munira MAK, Dhar PS, Hemeg HA, Iriti M, Imran M. Targeted therapeutic management based on phytoconstituents for sickle cell anemia focusing on molecular mechanisms: Current trends and future perspectives. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 133:155936. [PMID: 39128304 DOI: 10.1016/j.phymed.2024.155936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 03/28/2024] [Accepted: 08/03/2024] [Indexed: 08/13/2024]
Abstract
The global epidemic of Sickle cell anemia (SCA) is causing thousands of children to die. SCA, a genetic disorder affecting the hemoglobin-globin chain, affects millions globally. The primary physiological issue in these patients is the polymerization of sickle hemoglobin within their red blood cells (RBCs) during their deoxygenating state. The RBC undergoes a sickle shape due to the polymerization of mutant hemoglobin within it and membrane deformation during anoxic conditions. To prevent complications, it is essential to effectively stop the sickling of RBCs of the patients. Various medications have been studied for treating SCA patients, focusing on antisickling, γ-globulin induction, and antiplatelet action. Natural and synthetic anti-sickling agents can potentially reduce patient clinical morbidity. Numerous clinical trials focused on using natural remedies for the symptomatic therapy of SCA. Medicinal plants and phytochemical agents have antisickling properties. Recent studies on plant extracts' natural compounds have primarily focused on in vitro RBCs sickling studies, with limited data on in vivo studies. This review discussed the potential role of phytoconstituents in the management of SCA.
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Affiliation(s)
- Md Rezaul Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka 1216, Bangladesh
| | - Abdur Rauf
- Department of Chemistry, University of Swabi, Anbar 23561, Khyber Pakhtunkhwa, Pakistan.
| | - Shopnil Akash
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka 1216, Bangladesh
| | - Muntasir Sharker
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka 1216, Bangladesh
| | - Mashiat Mahreen
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka 1216, Bangladesh
| | - Most Ayesha Khatun Munira
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka 1216, Bangladesh
| | - Puja Sutro Dhar
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka 1216, Bangladesh
| | - Hassan A Hemeg
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taibah University, Al-Madinah Al-Monawara, Saudi Arabia
| | - Marcello Iriti
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, via Celoria 2, 20133, Milan, Italy; National Interuniversity Consortium of Materials Science and Technology (INSTM), 50121 Firenze, Italy.
| | - Muhammad Imran
- Chemistry Department, Faculty of Science, King Khalid University, P.O. Box 9004, Abha 61413, Saudi Arabia
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Xue J, Li XA. Therapeutics for sickle cell disease intravascular hemolysis. Front Physiol 2024; 15:1474569. [PMID: 39345787 PMCID: PMC11427376 DOI: 10.3389/fphys.2024.1474569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Accepted: 09/02/2024] [Indexed: 10/01/2024] Open
Abstract
Sickle cell disease (SCD) is a genetic disorder predominantly affecting individuals of African descent, with a significant global health burden. SCD is characterized by intravascular hemolysis, driven by the polymerization of mutated hemoglobin within red blood cells (RBCs), leading to vascular inflammation, organ damage, and heme toxicity. Clinical manifestations include acute pain crises, hemolytic anemia, and multi-organ dysfunction, imposing substantial morbidity and mortality challenges. Current therapeutic strategies mitigate these complications by increasing the concentration of RBCs with normal hemoglobin via transfusion, inducing fetal hemoglobin, restoring nitric oxide signaling, inhibiting platelet-endothelium interaction, and stabilizing hemoglobin in its oxygenated state. While hydroxyurea and gene therapies show promise, each faces distinct challenges. Hydroxyurea's efficacy varies among patients, and gene therapies, though effective, are limited by issues of accessibility and affordability. An emerging frontier in SCD management involves harnessing endogenous clearance mechanisms for hemolysis products. A recent work by Heggland et al. showed that CD-36-like proteins mediate heme absorption in hematophagous ectoparasite, a type of parasite that feeds on the blood of its host. This discovery underscores the need for further investigation into scavenger receptors (e.g., CD36, SR-BI, SR-BII) for their possible role in heme uptake and detoxification in mammalian species. In this review, we discussed current SCD therapeutics and the specific stages of pathophysiology they target. We identified the limitations of existing treatments and explored potential future developments for novel SCD therapies. Novel therapeutic targets, including heme scavenging pathways, hold the potential for improving outcomes and reducing the global burden of SCD.
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Affiliation(s)
- Jianyao Xue
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, United States
| | - Xiang-An Li
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, United States
- Lexington VA Healthcare System, Lexington, KY, United States
- Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, United States
- Saha Cardiovascular Research Center, University of Kentucky College of Medicine, Lexington, KY, United States
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Kearson L, Dandar C, Hoyt C, Longoria J, Okhomina V, Raches D, Potter B, Kang G, Hankins J, Takemoto C, Heitzer A. Prediction of Functional Academic Outcomes by Fine Motor Skills in Individuals With Sickle Cell Disease. Am J Occup Ther 2024; 78:7805205180. [PMID: 39102271 PMCID: PMC11526265 DOI: 10.5014/ajot.2024.050684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/06/2024] Open
Abstract
IMPORTANCE Individuals with sickle cell disease (SCD) are at heightened risk of poor neurocognitive and academic outcomes. The relationship between fine motor skills and academic outcomes is not well understood. OBJECTIVE To compare the fine motor skills of individuals with SCD with normative expectations, test whether demographic and medical factors are associated with fine motor performance, and determine the impact of fine motor performance on academic performance. DESIGN Cross-sectional. SETTING St. Jude Children's Research Hospital. PARTICIPANTS Individuals with SCD (N = 376; ages 8-24 yr). OUTCOMES AND MEASURES Fine motor outcomes included visual-motor integration, manual dexterity, and graphomotor speed. Academic outcomes included math fluency and word reading. Demographic and medical variables were obtained via medical records and interviews. RESULTS Compared with normative expectations, the performance of individuals with SCD on all fine motor measures was lower than expected. Male sex, lower socioeconomic status, and lower oxygen saturation was associated with slower graphomotor speed. Lower socioeconomic status and older age were associated with lower visual-motor integration scores. Performance on all fine motor measures was positively associated with math fluency and word reading. CONCLUSIONS AND RELEVANCE Individuals with SCD exhibited poorer than expected fine motor skills across multiple motor domains, and these deficits were associated with poorer academic outcomes. Early referral to intervention services for fine motor skills may facilitate improved academic outcomes for individuals with SCD. Plain-Language Summary: This study had three objectives: (1) Compare the fine motor skills of people with sickle cell disease (SCD) with normative expectations, (2) test whether demographic and medical factors are associated with fine motor performance, and (3) determine the impact of fine motor performance on academic performance. We found that SCD is a risk factor for lower than expected fine motor performance across multiple fine motor domains and that these deficits also affect functional academic skills.
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Affiliation(s)
- Lakia Kearson
- Lakia Kearson, PsyD, is Neuropsychology Fellow, Department of Psychology and Biobehavioral Sciences, St. Jude Children's Research Hospital, Memphis, TN
| | - Christina Dandar
- Christina Dandar, MA, is Neuropsychology Intern, Department of Psychology and Biobehavioral Sciences, St. Jude Children's Research Hospital, Memphis, TN
| | - Catherine Hoyt
- Catherine Hoyt, PhD, OTD, FAOTA, OTR/L, is Assistant Professor of Occupational Therapy, Neurology, and Pediatrics, Department of Pediatrics and Medicine, School of Medicine, Washington University in St. Louis, St. Louis, MO
| | - Jennifer Longoria
- Jennifer Longoria, PhD, is Neuropsychologist, Department of Psychology and Biobehavioral Sciences, St. Jude Children's Research Hospital, Memphis, TN
| | - Victoria Okhomina
- Victoria Okhomina, MPH, MS, is Biostatistician, Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN
| | - Darcy Raches
- Darcy Raches, PhD, is Neuropsychologist, Department of Psychology and Biobehavioral Sciences, St. Jude Children's Research Hospital, Memphis, TN
| | - Brian Potter
- Brian Potter, PhD, is Neuropsychologist, Department of Psychology and Biobehavioral Sciences, St. Jude Children's Research Hospital, Memphis, TN
| | - Guolian Kang
- Guolian Kang, PhD, is Biostatistician, Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN
| | - Jane Hankins
- Jane Hankins, MD, is Director of Global Hematology Program, Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN
| | - Clifford Takemoto
- Clifford Takemoto, MD, is Director of Clinical Hematology, Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN
| | - Andrew Heitzer
- Andrew Heitzer, PhD, is Neuropsychologist, Department of Psychology and Biobehavioral Sciences, St. Jude Children's Research Hospital, Memphis, TN;
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Ahmad L, Aljoujou AA, Nadra R, Mashlah AM, Al Beesh FA, Alyafi A, Moulay Driss H. The Association Between Dental Caries and Salivary Buffering Capacity in Syrian Patients Diagnosed with Sickle Cell Disease. Cureus 2024; 16:e64887. [PMID: 39156342 PMCID: PMC11330576 DOI: 10.7759/cureus.64887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/19/2024] [Indexed: 08/20/2024] Open
Abstract
Background Sickle cell disease (SCD) is a genetic disorder caused by mutations in the HBB gene, resulting in the abnormal shape of red blood cells. This condition is accompanied by various oral manifestations including salivary gland dysfunction leading to a heightened susceptibility to dental caries. This disorder is primarily treated with hydroxyurea. This study aims to assess dental caries utilizing the decay, missing, filling teeth (DMFT) index and evaluate salivary buffering capacity in patients diagnosed with SCD (HbSS type). The study also aims to assess the relationship between DMFT and salivary buffering capacity. Additionally, the study aimed to find a correlation between treatment with hydroxyurea and changes in both dental caries and salivary buffering capacity. Methods This case-control study enrolled a total of 100 participants aged between 20 and 50 years. The participants were divided into two groups: the study group, which comprised 70 individuals diagnosed with SCD (HbSS type), who were asked to report their current use of hydroxyurea, and the control group, which included 30 healthy individuals. Dental caries were assessed using the DMFT index, while salivary buffering capacity was measured using a pH meter model 420A device. Results The study group exhibited a mean DMFT index value of 6.39 compared to 5.20 in the control group. This difference was statistically significant (P-value=0.037), indicating higher DMFT values among patients with SCD. Salivary buffering capacity was significantly lower in the study group compared to the control group, with average values of 6.47 and 6.88, (P-value=.022). Interestingly, the administration of hydroxyurea impacted salivary buffering capacity, resulting in lower values for individuals using the drug (P-value=0.039). Conversely, hydroxyurea did not have a significant effect on DMFT values (P-value=0.317). Conclusion SCD increases susceptibility to dental caries and is associated with significant changes in salivary composition. At the same time, the potential negative impact of hydroxyurea is acknowledged.
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Affiliation(s)
- Lynn Ahmad
- Department of Oral Medicine and Radiology, University of Damascus, Faculty of Dentistry, Damascus, SYR
| | - Abeer A Aljoujou
- Department of Oral Medicine and Radiology, University of Damascus, Faculty of Dentistry, Damascus, SYR
| | - Reem Nadra
- Department of Biology, University of Damascus, Faculty of Dentistry, Damascus, SYR
| | - Ammar Mahmoud Mashlah
- Department of Oral Medicine and Radiology, University of Damascus, Faculty of Dentistry, Damascus, SYR
| | - Fatima AlZahraa Al Beesh
- Department of Oral Medicine and Radiology, University of Damascus, Faculty of Dentistry, Damascus, SYR
| | - Amr Alyafi
- Department of Oral Medicine and Radiology, University of Damascus, Faculty of Dentistry, Damascus, SYR
| | - Haina Moulay Driss
- Department of Dentistry, University of Damascus, Faculty of Dentistry, Damascus, SYR
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Bhatt S, Argueta DA, Gupta K, Kundu S. Red Blood Cells as Therapeutic Target to Treat Sickle Cell Disease. Antioxid Redox Signal 2024; 40:1025-1049. [PMID: 37975291 DOI: 10.1089/ars.2023.0348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2023]
Abstract
Significance: Sickle cell disease (SCD) is the most common inherited diathesis affecting mostly underserved populations globally. SCD is characterized by chronic pain and fatigue, severe acute painful crises requiring hospitalization and opioids, strokes, multiorgan damage, and a shortened life span. Symptoms may appear shortly after birth, and, in less developed countries, most children with SCD die before attaining age 5. Hematopoietic stem cell transplant and gene therapy offer a curative therapeutic approach, but, due to many challenges, are limited in their availability and effectiveness for a majority of persons with SCD. A critical unmet need is to develop safe and effective novel targeted therapies. A wide array of drugs currently undergoing clinical investigation hold promise for an expanded pharmacological armamentarium against SCD. Recent Advances: Hydroxyurea, the most widely used intervention for SCD management, has improved the survival in the Western world and more recently, voxelotor (R-state-stabilizer), l-glutamine, and crizanlizumab (anti-P-selectin antibody) have been approved by the Food and Drug Administration (FDA) for use in SCD. The recent FDA approval emphasizes the need to revisit the advances in understanding the core pathophysiology of SCD to accelerate novel evidence-based strategies to treat SCD. The biomechanical breakdown of erythrocytesis, the core pathophysiology of SCD, is associated with intrinsic factors, including the composition of hemoglobin, membrane integrity, cellular volume, hydration, andoxidative stress. Critical Issues and Future Directions: In this context, this review focuses on advances in emerging nongenetic interventions directed toward the therapeutic targets intrinsic to sickle red blood cells (RBCs), which can prevent impaired rheology of RBCs to impede disease progression and reduce the sequelae of comorbidities, including pain, vasculopathy, and organ damage. In addition, given the intricate pathophysiology of the disease, it is unlikely that a single pharmacotherapeutic intervention will comprehensively ameliorate the multifaceted complications associated with SCD. However, the availability of multiple drug options affords the opportunity for individualized therapeutic regimens tailored to specific SCD-related complications. Furthermore, it opens avenues for combination drug therapy, capitalizing on distinct mechanisms of action and profiles of adverse effects.
