Monitoring retinal pathology and cerebral injury in sickle cell disease using spectral-domain optical coherence tomography in pediatric patients.

PURPOSE: This study aimed to confirm the correlation between sickle cell disease (SCD) genotype and retinal damage identified by spectral-domain optical coherence tomography (SD-OCT), and examine a potential link between hypoxic ischemic injury in the retina and brain. METHODS: In this prospective, observational case series, 117 patients (56 males) aged 5-20 years with SCD (36 SC, 68 SS, eight Sß+ thalassemia, five Sß0 thalassemia) underwent ophthalmologic examination including funduscopy and SD-OCT imaging. Comparison of SCD genotypes and association between ocular findings and cerebrovascular disease (CVD) in subjects with SS/Sß0 genotype were investigated. RESULTS: Visual acuity ranged from 20/20 to 20/40. On funduscopic exam, 16 of 117 (13.7%) had retinopathy; 69 of 117 (59.0%) showed inner retina thinning on SD-OCT. Patients with SS/Sß0 showed a higher frequency of sickle cell retinopathy (SCR) change (68.5% vs. 47.2%), bilateral SCR (49.9% vs. 25.0%), and foveal involvement (15.1% vs. 0) than the SC genotype. While funduscopic findings in our cohort with SS/Sß0 genotype showed no correlation with CVD, 20 of 21 patients with CVD had abnormal SD-OCT. Elevated reticulocyte percentage and aspartate aminotransferase are associated with SD-OCT changes and CVD. CONCLUSIONS: SD-OCT was better than funduscopy in detecting retinal changes, higher frequency, and more extensive retinal changes in the more severe SCD genotypes SS and Sß0 as compared with SC. The correlation between abnormal SD-OCT and CVD strongly suggests that retinal exam using SD-OCT may aid in detection and monitoring SCD-related CVD. Retinopathy may be another component of the hemolytic subphenotype of SCD.

Psychosocial Screening in Sickle Cell Disease: Validation of the Psychosocial Assessment Tool.

OBJECTIVE: Families of youth with Sickle Cell Disease (SCD) can face psychosocial adversity including emotional distress, functional impairments, and sociodemographic risk factors. Systematic screening of psychosocial risk can identify families who may benefit from further assessment and evidence-based care. The Psychosocial Assessment Tool (PAT) is a brief caregiver-report screener based on the tri-level Pediatric Psychosocial Preventative Health Model (PPPHM). METHODS: Findings are presented from the baseline assessment of a longitudinal study validating a Sickle Cell version of the PAT 2.0. Primary caregivers of 136 youth with SCD receiving care through a multidisciplinary SCD clinic in a children's hospital completed the PAT and validation measures. A subset of 25 caregivers completed the PAT a second time within 3-5 weeks. RESULTS: Internal consistency for the total score was strong (α = .87), and for the subscales was moderate to strong (α = .74-.94), with the exception of the Family Structure (α = .38), Caregiver Beliefs (α = .48), and Stress Reactions (α = .56) subscales. Test-retest reliability was also strong (r = .86, p < .001). Moderate to strong correlations with all except two criteria measures provided validation for the total and subscale scores. Validation measures varied significantly across the three levels of the PPPHM. CONCLUSIONS: Results provide support for the reliability and validity of the PAT in SCD. Systematic screening with the PAT can help identify families of youth with SCD at risk for psychosocial problems and potentially help connect them to appropriate services.

Family Resilience From the Perspective of Caregivers of Youth With Sickle Cell Disease.

Families coping with sickle cell disease (SCD) often face heightened psychosocial risk factors, and research in pediatric SCD has often focused more on this area than resiliency factors. The aim of this study was to gain a better understanding of family resiliency in SCD based on caregiver perspectives. A secondary qualitative analysis was conducted with data from a mixed-methods study of caregivers of youth with SCD (n=22). Qualitative analyses involved coding based on 2 resiliency frameworks, organizing coding categories into themes, and systematically reintegrating these themes into a conceptualization that reflected family resiliency. Themes aligned well with the resiliency frameworks and related to family belief systems and meaning-making around SCD (acceptance of SCD, positive attitude, religious faith), family organization and adaptation (flexibility, stability, social supports), and the importance of communication and problem-solving. Study findings emphasize the importance of assessing resilience in families of youth with SCD and suggest the potential clinical benefits of developing psychosocial interventions based on family strengths.

