scholarly journals Targeting pain at its source in sickle cell disease

2018 ◽  
Vol 315 (1) ◽  
pp. R104-R112 ◽  
Author(s):  
Kanika Gupta ◽  
Om Jahagirdar ◽  
Kalpna Gupta
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Genetic Disorder ◽  
Somatosensory System ◽  
Organ Damage ◽  
Mast Cell Activation ◽  
Cell Disease ◽  
Central Nervous Systems

Sickle cell disease (SCD) is a genetic disorder associated with hemolytic anemia, end-organ damage, reduced survival, and pain. One of the unique features of SCD is recurrent and unpredictable episodes of acute pain due to vasoocclusive crisis requiring hospitalization. Additionally, patients with SCD often develop chronic persistent pain. Currently, sickle cell pain is treated with opioids, an approach limited by adverse effects. Because pain can start at infancy and continue throughout life, preventing the genesis of pain may be relatively better than treating the pain once it has been evoked. Therefore, we provide insights into the cellular and molecular mechanisms of sickle cell pain that contribute to the activation of the somatosensory system in the peripheral and central nervous systems. These mechanisms include mast cell activation and neurogenic inflammation, peripheral nociceptor sensitization, maladaptation of spinal signals, central sensitization, and modulation of neural circuits in the brain. In this review, we describe potential preventive/therapeutic targets and their targeting with novel pharmacologic and/or integrative approaches to ameliorate sickle cell pain.

scholarly journals Protection of Microvascular Liver Perfusion with 5-Hydroxymethylfurfural in Sickle Cell Disease Mice Following Hypoxia-Induced Vasoocclusion

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3382-3382 ◽  
Author(s):  
Michael Wright ◽  
Derek Sim ◽  
Magdalena Alonso-Galicia ◽  
Katalin Kauser ◽  
Keith Abe
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Genetic Disorder ◽  
Liver Perfusion ◽  
Organ Damage ◽  
Extramedullary Hematopoiesis ◽  
T Test ◽  
Vehicle Group ◽  
Cell Disease ◽  
And Control