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Affiliation(s)
- Shruti Bhatt
- Department of Biochemistry, University of Delhi South Campus, New Delhi, India
| | - Donovan A Argueta
- Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, Irvine, California, USA
| | - Kalpna Gupta
- Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, Irvine, California, USA
| | - Suman Kundu
- Department of Biochemistry, University of Delhi South Campus, New Delhi, India
- Department of Biological Sciences, Birla Institute of Technology and Science Pilani, KK Birla Goa Campus, Goa, India
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17
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Bossy AO, Yahaya JJ, Jumanne S. Prevalence and predictors of iron deficiency anaemia among children with sickle cell disease in Dodoma, Tanzania: a cross-sectional study. BMC Public Health 2024; 24:1026. [PMID: 38609881 PMCID: PMC11015568 DOI: 10.1186/s12889-024-18438-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 03/26/2024] [Indexed: 04/14/2024] Open
Abstract
BACKGROUND Patients with sickle cell disease (SCD) are prone to iron profile derangements. This study aimed to determine the prevalence of iron deficiency anaemia (IDA) and their predictors among children with SCD aged between 6 months and 14 years. Assessment of the prevalence of IDA and its predictors helps to understand ways of alleviating the magnitude of the problem so as to prevent possible complications such as shortness of breath and chest pain. METHODS This was a cross-sectional analytical hospital-based study which included 174 patients with SCD attending SCD clinics at St. Gema hospital and Dodoma regional referral hospital in Dodoma city from October 2020 to March 2021. The cut-off points for detection of IDA was serum ferritin level < 30 µg/L and low mean corpuscular volume (MCV) for age. Data were analyzed using SPSS software version 25.0. Multivariate logistic regression analysis was used to determine the predictors of IDA. P-value less than 0.05 was considered significant. RESULTS The prevalence of IDA in this study was (16.1%, n = 28). Family income of less than 70,000/= TZS/month (AOR = 2.2, 95% CI = 1.07-2.49, p = 0.023), being transfused with blood less than 3 times from the time of being diagnosed with SCD (AOR = 5.5, 95% CI = 1.03-8.91, p = 0.046), and eating red meat at least once per month (AOR = 3.60, 95% CI = 1.37-9.46, p = 0.010) remained the independent predictors of IDA in multivariate regression analysis. CONCLUSION The findings of this study have shown that, support of families with children suffering from SCD in terms of financial support for improving medical services including optimal blood transfusion and affordability of diet which is rich in iron such as red meat is imperative.
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Affiliation(s)
- Asha O Bossy
- Department of Pediatrics and Child Health, School of Medicine and Dentistry, University of Dodoma, Dodoma, Tanzania
- Department of Pediatrics and Child Health, Morogoro Regional Referral Hospital, Morogoro, Tanzania
| | - James J Yahaya
- Department of Pathology, School of Health Sciences, Soroti University, Soroti, P. O. Box 211, Uganda.
| | - Shakilu Jumanne
- Department of Pediatrics and Child Health, School of Medicine and Dentistry, University of Dodoma, Dodoma, Tanzania
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Pistoia L, Meloni A, Positano V, Longo F, Borsellino Z, Spasiano A, Righi R, Renne S, Izzo D, Savino K, Mavrogeni S, Quaia E, Cademartiri F, Pepe A. Multiparametric Cardiac Magnetic Resonance Assessment in Sickle Beta Thalassemia. Diagnostics (Basel) 2024; 14:691. [PMID: 38611604 PMCID: PMC11012026 DOI: 10.3390/diagnostics14070691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 03/18/2024] [Accepted: 03/21/2024] [Indexed: 04/14/2024] Open
Abstract
Cardiac involvement in sickle beta thalassemia (Sβ-thal) patients has been poorly investigated. We aimed to evaluate cardiac function and myocardial iron overload by cardiovascular magnetic resonance (CMR) in patients with Sβ-thal. One-hundred and eleven Sβ-thal patients consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) network were studied and compared with 46 sickle cell anemia (SCA) patients and with 111 gender- and age- matched healthy volunteers. Cine images were acquired to quantify biventricular function. Myocardial iron overload (MIO) was assessed by the T2* technique, while macroscopic myocardial fibrosis was evaluated by the late gadolinium enhancement (LGE) technique. In Sβ-thal and SCA patients, the morphological and functional CMR parameters were not significantly different, except for the left atrial area and left ventricular (LV) stroke volume, indexed by body surface area (p = 0.023 and p = 0.048, respectively), which were significantly higher in SCA patients. No significant differences between the two groups were found in terms of myocardial iron overload and macroscopic myocardial fibrosis. When compared to healthy subjects, Sβ-thal patients showed significantly higher bi-atrial and biventricular parameters, except for LV ejection fraction, which was significantly lower. The CMR analysis confirmed that Sβ-thal and SCA patients are phenotypically similar. Since Sβ-thal patients showed markedly different morphological and functional indices from healthy subjects, it would be useful to identify Sβ-thal/SCA-specific bi-atrial and biventricular reference values.
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Affiliation(s)
- Laura Pistoia
- Unità Operativa Complessa Ricerca Clinica, Fondazione G. Monasterio CNR—Regione Toscana, 56124 Pisa, Italy;
- Department of Radiology, Fondazione G. Monasterio CNR—Regione Toscana, 56124 Pisa, Italy; (A.M.); (V.P.); (F.C.)
| | - Antonella Meloni
- Department of Radiology, Fondazione G. Monasterio CNR—Regione Toscana, 56124 Pisa, Italy; (A.M.); (V.P.); (F.C.)
- Bioengineering Unit, Fondazione G. Monasterio CNR—Regione Toscana, 56124 Pisa, Italy
| | - Vincenzo Positano
- Department of Radiology, Fondazione G. Monasterio CNR—Regione Toscana, 56124 Pisa, Italy; (A.M.); (V.P.); (F.C.)
- Bioengineering Unit, Fondazione G. Monasterio CNR—Regione Toscana, 56124 Pisa, Italy
| | - Filomena Longo
- Unità Operativa Day Hospital della Talassemia e delle Emoglobinopatie, Azienda Ospedaliero-Universitaria “S. Anna”, 44124 Ferrara, Italy;
| | - Zelia Borsellino
- Unità Operativa Complessa Ematologia con Talassemia, ARNAS Civico “Benfratelli-Di Cristina”, 90134 Palermo, Italy;
| | - Anna Spasiano
- Unità Operativa Semplice Dipartimentale Malattie Rare del Globulo Rosso, Azienda Ospedaliera di Rilievo Nazionale “A. Cardarelli”, 80131 Napoli, Italy;
| | - Riccardo Righi
- Diagnostica per Immagini e Radiologia Interventistica, Ospedale del Delta, 44023 Ferrara, Italy;
| | - Stefania Renne
- Struttura Complessa di Cardioradiologia-UTIC, Presidio Ospedaliero “Giovanni Paolo II”, 88046 Cosenza, Italy;
| | - Daniela Izzo
- Unità Operativa Complessa di Cardiologia-UTIC, Presidio Ospedaliero “D.ssa Anastasia Guerriero”, 81025 Caserta, Italy;
| | - Ketty Savino
- Sezione di Cardiologia e Fisiopatologia Cardiovascolare, Dipartimento di Medicina e Chirurgia, Università degli Studi di Perugia, 06132 Perugia, Italy;
| | | | - Emilio Quaia
- Istituto di Radiologia, Dipartimento di Medicina, Università di Padova, 35128 Padova, Italy;
| | - Filippo Cademartiri
- Department of Radiology, Fondazione G. Monasterio CNR—Regione Toscana, 56124 Pisa, Italy; (A.M.); (V.P.); (F.C.)
| | - Alessia Pepe
- Istituto di Radiologia, Dipartimento di Medicina, Università di Padova, 35128 Padova, Italy;
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Gupta P, Kumar R. Nitric oxide: A potential etiological agent for vaso-occlusive crises in sickle cell disease. Nitric Oxide 2024; 144:40-46. [PMID: 38316197 DOI: 10.1016/j.niox.2024.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 12/27/2023] [Accepted: 01/29/2024] [Indexed: 02/07/2024]
Abstract
Nitric oxide (NO), a vasodilator contributes to the vaso-occlusive crisis associated with the sickle cell disease (SCD). Vascular nitric oxide helps in vasodilation, controlled platelet aggregation, and preventing adhesion of sickled red blood cells to the endothelium. It decreases the expression of pro-inflammatory genes responsible for atherogenesis associated with SCD. Haemolysis and activated endothelium in SCD patients reduce the bioavailability of NO which promotes the severity of sickle cell disease mainly causes vaso-occlusive crises. Additionally, NO depletion can also contribute to the formation of thrombus, which can cause serious complications such as stroke, pulmonary embolism etc. Understanding the multifaceted role of NO provides valuable insights into its therapeutic potential for managing SCD and preventing associated complications. Various clinical trials and studies suggested the importance of artificially induced nitric oxide and its supplements in the reduction of severity. Further research on the mechanisms of NO depletion in SCD is needed to develop more effective treatment strategies and improve the management of this debilitating disease.
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Affiliation(s)
- Parul Gupta
- ICMR-National Institute of Research in Tribal Health, India
| | - Ravindra Kumar
- ICMR-National Institute of Research in Tribal Health, India.
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20
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Elia E, Caneparo C, McMartin C, Chabaud S, Bolduc S. Tissue Engineering for Penile Reconstruction. Bioengineering (Basel) 2024; 11:230. [PMID: 38534504 DOI: 10.3390/bioengineering11030230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 02/19/2024] [Accepted: 02/23/2024] [Indexed: 03/28/2024] Open
Abstract
The penis is a complex organ with a development cycle from the fetal stage to puberty. In addition, it may suffer from either congenital or acquired anomalies. Penile surgical reconstruction has been the center of interest for many researchers but is still challenging due to the complexity of its anatomy and functionality. In this review, penile anatomy, pathologies, and current treatments are described, including surgical techniques and tissue engineering approaches. The self-assembly technique currently applied is emphasized since it is considered promising for an adequate tissue-engineered penile reconstructed substitute.