Relationship of Omega-3 fatty acids DHA and EPA with the inflammatory biomarker hs-CRP in children with sickle cell anemia.

BACKGROUND: Inflammation and vaso-occlusion play key roles in Sickle Cell Disease (SCD) pathophysiology. Lipoxygenase products of the omega-3 fatty acids (O3FAs), docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids, are potent anti-inflammatory mediators modulating pain. O3FAs decrease episodes of vaso-occlusion in SCD. METHODS: We assessed erythrocyte fatty acid composition in two major cell membrane phospholipids, phosphatidylcholine and phosphatidylethanolamine, in children with SCD HbSS-disease (n = 38) and age/race-matched HbAA-controls (n = 18). Ratio of pro-inflammatory arachidonic acid (AA) to anti-inflammatory DHA and EPA (FA-Ratio), and its relationship to hs-CRP were evaluated. RESULTS: FA-Ratios were increased in both phosphatidylcholine and phosphatidylethanolamine in HbSS compared to controls. Correlations were noted in HbSS subjects between hs-CRP and FA-Ratios (p = 0.011). FA-Ratios increased with age (p = 0.0007) due to an increase in pro-inflammatory AA with a concomitant decrease in anti-inflammatory DHA. CONCLUSIONS: Findings demonstrate relative deficiencies in HbSS of the anti-inflammatory precursor fatty acids DHA and EPA, which correlates positively with hs-CRP.

Quantitative sensory testing in children with sickle cell disease: additional insights and future possibilities.

Quantitative sensory testing (QST) is used in a variety of pain disorders to characterize pain and predict prognosis and response to specific therapies. In this study, we aimed to confirm results in the literature documenting altered QST thresholds in sickle cell disease (SCD) and assess the test-retest reliability of results over time. Fifty-seven SCD and 60 control subjects aged 8-20 years underwent heat and cold detection and pain threshold testing using a Medoc TSAII. Participants were tested at baseline and 3 months; SCD subjects were additionally tested at 6 months. An important facet of our study was the development and use of a novel QST modelling approach, allowing us to model all data together across modalities. We have not demonstrated significant differences in thermal thresholds between subjects with SCD and controls. Thermal thresholds were consistent over a 3- to 6-month period. Subjects on whom hydroxycarbamide (HC) was initiated shortly before or after baseline testing (new HC users) exhibited progressive decreases in thermal sensitivity from baseline to 6 months, suggesting that thermal testing may be sensitive to effective therapy to prevent vasoocclusive pain. These findings inform the use of QST as an endpoint in the evaluation of preventative pain therapies.

Update on pediatric leukemia and lymphoma imaging.

Together, leukemia and lymphoma account for half of all childhood malignancies. Leukemia and lymphoma arise from similar cell lines and can have overlapping imaging features; however, the clinical presentation, imaging strategies, and treatment protocols can vary substantially based on the specific subtype. Although imaging does not play a central role in staging or monitoring disease in childhood leukemia, findings on imaging may be the first indication of the diagnosis. Advanced imaging, especially positron emission tomography/computed tomography, has moved to the forefront of staging and treatment response evaluation in Hodgkin's disease and non-Hodgkin's lymphoma. Imaging also plays a key role in evaluating the myriad of treatment complications that are commonly seen with chemotherapy and associated neutropenia. Future efforts will be largely focused on decreasing radiation exposure to these children, utilizing reduced or radiation-free modalities, such as positron emission tomography/magnetic resonance and diffusion-weighted whole-body imaging with background suppression, as well as refining surveillance imaging strategies. The purpose of this article is to briefly review the classification of pediatric leukemia and lymphoma, illustrate common imaging findings at presentation throughout the body, describe staging and therapeutic response evaluation, and show a spectrum of commonly encountered complications of treatment.

Rituximab as potential therapy for paraneoplastic cerebellar degeneration in pediatric Hodgkin disease.

Paraneoplastic cerebellar degeneration (PCD) is a rare neurological syndrome associated with lung cancer, breast adenocarcinoma,ovarian adenocarcinoma, and Hodgkin disease. It is rarely seen in pediatrics. We report a case of a 10-year-old boy with a 2-year prodrome that led to a diagnosis of PCD in association with stage IV Hodgkin disease. He received radiation and chemotherapy for his Hodgkin disease with resolution of his lymphoma. Based on promising data in adults on the efficacy of rituximab over other immuno suppressive agents in paraneoplastic disorders, he was treated with rituximab with marked improvement of the cerebellar syndrome.

