Congenital dyserythropoietic anemias (CDAs) are characterized by ineffective erythropoiesis and d... more Congenital dyserythropoietic anemias (CDAs) are characterized by ineffective erythropoiesis and distinctive erythroblast abnormalities; the diagnosis is often missed or delayed due to significant phenotypic heterogeneity. We established the CDA Registry of North America (CDAR) to study the natural history of CDA and create a biorepository to investigate the pathobiology of this heterogeneous disease. Seven of 47 patients enrolled so far in CDAR have CDA-I due to biallelic CDAN1 mutations. They all presented with perinatal anemia and required transfusions during infancy. Anemia spontaneously improved during infancy in three patients; two became transfusion-independent rapidly after starting interferon-α2; and two remain transfusion-dependent at last follow-up at ages 5 and 30 y.o. One of the transfusion-dependent patients underwent splenectomy at 11 y.o due to misdiagnosis and returned to medical attention at 27 y.o with severe hemolytic anemia and pulmonary hypertension. All patients developed iron overload even without transfusions; four were treated with chelation. Genetic testing allowed for more rapid and accurate diagnosis; the median age of confirmed diagnosis in our cohort was 3 y.o compared to 17.3 y.o historically. In conclusion, CDAR provides an organized research network for multidisciplinary clinical and research collaboration to conduct natural history and biologic studies in CDA.
Background: Sickle cell disease (SCD) is associated with significant medical challenges that ofte... more Background: Sickle cell disease (SCD) is associated with significant medical challenges that often worsen in adolescence when caregivers are beginning to transfer responsibility for disease management. Behavioral activation (BA) is an important precedent to improvements in selfmanagement and ultimately health outcomes; however, few interventions targeting BA have been developed for the SCD population. The goal of the present study was to evaluate a technologyenhanced self-management intervention for adolescents and young adults (AYA) with SCD targeting BA domains (i.e., disease knowledge, self-efficacy, motivation, and self-management skills). Design/Methods: Participants were randomized to one of two study arms. SCThrive participants (N=26) completed six weekly group sessions, an in-person booster session, and used a companion app (iManage) to record symptoms, progress on goals, and connect with other group members. Each SCHealthEd participant (N=27) received six weekly phone calls on SCD-related and general health education topics. All AYAs completed questionnaires assessing BA at baseline and post-treatment.
Background: Sickle cell anemia (SCA) is a leading cause of stroke and neurologic disability in ch... more Background: Sickle cell anemia (SCA) is a leading cause of stroke and neurologic disability in children. In the 20 years since the publication of the STOP trial, chronic transfusion therapy and hydroxyurea have shown efficacy as disease-modifying therapies, especially by improvement of transcranial Doppler (TCD) velocities and reduction in the incidence of overt stroke. Despite the publication of the SIT Trial 2014, screening for silent stroke is not universally implemented. Here we report our center’s experience with screening neuroimaging in young children with SCA. Methods: This is a single center, retrospective case series of patients with SCA (HbSS and HbSb 0 -thalassemia) managed in a comprehensive sickle cell center. Patients undergo TCD screening per STOP guidelines beginning at age 24 months. Screening MRI/MRA brain are also recommended at 5, 10, 15, and 20 years of age. Imaging data for the children 5-9 years of age are reported. Results: There were 39 subjects within the ...
Reticuloendothelial system MRI signal hypointensity is common in pediatric oncology patients with... more Reticuloendothelial system MRI signal hypointensity is common in pediatric oncology patients with solid abdominal tumors. To assess changes in liver, spleen and bone marrow T2-weighted MRI signal intensity over time and their relationship to blood transfusion history in children with solid abdominal tumors. In this retrospective study we measured liver, spleen and bone marrow signal intensity on axial T2-weighted MR images obtained December 2009 through February 2016 in children with hepatoblastoma, neuroblastoma, ganglioneuroblastoma and Wilms tumor. All signal intensity measurements were normalized to paraspinal muscle signal intensity. We used linear mixed models (including a day*day quadratic term) to determine whether organ signal intensity changed over time and whether change was associated with blood transfusion volume or tumor type. We included 133 children (mean age at diagnosis =2.9 years); 56 had neuroblastoma, 42 hepatoblastoma, 28 Wilms tumor and 7 ganglioneuroblastoma....