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Affiliation(s)
- Elissa Elia
- Centre de Recherche en Organogénèse Expérimentale/LOEX, Regenerative Medicine Division, CHU de Québec-Université Laval Research Center, Québec, QC G1J 1Z4, Canada
| | - Christophe Caneparo
- Centre de Recherche en Organogénèse Expérimentale/LOEX, Regenerative Medicine Division, CHU de Québec-Université Laval Research Center, Québec, QC G1J 1Z4, Canada
| | - Catherine McMartin
- Division of Urology, Department of Surgery, CHU de Québec-Université Laval, Québec, QC G1V 4G2, Canada
| | - Stéphane Chabaud
- Centre de Recherche en Organogénèse Expérimentale/LOEX, Regenerative Medicine Division, CHU de Québec-Université Laval Research Center, Québec, QC G1J 1Z4, Canada
| | - Stéphane Bolduc
- Centre de Recherche en Organogénèse Expérimentale/LOEX, Regenerative Medicine Division, CHU de Québec-Université Laval Research Center, Québec, QC G1J 1Z4, Canada
- Division of Urology, Department of Surgery, CHU de Québec-Université Laval, Québec, QC G1V 4G2, Canada
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21
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Sani A, Idrees Khan M, Shah S, Tian Y, Zha G, Fan L, Zhang Q, Cao C. Diagnosis and screening of abnormal hemoglobins. Clin Chim Acta 2024; 552:117685. [PMID: 38030031 DOI: 10.1016/j.cca.2023.117685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 11/21/2023] [Accepted: 11/24/2023] [Indexed: 12/01/2023]
Abstract
Hemoglobin (Hb) abnormalities, such as thalassemia and structural Hb variants, are among the most prevalent inherited diseases and are associated with significant mortality and morbidity worldwide. However, there were not comprehensive reviews focusing on different clinical analytical techniques, research methods and artificial intelligence (AI) used in clinical screening and research on hemoglobinopathies. Hence the review offers a comprehensive summary of recent advancements and breakthroughs in the detection of aberrant Hbs, research methods and AI uses as well as the present restrictions anddifficulties in hemoglobinopathies. Recent advances in cation exchange high performance liquid chromatography (HPLC), capillary zone electrophoresis (CZE), isoelectric focusing (IEF), flow cytometry, mass spectrometry (MS) and polymerase chain reaction (PCR) etc have allowed for the definitive detection by using advanced AIand portable point of care tests (POCT) integrating with smartphone microscopic classification, machine learning (ML) model, complete blood counts (CBC), imaging-based method, speedy immunoassay, and electrochemical-, microfluidic- and sensing-related platforms. In addition, to confirm and validate unidentified and novel Hbs, highly specialized genetic based techniques like PCR, reverse transcribed (RT)-PCR, DNA microarray, sequencing of genomic DNA, and sequencing of RT-PCR amplified globin cDNA of the gene of interest have been used. Hence, adequate utilization and improvement of available diagnostic and screening technologies are important for the control and management of hemoglobinopathies.
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Affiliation(s)
- Ali Sani
- School of Sensing Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Muhammad Idrees Khan
- School of Sensing Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Saud Shah
- School of Sensing Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Youli Tian
- School of Sensing Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China; School of Life Science and Biotechnology, State Key Laboratory of Microbial Metabolism, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Genhan Zha
- School of Sensing Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Liuyin Fan
- Student Innovation Center, Shanghai Jiao Tong University, Shanghai 200240, China.
| | - Qiang Zhang
- School of Sensing Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China.
| | - Chengxi Cao
- School of Sensing Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China; School of Life Science and Biotechnology, State Key Laboratory of Microbial Metabolism, Shanghai Jiao Tong University, Shanghai, 200240, China.
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22
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Desai G, Dave K, Devare S, Desai S. Ethical and Clinical Considerations in the Use of Hydroxyurea in Pregnant Women with Sickle Cell Disease. Hemoglobin 2024; 48:66-68. [PMID: 38326997 DOI: 10.1080/03630269.2024.2310283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 01/19/2024] [Indexed: 02/09/2024]
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23
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Eliseo S, Berlin L, Mansour AM, Hansen S, Ranganath B, Wallace SJ. Microsurgery in the Sickle Cell Trait Population: Can it Be Safely and Successfully Performed? PLASTIC AND RECONSTRUCTIVE SURGERY-GLOBAL OPEN 2023; 11:e5377. [PMID: 37941817 PMCID: PMC10629739 DOI: 10.1097/gox.0000000000005377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 09/12/2023] [Indexed: 11/10/2023]
Abstract
Free-tissue transfer reconstruction in patients with sickle cell anemia risks failure due to polymerization of sickle hemoglobin within the flap microcirculation. However, outcomes vary, as the amount of polymerization is dependent on factors such as disease phenotype/diagnosis, degree of hypoxia, and intracellular dehydration. Most of the literature focuses on patients with sickle cell disease, which produces higher concentrations of sickle hemoglobin and, therefore, is a contraindication to microvascular reconstruction. Fewer reports describe microsurgery in patients with sickle cell trait (SCT) who carry the heterozygous phenotype. Here, we present a case in which a patient with SCT underwent microsurgical breast reconstruction with deep inferior epigastric perforator free-tissue transfer. The 52-year-old woman had previously experienced a failed alloplastic-based reconstruction after radiation therapy for breast cancer. In our case, clinical and Doppler examinations demonstrated that arterial and venous anastomoses had remained patent; so the patient was discharged on postoperative day 4. Blistering developed on postoperative day 8, and by day 15 there was partial necrosis of the inferior-lateral aspect of the deep inferior epigastric perforator flap. Debridement and closure resolved the issue, and at 5 months postprocedure, the flap remained well-perfused and well-incorporated. This case, presented here with patient consent, reports a successful outcome of microsurgical reconstruction in a patient with SCT. It expands the limited evidence to support the safety and feasibility of autologous surgical interventions for patients with the heterozygous phenotype of sickle cell anemia.
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Affiliation(s)
- Sara Eliseo
- From Philadelphia College of Osteopathic Medicine, Moultrie, Ga
| | | | | | | | | | - Sean J. Wallace
- George Washington University Plastic Surgery, Washington, D.C
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24
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Inusa BP, Atoyebi W, Andemariam B, Hourani JN, Omert L. Global burden of transfusion in sickle cell disease. Transfus Apher Sci 2023; 62:103764. [PMID: 37541800 DOI: 10.1016/j.transci.2023.103764] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 07/14/2023] [Accepted: 07/16/2023] [Indexed: 08/06/2023]
Abstract
Sickle cell disease (SCD) is the most common hereditary hemoglobinopathy. The underlying pathophysiology of the red blood cell (RBC) leads to pan-systemic complications which manifest at an early age. While curative and disease-modifying treatments exist for SCD, a key intervention in the management and treatment of SCD is RBC transfusion, which can alleviate or prevent many complications. SCD patients often require chronic RBC transfusion therapy which can result in complications, such as iron overload, alloimmunization and infection. In low- and middle-income countries (LMICs), SCD patients lack appropriate access to healthcare such as newborn screening, health education, prophylaxis for infection, and treatments to reduce both mortality and SCD-related adverse effects. Poor access to RBCs for transfusion, coupled with donated blood not meeting safety standards set by the World Health Organization, presents a significant barrier for patients requiring chronic transfusions in LMICs. Unmet needs associated with blood collection, blood component processing and recipient matching all pose a serious problem in many LMICs, although this varies depending on geographic location, political organizations and economy. This review aims to provide an overview of the global burden of SCD, focusing on the availability of current treatments and the burden of chronic RBC transfusions in patients with SCD.
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Affiliation(s)
- Baba Pd Inusa
- Guy's and Saint Thomas' NHS Foundation Trust, London, UK.
| | | | - Biree Andemariam
- New England Sickle Cell Institute, University of Connecticut Health, Farmington, CT, USA
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25
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Hardouin G, Magrin E, Corsia A, Cavazzana M, Miccio A, Semeraro M. Sickle Cell Disease: From Genetics to Curative Approaches. Annu Rev Genomics Hum Genet 2023; 24:255-275. [PMID: 37624668 DOI: 10.1146/annurev-genom-120122-081037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/27/2023]
Abstract
Sickle cell disease (SCD) is a monogenic blood disease caused by a point mutation in the gene coding for β-globin. The abnormal hemoglobin [sickle hemoglobin (HbS)] polymerizes under low-oxygen conditions and causes red blood cells to sickle. The clinical presentation varies from very severe (with acute pain, chronic pain, and early mortality) to normal (few complications and a normal life span). The variability of SCD might be due (in part) to various genetic modulators. First, we review the main genetic factors, polymorphisms, and modifier genes that influence the expression of globin or otherwise modulate the severity of SCD. Considering SCD as a complex, multifactorial disorder is important for the development of appropriate pharmacological and genetic treatments. Second, we review the characteristics, advantages, and disadvantages of the latest advances in gene therapy for SCD, from lentiviral-vector-based approaches to gene-editing strategies.
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Affiliation(s)
- Giulia Hardouin
- Laboratory of Chromatin and Gene Regulation During Development, Imagine Institute, INSERM UMR 1163, Université Paris Cité, Paris, France; ,
- Centre d'Investigation Clinique Spécialisé en Biothérapie, Département de Biothérapie, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France; ,
- Human Lymphohematopoiesis Laboratory, Imagine Institute, INSERM UMR 1163, Université Paris Cité, Paris, France;
| | - Elisa Magrin
- Centre d'Investigation Clinique Spécialisé en Biothérapie, Département de Biothérapie, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France; ,
| | - Alice Corsia
- Human Lymphohematopoiesis Laboratory, Imagine Institute, INSERM UMR 1163, Université Paris Cité, Paris, France;
| | - Marina Cavazzana
- Centre d'Investigation Clinique Spécialisé en Biothérapie, Département de Biothérapie, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France; ,
- Imagine Institute, INSERM UMR 1163, Université Paris Cité, Paris, France
- Université Paris Cité, Paris, France
| | - Annarita Miccio
- Laboratory of Chromatin and Gene Regulation During Development, Imagine Institute, INSERM UMR 1163, Université Paris Cité, Paris, France; ,
| | - Michaela Semeraro
- Université Paris Cité, Paris, France
- Centre d'Investigation Clinique and Unité de Recherche Clinique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France;
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26
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Schmidt HM, DeVallance ER, Lewis SE, Wood KC, Annarapu GK, Carreño M, Hahn SA, Seman M, Maxwell BA, Hileman EA, Xu JZ, Velayutham M, Geldenhuys WJ, Vitturi DA, Shiva S, Kelley EE, Straub AC. Release of hepatic xanthine oxidase (XO) to the circulation is protective in intravascular hemolytic crisis. Redox Biol 2023; 62:102636. [PMID: 36906950 PMCID: PMC10025133 DOI: 10.1016/j.redox.2023.102636] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 02/09/2023] [Accepted: 02/11/2023] [Indexed: 02/15/2023] Open
Abstract
Xanthine oxidase (XO) catalyzes the catabolism of hypoxanthine to xanthine and xanthine to uric acid, generating oxidants as a byproduct. Importantly, XO activity is elevated in numerous hemolytic conditions including sickle cell disease (SCD); however, the role of XO in this context has not been elucidated. Whereas long-standing dogma suggests elevated levels of XO in the vascular compartment contribute to vascular pathology via increased oxidant production, herein, we demonstrate, for the first time, that XO has an unexpected protective role during hemolysis. Using an established hemolysis model, we found that intravascular hemin challenge (40 μmol/kg) resulted in a significant increase in hemolysis and an immense (20-fold) elevation in plasma XO activity in Townes sickle cell phenotype (SS) sickle mice compared to controls. Repeating the hemin challenge model in hepatocyte-specific XO knockout mice transplanted with SS bone marrow confirmed the liver as the source of enhanced circulating XO as these mice demonstrated 100% lethality compared to 40% survival in controls. In addition, studies in murine hepatocytes (AML12) revealed hemin mediates upregulation and release of XO to the medium in a toll like receptor 4 (TLR4)-dependent manner. Furthermore, we demonstrate that XO degrades oxyhemoglobin and releases free hemin and iron in a hydrogen peroxide-dependent manner. Additional biochemical studies revealed purified XO binds free hemin to diminish the potential for deleterious hemin-related redox reactions as well as prevents platelet aggregation. In the aggregate, data herein reveals that intravascular hemin challenge induces XO release by hepatocytes through hemin-TLR4 signaling, resulting in an immense elevation of circulating XO. This increased XO activity in the vascular compartment mediates protection from intravascular hemin crisis by binding and potentially degrading hemin at the apical surface of the endothelium where XO is known to be bound and sequestered by endothelial glycosaminoglycans (GAGs).
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Affiliation(s)
- Heidi M Schmidt
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Evan R DeVallance
- Center for Inhalation Toxicology, West Virginia University School of Medicine, Morgantown, WV, USA; Department of Physiology and Pharmacology, Health Sciences Center, West Virginia University, Morgantown, WV, USA
| | - Sara E Lewis
- Department of Physiology and Pharmacology, Health Sciences Center, West Virginia University, Morgantown, WV, USA
| | - Katherine C Wood
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Gowtham K Annarapu
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Mara Carreño
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Scott A Hahn
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Madison Seman
- Department of Physiology and Pharmacology, Health Sciences Center, West Virginia University, Morgantown, WV, USA
| | - Brooke A Maxwell
- Department of Physiology and Pharmacology, Health Sciences Center, West Virginia University, Morgantown, WV, USA
| | - Emily A Hileman
- Department of Physiology and Pharmacology, Health Sciences Center, West Virginia University, Morgantown, WV, USA
| | - Julia Z Xu
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA; Division of Hematology /Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | | | - Werner J Geldenhuys
- Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV, USA; Department of Neuroscience, School of Medicine, West Virginia University, Morgantown, WV, USA
| | - Dario A Vitturi
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA; Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Sruti Shiva
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA; Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Eric E Kelley
- Department of Physiology and Pharmacology, Health Sciences Center, West Virginia University, Morgantown, WV, USA.
| | - Adam C Straub
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA; Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA.
