Food insecurity and quality of life in patients with sickle cell disease.

Little is known about the relationship between quality of life (QOL) and food insecurity (FI) among patients with sickle cell disease (SCD). We hypothesized FI is associated with lower QOL in children and young adults with SCD. Overall (N = 99), 22% screened positive for FI. Supplemental Nutrition Assistance Program (SNAP) enrollment was 50 and 71% among people from food secure and FI households, respectively. A higher FI score was correlated with lower overall QOL (r = -0.22, p = .03), specifically lower QOL in worry and communication domains. Interventions for FI beyond SNAP may be important for QOL among people living with SCD.

Circulating extracellular vesicles from patients with acute chest syndrome disrupt adherens junctions between endothelial cells.

BACKGROUND: Small cell-derived extracellular vesicles (EVs) can affect endothelial function. We previously found that patients with sickle cell disease (SCD) have greater numbers of circulating EVs than subjects without the disease, and the EVs differentially disrupt endothelial integrity in vitro. Because endothelial disruption is a critical component of acute chest syndrome (ACS), we hypothesized that EVs isolated during ACS would induce greater endothelial damage than those isolated at baseline. METHODS: Nine pediatric subjects had plasma isolated at baseline and during ACS from which EVs were isolated. Cultured microvascular endothelial cells were treated with EVs and then studied by immunofluorescence microscopy to localize VE-cadherin and F-actin. RESULTS: The EVs had a diameter of 95 nm. They contained CD63 and flotillin-1, which were increased in SCD patients (5-13-fold compared to control) and further increased between baseline and ACS (24-57%). The EVs contained hemoglobin, glycophorin A, and ferritin. Treatment with baseline EVs caused modest separation of endothelial cells, while ACS EVs caused substantial disruptions of the endothelial cell monolayers. EVs from subjects with ACS also caused a 50% decrease in protein levels of VE-cadherin. CONCLUSIONS: These results suggest that circulating EVs can modulate endothelial integrity contributing to the development of ACS in SCD patients by altering cadherin-containing intercellular junctions. IMPACT: Sickle cell disease patients have circulating extracellular vesicles (EVs) that modulate endothelial integrity by altering cadherin-containing intercellular junctions. Disruption is more severe by EVs obtained during acute chest syndrome (ACS). These results expand our knowledge of the pathophysiology of acute chest syndrome and the vasculopathies of sickle cell disease.

Gap Junctions between Endothelial Cells Are Disrupted by Circulating Extracellular Vesicles from Sickle Cell Patients with Acute Chest Syndrome.

Intercellular junctions maintain the integrity of the endothelium. We previously found that the adherens and tight junctions between endothelial cells are disrupted by plasma extracellular vesicles from patients with sickle cell disease (especially those with Acute Chest Syndrome). In the current study, we evaluated the effects of these vesicles on endothelial gap junctions. The vesicles from sickle cell patients (isolated during episodes of Acute Chest Syndrome) disrupted gap junction structures earlier and more severely than the other classes of intercellular junctions (as detected by immunofluorescence). These vesicles were much more potent than those isolated at baseline from the same subject. The treatment of endothelial cells with these vesicles led to reduced levels of connexin43 mRNA and protein. These vesicles severely reduced intercellular communication (transfer of microinjected Neurobiotin). Our data suggest a hierarchy of progressive disruption of different intercellular connections between endothelial cells by circulating extracellular vesicles that may contribute to the pathophysiology of the endothelial disturbances in sickle cell disease.

Extracellular microvesicle microRNAs in children with sickle cell anaemia with divergent clinical phenotypes.

Sickle cell anaemia (SCA) is the most frequent genetic haemoglobinopathy, which exhibits a highly variable clinical course characterized by hyper-coagulable and pro-inflammatory states, as well as endothelial dysfunction. Extracellular microvesicles are released into biological fluids and play a role in modifying the functional phenotype of target cells. We hypothesized that potential differences in plasma-derived extracellular microvesicles (EV) function and cargo from SCA patients may underlie divergent clinical trajectories. Plasma EV from SCA patients with mild, intermediate and severe clinical disease course were isolated, and primary endothelial cell cultures were exposed. Endothelial cell activation, monocyte adhesion, barrier disruption and exosome cargo (microRNA microarrays) were assessed. EV disrupted the endothelial barrier and induced expression of adhesion molecules and monocyte adhesion in a SCA severity-dependent manner compared to healthy children. Microarray approaches identified a restricted signature of exosomal microRNAs that readily distinguished severe from mild SCA, as well as from healthy children. The microRNA candidates were further validated using quantitative real time polymerase chain reaction assays, and revealed putative gene targets. Circulating exosomal microRNAs may play important roles in predicting the clinical course of SCA, and in delineation of individually tailored, mechanistically-based clinical treatment approaches of SCA patients in the near future.