The purpose of this study is determine if both liver T2* and cardiac T2* can be measured on a sin... more The purpose of this study is determine if both liver T2* and cardiac T2* can be measured on a single breath-hold acquisition. For this IRB-approved retrospective study, 137 patients with dedicated Cardiac MRI and Liver MRI examinations obtained sequentially on 1.5T scanners and on the same day were included for analysis. Both the cardiac and liver MRI examinations utilized GRE sequences for quantification of tissue iron. Specifically, T2* was measured using an 8-echo, multi-echo gradient echo single breath-hold sequence. Liver T2* was measured in a blinded manner on images from each of the cardiac and dedicated liver MRI examinations and were correlated. Bland-Altman difference plot was used to assess mean bias. 137 examinations from 93 subjects met inclusion criteria. 10 examination pairs were excluded because the first echo time (TE) on the cardiac MRI was insufficiently short for the very high liver iron content. After exclusion, 127 studies from 89 subjects (67.4% males) were in...
Sickle cell disease (SCD) is a significant healthcare burden worldwide, but most affected individ... more Sickle cell disease (SCD) is a significant healthcare burden worldwide, but most affected individuals reside in low-resource areas where access to diagnostic testing may be limited. We developed and validated a rapid, inexpensive, disposable diagnostic test, the HemoTypeSC(™) , based on novel monoclonal antibodies (MAbs) that differentiate normal adult haemoglobin (Hb A), sickle haemoglobin (Hb S) and haemoglobin C (Hb C). In competitive enzyme-linked immunosorbent assays, each MAb bound only its target with <0·1% cross-reactivity. With the HemoTypeSC(™) test procedure, the sensitivity for each variant was <5·0 g/l. The accuracy of HemoTypeSC(™) was evaluated on 100 whole blood samples from individuals with common relevant haemoglobin phenotypes, including normal (Hb AA, N = 20), carrier or trait (Hb AS, N = 22; Hb AC, N = 20), SCD (Hb SS, N = 22; Hb SC, N = 13), and Hb C disease (Hb CC, N = 3). The correct haemoglobin phenotype was identified in 100% of these samples. The acc...
Paradoxical" embolization via intracardiac or intrapulmonary right-to-left shunts (RLS) is an est... more Paradoxical" embolization via intracardiac or intrapulmonary right-to-left shunts (RLS) is an established cause of stroke. Hypercoagulable states and increased right heart pressure, which both occur in SCA, predispose to paradoxical embolization. We hypothesized that children with SCA and overt stroke have an increased prevalence of potential RLS. We performed contrasted transthoracic echocardiograms on 147 children (ages 2-19y) with SCA and overt stroke (SCA+stroke; mean age 12.7±4.8 years, 54.4% male) and a control group without SCA or stroke (n=123; mean age 12.1±4.9 years, 53.3% male). RLS was defined as any potential RLS detected by any method, including intrapulmonary shunting. Echocardiograms were masked and adjudicated centrally. The prevalence of potential RLS was significantly higher in the SCA+stroke group than controls (45.6% vs. 23.6%, p<0.001). The odds ratio for potential RLS in the SCA+stroke group was 2.7 (95% confidence interval: 1.6-4.6) vs controls. In post hoc analyses, the SCA+stroke group had a higher prevalence of intrapulmonary (23.8% vs. 5.7%, p<0.001) but not intracardiac shunting (21.8% vs. 18.7%, p=0.533). SCA patients with potential RLS were more likely to report headache at stroke onset than those without. Intrapulmonary and intracardiac shunting may be an overlooked, independent, and potentially modifiable risk factor for stroke in SCA.
Hemolysis is a key feature of sickle cell anemia (HbSS). Direct quantitation of hemolysis could b... more Hemolysis is a key feature of sickle cell anemia (HbSS). Direct quantitation of hemolysis could be used as an objective outcome in clinical trials of new therapeutics for HbSS and would also enable better human studies of the pathogenesis of complications of HbSS that are ostensibly hemolysis-related, such as pulmonary hypertension. However, contemporary human studies in HbSS have used only surrogate markers of hemolysis rather than direct measurements of RBC survival. We directly quantified hemolysis in HbSS by measuring survival of an age cohort of RBCs labeled with a stable isotope, administered orally as (15) N-glycine, a metabolic precursor of heme. The atomic excess of (15) N in heme extracted from blood was monitored by mass spectrometry over time. We performed 13 labeling experiments in 11 individuals with HbSS. Mean RBC survival was 31.9 days (range 14.1 - 53.6). Both HbF level, a known determinant of hemolysis, and absolute reticulocyte count (ARC), an index of the marrow&...