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27
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Williams JD, Kumar R, Afolabi JM, Park F, Adebiyi A. Rhabdomyolysis aggravates renal iron accumulation and acute kidney injury in a humanized mouse model of sickle cell disease. Free Radic Res 2023; 57:404-412. [PMID: 37840281 PMCID: PMC11259575 DOI: 10.1080/10715762.2023.2269313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 09/29/2023] [Indexed: 10/17/2023]
Abstract
Individuals with sickle cell disease (SCD) are at greater risk of rhabdomyolysis, a potentially life-threatening condition resulting from the breakdown of skeletal muscle fibers. Acute kidney injury (AKI) is one of the most severe complications of rhabdomyolysis. Chronic kidney and cardiovascular disease, which account for SCD mortality, are long-term consequences of AKI. Although SCD elevates the risks of rhabdomyolysis-induced sudden death, the mechanisms that underlie rhabdomyolysis-induced AKI in SCD are unclear. In the present study, we show that, unlike their control non-sickling (AA) counterparts, transgenic homozygous SCD (SS; Townes model) mice exhibited 100% mortality 8-24 h after intramuscular glycerol injection. Five hours after glycerol injection, SS mice showed a more significant increase in myoglobinuria and plasma creatine kinase levels than AA mice. Basal plasma heme and kidney tissue iron levels were significantly higher in SS than in AA mice. In contrast to AA, glycerol-induced rhabdomyolysis aggravated these parameters in SS mice. Rhabdomyolysis also amplified oxidative stress in SS compared to AA mice. Glycerol-treated SS mice exhibited worse renal function, exemplified by a reduction in GFR with a corresponding increase in plasma and urinary biomarkers of early AKI and renal tubular damage. The free radical scavenger and Fenton chemistry inhibitor, TEMPOL, ameliorated rhabdomyolysis-induced AKI in the SS mice. These findings demonstrate that oxidative stress driven by renal iron accumulation amplifies rhabdomyolysis-induced AKI in SCD mice.
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Affiliation(s)
- Jada D. Williams
- Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Ravi Kumar
- Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri
| | - Jeremiah M. Afolabi
- Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Frank Park
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Adebowale Adebiyi
- Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri
- NextGen Precision Health, University of Missouri, Columbia, Missouri
- Department of Anesthesiology and Perioperative Medicine, University of Missouri, Columbia, Missouri
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28
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Meloni A, Pistoia L, Quota A, Messina G, Ricchi P, Bagnato S, Gerardi C, Lisi R, Cuccia L, Renne S, Vallone A, Righi R, Positano V, Pepe A, Cademartiri F. Prognostic value of multiparametric cardiac magnetic resonance in sickle cell patients. Ann Hematol 2023; 102:261-270. [PMID: 36459182 DOI: 10.1007/s00277-022-05057-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 11/11/2022] [Indexed: 12/03/2022]
Abstract
The aim of this multicenter study was to prospectively assess the predictive value of multiparametric cardiac magnetic resonance (CMR) for cardiovascular complications in sickle cell disease (SCD) patients. Among all patients with hemoglobinopathies consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) Network, we selected 102 SCD patients (34.38 ± 12.67 years, 49 females). Myocardial iron overload (MIO) was measured by the multislice multiecho T2* technique. Atrial dimensions and biventricular function parameters were quantified by cine images. Late gadolinium enhancement (LGE) images were acquired to detect focal myocardial fibrosis. At baseline CMR, only two patients had significant MIO (global heart T2* < 20 ms). During a mean follow-up of 63.01 ± 24.95 months, 11 cardiovascular events (10.8%) were registered: 3 pulmonary hypertension, 2 supraventricular arrhythmias, 1 heart failure, 1 death for heart failure, 1 pulmonary embolism, 1 peripheral vascular disease, 1 transient ischemic attack, and 1 death after acute chest syndrome. In the multivariate analysis, the independent CMR predictors of cardiovascular events were left ventricular (LV) ejection fraction (hazard ratio-HR = 0.88; p = 0.025) and right ventricular (RV) mass index (HR = 1.09; p = 0.047). According to the receiver-operating characteristic curve analysis for adverse events, an LV ejection fraction < 58.9% and an RV mass index > 31 g/m2 were optimal cut-off values. Reduced left ventricular ejection fraction and increased right ventricular mass index showed a significant prognostic value in patients with SCD. Our data seem to suggest that CMR may be added as a screening tool for identifying SCD patients at high risk for cardiopulmonary and vascular diseases.
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Affiliation(s)
- Antonella Meloni
- Department of Radiology, Fondazione G. Monasterio CNR-Regione Toscana, Via Moruzzi, 1 - 56124, Pisa, Italy.,U.O.C. Bioingegneria, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
| | - Laura Pistoia
- Department of Radiology, Fondazione G. Monasterio CNR-Regione Toscana, Via Moruzzi, 1 - 56124, Pisa, Italy
| | - Alessandra Quota
- Servizio Di Talassemia, Ospedale V. Emanuele III, Gela, CL, Italy
| | - Giuseppe Messina
- Centro Microcitemie, Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli, Reggio Calabria, Italy
| | - Paolo Ricchi
- U.O.S.D. Malattie Rare del Globulo Rosso, Azienda Ospedaliera Di Rilievo Nazionale "A. Cardarelli", Naples, Italy
| | - Sergio Bagnato
- Ematologia Microcitemia, Ospedale San Giovanni di Dio - ASP Crotone, Crotone, Italy
| | - Calogera Gerardi
- Unità Operativa Semplice Di Talassemia, Presidio Ospedaliero Giovanni Paolo II - Distretto AG2 Di Sciacca, Sciacca, AG, Italy
| | - Roberto Lisi
- Unità Operativa Dipartimentale Talassemia, Azienda Ospedaliera Garibaldi Presidio Ospedaliero Garibaldi-Centro, Catania, Italy
| | - Liana Cuccia
- Unità Operativa Complessa Ematologia Con Talassemia, ARNAS Civico Benfratelli-Di Cristina, Palermo, Italy
| | - Stefania Renne
- Struttura Complessa Di Cardioradiologia-UTIC, Presidio Ospedaliero "Giovanni Paolo II", Lamezia Terme, Italy
| | - Antonino Vallone
- Reparto Di Radiologia, Azienda Ospedaliera Garibaldi Presidio Ospedaliero Nesima, Catania, Italy
| | - Riccardo Righi
- Diagnostica Per Immagini e Radiologia Interventistica, Ospedale del Delta, Lagosanto, FE, Italy
| | - Vincenzo Positano
- Department of Radiology, Fondazione G. Monasterio CNR-Regione Toscana, Via Moruzzi, 1 - 56124, Pisa, Italy.,U.O.C. Bioingegneria, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
| | - Alessia Pepe
- Institute of Radiology, Department of Medicine, University of Padua, Padua, Italy
| | - Filippo Cademartiri
- Department of Radiology, Fondazione G. Monasterio CNR-Regione Toscana, Via Moruzzi, 1 - 56124, Pisa, Italy.
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29
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Prevalence of orofacial alterations in patients with sickle-cell disease: Systematic review and meta-analysis. Oral Surg Oral Med Oral Pathol Oral Radiol 2022; 135:642-660. [PMID: 36858858 DOI: 10.1016/j.oooo.2022.12.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 12/18/2022] [Accepted: 12/21/2022] [Indexed: 12/28/2022]
Abstract
OBJECTIVE The aim of this study was to identify the prevalence of orofacial alterations in sickle-cell disease (SCD) and to compare it with the general population. STUDY DESIGN This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. The search was conducted on PubMed, Embase, Scientific Electronic Library Online, Web of Science, Cochrane Library, gray literature, and references of the included articles. RESULTS A total of 770 records were found, and 28 studies were selected. In SCD, the prevalence of decreased bone density was 57% (95% CI: 35%-80%), with Q: P < .01 and I2 = 95%; for stepladder pattern was 30% (IC: 13%-47%), Q: P < .01 and I²: 93%; for delayed eruption was 20% (95% CI: 6%-34%), with Q: P < .01 and I2 = 86, Q: P < .01 and I2 = 99%; and for malocclusion, 66% (95% CI: 39%-92%), Q: P < .01 and I2 = 98%. A high risk of bias was observed in relation to the sample size of the studies. A limited number of articles compared the prevalence of orofacial alterations in patients with SCD and healthy individuals. CONCLUSIONS Decreased bone density, malocclusion, orofacial pain, tooth necrosis, eruption delay, periodontal disease, and neuropathies may be present in patients with SCD with variable prevalence.
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30
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Cai Y, Ji Z, Wang S, Zhang W, Qu J, Belmonte JCI, Liu GH. Genetic enhancement: an avenue to combat aging-related diseases. LIFE MEDICINE 2022; 1:307-318. [PMID: 39872744 PMCID: PMC11749557 DOI: 10.1093/lifemedi/lnac054] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 11/14/2022] [Indexed: 01/30/2025]
Abstract
Aging is a major risk factor for multiple diseases, including cardiovascular diseases, neurodegenerative disorders, osteoarthritis, and cancer. It is accompanied by the dysregulation of stem cells and other differentiated cells, and the impairment of their microenvironment. Cell therapies to replenish the abovementioned cells provide a promising approach to restore tissue homeostasis and alleviate aging and aging-related chronic diseases. Importantly, by leveraging gene editing technologies, genetic enhancement, an enhanced strategy for cell therapy, can be developed to improve the safety and efficacy of transplanted therapeutic cells. In this review, we provide an overview and discussion of the current progress in the genetic enhancement field, including genetic modifications of mesenchymal stem cells, neural stem cells, hematopoietic stem cells, vascular cells, and T cells to target aging and aging-associated diseases. We also outline questions regarding safety and current limitations that need to be addressed for the continued development of genetic enhancement strategies for cell therapy to enable its further applications in clinical trials to combat aging-related diseases.
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Affiliation(s)
- Yusheng Cai
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Zhejun Ji
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Si Wang
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Weiqi Zhang
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
- China National Center for Bioinformation, Beijing 100101, China
| | - Jing Qu
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | | | - Guang-Hui Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China
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Khan MI, Patel N, Meda RT, Nuguru SP, Rachakonda S, Sripathi S. Sickle Cell Disease and Its Respiratory Complications. Cureus 2022; 14:e28528. [PMID: 36185937 PMCID: PMC9517690 DOI: 10.7759/cureus.28528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/29/2022] [Indexed: 11/10/2022] Open
Abstract
Sickle cell disease (SCD) is a hematological disorder that is inherited in an autosomal recessive (AR) fashion. It is caused by mutations in the genes encoding for the globin apoprotein of hemoglobin (Hb), leading to diminished oxygen-carrying ability. Its pathophysiologic mechanism affects multiple organ systems, making it crucial to understand the complications of SCD and find the best ways to prevent and treat them. Some important ways that SCD manifests in the respiratory system are acute chest syndrome (ACS), pulmonary hypertension (PH), asthma, and venous thromboembolism (VTE). This article summarizes their salient features, including pathogenesis related to the adverse outcomes, screening practices, and management guidelines, with the intent to provide greater insight into forming better practices that increase the quality of life in SCD patients.
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Estepp JH, Kalpatthi R, Woods G, Trompeter S, Liem RI, Sims K, Inati A, Inusa BPD, Campbell A, Piccone C, Abboud MR, Smith-Whitley K, Dixon S, Tonda M, Washington C, Griffin NM, Brown C. Safety and efficacy of voxelotor in pediatric patients with sickle cell disease aged 4 to 11 years. Pediatr Blood Cancer 2022; 69:e29716. [PMID: 35451176 DOI: 10.1002/pbc.29716] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 03/02/2022] [Accepted: 03/25/2022] [Indexed: 11/07/2022]
Abstract
BACKGROUND Sickle cell disease (SCD) is a devastating, multisystemic disorder that affects millions of people worldwide. The earliest clinical manifestations of SCD can affect infants as young as 6 months of age, and pediatric patients are at risk for acute and life-threatening complications. Early intervention with treatments that target the underlying pathophysiological mechanism of SCD, sickle hemoglobin (HbS) polymerization, are expected to slow disease progression and circumvent disease-associated morbidity and mortality. PROCEDURE The HOPE-KIDS 1 trial (NCT02850406) is an ongoing four-part, phase 2a, open-label, single- and multiple-dose study to evaluate the pharmacokinetics, efficacy, and safety of voxelotor-a first-in-class HbS polymerization inhibitor-in patients aged 6 months to 17 years with SCD. Initial findings from a cohort of 45 patients aged 4 to 11 years who received voxelotor treatment for up to 48 weeks are reported. RESULTS Hemoglobin (Hb) response, defined as a >1.0 g/dl increase from baseline, was achieved at week 24 by 47% (n = 16/34) of patients with Hb measurements at baseline and week 24. At week 24, 35% (n = 12/34) and 21% (n = 7/34) of patients had a >1.5 g/dl increase and a >2.0 g/dl increase from baseline in Hb concentration, respectively. Concurrent improvements in hemolytic markers were observed. Voxelotor was well tolerated in this young cohort, with no newly emerging safety signals. CONCLUSIONS Based on its mechanism as an HbS polymerization inhibitor, voxelotor improves Hb levels and markers of hemolysis and has the potential to mitigate SCD-related complications; these results support its use in patients aged ≥4 years.