Circulating Small Extracellular Vesicles May Contribute to Vaso-Occlusive Crises in Sickle Cell Disease.

We previously found that the plasma of patients with sickle cell disease (SCD) contains large numbers of small extracellular vesicles (EVs) and that the EVs disrupt the integrity of endothelial cell monolayers (especially if obtained during episodes of acute chest syndrome, ACS). The present study was designed to test the generality of this finding to other complications of SCD, specifically to evaluate the possibility that circulating EVs isolated during a vaso-occlusive crises (VOC) also cause damage to the intercellular connections between endothelial cells. Plasma was obtained from nine pediatric subjects at baseline and during VOC episodes. EVs isolated from these samples were added to cultures of microvascular endothelial cells. Immunofluorescence microscopy was employed to assess monolayer integrity and to localize two intercellular junction proteins (VE-cadherin and connexin43). The EVs isolated during VOC caused significantly greater monolayer disruption than those isolated at baseline. The extent of disruption varied between different episodes of VOC or ACS in the same patient. The VOC EVs disrupted the integrity of both junction proteins at appositional membranes. These results suggest that circulating EVs may be involved in modulating endothelial integrity contributing to the pathogenesis of different complications of SCD.

Sickle cell trait and multisystem trauma: an unaddressed urgent knowledge gap.

Sickle cell trait (SCT) has historically been considered a benign condition, but SCT-positive patients have increased baseline risk of venous thromboembolism and chronic kidney disease, as well as increased risk of sickled erythrocytes in settings of hypoxia, acidosis, and hypovolemia. Multisystem traumatic injuries are a common clinical scenario, in which hypoxia, acidosis, and hypovolemia occur; however, little is known about how SCT-positive status impacts outcomes in multisystem trauma. We conducted a scoping literature review to investigate what was known about SCT in the setting of multisystem trauma. In the 110+ years that sickle cell hemoglobinopathies have been known, only three studies have ever examined the relationship between SCT and multisystem traumas. All three articles were case reports. None of the articles intentionally measured the association between SCT and multisystem trauma outcomes; they only incidentally captured information on SCT. Our article then examines historical reasons why so little research has studied the pathophysiology of the multisystem trauma in patients with SCT. Among the reasons is that historical and logistical factors have long prevented patients from knowing their SCT-status: historical discriminations against SCT-positive patients in the 1960s and 1970s delayed federal mandating of SCT newborn screening until 2006, whereas difficulties communicating known SCT-status to afflicted children also contributed to lack of patient knowledge. In light of our findings, we offer specific calls to action for the trauma surgery research community: (1) consider testing for SCT in trauma patients that have unexpected complications, particularly venous thromboembolism, rhabdomyolysis, or renal failure and (2) support research to understand how SCT impacts multisystem trauma outcomes. We also offer specific guidelines about how to 'proceed with caution' in implementation of these goals in light of the troubled history of SCT testing and policy in the USA.

Circulating Extracellular Vesicles and Endothelial Damage in Sickle Cell Disease.

Endothelial damage is central to the pathogenesis of many of the complications of sickle cell disease. Circulating extracellular vesicles (EVs) have been implicated in modulating endothelial behavior in a variety of different, diseases with vascular pathologies. As seen in other hemolytic diseases, the plasma of sickle cell patients contains EVs of different sizes and cellular sources. The medium-sized vesicles (microparticles) primarily derive from mature red blood cells and platelets; some of these EVs have procoagulant properties, while others stimulate inflammation or endothelial adhesiveness. Most of the small EVs (including exosomes) derive from erythrocytes and erythrocyte precursors, but some also originate from platelets, white blood cells, and endothelial cells. These small EVs may alter the behavior of target cells by delivering cargo including proteins and nucleic acids. Studies in model systems implicate small EVs in promoting vaso-occlusion and disruption of endothelial integrity. Thus, both medium and small EVs may contribute to the increased endothelial damage in sickle cell disease. Development of a detailed understanding of the composition and roles of circulating EVs represents a promising approach toward novel predictive diagnostics and therapeutic approaches in sickle cell disease.

Exosomes contribute to endothelial integrity and acute chest syndrome risk: Preliminary findings.