Our page 1 stories look at treatment for sex-trafficked youth, and the link between mental illnes... more Our page 1 stories look at treatment for sex-trafficked youth, and the link between mental illness and sickle cell disease.
Background— Diabetic patients have increased interstitial myocardial fibrosis on histological exa... more Background— Diabetic patients have increased interstitial myocardial fibrosis on histological examination. Magnetic resonance imaging (MRI) T 1 mapping is a previously validated imaging technique that can quantify the burden of global and regional interstitial fibrosis. However, the association between MRI T 1 mapping and subtle left ventricular (LV) dysfunction in diabetic patients is unknown. Methods and Results— Fifty diabetic patients with normal LV ejection fraction (EF) and no underlying coronary artery disease or regional macroscopic scar on MRI delayed enhancement were prospectively recruited. Diabetic patients were compared with 19 healthy controls who were frequency matched in age, sex and body mass index. There were no significant differences in mean LV end-diastolic volume index, end-systolic volume index and LVEF between diabetic patients and healthy controls. Diabetic patients had significantly shorter global contrast-enhanced myocardial T 1 time (425±72 ms vs. 504±34 ...
Andrew A. Pieper*, A. John Rush+, Annie John*, Lindsay Choate*, Amy Gibson*, Sharon Ayacannoo*, K... more Andrew A. Pieper*, A. John Rush+, Annie John*, Lindsay Choate*, Amy Gibson*, Sharon Ayacannoo*, Krista R. Noack*, Tina W. Han*, Charles Quinn*, Tokuku Ihara*, Brandon Probst*, and Steven L. McKnight* ... Departments of Biochemistry* and Psychiatry+ ...
Journal of investigative medicine : the official publication of the American Federation for Clinical Research, 2009
Writing clearly is critical to the success of your scientific career. Unfortunately, this skill i... more Writing clearly is critical to the success of your scientific career. Unfortunately, this skill is not taught in medical school or postgraduate training. This article summarizes our approach to the writing and publication of your research. Here we focus on empirical or experimental reports of translational and clinically oriented research. We review the process of choosing what to write, how to write it clearly, and how to navigate the process of submission and publication.
A 14-year-old boy with acute lymphoblastic leukemia in remission developed headaches characterist... more A 14-year-old boy with acute lymphoblastic leukemia in remission developed headaches characteristic of migraines. His neurologic examination was normal, serial studies of cerebrospinal fluid were unremarkable, and the headaches responded promptly to antimigraine therapy. Ultimately, radiographic and pathologic examinations demonstrated a choroid plexus carcinoma.
Proceedings of the National Academy of Sciences, 2016
Cardiopulmonary complications are the leading cause of mortality in sickle cell anemia (SCA). Ele... more Cardiopulmonary complications are the leading cause of mortality in sickle cell anemia (SCA). Elevated tricuspid regurgitant jet velocity, pulmonary hypertension, diastolic, and autonomic dysfunction have all been described, but a unifying pathophysiology and mechanism explaining the poor prognosis and propensity to sudden death has been elusive. Herein, SCA mice underwent a longitudinal comprehensive cardiac analysis, combining state-of-the-art cardiac imaging with electrocardiography, histopathology, and molecular analysis to determine the basis of cardiac dysfunction. We show that in SCA mice, anemia-induced hyperdynamic physiology was gradually superimposed with restrictive physiology, characterized by progressive left atrial enlargement and diastolic dysfunction with preserved systolic function. This phenomenon was absent in WT mice with experimentally induced chronic anemia of similar degree and duration. Restrictive physiology was associated with microscopic cardiomyocyte loss and secondary fibrosis detectable as increased extracellular volume by cardiac-MRI. Ultrastructural mitochondrial changes were consistent with severe chronic hypoxia/ischemia and sarcomere diastolic-length was shortened. Transcriptome analysis revealed up-regulation of genes involving angiogenesis, extracellular-matrix, circadian-rhythm, oxidative stress, and hypoxia, whereas ion-channel transport and cardiac conduction were down-regulated. Indeed, progressive corrected QT prolongation, arrhythmias, and ischemic changes were noted in SCA mice before sudden death. Sudden cardiac death is common in humans with restrictive cardiomyopathies and long QT syndromes. Our findings may thus provide a unifying cardiac pathophysiology that explains the reported cardiac abnormalities and sudden death seen in humans with SCA.