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Affiliation(s)
| | - Ram Kalpatthi
- UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Gerald Woods
- Children's Mercy Hospital, Kansas City, Missouri, USA
| | - Sara Trompeter
- University College London Hospitals NHS Foundation Trust, London, UK
| | - Robert I Liem
- Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA
| | - Kacie Sims
- St. Jude Affiliate Clinic Baton Rouge, Baton Rouge, Los Angeles, USA
| | - Adlette Inati
- School of Medicine, Byblos and Nini Hospital, Lebanese American University, Tripoli, Lebanon
| | - Baba P D Inusa
- Guy's and Saint Thomas' NHS Foundation Trust, London, UK
| | - Andrew Campbell
- Division of Hematology, Children's National Hospital, Washington, District of Columbia, USA
| | - Connie Piccone
- Department of Pediatric Hematology, Carle Foundation Hospital, Urbana, Illinois, USA
| | - Miguel R Abboud
- American University of Beirut Medical Center, Beirut, Lebanon
| | - Kim Smith-Whitley
- Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Sandra Dixon
- Global Blood Therapeutics, South San Francisco, California, USA
| | - Margaret Tonda
- Global Blood Therapeutics, South San Francisco, California, USA
| | | | | | - Clark Brown
- Emory + Children's Pediatric Institute, Atlanta, Georgia, USA
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Torres LS, Asada N, Weiss MJ, Trumpp A, Suda T, Scadden DT, Ito K. Recent advances in "sickle and niche" research - Tribute to Dr. Paul S Frenette. Stem Cell Reports 2022; 17:1509-1535. [PMID: 35830837 PMCID: PMC9287685 DOI: 10.1016/j.stemcr.2022.06.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 06/08/2022] [Accepted: 06/09/2022] [Indexed: 10/27/2022] Open
Abstract
In this retrospective, we review the two research topics that formed the basis of the outstanding career of Dr. Paul S. Frenette. In the first part, we focus on sickle cell disease (SCD). The defining feature of SCD is polymerization of the deoxygenated mutant hemoglobin, which leads to a vicious cycle of hemolysis and vaso-occlusion. We survey important discoveries in SCD pathophysiology that have led to recent advances in treatment of SCD. The second part focuses on the hematopoietic stem cell (HSC) niche, the complex microenvironment within the bone marrow that controls HSC function and homeostasis. We detail the cells that constitute this niche, and the factors that these cells use to exert control over hematopoiesis. Here, we trace the scientific paths of Dr. Frenette, highlight key aspects of his research, and identify his most important scientific contributions in both fields.
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Affiliation(s)
- Lidiane S Torres
- Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA; Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA
| | - Noboru Asada
- Department of Hematology and Oncology, Okayama University Hospital, Okayama 700-8558, Japan
| | - Mitchell J Weiss
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Andreas Trumpp
- Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, 69117 Heidelberg, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
| | - Toshio Suda
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - David T Scadden
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Keisuke Ito
- Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA; Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA; Montefiore Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA; Einstein Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY, USA.
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Alabi OJ, Adegboyega FN, Olawoyin DS, Babatunde OA. Functional foods: promising therapeutics for Nigerian Children with sickle cell diseases. Heliyon 2022; 8:e09630. [PMID: 35677416 PMCID: PMC9167986 DOI: 10.1016/j.heliyon.2022.e09630] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 11/30/2021] [Accepted: 05/26/2022] [Indexed: 11/21/2022] Open
Abstract
Sickle cell disease (SCD), also known as sickle cell anemia (SCA) is one of the structural hemoglobinopathies that occurs due to a single nucleotide mutation from GAG to GTG, which changes the amino acid of a β-globin chain of hemoglobin (Hb) from glutamate to valine. This singular mutation results to disorderliness in red blood cells (RBCs) with advent of changes in RBC morphology and other pathological conditions. In the 1980s, intermittent red blood cell transfusions, opioids, and penicillin prophylaxis were the only available therapy for SCA and were commonly reserved for acute, life threatening complications. So far, the US Food and Drug Administration (FDA) has granted a total of four drugs approval for the prophylaxis and treatment of the clinical complications of SCD. Due to limitations (adherence, safety, adverse effects) of existing therapies in the prophylaxis and treatment of SCD complications in Nigerian children and their inaccessibility to approved drugs, the present study discusses the therapeutic effects of readily available functional food as one of the therapies or an adjunct therapy to tackle the sickle cell crisis in Nigerian Children.
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Affiliation(s)
- Oladeji John Alabi
- Department of Biochemistry, Faculty of Basic Medical Sciences, Ladoke Akintola University of Technology, Ogbomoso, Nigeria
- Department of Biochemistry, Institute for Agriculture & Natural Sciences, College of Arts & Sciences, University of Nebraska-Lincoln, USA
| | - Fikayo Noah Adegboyega
- Department of Biochemistry, Faculty of Basic Medical Sciences, Ladoke Akintola University of Technology, Ogbomoso, Nigeria
- Department of Biotechnology, Egypt-Japan University of Science and Technology, Alexandria, Egypt
| | - Dolapo Samuel Olawoyin
- Department of Biochemistry, Faculty of Basic Medical Sciences, Ladoke Akintola University of Technology, Ogbomoso, Nigeria
- School of Food Science and Nutrition, University of Leeds, Leeds, UK
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TGF-β1 Reduces Neutrophil Adhesion and Prevents Acute Vaso-Occlusive Processes in Sickle Cell Disease Mice. Cells 2022; 11:cells11071200. [PMID: 35406764 PMCID: PMC8998040 DOI: 10.3390/cells11071200] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 03/28/2022] [Accepted: 03/29/2022] [Indexed: 12/26/2022] Open
Abstract
Sickle cell disease (SCD) patients experience chronic inflammation and recurrent vaso-occlusive episodes during their entire lifetime. Inflammation in SCD occurs with the overexpression of several inflammatory mediators, including transforming growth factor beta-1 (TGF-β1), a major immune regulator. In this study, we aimed to investigate the role played by TGF-β1 in vascular inflammation and vaso-occlusion in an animal model of SCD. Using intravital microscopy, we found that a daily dose of recombinant TGF-β1 administration for three consecutive days significantly reduced TNFα-induced leukocyte rolling, adhesion, and extravasation in the microcirculation of SCD mice. In contrast, immunological neutralization of TGF-β, in the absence of inflammatory stimulus, considerably increased these parameters. Our results indicate, for the first time, that TGF-β1 may play a significant ameliorative role in vascular SCD pathophysiology, modulating inflammation and vaso-occlusion. The mechanisms by which TGF-β1 exerts its anti-inflammatory effects in SCD, however, remains unclear. Our in vitro adhesion assays with TNFα-stimulated human neutrophils suggest that TGF-β1 can reduce the adhesive properties of these cells; however, direct effects of TGF-β1 on the endothelium cannot be ruled out. Further investigation of the wide range of the complex biology of this cytokine in SCD pathophysiology and its potential therapeutical use is needed.
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Aljahdali AS, Musayev FN, Burgner JW, Ghatge MS, Shekar V, Zhang Y, Omar AM, Safo MK. Molecular insight into 2-phosphoglycolate activation of the phosphatase activity of bisphosphoglycerate mutase. Acta Crystallogr D Struct Biol 2022; 78:472-482. [PMID: 35362470 PMCID: PMC8972806 DOI: 10.1107/s2059798322001802] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 02/16/2022] [Indexed: 11/14/2022] Open
Abstract
Bisphosphoglycerate mutase (BPGM) is an erythrocyte-specific multifunctional enzyme that is responsible for the regulation of 2,3-bisphosphoglycerate (2,3-BPG) in red blood cells through its synthase and phosphatase activities; the latter enzymatic function is stimulated by the endogenous activator 2-phosphoglycolate (2-PG). 2,3-BPG is a natural allosteric effector of hemoglobin (Hb) that is responsible for decreasing the affinity of Hb for oxygen to facilitate tissue oxygenation. Here, crystal structures of BPGM with 2-PG in the presence and absence of 3-phosphoglycerate are reported at 2.25 and 2.48 Å resolution, respectively. Structure analysis revealed a new binding site for 2-PG at the dimer interface for the first time, in addition to the expected active-site binding. Also, conformational non-equivalence of the two active sites was observed as one of the sites was found in an open conformation, with the residues at the active-site entrance, including Arg100, Arg116 and Arg117, and the C-terminus disordered. The kinetic result is consistent with the binding of 2-PG to an allosteric or noncatalytic site as well as the active site. This study paves the way for the rational targeting of BPGM for therapeutic purposes, especially for the treatment of sickle cell disease.
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Affiliation(s)
- Anfal S. Aljahdali
- Department of Pharmaceutical Chemistry, King Abdulaziz University, Alsulaymanyah, Jeddah 21589, Saudi Arabia
- Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA
- The Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA
| | - Faik N. Musayev
- Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA
- The Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA
| | - John W. Burgner
- Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA
- The Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA
| | - Mohini S. Ghatge
- Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA
- The Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA
| | - Vibha Shekar
- The Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA
| | - Yan Zhang
- Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA
| | - Abdelsattar M. Omar
- Department of Pharmaceutical Chemistry, King Abdulaziz University, Alsulaymanyah, Jeddah 21589, Saudi Arabia
- Department of Pharmaceutical Chemistry, Al-Azhar University, Cairo 11884, Egypt
| | - Martin K. Safo
- Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA
- The Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA
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Schroeder P, Fulzele K, Forsyth S, Ribadeneira MD, Guichard S, Wilker E, Marshall CG, Drake A, Fessler R, Konstantinidis DG, Seu KG, Kalfa TA. Etavopivat, a Pyruvate Kinase Activator in Red Blood Cells, for the Treatment of Sickle Cell Disease. J Pharmacol Exp Ther 2022; 380:210-219. [PMID: 35031585 DOI: 10.1124/jpet.121.000743] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 12/21/2021] [Indexed: 11/22/2022] Open
Abstract
Etavopivat is an investigational, oral, small molecule activator of erythrocyte pyruvate kinase (PKR) in development for the treatment of sickle cell disease (SCD) and other hemoglobinopathies. PKR activation is proposed to ameliorate the sickling of SCD red blood cells (RBCs) through multiple mechanisms, including reduction of 2,3-diphosphoglycerate (2,3-DPG), which consequently increases hemoglobin (Hb)-oxygen affinity; increased binding of oxygen reduces sickle hemoglobin polymerization and sickling. In addition, PKR activation increases adenosine triphosphate (ATP) produced via glycolytic flux, which helps preserve membrane integrity and RBC deformability. We evaluated the pharmacodynamic response to etavopivat in nonhuman primates (NHPs) and in healthy human subjects and evaluated the effects in RBCs from patients with SCD after ex vivo treatment with etavopivat. A single dose of etavopivat decreased 2,3-DPG in NHPs and healthy subjects. Hb-oxygen affinity was significantly increased in healthy subjects after 24 hours. After daily dosing of etavopivat over 5 consecutive days in NHPs, ATP was increased by 38% from baseline. Etavopivat increased Hb-oxygen affinity and reduced sickling in RBCs collected from patients with SCD with either homozygous hemoglobin S or hemoglobin S and C disease. Collectively, these results demonstrate the ability of etavopivat to decrease 2,3-DPG and increase ATP, resulting in increased Hb-oxygen affinity and improved sickle RBC function. Etavopivat is currently being evaluated in clinical trials for the treatment of SCD. SIGNIFICANCE STATEMENT: Etavopivat, a small molecule activator of the glycolytic enzyme erythrocyte pyruvate kinase, decreased 2,3-diphosphoglycerate in red blood cells (RBCs) from nonhuman primates and healthy subjects and significantly increased hemoglobin (Hb)-oxygen affinity in healthy subjects. Using ex vivo RBCs from donors with sickle cell disease (SCD) (homozygous hemoglobin S or hemoglobin S and C genotype), etavopivat increased Hb-oxygen affinity and reduced sickling under deoxygenation. Etavopivat shows promise as a treatment for SCD that could potentially reduce vaso-occlusion and improve anemia.