Abstract Introduction: Sickle cell disease (SCD) is a debilitating genetic disorder, and the resultant "sickling" deformity of red blood cells leads to acute vasoocclusive (VOC) events and chronic disease in multiple organs. Sickle cell hepatopathy, arising from VOC events in the hepatic sinusoids, which can lead to fatal sickle cell intrahepatic cholestasis, is estimated to occur in approximately 10% of the SCD population. Using contrast-enhanced ultrasound (CEUS), we measured microvascular liver perfusion (MVLP) in SCD and control mice at basal levels to determine if noninvasive CEUS can be utilized to assess the underlying extent of disease and also investigated the effect of hypoxia-induced VOC with and without treatment with an antisickling agent, 5-hyroxymethylfurfural (5-HMF). Methods: Townes sickle cell mice (SCD), homozygous for hα:βs -globulin, approximately 7−9 weeks of age (n=28), and control mice, homozygous for hα:β-globulin (n=11), were used in these studies. CEUS perfusion imaging (Vevo® 2100) was performed on a central cross-section of the liver at the renal artery. Contrast agent was administered as an intravenous bolus via tail vein to anesthetized mice (isoflurane with ~21% O2); peak enhancement (PE) was analyzed with VisualSonics software. CEUS measurements were obtained at baseline and following either (1) hypoxia, 60 minutes with 5.5.% O2 followed by ~60 minutes of reoxygenation at room oxygen (~21% O2) or (2) normoxia, ~120 minutes at room oxygen. 5-HMF at 20 and 200 mg/kg PO or vehicle was administered following baseline PE measurement and approximately 30 minutes before start of hypoxia. Results: MVLP in SCD (n=28) was significantly reduced by approximately 40% compared with controls (n=11) at baseline (PE of 14.0±0.7 linear arbitrary units [l.a.u.] vs. 23.6±2.1 l.a.u.), respectively, P<0.001 [Student t test]). Normoxic SCD maintained similar PE to baseline levels (Table 1); however, hypoxia significantly reduced MVLP by 49% in SCD mice. In contrast, hypoxia had no significant effect in control mice. 5-HMF at 20 and 200 mg/kg resulted in a dose-dependent increase in posthypoxia MVLP. 5-HMF at 200 mg/kg was not significantly different from baseline PE, and 5-HMF at 20 mg/kg increased MVLP by approximately 50% compared with the vehicle group posthypoxia (26% vs 49% reduction in MVLP, respectively). Pathologic evaluation of naive SCD formalin-fixed liver tissues (n=10) showed congestion, necrosis, hepatocellular hypertrophy, and extramedullary hematopoiesis. Table 1. CEUS-Acquired Microvascular Liver Perfusion in SCD and Control Mice (mean ± SEM) Strain Dose Oxygen Status Mice, n Baseline PE, l.a.u. Posthypoxia/Normoxia PE, l.a.u. Change From Baseline, % Control Vehicle Hypoxic 11 23.6±2.1 22.1±2.1 -7 SCD Vehicle Normoxic 4 14.0±2.1 13.3±1.6 -3 SCD Vehicle Hypoxic 8 15.4 ±1.6 7.0±0.9* -49 SCD HMF, 20 mg/kg Hypoxic 8 12.8±0.9 9.2±0.7* -26 SCD HMF, 200 mg/kg Hypoxic 8 13.8±1.5 11.9±1.2 -12 *Statistically significant reduction compared with baseline PE (P <0.01, Student t test). Summary: CEUS measured lower basal levels of MVLP in SCD compared with control mice, which correlated with pathologic findings of congestion and necrosis in the livers of SCD mice. The hypoxia-induced VOC decrease in MVLP was present only in the SCD mice; no effect was observed in control mice. Treatment with the antisickling agent, 5-HMF, dose-dependently ameliorated the hypoxia-induced VOC decrease in MVLP in SCD mice. Based on these results, CEUS may be considered as a noninvasive method to measure acute and chronic organ perfusion changes for evaluating new therapeutics for sickle cell-mediated VOC events and end-organ damage. Disclosures Wright: Bayer HealthCare LLC: Employment. Sim:Bayer HealthCare LLC: Employment. Alonso-Galicia:Bayer HealthCare LLC: Employment. Kauser:Bayer HealthCare LLC: Employment. Abe:Bayer HealthCare LLC: Employment.

scholarly journals 24-Hour Profile of Microvascular Liver Perfusion in Sickle Cell Disease Mice Following Hypoxia-Induced Vaso-Occlusion

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1300-1300
Author(s):  
Keith Abe ◽  
Michael Wright ◽  
Derek Sim ◽  
Magdalena Alonso-Galicia ◽  
Katalin Kauser
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Genetic Disorder ◽  
Liver Perfusion ◽  
Organ Damage ◽  
Hypoxic Exposure ◽  
Organ Perfusion ◽  
Cell Disease ◽  
Cell Counts ◽  
Baseline Levels