Stroke, a devastating complication of sickle cell anemia (SCA), can cause irreversible brain inju... more Stroke, a devastating complication of sickle cell anemia (SCA), can cause irreversible brain injury with physical and cognitive deficits. Transcranial Doppler ultrasonography (TCD) is a non-invasive tool for identifying children with SCA at highest risk of stroke. National guidelines recommend that TCD screening begin at age 2 years, yet there is research to suggest less than half of young children undergo screening. The purpose of this project was to use quality improvement methods to improve the proportion of patients aged 24-27 months who successfully completed their initial TCD from 25% to 75% by December 31, 2013. Quality improvement methods (e.g., process mapping, simplified failure mode effect analysis, and plan-do-study-act cycles) were used to develop and test processes for identifying eligible patients, scheduling TCDs, preparing children and families for the first TCD, and monitoring outcomes (i.e., TCD protocol). Progress was tracked using a report of eligible patients a...
Acute chest syndrome (ACS) in patients with sickle cell disease (SCD) has historically been manag... more Acute chest syndrome (ACS) in patients with sickle cell disease (SCD) has historically been managed with oxygen, antibiotics, and blood transfusions. Recently high-dose corticosteroid therapy was shown to reduce the duration of hospitalization in children with SCD and vaso-occlusive crisis. Therefore, we chose to assess the use of glucocorticoids in ACS. We conducted a randomized, double-blind placebo-controlled trial to evaluate the efficacy and toxicity of intravenous dexamethasone (0.3 mg/kg every 12 hours x 4 doses) in children with SCD hospitalized with mild to moderately severe ACS. Forty-three evaluable episodes of ACS occurred in 38 children (median age, 6.7 years). Twenty-two patients received dexamethasone and 21 patients received placebo. There were no statistically significant differences in demographic, clinical, or laboratory characteristics between the two groups. Mean hospital stay was shorter in the dexamethasone-treated group (47 hours v 80 hours; P = .005). Dexamethasone therapy prevented clinical deterioration and reduced the need for blood transfusions (P &lt; .001 and = .013, respectively). Mean duration of oxygen and analgesic therapy, number of opioid doses, and the duration of fever was also significantly reduced in the dexamethasone-treated patients. Of seven patients readmitted within 72 hours after discharge (six after dexamethasone; P = .095), only one had respiratory complications (P = 1.00). No side effects clearly related to dexamethasone were observed. In a stepwise multiple linear regression analysis, gender and previous episodes of ACS were the only variables that appeared to predict response to dexamethasone, as measured by lengh of hospital stay. Intravenous dexamethasone has a beneficial effect in children with SCD hospitalized with mild to moderately severe acute chest syndrome. Further study of this therapeutic modality is indicated.
The Cooperative Study of Sickle Cell Disease reported that dactylitis, severe anemia, and leukocy... more The Cooperative Study of Sickle Cell Disease reported that dactylitis, severe anemia, and leukocytosis in very young children with sickle cell disease (SCD) increased the risk of later adverse outcomes, including death, stroke, frequent pain, and recurrent acute chest syndrome. This model has not been validated in other cohorts. We evaluated its performance in the Dallas Newborn Cohort, a newborn inception cohort of children with SCD. We studied 168 children (55% male, 97% sickle cell anemia) with a mean follow-up of 7.1 years who provided 1188 patient-years of observation. Of the 23 (13.7%) subjects who experienced adverse events, 2 (1.2%) died, 14 (8.3%) had a stroke, 4 (2.4%) had frequent pain, and 3 (1.8%) had recurrent acute chest syndrome. No relationship existed between early clinical predictors and later adverse outcomes, with the possible exception of leukocyte count. Most subjects who experienced adverse events were predicted to be at low risk for those events. No subject who was predicted to be at high risk actually experienced an adverse outcome. The sensitivity of the model did not rise above 20% until specificity fell below 60%. We suggest that this model not be used as a criterion to initiate early interventions for SCD.
Background: Irregular, sporadic episodes of ischemic brain injury are known to occur in sickle ce... more Background: Irregular, sporadic episodes of ischemic brain injury are known to occur in sickle cell anemia (SCA), resulting in overt stroke and silent cerebral infarction. Ongoing ischemia in other organs is common in SCA but has never been documented in the brain.