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Affiliation(s)
- Patricia Schroeder
- Forma Therapeutics, Watertown, Massachusetts (P.S., K.F., S.F., M.D.R., S.G.); Tango Therapeutics, Cambridge, Massachusetts (E.W.); Repare Therapeutics, Cambridge, Massachusetts (C.G.M.); Ichnos Sciences, Epalinges, Switzerland (A.D.); Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (R.F., D.G.K., K.G.S., T.A.K.); and Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio (T.A.K.)
| | - Keertik Fulzele
- Forma Therapeutics, Watertown, Massachusetts (P.S., K.F., S.F., M.D.R., S.G.); Tango Therapeutics, Cambridge, Massachusetts (E.W.); Repare Therapeutics, Cambridge, Massachusetts (C.G.M.); Ichnos Sciences, Epalinges, Switzerland (A.D.); Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (R.F., D.G.K., K.G.S., T.A.K.); and Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio (T.A.K.)
| | - Sanjeev Forsyth
- Forma Therapeutics, Watertown, Massachusetts (P.S., K.F., S.F., M.D.R., S.G.); Tango Therapeutics, Cambridge, Massachusetts (E.W.); Repare Therapeutics, Cambridge, Massachusetts (C.G.M.); Ichnos Sciences, Epalinges, Switzerland (A.D.); Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (R.F., D.G.K., K.G.S., T.A.K.); and Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio (T.A.K.)
| | - Maria D Ribadeneira
- Forma Therapeutics, Watertown, Massachusetts (P.S., K.F., S.F., M.D.R., S.G.); Tango Therapeutics, Cambridge, Massachusetts (E.W.); Repare Therapeutics, Cambridge, Massachusetts (C.G.M.); Ichnos Sciences, Epalinges, Switzerland (A.D.); Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (R.F., D.G.K., K.G.S., T.A.K.); and Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio (T.A.K.)
| | - Sylvie Guichard
- Forma Therapeutics, Watertown, Massachusetts (P.S., K.F., S.F., M.D.R., S.G.); Tango Therapeutics, Cambridge, Massachusetts (E.W.); Repare Therapeutics, Cambridge, Massachusetts (C.G.M.); Ichnos Sciences, Epalinges, Switzerland (A.D.); Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (R.F., D.G.K., K.G.S., T.A.K.); and Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio (T.A.K.)
| | - Erik Wilker
- Forma Therapeutics, Watertown, Massachusetts (P.S., K.F., S.F., M.D.R., S.G.); Tango Therapeutics, Cambridge, Massachusetts (E.W.); Repare Therapeutics, Cambridge, Massachusetts (C.G.M.); Ichnos Sciences, Epalinges, Switzerland (A.D.); Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (R.F., D.G.K., K.G.S., T.A.K.); and Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio (T.A.K.)
| | - C Gary Marshall
- Forma Therapeutics, Watertown, Massachusetts (P.S., K.F., S.F., M.D.R., S.G.); Tango Therapeutics, Cambridge, Massachusetts (E.W.); Repare Therapeutics, Cambridge, Massachusetts (C.G.M.); Ichnos Sciences, Epalinges, Switzerland (A.D.); Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (R.F., D.G.K., K.G.S., T.A.K.); and Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio (T.A.K.)
| | - Adam Drake
- Forma Therapeutics, Watertown, Massachusetts (P.S., K.F., S.F., M.D.R., S.G.); Tango Therapeutics, Cambridge, Massachusetts (E.W.); Repare Therapeutics, Cambridge, Massachusetts (C.G.M.); Ichnos Sciences, Epalinges, Switzerland (A.D.); Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (R.F., D.G.K., K.G.S., T.A.K.); and Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio (T.A.K.)
| | - Rose Fessler
- Forma Therapeutics, Watertown, Massachusetts (P.S., K.F., S.F., M.D.R., S.G.); Tango Therapeutics, Cambridge, Massachusetts (E.W.); Repare Therapeutics, Cambridge, Massachusetts (C.G.M.); Ichnos Sciences, Epalinges, Switzerland (A.D.); Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (R.F., D.G.K., K.G.S., T.A.K.); and Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio (T.A.K.)
| | - Diamantis G Konstantinidis
- Forma Therapeutics, Watertown, Massachusetts (P.S., K.F., S.F., M.D.R., S.G.); Tango Therapeutics, Cambridge, Massachusetts (E.W.); Repare Therapeutics, Cambridge, Massachusetts (C.G.M.); Ichnos Sciences, Epalinges, Switzerland (A.D.); Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (R.F., D.G.K., K.G.S., T.A.K.); and Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio (T.A.K.)
| | - Katie G Seu
- Forma Therapeutics, Watertown, Massachusetts (P.S., K.F., S.F., M.D.R., S.G.); Tango Therapeutics, Cambridge, Massachusetts (E.W.); Repare Therapeutics, Cambridge, Massachusetts (C.G.M.); Ichnos Sciences, Epalinges, Switzerland (A.D.); Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (R.F., D.G.K., K.G.S., T.A.K.); and Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio (T.A.K.)
| | - Theodosia A Kalfa
- Forma Therapeutics, Watertown, Massachusetts (P.S., K.F., S.F., M.D.R., S.G.); Tango Therapeutics, Cambridge, Massachusetts (E.W.); Repare Therapeutics, Cambridge, Massachusetts (C.G.M.); Ichnos Sciences, Epalinges, Switzerland (A.D.); Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (R.F., D.G.K., K.G.S., T.A.K.); and Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio (T.A.K.)
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Abstract
Sickle cell disease (SCD) is characterized by vaso-occlusion, hemolysis, and systemic manifestations that form the hallmark of the disease. Apart from morbidity, SCD is also associated with increased mortality and decreased quality of life. Aging is a natural phenomenon that is associated with changes at cellular, tissue, and organ levels, in addition to the loss of physical fitness, increased susceptibility to diseases, and a higher likelihood of mortality. Some of the cellular mechanisms involved in normal (or physiological) aging include abnormalities of sphingolipids (ceramides) and reduced length of the telomere. These changes have also been documented in SCD. Cellular, organs, and physical manifestations of SCD resemble an accelerated aging syndrome. Sickle erythrocytes also acquire morphological features similar to that of aged normal erythrocytes and are thus picked up early by the macrophages for destruction. Brain, kidney, heart, innate and adaptive immune system, and musculoskeletal system of patients with SCD exhibit morphological and functional changes that are ordinarily seen in the elderly in the general population. Stroke, silent cerebral infarcts, cardiomegaly, heart failure, pulmonary hypertension, nephropathy with proteinuria, osteopenia, osteoporosis, osteonecrosis, gout, and infections are exceedingly common in SCD. In this review, we have attempted to draw parallels between SCD and accelerated aging syndromes.
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Affiliation(s)
- Ibrahim M Idris
- Department of Hematology Aminu Kano Teaching Hospital and Bayero University, Kano 11399, Nigeria
| | - Edward A Botchwey
- Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Hyacinth I Hyacinth
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
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Sales RR, Nogueira BL, Tosatti JAG, Gomes KB, Luizon MR. Do Genetic Polymorphisms Affect Fetal Hemoglobin (HbF) Levels in Patients With Sickle Cell Anemia Treated With Hydroxyurea? A Systematic Review and Pathway Analysis. Front Pharmacol 2022; 12:779497. [PMID: 35126118 PMCID: PMC8814522 DOI: 10.3389/fphar.2021.779497] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Accepted: 12/31/2021] [Indexed: 01/23/2023] Open
Abstract
Hydroxyurea has long been used for the treatment of sickle cell anemia (SCA), and its clinical effectiveness is related to the induction of fetal hemoglobin (HbF), a major modifier of SCA phenotypes. However, there is substantial variability in response to hydroxyurea among patients with SCA. While some patients show an increase in HbF levels and an ameliorated clinical condition under low doses of hydroxyurea, other patients present a poor effect or even develop toxicity. However, the effects of genetic polymorphisms on increasing HbF levels in response to hydroxyurea in patients with SCA (Hb SS) have been less explored. Therefore, we performed a systematic review to assess whether single-nucleotide polymorphisms (SNPs) affect HbF levels in patients with SCA treated with hydroxyurea. Moreover, we performed pathway analysis using the set of genes with SNPs found to be associated with changes in HbF levels in response to hydroxyurea among the included studies. The systematic literature search was conducted on Medline/PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, and Web of Science. Seven cohort studies were included following our inclusion and exclusion criteria. From the 728 genetic polymorphisms examined in the included studies, 50 different SNPs of 17 genes were found to be associated with HbF changes in patients with SCA treated with hydroxyurea, which are known to affect baseline HbF but are not restricted to them. Enrichment analysis of this gene set revealed reactome pathways with the lowest adjusted p-values and highest combined scores related to VEGF ligand–receptor interactions (R-HSA-194313; R-HSA-195399) and the urea cycle (R-HSA-70635). Pharmacogenetic studies of response to hydroxyurea therapy in patients with SCA are still scarce and markedly heterogeneous regarding candidate genes and SNPs examined for association with HbF changes and outcomes, suggesting that further studies are needed. The reviewed findings highlighted that similar to baseline HbF, changes in HbF levels upon hydroxyurea therapy are likely to be regulated by multiple loci. There is evidence that SNPs in intron 2 of BCL11A affect HbF changes in response to hydroxyurea therapy, a potential application that might improve the clinical management of SCA. Systematic Review Registration: (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=208790).
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Affiliation(s)
- Rahyssa Rodrigues Sales
- Graduate Program in Genetics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
- *Correspondence: Rahyssa Rodrigues Sales, ; Marcelo Rizzatti Luizon,
| | - Bárbara Lisboa Nogueira
- Graduate Program in Genetics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Jéssica Abdo Gonçalves Tosatti
- Department of Clinical and Toxicological Analyzes, Faculty of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Karina Braga Gomes
- Department of Clinical and Toxicological Analyzes, Faculty of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Marcelo Rizzatti Luizon
- Graduate Program in Genetics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
- Department of Genetics, Ecology and Evolution, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
- *Correspondence: Rahyssa Rodrigues Sales, ; Marcelo Rizzatti Luizon,
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Martins SR, Toledo SLDO, da Silva AJ, Mendes FS, de Oliveira MM, Ferreira LGR, Dusse LMS, Carvalho MDG, Rios DRA, Alpoim PN, Pinheiro MDB. Endothelial dysfunction biomarkers in sickle cell disease: is there a role for ADMA and PAI-1? Ann Hematol 2021; 101:273-280. [PMID: 34665295 DOI: 10.1007/s00277-021-04695-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 10/10/2021] [Indexed: 01/26/2023]
Abstract
Within the spectrum of sickle cell disease (SCD) are sickle cell anemia (SCA), presence of hemoglobin SS (HbSS), hemoglobin SC disease (HbSC), and sickle cell β-thalassemia (Sβ-thal). Asymmetric dimethylarginine (ADMA) competitively inhibits the binding of arginine to NOS, reducing NO production. In patients with HbSS, increased levels of ADMA have been reported, as well as changes in many hemostatic biomarkers, including the plasminogen activator inhibitor type 1 (PAI-1). We hypothesized that high levels of ADMA and PAI-1 may be associated with more severe SCD. Thus, ADMA and PAI-1 levels were determined in 78 individuals including 38 adult patients with SCD and 40 control subjects. Higher levels of ADMA were shown in HbSS and Sβ-thal patients compared to controls. Concerning PAI-1, all patients showed high levels of PAI-1 compared to controls. As a role of NO in the pathogenesis of SCD has already been established, we concluded that high levels of ADMA should compromise, at least in part, NO synthesis, resulting in endothelial dysfunction. Elevated plasma levels of PAI-1 in all patients may indicate not only endothelial dysfunction but also a hypofibrinolytic state favoring thrombotic complications. Finally, high levels of ADMA and PAI-1 may be associated with more severe SCD.