Abstract Introduction: Sickle cell disease (SCD) is a debilitating genetic disorder of the red blood cells, leading to acute vaso-occlusive (VOC) events and chronic disease in multiple organs. In the liver, VOC events in the hepatic sinusoids can lead to fatal sickle cell intrahepatic cholestasis (SCIC), which is estimated to occur in approximately 10% of the SCD population. Using contrast enhanced ultrasound (CEUS), we have previously shown that microvascular liver perfusion (MVLP) at basal levels in SCD mice is significantly reduced compared with non-SCD control mice and that MVLP in SCD mice can be further reduced by hypoxia-induced VOC events. Additionally, treatment with the antisickling agent, 5-Hyroxymethylfurfural (5-HMF), can prevent hypoxia-induced VOC reduction in MVLP in SCD mice. A prior study investigated a single time point (1 hour) posthypoxia; the duration and effect beyond 1 hour posthypoxia remained unknown. This investigation was performed to address the duration of the reduction in MVLP and the preventative effect of 5-HMF over a 24-hour period. Methods: Townes sickle cell mice (SCD), homozygous for hα:βs-globulin, approximately 7−9 weeks of age (n=15) were utilized in these studies. CEUS perfusion imaging (Vevo® 2100) was performed on a central cross-section of the liver at the renal artery. Contrast agent was administered as an intravenous bolus via tail vein to anesthetized mice (isoflurane with ~21% O2) and peak perfusion intensity [PPI] measured in linear arbitrary units [l.a.u.]), and data were analyzed with VisualSonics software. Repeated CEUS measurements were obtained on SCD mice at baseline (prehypoxia), 1, 4, and 24 hours posthypoxic exposure (hypoxic exposure: 60 minutes with approximately 5.5.% O2). 5-HMF at 200 mg/kg PO or vehicle was administered following baseline PPI measurement and approximately 30 minutes before start of hypoxia. Results:Following hypoxia-induced VOC,MVLP in vehicle-treated SCD was significantly reduced by approximately 25% from baseline levels at 1 and 4 hours posthypoxia, before returning to baseline levels at 24 hours posthypoxia (Table 1). In contrast, SCD mice administered 5-HMF at 200 mg/kg PO showed no reduction in MVLP at 1, 4, and 24 hours posthypoxia. Sickle cell counts were obtained on surrogate animals and data are still pending. *Significant reduction from baseline, P<0.05, ANOVA with Tukey's multiple comparison test. Summary: CEUS measured a reduction in MVLP in vehicle-treated SCD mice following hypoxia-induced VOC with a duration of at least 4 hours posthypoxia. By 24 hours posthypoxia, MVLP had returned to baseline (prehypoxia) levels. Prehypoxia treatment with the antisickling agent 5-HMF was able to prevent the hypoxia-induced VOC reduction in MVLP in SCD mice for the entire 24-hour period. These data suggest that prophylactic treatment with an antisickling agent prior to a VOC event may benefit SCD patients by maintaining organ perfusion. These results further validate CEUS as a noninvasive method to measure acute and chronic organ perfusion changes for evaluating new therapeutics for sickle cell-mediated VOC events and end-organ damage. Table Microvascular Liver Perfusion (PPI in l.a.u.) Over 24 Hours in SCD Mice With and Without 5-HMF (Mean ± SD) Table. Microvascular Liver Perfusion (PPI in l.a.u.) Over 24 Hours in SCD Mice With and Without 5-HMF (Mean ± SD) Disclosures Abe: Bayer: Employment. Sim:Bayer: Employment. Alonso-Galicia:Bayer: Employment. Kauser:Bayer: Employment.

scholarly journals Agonistic Anti-CD40 Antibody Triggers an Acute Liver Crisis With Systemic Inflammation in Humanized Sickle Cell Disease Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Ayla Yalamanoglu ◽  
Irina L. Dubach ◽  
Nadja Schulthess ◽  
Giada Ingoglia ◽  
Delaney C. Swindle ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Systemic Inflammation ◽  
Cell Activation ◽  
Globin Gene ◽  
Vascular Occlusion ◽  
Organ Damage ◽  
Cell Disease ◽  
Endothelial Cell Activation ◽  
Adhesive Properties

Sickle cell disease (SCD) is an inherited hemolytic disorder, defined by a point mutation in the β-globin gene. Stress conditions such as infection, inflammation, dehydration, and hypoxia trigger erythrocyte sickling. Sickled red blood cells (RBCs) hemolyze more rapidly, show impaired deformability, and increased adhesive properties to the endothelium. In a proinflammatory, pro-coagulative environment with preexisting endothelial dysfunction, sickled RBCs promote vascular occlusion. Hepatobiliary involvement related to the sickling process, such as an acute sickle hepatic crisis, is observed in about 10% of acute sickle cell crisis incidents. In mice, ligation of CD40 with an agonistic antibody leads to a macrophage activation in the liver, triggering a sequence of systemic inflammation, endothelial cell activation, thrombosis, and focal ischemia. We found that anti-CD40 antibody injection in sickle cell mice induces a systemic inflammatory and hemodynamic response with accelerated hemolysis, extensive vaso-occlusion, and large ischemic infarctions in the liver mimicking an acute hepatic crisis. Administration of the tumor necrosis factor-α (TNF-α) blocker, etanercept, and the heme scavenger protein, hemopexin attenuated end-organ damage. These data collectively suggest that anti-CD40 administration offers a novel acute liver crisis model in humanized sickle mice, allowing for evaluation of therapeutic proof-of-concept.