Congenital dyserythropoietic anemias (CDAs) are characterized by ineffective erythropoiesis and d... more Congenital dyserythropoietic anemias (CDAs) are characterized by ineffective erythropoiesis and distinctive erythroblast abnormalities; the diagnosis is often missed or delayed due to significant phenotypic heterogeneity. We established the CDA Registry of North America (CDAR) to study the natural history of CDA and create a biorepository to investigate the pathobiology of this heterogeneous disease. Seven of 47 patients enrolled so far in CDAR have CDA-I due to biallelic CDAN1 mutations. They all presented with perinatal anemia and required transfusions during infancy. Anemia spontaneously improved during infancy in three patients; two became transfusion-independent rapidly after starting interferon-α2; and two remain transfusion-dependent at last follow-up at ages 5 and 30 y.o. One of the transfusion-dependent patients underwent splenectomy at 11 y.o due to misdiagnosis and returned to medical attention at 27 y.o with severe hemolytic anemia and pulmonary hypertension. All patients developed iron overload even without transfusions; four were treated with chelation. Genetic testing allowed for more rapid and accurate diagnosis; the median age of confirmed diagnosis in our cohort was 3 y.o compared to 17.3 y.o historically. In conclusion, CDAR provides an organized research network for multidisciplinary clinical and research collaboration to conduct natural history and biologic studies in CDA.
Background: Sickle cell disease (SCD) is associated with significant medical challenges that ofte... more Background: Sickle cell disease (SCD) is associated with significant medical challenges that often worsen in adolescence when caregivers are beginning to transfer responsibility for disease management. Behavioral activation (BA) is an important precedent to improvements in selfmanagement and ultimately health outcomes; however, few interventions targeting BA have been developed for the SCD population. The goal of the present study was to evaluate a technologyenhanced self-management intervention for adolescents and young adults (AYA) with SCD targeting BA domains (i.e., disease knowledge, self-efficacy, motivation, and self-management skills). Design/Methods: Participants were randomized to one of two study arms. SCThrive participants (N=26) completed six weekly group sessions, an in-person booster session, and used a companion app (iManage) to record symptoms, progress on goals, and connect with other group members. Each SCHealthEd participant (N=27) received six weekly phone calls on SCD-related and general health education topics. All AYAs completed questionnaires assessing BA at baseline and post-treatment.
Background: Sickle cell anemia (SCA) is a leading cause of stroke and neurologic disability in ch... more Background: Sickle cell anemia (SCA) is a leading cause of stroke and neurologic disability in children. In the 20 years since the publication of the STOP trial, chronic transfusion therapy and hydroxyurea have shown efficacy as disease-modifying therapies, especially by improvement of transcranial Doppler (TCD) velocities and reduction in the incidence of overt stroke. Despite the publication of the SIT Trial 2014, screening for silent stroke is not universally implemented. Here we report our center’s experience with screening neuroimaging in young children with SCA. Methods: This is a single center, retrospective case series of patients with SCA (HbSS and HbSb 0 -thalassemia) managed in a comprehensive sickle cell center. Patients undergo TCD screening per STOP guidelines beginning at age 24 months. Screening MRI/MRA brain are also recommended at 5, 10, 15, and 20 years of age. Imaging data for the children 5-9 years of age are reported. Results: There were 39 subjects within the ...
Reticuloendothelial system MRI signal hypointensity is common in pediatric oncology patients with... more Reticuloendothelial system MRI signal hypointensity is common in pediatric oncology patients with solid abdominal tumors. To assess changes in liver, spleen and bone marrow T2-weighted MRI signal intensity over time and their relationship to blood transfusion history in children with solid abdominal tumors. In this retrospective study we measured liver, spleen and bone marrow signal intensity on axial T2-weighted MR images obtained December 2009 through February 2016 in children with hepatoblastoma, neuroblastoma, ganglioneuroblastoma and Wilms tumor. All signal intensity measurements were normalized to paraspinal muscle signal intensity. We used linear mixed models (including a day*day quadratic term) to determine whether organ signal intensity changed over time and whether change was associated with blood transfusion volume or tumor type. We included 133 children (mean age at diagnosis =2.9 years); 56 had neuroblastoma, 42 hepatoblastoma, 28 Wilms tumor and 7 ganglioneuroblastoma....
