Systemic proteome phenotypes reveal defective metabolic flexibility in Mecp2 mutants.

Genes mutated in monogenic neurodevelopmental disorders are broadly expressed. This observation supports the concept that monogenic neurodevelopmental disorders are systemic diseases that profoundly impact neurodevelopment. We tested the systemic disease model focusing on Rett syndrome, which is caused by mutations in MECP2. Transcriptomes and proteomes of organs and brain regions from Mecp2-null mice as well as diverse MECP2-null male and female human cells were assessed. Widespread changes in the steady-state transcriptome and proteome were identified in brain regions and organs of presymptomatic Mecp2-null male mice as well as mutant human cell lines. The extent of these transcriptome and proteome modifications was similar in cortex, liver, kidney, and skeletal muscle and more pronounced than in the hippocampus and striatum. In particular, Mecp2- and MECP2-sensitive proteomes were enriched in synaptic and metabolic annotated gene products, the latter encompassing lipid metabolism and mitochondrial pathways. MECP2 mutations altered pyruvate-dependent mitochondrial respiration while maintaining the capacity to use glutamine as a mitochondrial carbon source. We conclude that mutations in Mecp2/MECP2 perturb lipid and mitochondrial metabolism systemically limiting cellular flexibility to utilize mitochondrial fuels.

In vivo lymph node CEST-Dixon MRI in breast cancer patients with metastatic lymph node involvement.

PURPOSE: Axillary lymph nodes (LNs) often present a reservoir for metastatic breast cancer, yet metastatic LN involvement cannot be discerned definitively using diagnostic imaging. This study investigated whether in vivo CEST may discriminate LNs with versus without metastatic involvement. METHODS: 3T MRI was performed in patients with breast cancer before clinically-indicated mastectomy or lumpectomy with LN removal, after which LN metastasic involvement was determined using histological evaluation. Non-contrast anatomical imaging, as well as B0 and B1 field maps, were acquired in sequence with three-point CEST-Dixon (3D turbo-gradient-echo; factor = 25; TR/TE1/ΔTE = 851/1.35/1.1 ms; spatial-resolution = 2.5 × 2.5 × 6 mm; slices = 10; four sinc-gauss pulses with duty-cycle = 0.5, total saturation duration = 701.7 ms; B1 = 1.5 µT; saturation offsets = -5.5 to +5.5 ppm; stepsize = 0.2 ppm; scan duration = 6 min 30 s). The mean z-spectrum from LNs with (n = 20) versus without (n = 22) metastatic involvement were analyzed and a Wilcoxon rank-sum test (significance: p < 0.05) was applied to evaluate differences in B0, B1 , and magnetization transfer ratio (MTR) in differing spectral regions of known proton exchange (nuclear Overhauser effect [NOE], amide, amine, and hydroxyl) between cohorts. RESULTS: No difference in axillary B1 (p = 0.634) or B0 (p = 0.689) was observed between cohorts. Elevated MTR was observed for the NOE (-1.7 ppm; MTR = 0.285 ± 0.075 vs. 0.248 ± 0.039; p = 0.048), amine (+2.5 ppm; MTR = 0.284 ± 0.067 vs. 0.234 ± 0.31; p = 0.005), and hydroxyl (+1 ppm; MTR = 0.394 ± 0.075 vs. 0.329 ± 0.055; p = 0.002) protons in LNs from participants with versus without metastatic involvement. CONCLUSIONS: Findings are consistent with a unique metastatic LN microenvironment detectable by CEST-Dixon and suggest that CEST MRI may have potential for mapping LN metastasis non-invasively in vivo.

Red cell exchange transfusions increase cerebral capillary transit times and may alter oxygen extraction in sickle cell disease.

Persons with sickle cell disease (SCD) suffer from chronic hemolytic anemia, reduced blood oxygen content, and lifelong risk of silent and overt stroke. Major conventional stroke risk factors are absent in most individuals with SCD, yet nearly 50% have evidence of brain infarcts by the age of 30 years, indicating alternative etiologies for ischemia. We investigated whether radiological evidence of accelerated blood water transit through capillaries, visible on arterial spin labeling (ASL) magnetic resonance imaging, reduces following transfusion-induced increases in hemoglobin and relates to oxygen extraction fraction (OEF). Neurological evaluation along with anatomical and hemodynamic imaging with cerebral blood flow (CBF)-weighted pseudocontinuous ASL and OEF imaging with T2 -relaxation-under-spin-tagging were applied in sequence before and after blood transfusion therapy (n = 32) and in a comparator cohort of nontransfused SCD participants on hydroxyurea therapy scanned at two time points to assess stability without interim intervention (n = 13). OEF was calculated separately using models derived from human hemoglobin-F, hemoglobin-A, and hemoglobin-S. Gray matter CBF and dural sinus signal, indicative of rapid blood transit, were evaluated at each time point and compared with OEF using paired statistical tests (significance: two-sided p < 0.05). No significant change in sinus signal was observed in nontransfused participants (p = 0.650), but a reduction was observed in transfused participants (p = 0.034), consistent with slower red cell transit following transfusion. The dural sinus signal intensity was inversely associated with OEF pretransfusion (p = 0.011), but not posttransfusion. Study findings suggest that transfusion-induced increases in total hemoglobin may lengthen blood transit times through cerebral capillaries and alter cerebral OEF in SCD.