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Affiliation(s)
- Suellen Rodrigues Martins
- Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Federal University of Minas Gerais, Avenida Antonio Carlos, 6627, Pampulha, Belo Horizonte, Minas Gerais, 31270901, Brazil
| | - Sílvia Letícia de Oliveira Toledo
- Federal University of São João del-Rei (UFSJ), Campus Centro-Oeste Dona Lindu, Sebastião Gonçalves Coelho Street, 400, Building: D, Room: 308.1, ChanadourDivinópolis, MG, 35501-296, Brazil
| | - Aislander Junio da Silva
- Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Federal University of Minas Gerais, Avenida Antonio Carlos, 6627, Pampulha, Belo Horizonte, Minas Gerais, 31270901, Brazil
| | - Fernanda Santos Mendes
- Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Federal University of Minas Gerais, Avenida Antonio Carlos, 6627, Pampulha, Belo Horizonte, Minas Gerais, 31270901, Brazil
| | - Marina Mendes de Oliveira
- Federal University of São João del-Rei (UFSJ), Campus Centro-Oeste Dona Lindu, Sebastião Gonçalves Coelho Street, 400, Building: D, Room: 308.1, ChanadourDivinópolis, MG, 35501-296, Brazil.,Fundação Centro de Hematologia E Hemoterapia Do Estado de Minas Gerais, (Hemominas), Divinópolis, MG, Brazil
| | - Leticia Gonçalves Resende Ferreira
- Federal University of São João del-Rei (UFSJ), Campus Centro-Oeste Dona Lindu, Sebastião Gonçalves Coelho Street, 400, Building: D, Room: 308.1, ChanadourDivinópolis, MG, 35501-296, Brazil
| | - Luci Maria Sant'Ana Dusse
- Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Federal University of Minas Gerais, Avenida Antonio Carlos, 6627, Pampulha, Belo Horizonte, Minas Gerais, 31270901, Brazil
| | - Maria das Graças Carvalho
- Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Federal University of Minas Gerais, Avenida Antonio Carlos, 6627, Pampulha, Belo Horizonte, Minas Gerais, 31270901, Brazil.,Federal University of São João del-Rei (UFSJ), Campus Centro-Oeste Dona Lindu, Sebastião Gonçalves Coelho Street, 400, Building: D, Room: 308.1, ChanadourDivinópolis, MG, 35501-296, Brazil
| | - Danyelle Romana Alves Rios
- Federal University of São João del-Rei (UFSJ), Campus Centro-Oeste Dona Lindu, Sebastião Gonçalves Coelho Street, 400, Building: D, Room: 308.1, ChanadourDivinópolis, MG, 35501-296, Brazil
| | - Patrícia Nessralla Alpoim
- Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Federal University of Minas Gerais, Avenida Antonio Carlos, 6627, Pampulha, Belo Horizonte, Minas Gerais, 31270901, Brazil.
| | - Melina de Barros Pinheiro
- Federal University of São João del-Rei (UFSJ), Campus Centro-Oeste Dona Lindu, Sebastião Gonçalves Coelho Street, 400, Building: D, Room: 308.1, ChanadourDivinópolis, MG, 35501-296, Brazil.
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Ogu UO, Reyes Gil M, Tolu SS, Acharya SA, Minniti CP. First Report of Compound Heterozygosity for Hb S ( HBB: c.20A>T) and Hb Haringey ( HBB: c.131A>G). Hemoglobin 2021; 45:136-139. [PMID: 34134586 DOI: 10.1080/03630269.2021.1926276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Sickle cell disease variants include hemoglobinopathies that result from inheritance of the sickle cell globin mutation with another globin mutation. The most common variants include the homozygous disease state (Hb SS disease), Hb S (HBB: c.20A>T)/Hb C (HBB: c.19G>A) disease and Hb S/β-thalassemia (Hb S/β-thal). Other rare/less common variants such as Hb S/Hb E (HBB: c.79G>A) and Hb S/HPFH [hereditary persistence of fetal hemoglobin (Hb)] disease exist. We report the first case of compound heterozygosity for Hb S and Hb Haringey (HBB: c.131A>G) in a 35-year-old male following a positive sickle screen test on hospital admission for pancreatitis. Ion exchange high performance liquid chromatography (HPLC), Hb electrophoresis and genetic sequencing were utilized to identify a new sickle Hb variant: Hb S/Hb Haringey. Hb S/Hb Haringey is a newly discovered sickle cell variant which seems to portray a mild/benign clinical phenotype of sickle cell disease.
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Affiliation(s)
- Ugochi O Ogu
- Division of Hematology, Department of Medicine, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.,Center for Sickle Cell Disease, University of Tennessee Health Science Center, Memphis, TN, USA
| | | | - Seda S Tolu
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Seetharama A Acharya
- Division of Hematology, Department of Medicine, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA
| | - Caterina P Minniti
- Division of Hematology, Department of Medicine, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA
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Hsien HC, Casarini DE, Carvalhaes JTDA, Ronchi FA, Oliveira LCGD, Braga JAP. Levels of angiotensin-converting enzyme 1 and 2 in serum and urine of children with Sickle Cell Disease. ACTA ACUST UNITED AC 2021; 43:303-310. [PMID: 33973994 PMCID: PMC8428630 DOI: 10.1590/2175-8239-jbn-2020-0174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 01/11/2021] [Indexed: 11/21/2022]
Abstract
Introduction: Sickle cell nephropathy begins in childhood and presents early increases in
glomerular filtration, which, over the long term, can lead to chronic renal
failure. Several diseases have increased circulating and urinary
angiotensin-converting enzyme (ACE) activity, but there is little
information about changes in ACEs activity in children with sickle cell
disease (SCD). Objective: We examined circulating and urinary ACE 1 activity in children with SCD. Methods: This cross-sectional study compared children who were carriers of SCD with
children who comprised a control group (CG). Serum and urinary activities of
ACE were evaluated, as were biochemical factors, urinary album/creatinine
rates, and estimated glomerular filtration rate. Results: Urinary ACE activity was significantly higher in patients with SCD than in
healthy children (median 0.01; range 0.00-0.07 vs median 0.00; range
0.00-0.01 mU/mL·creatinine, p < 0.001. No significant difference in serum
ACE activities between the SCD and CG groups was observed (median 32.25;
range 16.2-59.3 vs median 40.9; range 18.0-53.4) mU/m`L·creatinine, p <
0.05. Conclusion: Our data revealed a high urinary ACE 1 activity, different than plasmatic
level, in SCD patients suggesting a dissociation between the intrarenal and
systemic RAAS. The increase of urinary ACE 1 activity in SCD patients
suggests higher levels of Ang II with a predominance of classical RAAS axis,
that can induce kidney damage.
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Affiliation(s)
- Ho Chi Hsien
- Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Pediatria, Disciplina de Nefrologia, São Paulo, SP, Brasil
| | - Dulce Elena Casarini
- Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Medicina, Disciplina de Nefrologia, São Paulo, SP, Brasil
| | - João Tomas de Abreu Carvalhaes
- Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Pediatria, Disciplina de Nefrologia, São Paulo, SP, Brasil
| | - Fernanda Aparecida Ronchi
- Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Pediatria, Disciplina de Nefrologia, São Paulo, SP, Brasil
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Armenis I, Kalotychou V, Tzanetea R, Konstantopoulos K, Rombos I. The effect of endothelial Nitric Oxide Synthase G894T and T786C polymorphisms on Hypoxia-Inducible Factor-1 alpha expression in Sickle Cell Disease. Nitric Oxide 2021; 111-112:31-36. [PMID: 33812003 DOI: 10.1016/j.niox.2021.03.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 02/01/2021] [Accepted: 03/27/2021] [Indexed: 10/21/2022]
Abstract
Hypoxia-Inducible Factor-1α (HIF-1α) expression is upregulated in Sickle Cell Disease (SCD) and correlates with various laboratory markers of disease severity. Nitric Oxide plays a pivotal role in SCD pathophysiology and endothelial Nitric Oxide Synthase (NOS3) polymorphisms affect prognosis and laboratory parameters. This study questions the effect of NOS3 G894T and T786C polymorphisms on HIF-1α expression in SCD. We show that G894T polymorphism is a significant predictor of HIF-1α expression. Its effect is exerted independently of hemolysis/hemoglobin fragment concentrations, as shown in multiple regression analysis. Our results establish a novel modulator of HIF-1α expression on the mRNA level and indirectly support the role of nitric oxide in the pathophysiology of SCD.
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Affiliation(s)
- Iakovos Armenis
- 1(st) Department of Internal Medicine, Laiko General Hospital, NKUA, Medical School, Agiou Thoma 17 Street, 11527, Athens, Greece; Department of Cardiology, Onassis Cardiac Surgery Center, Syggrou 356 Avenue, 17674, Kallithea, Greece.
| | - Vassiliki Kalotychou
- 1(st) Department of Internal Medicine, Laiko General Hospital, NKUA, Medical School, Agiou Thoma 17 Street, 11527, Athens, Greece
| | - Revekka Tzanetea
- 1(st) Department of Internal Medicine, Laiko General Hospital, NKUA, Medical School, Agiou Thoma 17 Street, 11527, Athens, Greece
| | - Kostas Konstantopoulos
- Department of Hematology, Laiko General Hospital, NKUA, Medical School, Agiou Thoma 17 Street, 11527, Athens, Greece
| | - Ioannis Rombos
- Department of Hematology, Metropolitan Hospital, Ethnarchou Makariou 9 Street, Piraeus, Greece
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Antwi-Boasiako C, Asare CP, Afriyie-Mensah JS, Hayfron-Benjamin C, Nuako I, Aryee R, Dankwah GB, Asare MM, Adutwum-Ofosu K. Exercise-induced haemoglobin oxygen desaturation in patients with SCD. AMERICAN JOURNAL OF CARDIOVASCULAR DISEASE 2021; 11:87-92. [PMID: 33815924 PMCID: PMC8012294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 12/24/2020] [Indexed: 06/12/2023]
Abstract
BACKGROUND Patients with sickle cell disease (SCD) may experience severe clinical complications when there is low tissue oxygenation due to the increased risk of the polymerization of haemoglobin S in deoxygenated environment. The predictors of oxygen desaturation after exercise is not clear in patients with SCD. The current study compared lung function and six-minute walk test (6MWT) between SCD patients with oxygen desaturation after exercise and those without oxygen desaturation. METHODOLOGY A cross-sectional study was conducted among adults with SCD (with HbSS and HbSC genotypes) at a large tertiary hospital in Accra, Ghana. Lung function and exercise tolerance (using the 6MWT) were performed for all the study subjects (n=119). Venous blood was collected from all the study subjects for determination of some haemolytic markers. Oxygen saturation was assessed before and after the 6MWT for all the study subjects, and individuals who had oxygen desaturation of ≥3% after the 6MWT were considered as having exercise-induced haemoglobin oxygen desaturation (EIHOD). The lung function and 6MWT were compared between these two groups. Predictors of EIHOD were determined in both HbSC and HbSS patients. RESULTS The prevalence of EIHOD in the HbSS and HbSC adults were 41% and 36.1% respectively. Haemoglobin, aspartate amino transaminase, indirect bilirubin, lactate dehydrogenase and six-minute walk distance did not differ in both HbSS and HbSC patients. Decreasing haemoglobin is a predictor of EIHOD in HbSC adults but not HbSS patients. Lung function abnormalities did not predict EIHOD in both HbSS and HbSC patients. CONCLUSION The study demonstrates that SCD patients with EIHOD have similar degree of haemolysis and lung function when compared to those without EIHOD.
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Affiliation(s)
- Charles Antwi-Boasiako
- Department of Physiology, University of Ghana Medical School, University of GhanaAccra, Ghana
| | - Chamila P Asare
- Department of Anaesthesia, Korle-Bu Teaching HospitalAccra, Ghana
| | | | - Charles Hayfron-Benjamin
- Department of Physiology, University of Ghana Medical School, University of GhanaAccra, Ghana
- Department of Physiotherapy, Tema General HospitalAccra, Ghana
| | - Isaac Nuako
- Department of Anaesthesia, 37 Military HospitalAccra, Ghana
| | - Robert Aryee
- Department of Physiology, University of Ghana Medical School, University of GhanaAccra, Ghana
| | - Gifty Boatemaa Dankwah
- Department of Physiology, University of Ghana Medical School, University of GhanaAccra, Ghana
| | - Michael M Asare
- Department of Anatomy, University of Ghana Medical School, University of GhanaAccra, Ghana
| | - Kevin Adutwum-Ofosu
- Department of Medicine and Therapeutics, University of Ghana Medical School, University of GhanaAccra, Ghana
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ADAMTS-13-VWF axis in sickle cell disease patients. Ann Hematol 2021; 100:375-382. [PMID: 33404693 DOI: 10.1007/s00277-020-04385-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 12/16/2020] [Indexed: 10/22/2022]
Abstract
Sickle cell disease (SCD) comprises a group of genetic disorders characterized by the presence of the hemoglobin (Hb) S in homozygosis or in heterozygosis with some other Hb variant or in interaction with thalassemia. SCD is characterized by a very complex pathophysiology, which determines a wide variability of clinical manifestations, including a chronic state of hypercoagulability responsible for the increased risk of thromboembolic events. ADAMTS13 and von Willebrand factor (VWF) play an important role in arterial and venous thrombosis. Thus, the aim of this study was to understand how the ADAMTS13-VWF axis behaves in sickle cell disease, as well as whether there is an association of these markers with the use of hydroxyurea (HU). This is a cross-sectional study conducted with 40 patients diagnosed with SCD and 40 healthy individuals. The analysis of the ADAMTS13-VWF axis was comparatively performed between groups of patients and controls and, afterwards, between patients with SCD who were users and non-users of HU. ADAMTS13 activity, ADAMTS13 activity/VWF:Ag, and ADAMTS13:Ag/VWF:Ag ratios were significantly lower and VWF:Ag levels significantly higher in SCD patients when compared to the controls. There was no statistically significant difference in ADAMTS13:Ag and VWF collagen binding (VWF:CB) levels between the groups evaluated. Among the categories of HU use, there was no statistically significant difference in any of the evaluated markers. As a conclusion, we could observe that the ADAMTS13-VWF axis is altered in SCD when compared to healthy individuals and that there is no association between these markers and the use of HU.