scholarly journals Sickle Cell Disease: Role of Oxidative Stress and Antioxidant Therapy

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 296
Author(s):  
Rosa Vona ◽  
Nadia Maria Sposi ◽  
Lorenza Mattia ◽  
Lucrezia Gambardella ◽  
Elisabetta Straface ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Globin Gene ◽  
Organ Damage ◽  
Cell Disease ◽  
Vessel Occlusion ◽  
Antioxidant Agents ◽  
Oxidant Status

Sickle cell disease (SCD) is the most common hereditary disorder of hemoglobin (Hb), which affects approximately a million people worldwide. It is characterized by a single nucleotide substitution in the β-globin gene, leading to the production of abnormal sickle hemoglobin (HbS) with multi-system consequences. HbS polymerization is the primary event in SCD. Repeated polymerization and depolymerization of Hb causes oxidative stress that plays a key role in the pathophysiology of hemolysis, vessel occlusion and the following organ damage in sickle cell patients. For this reason, reactive oxidizing species and the (end)-products of their oxidative reactions have been proposed as markers of both tissue pro-oxidant status and disease severity. Although more studies are needed to clarify their role, antioxidant agents have been shown to be effective in reducing pathological consequences of the disease by preventing oxidative damage in SCD, i.e., by decreasing the oxidant formation or repairing the induced damage. An improved understanding of oxidative stress will lead to targeted antioxidant therapies that should prevent or delay the development of organ complications in this patient population.

scholarly journals The gut microbiome in sickle cell disease: Characterization and potential implications

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0255956
Author(s):  
Hassan Brim ◽  
James Taylor ◽  
Muneer Abbas ◽  
Kimberly Vilmenay ◽  
Mohammad Daremipouran ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Gut Microbiome ◽  
Tissue Injury ◽  
Organ Damage ◽  
Composition Analysis ◽  
Cell Disease ◽  
Blood Disorder ◽  
Major Player ◽  
Next Generation Sequencing Ngs

Background Sickle Cell Disease (SCD) is an inherited blood disorder that leads to hemolytic anemia, pain, organ damage and early mortality. It is characterized by polymerized deoxygenated hemoglobin, rigid sickle red blood cells and vaso-occlusive crises (VOC). Recurrent hypoxia-reperfusion injury in the gut of SCD patients could increase tissue injury, permeability, and bacterial translocation. In this context, the gut microbiome, a major player in health and disease, might have significant impact. This study sought to characterize the gut microbiome in SCD. Methods Stool and saliva samples were collected from healthy controls (n = 14) and SCD subjects (n = 14). Stool samples were also collected from humanized SCD murine models including Berk, Townes and corresponding control mice. Amplified 16S rDNA was used for bacterial composition analysis using Next Generation Sequencing (NGS). Pairwise group analyses established differential bacterial groups at many taxonomy levels. Bacterial group abundance and differentials were established using DeSeq software. Results A major dysbiosis was observed in SCD patients. The Firmicutes/Bacteroidetes ratio was lower in these patients. The following bacterial families were more abundant in SCD patients: Acetobacteraceae, Acidaminococcaceae, Candidatus Saccharibacteria, Peptostreptococcaceae, Bifidobacteriaceae, Veillonellaceae, Actinomycetaceae, Clostridiales, Bacteroidacbactereae and Fusobacteriaceae. This dysbiosis translated into 420 different operational taxonomic units (OTUs). Townes SCD mice also displayed gut microbiome dysbiosis as seen in human SCD. Conclusion A major dysbiosis was observed in SCD patients for bacteria that are known strong pro-inflammatory triggers. The Townes mouse showed dysbiosis as well and might serve as a good model to study gut microbiome modulation and its impact on SCD pathophysiology.

scholarly journals Prevalence of Sickle Cell Disease and Other Haemoglobin Variants in Calabar, Cross River State, Nigeria