The purpose of this study is determine if both liver T2* and cardiac T2* can be measured on a sin... more The purpose of this study is determine if both liver T2* and cardiac T2* can be measured on a single breath-hold acquisition. For this IRB-approved retrospective study, 137 patients with dedicated Cardiac MRI and Liver MRI examinations obtained sequentially on 1.5T scanners and on the same day were included for analysis. Both the cardiac and liver MRI examinations utilized GRE sequences for quantification of tissue iron. Specifically, T2* was measured using an 8-echo, multi-echo gradient echo single breath-hold sequence. Liver T2* was measured in a blinded manner on images from each of the cardiac and dedicated liver MRI examinations and were correlated. Bland-Altman difference plot was used to assess mean bias. 137 examinations from 93 subjects met inclusion criteria. 10 examination pairs were excluded because the first echo time (TE) on the cardiac MRI was insufficiently short for the very high liver iron content. After exclusion, 127 studies from 89 subjects (67.4% males) were in...
Sickle cell disease (SCD) is a significant healthcare burden worldwide, but most affected individ... more Sickle cell disease (SCD) is a significant healthcare burden worldwide, but most affected individuals reside in low-resource areas where access to diagnostic testing may be limited. We developed and validated a rapid, inexpensive, disposable diagnostic test, the HemoTypeSC(™) , based on novel monoclonal antibodies (MAbs) that differentiate normal adult haemoglobin (Hb A), sickle haemoglobin (Hb S) and haemoglobin C (Hb C). In competitive enzyme-linked immunosorbent assays, each MAb bound only its target with <0·1% cross-reactivity. With the HemoTypeSC(™) test procedure, the sensitivity for each variant was <5·0 g/l. The accuracy of HemoTypeSC(™) was evaluated on 100 whole blood samples from individuals with common relevant haemoglobin phenotypes, including normal (Hb AA, N = 20), carrier or trait (Hb AS, N = 22; Hb AC, N = 20), SCD (Hb SS, N = 22; Hb SC, N = 13), and Hb C disease (Hb CC, N = 3). The correct haemoglobin phenotype was identified in 100% of these samples. The acc...
Paradoxical" embolization via intracardiac or intrapulmonary right-to-left shunts (RLS) is an est... more Paradoxical" embolization via intracardiac or intrapulmonary right-to-left shunts (RLS) is an established cause of stroke. Hypercoagulable states and increased right heart pressure, which both occur in SCA, predispose to paradoxical embolization. We hypothesized that children with SCA and overt stroke have an increased prevalence of potential RLS. We performed contrasted transthoracic echocardiograms on 147 children (ages 2-19y) with SCA and overt stroke (SCA+stroke; mean age 12.7±4.8 years, 54.4% male) and a control group without SCA or stroke (n=123; mean age 12.1±4.9 years, 53.3% male). RLS was defined as any potential RLS detected by any method, including intrapulmonary shunting. Echocardiograms were masked and adjudicated centrally. The prevalence of potential RLS was significantly higher in the SCA+stroke group than controls (45.6% vs. 23.6%, p<0.001). The odds ratio for potential RLS in the SCA+stroke group was 2.7 (95% confidence interval: 1.6-4.6) vs controls. In post hoc analyses, the SCA+stroke group had a higher prevalence of intrapulmonary (23.8% vs. 5.7%, p<0.001) but not intracardiac shunting (21.8% vs. 18.7%, p=0.533). SCA patients with potential RLS were more likely to report headache at stroke onset than those without. Intrapulmonary and intracardiac shunting may be an overlooked, independent, and potentially modifiable risk factor for stroke in SCA.
Hemolysis is a key feature of sickle cell anemia (HbSS). Direct quantitation of hemolysis could b... more Hemolysis is a key feature of sickle cell anemia (HbSS). Direct quantitation of hemolysis could be used as an objective outcome in clinical trials of new therapeutics for HbSS and would also enable better human studies of the pathogenesis of complications of HbSS that are ostensibly hemolysis-related, such as pulmonary hypertension. However, contemporary human studies in HbSS have used only surrogate markers of hemolysis rather than direct measurements of RBC survival. We directly quantified hemolysis in HbSS by measuring survival of an age cohort of RBCs labeled with a stable isotope, administered orally as (15) N-glycine, a metabolic precursor of heme. The atomic excess of (15) N in heme extracted from blood was monitored by mass spectrometry over time. We performed 13 labeling experiments in 11 individuals with HbSS. Mean RBC survival was 31.9 days (range 14.1 - 53.6). Both HbF level, a known determinant of hemolysis, and absolute reticulocyte count (ARC), an index of the marrow&...