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Nlemadim A, Okpara H, Uzomba C, Anah M, Meremikwu M. Hypocalcemia and vaso-occlusive painful crises in pediatric sickle cell anaemia. NIGERIAN JOURNAL OF MEDICINE 2021. [DOI: 10.4103/njm.njm_154_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Maddray AB, Phillips SM. Instruments to Measure Perceptions in the Emergency Department Provider-Patient with Sickle Cell Disease Interaction: Findings of an Integrative Review from a Ph.D. Project. Open Nurs J 2020. [DOI: 10.2174/1874434602014010263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Background & Purpose:
The purpose of this review is to examine instruments that measure providers' perceptions of adult patients with Sickle Cell Disease (SCD), examine instruments that measure adult patients with SCD perceptions of providers' behaviors, and determine optimal instruments to use in evaluating the perceptions of Emergency Department (ED) providers and adult patients with SCD of one another's behaviors after an interaction in the ED.
Methods:
An integrative review was conducted searching EBSCOhost and PubMed databases using the keywords: measure [OR] measure* [OR] assess* [OR] scale [OR] survey [OR] tool [AND] stigma* [OR] stereotype [OR] prejudice [OR] bias [OR] perception [OR] attitude [OR] discrimination [OR] racism [OR] behavior [AND] interaction [OR] relationship [OR] communication [AND] sickle cell. Initial search located 256 articles, but only 15 articles were included in the final review.
Results:
Fifteen articles reporting six instruments were reviewed. Four instruments evaluated a provider’s perceptions of patients with SCD behaviors, and two instruments evaluated how patients with SCD perceived provider behaviors. The two patient-focused instruments and three provider-focused instruments were found to be adequately reliable and valid according to the Psychometric Grading Framework (PGF).
Conclusions:
The findings suggest that the General Perceptions About Sickle Cell Disease Patients Scale would be an optimal instrument to evaluate ED providers' perceptions of adult patients with SCD behaviors. One patient-focused instrument, The Sickle Cell Health-Related Stigma Scale (SCD-HRSS), reported adequate reliability and validity but was not specific to measuring the patient's perceptions of ED providers' behaviors, nor was it administered in the ED environment. The SCD-HRSS Doctors subscale has potential adaptability for use in measuring patients with SCD perceptions of ED provider behaviors in the ED environment.
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Cruz LJ, van Dijk T, Vepris O, Li TMWY, Schomann T, Baldazzi F, Kurita R, Nakamura Y, Grosveld F, Philipsen S, Eich C. PLGA-Nanoparticles for Intracellular Delivery of the CRISPR-Complex to Elevate Fetal Globin Expression in Erythroid Cells. Biomaterials 2020; 268:120580. [PMID: 33321292 DOI: 10.1016/j.biomaterials.2020.120580] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 11/16/2020] [Accepted: 11/23/2020] [Indexed: 12/16/2022]
Abstract
Ex vivo gene editing of CD34+ hematopoietic stem and progenitor cells (HSPCs) offers great opportunities to develop new treatments for a number of malignant and non-malignant diseases. Efficient gene-editing in HSPCs has been achieved using electroporation and/or viral transduction to deliver the CRISPR-complex, but cellular toxicity is a drawback of currently used methods. Nanoparticle (NP)-based gene-editing strategies can further enhance the gene-editing potential of HSPCs and provide a delivery system for in vivo application. Here, we developed CRISPR/Cas9-PLGA-NPs efficiently encapsulating Cas9 protein, single gRNA and a fluorescent probe. The initial 'burst' of Cas9 and gRNA release was followed by a sustained release pattern. CRISPR/Cas9-PLGA-NPs were taken up and processed by human HSPCs, without inducing cellular cytotoxicity. Upon escape from the lysosomal compartment, CRISPR/Cas9-PLGA-NPs-mediated gene editing of the γ-globin gene locus resulted in elevated expression of fetal hemoglobin (HbF) in primary erythroid cells. The development of CRISPR/Cas9-PLGA-NPs provides an attractive tool for the delivery of the CRISPR components to target HSPCs, and could provide the basis for in vivo treatment of hemoglobinopathies and other genetic diseases.
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Affiliation(s)
- Luis J Cruz
- Translational Nanobiomaterials and Imaging, Department of Radiology, Leiden University Medical Center, the Netherlands
| | - Thamar van Dijk
- Erasmus University Medical Center, Department of Cell Biology, Rotterdam, the Netherlands
| | - Olena Vepris
- Translational Nanobiomaterials and Imaging, Department of Radiology, Leiden University Medical Center, the Netherlands
| | - Tracy M W Y Li
- Translational Nanobiomaterials and Imaging, Department of Radiology, Leiden University Medical Center, the Netherlands
| | - Timo Schomann
- Translational Nanobiomaterials and Imaging, Department of Radiology, Leiden University Medical Center, the Netherlands; Percuros B.V, Leiden, the Netherlands
| | - Fabio Baldazzi
- Translational Nanobiomaterials and Imaging, Department of Radiology, Leiden University Medical Center, the Netherlands
| | - Ryo Kurita
- Central Blood Institute, Research and Development Department, Blood Service Headquarters, Japanese Red Cross Society, Tokyo, Japan
| | - Yukio Nakamura
- RIKEN BioResource Research Center, Cell Engineering Division, National Research and Development Corporation, Tsukuba, Japan
| | - Frank Grosveld
- Erasmus University Medical Center, Department of Cell Biology, Rotterdam, the Netherlands
| | - Sjaak Philipsen
- Erasmus University Medical Center, Department of Cell Biology, Rotterdam, the Netherlands
| | - Christina Eich
- Translational Nanobiomaterials and Imaging, Department of Radiology, Leiden University Medical Center, the Netherlands.
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Ranabothu S, Hafeman M, Manwani D, Reidy K, Morrone K, Lorenzo J, Tria B, Kaskel F, Mahgerefteh J. Ambulatory Hypertension in Pediatric Patients With Sickle Cell Disease and Its Association With End-Organ Damage. Cureus 2020; 12:e11707. [PMID: 33391940 PMCID: PMC7769822 DOI: 10.7759/cureus.11707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Background Sickle cell disease (SCD), a chronic hemolytic disorder, results in cumulative end-organ damage affecting major organs such as the cardiovascular, renal, and central nervous systems. Effects of modifiable risk factors, such as blood pressure (BP), on the development of end-organ complications in SCD have not been well studied, particularly among the pediatric population. Relative hypertension in patients with SCD increases their risks of stroke, cardiovascular complications, and death. The primary hypothesis of this study was that abnormal BP patterns are common among patients with SCD and they impact end-organ complications. Methods Patients with SCD (HbSS, HbSβ0) were enrolled from the Children’s Hospital at Montefiore (N = 100). For each patient, demographic data were collected, biochemical variables in urine and blood samples were analyzed, BP was determined with ambulatory blood pressure monitoring (ABPM), and an echocardiogram was performed. The prevalence of abnormalities in BP parameters was defined, and their relationships with measures of SCD severity and end-organ damage were assessed. Results Sufficient ABPM data were available for 67 patients. Enrolled children were 13 ± 4 years (40% were males). Assessment of diurnal variation demonstrated that 81% of patients had abnormal systolic nocturnal dipping and 61% had abnormal diastolic nocturnal dipping. Abnormalities in the diurnal pattern were associated with reticulocytosis and hyperfiltration. Microalbuminuria was present in 19% (n = 13) of patients, of which 77% (n = 10) were females (p = 0.014). Diastolic load and abnormal nocturnal dipping were associated with hyperfiltration but not with microalbuminuria. Conclusions BP abnormalities detected with ABPM in SCD patients are prevalent and perhaps are a risk factor for end-organ complications. Further studies are required to identify the mechanisms underlying these relationships and their longitudinal changes.
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Affiliation(s)
- Saritha Ranabothu
- Pediatrics, University of Arkansas for Medical Sciences, Little Rock, USA
| | | | - Deepa Manwani
- Hematology, Children's Hospital at Montefiore, Bronx, USA
| | - Kimberly Reidy
- Nephrology, Children's Hospital at Montefiore, Bronx, USA
| | - Kerry Morrone
- Hematology, Children's Hospital at Montefiore, Bronx, USA
| | | | - Barbara Tria
- Cardiology, Children's Hospital at Montefiore, Bronx, USA
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Kosiyo P, Otieno W, Gitaka J, Munde EO, Ouma C. Association between haematological parameters and sickle cell genotypes in children with Plasmodium falciparum malaria resident in Kisumu County in Western Kenya. BMC Infect Dis 2020; 20:887. [PMID: 33238928 PMCID: PMC7690073 DOI: 10.1186/s12879-020-05625-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 11/17/2020] [Indexed: 02/08/2023] Open
Abstract
Background Sickle cell disease (SCD) is a monogenic disorder due to point mutation in the β-globin gene resulting in substitution of Valine for Glutamic acid. The SCD is prevalent in P. falciparum endemic regions such as western Kenya. Carriage of different sickle cell genotypes may influence haematological parameter during malaria. Children resident in malaria holoendemic regions suffer more from malaria-related complications and this is moderated by the presence of the SCD. In the current study, we determined the association between sickle cell genotypes and haematological parameters in children with P. falciparum malaria resident in Kisumu County in Western Kenya. Methodology Children (n = 217, aged 1–192 months) with acute febrile condition were recruited at Jaramogi Oginga Odinga Teaching and Referral Hospital. Chi-square (χ2) analysis was used to determine differences between proportions. Differences in haematological parameters were compared across groups using Kruskal Wallis test and between groups using Mann Whitney U test. Multivariate logistic regression analysis controlling for infection status was used to determine the association between sickle cell genotypes and haematological parameters. Results Using HbAA as the reference group, multivariate logistic regression analysis revealed that carriage of HbSS was associated with reduced haemoglobin [OR = 0.310, 95% CI = 0.101–0.956, P = 0.041], reduced haematocrit [OR = 0.318, 95% CI = 0.128–0.793, P = 0.014], reduced RBC count [OR = 0.124, 95% CI = 0.045–0.337, P = 0.001], reduced MCHC [OR = 0.325, 95% CI = 0.118–0.892, P = 0.029], increased leucocytosis [OR = 9.283, 95% CI = 3.167–27.210, P = 0.001] and reduced monocytosis [OR = 0.319, 95% CI = 0.123–0.830, P = 0.019]. However, carriage of HbAS was only associated with increased micro-platelets [OR = 3.629, 95% CI = 1.291–8.276, P = 0.012]. Conclusion Results show that carriage of HbSS in children influence the levels of haemoglobin, haematocrit, RBC, MCHC, WBC and Monocytes. Therefore prior knowledge of HbSS should be considered to improve clinical management of haematological alterations during malaria in children. Supplementary Information The online version contains supplementary material available at 10.1186/s12879-020-05625-z.
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Affiliation(s)
- Paul Kosiyo
- Department of Biomedical Science and Technology, School of Pub;ic Health and Community Development, Maseno University, Maseno, Kenya.,Department of Medical Laboratory Sciences, School of Medicine, Kisii University, P.O. Box 408-40200, Kisii, Kenya
| | - Walter Otieno
- Department of Paediatrics and Child Health, School of Medicine, Maseno University, Private Bag, Maseno, Kenya
| | - Jesse Gitaka
- School of Clinical Medicine, Mount Kenya University, Gen Kago Rd, P.O. Box 342 01000, Thika, Kenya
| | - Elly O Munde
- Department of Clinical Medicine, School of Health Sciences, Kirinyaga University, P.O Box 143-10300, Kerugoya, Kenya
| | - Collins Ouma
- Department of Biomedical Science and Technology, School of Pub;ic Health and Community Development, Maseno University, Maseno, Kenya.
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