2019 ◽  
pp. 1-6
Author(s):  
Akaba Kingsley ◽  
Ofem Enang ◽  
Ofonime Essien ◽  
Annette Legogie ◽  
Omini Cletus ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Genetic Disorder ◽  
Globin Gene ◽  
Specific Gene ◽  
Cell Disease ◽  
Cellulose Acetate Electrophoresis ◽  
Genetic Changes ◽  
Female Ratio ◽  
Cross River State

Background: Sickle cell disease (SCD) is the commonest genetic disorder worldwide with a global prevalence of 20-25 million. About 12-15 million affected persons are in Sub-Sahara Africa with Nigeria bearing the highest burden of people living with sickle cell disease. SCD is a disease characterized as an autosomal, recessive, heterogeneous, and a monogenetic disorder caused by an A-to-T point mutation in the β-globin gene responsible for the production of abnormal hemoglobin S (HbS), which polymerizes in the deoxygenated state and results in the sickling of erythrocytes.  Haemoglobin variants are mutant forms of haemoglobin in a population usually occurring as a result of genetic changes in specific genes, or globins that causes change on alterations in the amino acid. They could affect the structure, behavior, the production rate and the stability of the specific gene. Well-known haemoglobin variants such as sick-cell anaemia are responsible for diseases and are considered haemoglobinopathies. Other variants cause no detectable pathology and are thus considered as non-pathological variants. Aim: The study is aimed at evaluating the burden of sickle cell disease and other haemoglobin variants in Calabar, South-South Nigeria. Methods: This is a retrospective study done at the haematology laboratory of University of Calabar Teaching Hospital, Calabar. Cellulose acetate electrophoresis at alkaline pH was used for the evaluation of haemoglobinopathies. The data were entered into Microsoft Excel 2016 spreadsheet and analysed with the IBM SPSS Version 22. Data were summarized into percentage of different phenotypes. Results: Results of the total 3648 haemoglobin electrophoresis recorded, 1368 (37.50%) were male while the remaining 2280 (62.5%) females given a male to female ratio of 1:1.7. Five haemoglobin phenotypes were identified as HbAA, HbAS, HbAC, HbSC and HbSS. The overall average values of their prevalence were HbAA 64.78%, HbAS 32.62%, HbSS 2.14%, HbAC 0.33%, HbSC 0.14%. Thus, the prevalence of SCD (Prevalence of HbSS+HbSC) was 2.28%. The highest proportion of SCD was observed in 2011 with least in 2016 and 2017 respectively. Conclusion: The prevalence of SCD and other haemoglobin variants in Calabar is similar to that of the national prevalence rate. There is need for continuous enlightenment and premarital counselling on the pattern of inheritance of SCD most especially with the increased burden of sickle traits in the environment has reported in this study.

scholarly journals Sickle Cell Disease Model Mice Lacking 2,3-Dpg Show Reduced RBC Sickling and Improvements in Markers of Hemolytic Anemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 27-28
Author(s):  
Kelly M. Knee ◽  
Amey Barakat ◽  
Lindsay Tomlinson ◽  
Lila Ramaiah ◽  
Zane Wenzel ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Blood Cell ◽  
Hemolytic Anemia ◽  
Sickle Cell ◽  
Red Blood Cell ◽  
Organ Damage ◽  
Complete Elimination ◽  
Cell Disease ◽  
The Impact ◽  
2,3 Dpg