Our page 1 stories look at treatment for sex-trafficked youth, and the link between mental illnes... more Our page 1 stories look at treatment for sex-trafficked youth, and the link between mental illness and sickle cell disease.
Background— Diabetic patients have increased interstitial myocardial fibrosis on histological exa... more Background— Diabetic patients have increased interstitial myocardial fibrosis on histological examination. Magnetic resonance imaging (MRI) T 1 mapping is a previously validated imaging technique that can quantify the burden of global and regional interstitial fibrosis. However, the association between MRI T 1 mapping and subtle left ventricular (LV) dysfunction in diabetic patients is unknown. Methods and Results— Fifty diabetic patients with normal LV ejection fraction (EF) and no underlying coronary artery disease or regional macroscopic scar on MRI delayed enhancement were prospectively recruited. Diabetic patients were compared with 19 healthy controls who were frequency matched in age, sex and body mass index. There were no significant differences in mean LV end-diastolic volume index, end-systolic volume index and LVEF between diabetic patients and healthy controls. Diabetic patients had significantly shorter global contrast-enhanced myocardial T 1 time (425±72 ms vs. 504±34 ...
Andrew A. Pieper*, A. John Rush+, Annie John*, Lindsay Choate*, Amy Gibson*, Sharon Ayacannoo*, K... more Andrew A. Pieper*, A. John Rush+, Annie John*, Lindsay Choate*, Amy Gibson*, Sharon Ayacannoo*, Krista R. Noack*, Tina W. Han*, Charles Quinn*, Tokuku Ihara*, Brandon Probst*, and Steven L. McKnight* ... Departments of Biochemistry* and Psychiatry+ ...
Journal of investigative medicine : the official publication of the American Federation for Clinical Research, 2009
Writing clearly is critical to the success of your scientific career. Unfortunately, this skill i... more Writing clearly is critical to the success of your scientific career. Unfortunately, this skill is not taught in medical school or postgraduate training. This article summarizes our approach to the writing and publication of your research. Here we focus on empirical or experimental reports of translational and clinically oriented research. We review the process of choosing what to write, how to write it clearly, and how to navigate the process of submission and publication.
A 14-year-old boy with acute lymphoblastic leukemia in remission developed headaches characterist... more A 14-year-old boy with acute lymphoblastic leukemia in remission developed headaches characteristic of migraines. His neurologic examination was normal, serial studies of cerebrospinal fluid were unremarkable, and the headaches responded promptly to antimigraine therapy. Ultimately, radiographic and pathologic examinations demonstrated a choroid plexus carcinoma.
Proceedings of the National Academy of Sciences, 2016
Cardiopulmonary complications are the leading cause of mortality in sickle cell anemia (SCA). Ele... more Cardiopulmonary complications are the leading cause of mortality in sickle cell anemia (SCA). Elevated tricuspid regurgitant jet velocity, pulmonary hypertension, diastolic, and autonomic dysfunction have all been described, but a unifying pathophysiology and mechanism explaining the poor prognosis and propensity to sudden death has been elusive. Herein, SCA mice underwent a longitudinal comprehensive cardiac analysis, combining state-of-the-art cardiac imaging with electrocardiography, histopathology, and molecular analysis to determine the basis of cardiac dysfunction. We show that in SCA mice, anemia-induced hyperdynamic physiology was gradually superimposed with restrictive physiology, characterized by progressive left atrial enlargement and diastolic dysfunction with preserved systolic function. This phenomenon was absent in WT mice with experimentally induced chronic anemia of similar degree and duration. Restrictive physiology was associated with microscopic cardiomyocyte loss and secondary fibrosis detectable as increased extracellular volume by cardiac-MRI. Ultrastructural mitochondrial changes were consistent with severe chronic hypoxia/ischemia and sarcomere diastolic-length was shortened. Transcriptome analysis revealed up-regulation of genes involving angiogenesis, extracellular-matrix, circadian-rhythm, oxidative stress, and hypoxia, whereas ion-channel transport and cardiac conduction were down-regulated. Indeed, progressive corrected QT prolongation, arrhythmias, and ischemic changes were noted in SCA mice before sudden death. Sudden cardiac death is common in humans with restrictive cardiomyopathies and long QT syndromes. Our findings may thus provide a unifying cardiac pathophysiology that explains the reported cardiac abnormalities and sudden death seen in humans with SCA.