BACKGROUND: Acute Chest Syndrome (ACS) is one of the leading causes of death among children with Sickle Cell Disease (SCD). Disruption of microvascular integrity is critical to the pathophysiology of ACS, but the factors governing its phenotypic variability are incompletely understood. Because circulating exosomes have been implicated in vascular dysfunction in various diseases, we hypothesized that exosomes induce endothelial dysfunction in patients who experience ACS. PROCEDURE: Cross-sectional cohort study including 33 outpatients with SCD (without new health-related complaints or recent transfusions) and a cohort of control patients. Exosomes were isolated from platelet-free plasma. RESULTS: ImageStream showed that exosome counts were greatly increased in patients with SCD compared with controls, but there were few differences in the concentrations of exosomes between patients who had experienced ACS (ACS(+)) and those who had not (ACS(-)). Exosomes were added to human microvascular endothelial cells, and the exosomal effects on monolayer integrity was determined using Electric Cell-substrate Impedance Sensing (ECIS). Exosomes from SCD patients without ACS differed minimally from control patients; however, exosomes from ACS(+) decreased endothelial cell resistance compared to ACS(-), (Relative resistance: ACS(+): 0.981 ± 0.055 vs ACS(-): 1.124 ± 0.042; P = 0.006). Treatment of endothelial cultures with exosomes from ACS(-) patients increased endothelial Nitric Oxide Synthase (eNOS) mRNA expression, while ACS(+)-derived exosomes were not able to increase eNOS expression above that of controls. CONCLUSIONS: These findings demonstrate that patients with SCD have circulating exosomes that produce differential effects that may contribute to the pathophysiology of ACS and may serve as risk-related biomarkers.

Neonatal Thrombocytopenia: Etiology and Diagnosis.

Neonatal thrombocytopenia has a broad range of possible etiologies. In this review, an asymptomatic newborn infant was found to have severe thrombocytopenia on laboratory testing for limited sepsis evaluation. The differential diagnosis for thrombocytopenia in the newborn period is discussed, along with recommendations for initial evaluation and follow up of isolated thrombocytopenia in an otherwise well-appearing infant. The clinician should be aware of findings associated with unusual causes of thrombocytopenia that should prompt additional evaluation in the nursery or in the general pediatrician's office. In this illustrative case, a high index of suspicion allowed early diagnosis of Wiskott-Aldrich syndrome and prompt curative therapy by stem cell transplant.

Anemia in the Neonate: The Differential Diagnosis and Treatment.

Anemia is a common problem in the neonatal period. Presenting symptoms may suggest numerous possible diagnoses ranging from anemia seen as a normal part of development to anemia due to critical pathology. An illustrative case is presented to highlight the appropriate evaluation of the neonate with significant anemia. Several important features of the evaluation of neonatal anemia are highlighted. The constellation of signs and symptoms that occur in conjunction with the anemia are critical for the evaluation. The evaluation should be performed in a step-wise process that starts by eliminating common causes of anemia. Manual review of the peripheral blood smear with a hematologist can be helpful.

A 3-year-old female with abdominal pain, vomiting, and an abdominal mass.

We present a case of a 3-year-old female with a 10-day history of lower abdominal pain, distention, and vomiting, as well as fatigue, low-grade fever, and subjective weight loss who was found to have utero-ovarian torsion with pathology revealing hemorrhagic and infarcted tissue. While the literature is limited, it suggests that utero-adnexal torsion in children may be more common than previously recognized. A missed, or even delayed, diagnosis of utero-adnexal torsion has the potential to result in irreversible ischemic damage. Utero-adnexal torsion should therefore be included in the differential diagnosis for girls presenting with acute abdominopelvic pain. Pelvic ultrasound to evaluate the uterus and adnexae is an important non-invasive first step in establishing the diagnosis. Computed tomography scan or magnetic resonance imaging can be considered in the case of indeterminate ultrasound. The diagnosis of utero-adnexal torsion must be made early, and surgical intervention must be timely in order to preserve fertility.

A neonate with a vesiculopustular rash.

Transient myeloproliferative disorder (TMD) is a unique form of acute megakaryocytic leukemia (AMKL) that spontaneously regresses and is found in 3% to 10% of neonates with Down syndrome (DS). We report the case of a neonate with DS who presented with a widespread vesiculopustular eruption as an initial sign of TMD. Complete blood count was normal but peripheral smear revealed circulating megakaryoblasts. The severity of skin lesions correlated with the blast count. By age 2 months the TMD resolved and the patient remains disease-free after 18 months of follow-up. Several important features of TMD are highlighted: skin findings may provide an important clinical clue to TMD diagnosis; manual review of the peripheral smear is necessary when TMD is suspected; and patients with a history of TMD have a very high (∼30%) risk of recurrence with a persistent AMKL within the first 3 years of life.