Sickle cell disease (SCD) is a severe genetic disorder caused by a mutation in hemoglobin (b6Glu-Val), which allows the mutant hemoglobin to assemble into long polymers when deoxygenated. Over time, these polymers build up and deform red blood cells, leading to hemolytic anemia, vaso-occlusion, and end organ damage. A number of recent therapies for SCD have focused on modulating the mutant hemoglobin directly, however, reduction or elimination of 2,3-DPG to reduce Hb S polymerization and RBC sickling has recently been proposed as a therapeutic strategy for SCD. Current clinical studies focus on activation of pyruvate kinase to reduce 2,3-DPG, however, direct targeting of the enzyme which produces 2,3-DPG; Bisphosphoglycerate Mutase (BPGM) may also be possible. In this study we evaluate the impact of elimination of 2,3-DPG on SCD pathology by complete knockout of BPGM in Townes model mice. Animals with complete knockout of BPGM (BPGM -/-) have no detectable 2,3-DPG, while animals that are heterozygous for BPGM (BPGM -/+) have 2,3-DPG levels comparable to Townes mice. Western Blot analysis confirms that BPGM -/- animals completely lack BPGM, while BPGM -/+ animals have BPGM levels that are nearly equivalent to Townes mice. As expected from the lack of 2,3-DPG, BPGM -/- animals have increased oxygen affinity, observed as a 39% decrease in p50 relative to Townes mice. Complete elimination of 2,3-DPG has significant effects on markers of hemolytic anemia in BPGM -/- mice. Mice lacking 2,3-DPG have a 60% increase in hemoglobin (3.7 g/dL), a 53% increase in red blood cell count, and a 29% increase in hematocrit relative to Townes mice. The BPGM -/- mice also have a 57% decrease in reticulocytes, and a 61% decrease in spleen weight relative to Townes animals, consistent with decreased extramedullary hematopoiesis. Consistent with the reduction in hemolysis, BPGM -/- animals had a 59% reduction in red blood cell sickling under robust hypoxic conditions. BPGM -/+ animals had hemoglobin, RBC, and hematocrit levels that were similar to Townes animals, and a similar degree of RBC sickling to Townes mice. Liver phenotype was similar across all variants, with areas of random necrosis observed in BPGM -/-, BPGM -/+ and Townes mice. Higher percentages of microcytic and/or hyperchromic RBCs were observed in BPGM -/- animals relative to BPGM -/+ or Townes animals. These results suggest that modulation of 2,3-DPG has a positive effect on RBC sickling and hemolytic anemia, which may have therapeutic benefits for SCD patients. However, the lack of improvement in organ damage suggests that modulation of 2,3-DPG alone may not be sufficient for complete elimination of SCD phenotypes, and further investigation of this therapeutic avenue may be necessary. Disclosures No relevant conflicts of interest to declare.

scholarly journals Sickle Cell Disease: An Overview of Oral Health Considerations for Pediatric Patients

2021 ◽  
Vol 2 (3) ◽  
pp. 9-17
Author(s):  
Dafni Eleftherou ◽  
Aristidis Arhakis ◽  
Sotiria Davidopoulou
Keyword(s):  
Oral Health ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Pediatric Patients ◽  
Genetic Disorder ◽  
The Body ◽  
Common Finding ◽  
Cell Disease ◽  
Preventive Dental Care ◽  
Periodontal Inflammation

Aim: This literature review aims to update the evidence for orofacial manifestations and current treatment recommendations for children and adolescents with sickle cell disease. Background: Sickle cell disease is a frequent hemoglobinopathy and a life-threatening genetic disorder. The lifelong condition is characterized by chronic hemolytic anemia and vaso-occlusive crisis that may occur in a variable range of clinical presentations in different regions of the body, including the oral cavity. Review results: This review explored the most common orofacial alterations of pediatric patients with SCD. Dental caries is a common finding in SCD pediatric patients, especially in those who are socio-economically vulnerable. Moreover, malocclusions occur in high prevalence in SCD pediatric patients. Other oral health complications seen in SCD patients include periodontal inflammation, bone changes, infections, mental nerve neuropathy, facial overgrowth, delayed tooth eruption, dental anomalies, pulp necrosis, soft tissue alterations and salivary changes. Dental infections may trigger a vaso-occlusive crisis leading the patient to a higher probability on arriving in hospital emergency departments and in need for further hospital admission to deal with the correlated complications. Thus, preventive dental care and non-invasive dental procedures are the principal focus in SCD patients in order to avoid possible subsequent complications. Conclusion: The review showed that in pediatric patients with SCD the risk for orofacial manifestations and complications depends not only on the presence of SCD but also on other confounding factors such as oral hygiene, diet habits and social conditions. Moreover, more well-designed epidemiological studies are necessary to assess the real link between SCD disease and its impact on stomatognathic health.

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