Stroke, a devastating complication of sickle cell anemia (SCA), can cause irreversible brain inju... more Stroke, a devastating complication of sickle cell anemia (SCA), can cause irreversible brain injury with physical and cognitive deficits. Transcranial Doppler ultrasonography (TCD) is a non-invasive tool for identifying children with SCA at highest risk of stroke. National guidelines recommend that TCD screening begin at age 2 years, yet there is research to suggest less than half of young children undergo screening. The purpose of this project was to use quality improvement methods to improve the proportion of patients aged 24-27 months who successfully completed their initial TCD from 25% to 75% by December 31, 2013. Quality improvement methods (e.g., process mapping, simplified failure mode effect analysis, and plan-do-study-act cycles) were used to develop and test processes for identifying eligible patients, scheduling TCDs, preparing children and families for the first TCD, and monitoring outcomes (i.e., TCD protocol). Progress was tracked using a report of eligible patients a...
Acute chest syndrome (ACS) in patients with sickle cell disease (SCD) has historically been manag... more Acute chest syndrome (ACS) in patients with sickle cell disease (SCD) has historically been managed with oxygen, antibiotics, and blood transfusions. Recently high-dose corticosteroid therapy was shown to reduce the duration of hospitalization in children with SCD and vaso-occlusive crisis. Therefore, we chose to assess the use of glucocorticoids in ACS. We conducted a randomized, double-blind placebo-controlled trial to evaluate the efficacy and toxicity of intravenous dexamethasone (0.3 mg/kg every 12 hours x 4 doses) in children with SCD hospitalized with mild to moderately severe ACS. Forty-three evaluable episodes of ACS occurred in 38 children (median age, 6.7 years). Twenty-two patients received dexamethasone and 21 patients received placebo. There were no statistically significant differences in demographic, clinical, or laboratory characteristics between the two groups. Mean hospital stay was shorter in the dexamethasone-treated group (47 hours v 80 hours; P = .005). Dexamethasone therapy prevented clinical deterioration and reduced the need for blood transfusions (P &lt; .001 and = .013, respectively). Mean duration of oxygen and analgesic therapy, number of opioid doses, and the duration of fever was also significantly reduced in the dexamethasone-treated patients. Of seven patients readmitted within 72 hours after discharge (six after dexamethasone; P = .095), only one had respiratory complications (P = 1.00). No side effects clearly related to dexamethasone were observed. In a stepwise multiple linear regression analysis, gender and previous episodes of ACS were the only variables that appeared to predict response to dexamethasone, as measured by lengh of hospital stay. Intravenous dexamethasone has a beneficial effect in children with SCD hospitalized with mild to moderately severe acute chest syndrome. Further study of this therapeutic modality is indicated.
The Cooperative Study of Sickle Cell Disease reported that dactylitis, severe anemia, and leukocy... more The Cooperative Study of Sickle Cell Disease reported that dactylitis, severe anemia, and leukocytosis in very young children with sickle cell disease (SCD) increased the risk of later adverse outcomes, including death, stroke, frequent pain, and recurrent acute chest syndrome. This model has not been validated in other cohorts. We evaluated its performance in the Dallas Newborn Cohort, a newborn inception cohort of children with SCD. We studied 168 children (55% male, 97% sickle cell anemia) with a mean follow-up of 7.1 years who provided 1188 patient-years of observation. Of the 23 (13.7%) subjects who experienced adverse events, 2 (1.2%) died, 14 (8.3%) had a stroke, 4 (2.4%) had frequent pain, and 3 (1.8%) had recurrent acute chest syndrome. No relationship existed between early clinical predictors and later adverse outcomes, with the possible exception of leukocyte count. Most subjects who experienced adverse events were predicted to be at low risk for those events. No subject who was predicted to be at high risk actually experienced an adverse outcome. The sensitivity of the model did not rise above 20% until specificity fell below 60%. We suggest that this model not be used as a criterion to initiate early interventions for SCD.
Background: Irregular, sporadic episodes of ischemic brain injury are known to occur in sickle ce... more Background: Irregular, sporadic episodes of ischemic brain injury are known to occur in sickle cell anemia (SCA), resulting in overt stroke and silent cerebral infarction. Ongoing ischemia in other organs is common in SCA but has never been documented in the brain.
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Papers by Charles Quinn