Incorporating a public health approach in drug law: lessons from local expansion of treatment capacity and access under California's Proposition 36.

A major state drug abuse initiative, California's Proposition 36 of 2000, mandated that adults convicted of drug possession be offered treatment in lieu of incarceration. While the law expanded public treatment for arrestees, the counties were given discretion in structuring their systems of care and procedures to manage clients. Using data from a study of key informants in eight counties, this article examines local planning to increase drug treatment capacity and manage clients' access to treatment. In both these planning domains, it describes the counties' strategies and concerns, reasons for their differences in approaches, and whether and how this state initiative, which explicitly incorporated treatment objectives into penal drug law, will shift the debate over drug abuse policy toward greater consideration of public health goals.

Reduced expression of NFAT-associated genes in UCB versus adult CD4+ T lymphocytes during primary stimulation.

The cellular and molecular mechanisms underlying the blunted allo-responsiveness of umbilical cord blood (UCB) T cells have not been fully elucidated. Protein expression of NFATc2 (nuclear factor of activated T cells c2), a critical transcription factor necessary for up-regulation of multiple cytokines known to amplify T-cell allogeneic responses, is reduced in UCB T cells. Affymetrix oligonucleotide microarrays were used to compare gene expression of primary purified CD4+ UCB T cells to adult peripheral blood CD4+ T cells (AB) at baseline, 6, and 16 hours of primary stimulation. NFAT-regulated genes exhibited lower expression in UCB CD4+ T cells including the following: granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin 3 (IL-3), IL-4, IL-5, IL-13, IL-2 receptor alpha (IL-2Ralpha; CD25), CD40L, and macrophage inflammatory protein 1 alpha (MIP-1alpha). Transcription factors involved in the NFAT pathway including C/EBPbeta, JunB, and Fosl1 (Fra-1), as well as Th1- and Th2-related transcription factors STAT4 (signal transducers and activators of transcription 4), T-bet, and c-maf showed reduced expression in UCB compared with AB during primary stimulation. Reduced cytokine, chemokine, and receptor expression was also found in UCB. Gene array data were confirmed using RNase protection assays, flow cytometry, and quantitative multiplexed cytokine measurements. Reduced global expression of NFAT-associated genes, as well as cytokines and chemokines, in UCB CD4+ T cells may contribute to the decreased graft-versus-host disease (GVHD) observed after UCB transplantation.

Reduced CTLA-4 protein and messenger RNA expression in umbilical cord blood T lymphocytes.

OBJECTIVE: A favorable incidence and severity of graft-vs-host disease is observed in patients transplanted with banked, unrelated, HLA-mismatched umbilical cord blood (UCB) grafts, while the incidence of malignant relapse remains low. CTLA-4 mediates negative T-cell signaling and may contribute to the development of allogeneic tolerance. In this study, we compared protein and mRNA expression of CTLA-4 in stimulated UCB and adult peripheral blood T cells. MATERIALS AND METHODS: T cells were isolated from UCB and adult peripheral blood and stimulated with anti-CD3 and anti-CD28 monoclonal antibodies. Cells were immunostained and analyzed by flow cytometry for both surface and intracellular expression of CTLA-4 in the presence and absence of cyclosporin A, and kinetics of CTLA-4 expression compared. CTLA-4 mRNA expression was measured using quantitative real-time polymerase chain reaction. NFAT1 protein levels were measured by Western blot analysis. RESULTS: These studies demonstrate reduced surface and intracellular expression of CTLA-4 in stimulated UCB T cells compared to adult controls. Furthermore, reduced CTLA-4 protein expression in UCB T cells was noted to be in part transcriptionally regulated, as CTLA-4 mRNA levels also were significantly lower. Reduced CLTA-4 expression by UCB T cells followed the kinetics of delayed and reduced expression of the transcription factor NFAT1 by UCB T lymphocytes during primary stimulation. Moreover, cyclosporin A, which is known to modulate NFAT activation, reduced CTLA-4 protein expression in adult and UCB T cells. CONCLUSION: Reduced expression of the key regulatory proteins CTLA-4 and NFAT-1 may contribute to favorable UCB T lymphocyte allogeneic responses.