Subcutaneous Adipose Tissue Edema in Lipedema Revealed by Noninvasive 3T MR Lymphangiography.

BACKGROUND: Lipedema exhibits excessive lower-extremity subcutaneous adipose tissue (SAT) deposition, which is frequently misidentified as obesity until lymphedema presents. MR lymphangiography may have relevance to distinguish lipedema from obesity or lymphedema. HYPOTHESIS: Hyperintensity profiles on 3T MR lymphangiography can identify distinct features consistent with SAT edema in participants with lipedema. STUDY TYPE: Prospective cross-sectional study. SUBJECTS: Participants (48 females, matched for age [mean = 44.8 years]) with lipedema (n = 14), lipedema with lymphedema (LWL, n = 12), cancer treatment-related lymphedema (lymphedema, n = 8), and controls without these conditions (n = 14). FIELD STRENGTH/SEQUENCE: 3T MR lymphangiography (nontracer 3D turbo-spin-echo). ASSESSMENT: Review of lymphangiograms in lower extremities by three radiologists was performed independently. Spatial patterns of hyperintense signal within the SAT were scored for extravascular (focal, diffuse, or not apparent) and vascular (linear, dilated, or not apparent) image features. STATISTICAL TESTS: Interreader reliability was computed using Fleiss Kappa. Fisher's exact test was used to evaluate the proportion of image features between study groups. Multinomial logistic regression was used to assess the relationship between image features and study groups. The odds ratio (OR) and 95% confidence interval (CI) of SAT extravascular and vascular features was reported in groups compared to lipedema. The threshold of statistical significance was P < 0.05. RESULTS: Reliable agreement was demonstrated between three independent, blinded reviewers (P < 0.001). The frequency of SAT hyperintensities in participants with lipedema (36% focal, 36% diffuse), LWL (42% focal, 33% diffuse), lymphedema (62% focal, 38% diffuse), and controls (43% focal, 0% diffuse) was significantly distinct. Compared with lipedema, SAT hyperintensities were less frequent in controls (focal: OR = 0.63, CI = 0.11-3.41; diffuse: OR = 0.05, CI = 0.00-1.27), similar in LWL (focal: OR = 1.29, CI = 0.19-8.89; diffuse: OR = 1.05, CI = 0.15-7.61), and more frequent in lymphedema (focal: OR = 9.00, CI = 0.30-274.12; diffuse: OR = 5.73, CI = 0.18-186.84). DATA CONCLUSION: Noninvasive MR lymphangiography identifies distinct signal patterns indicating SAT edema and lymphatic load in participants with lipedema. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 1.

Mitochondrial Proteostasis Requires Genes Encoded in a Neurodevelopmental Syndrome Locus.

Eukaryotic cells maintain proteostasis through mechanisms that require cytoplasmic and mitochondrial translation. Genetic defects affecting cytoplasmic translation perturb synapse development, neurotransmission, and are causative of neurodevelopmental disorders, such as Fragile X syndrome. In contrast, there is little indication that mitochondrial proteostasis, either in the form of mitochondrial protein translation and/or degradation, is required for synapse development and function. Here we focus on two genes deleted in a recurrent copy number variation causing neurodevelopmental disorders, the 22q11.2 microdeletion syndrome. We demonstrate that SLC25A1 and MRPL40, two genes present in the microdeleted segment and whose products localize to mitochondria, interact and are necessary for mitochondrial ribosomal integrity and proteostasis. Our Drosophila studies show that mitochondrial ribosome function is necessary for synapse neurodevelopment, function, and behavior. We propose that mitochondrial proteostasis perturbations, either by genetic or environmental factors, are a pathogenic mechanism for neurodevelopmental disorders.SIGNIFICANCE STATEMENT The balance between cytoplasmic protein synthesis and degradation, or cytoplasmic proteostasis, is required for normal synapse function and neurodevelopment. Cytoplasmic and mitochondrial ribosomes are necessary for two compartmentalized, yet interdependent, forms of proteostasis. Proteostasis dependent on cytoplasmic ribosomes is a well-established target of genetic defects that cause neurodevelopmental disorders, such as autism. Here we show that the mitochondrial ribosome is a neurodevelopmentally regulated organelle whose function is required for synapse development and function. We propose that defective mitochondrial proteostasis is a mechanism with the potential to contribute to neurodevelopmental disease.

Elevated magnetic resonance imaging measures of adipose tissue deposition in women with breast cancer treatment-related lymphedema.

PURPOSE: Breast cancer treatment-related lymphedema (BCRL) is a common co-morbidity of breast cancer therapies, yet factors that contribute to BCRL progression remain incompletely characterized. We investigated whether magnetic resonance imaging (MRI) measures of subcutaneous adipose tissue were uniquely elevated in women with BCRL. METHODS: MRI at 3.0 T of upper extremity and torso anatomy, fat and muscle tissue composition, and T2 relaxometry were applied in left and right axillae of healthy control (n = 24) and symptomatic BCRL (n = 22) participants to test the primary hypothesis that fat-to-muscle volume fraction is elevated in symptomatic BCRL relative to healthy participants, and the secondary hypothesis that fat-to-muscle volume fraction is correlated with MR relaxometry of affected tissues and BCRL stage (significance criterion: two-sided p < 0.05). RESULTS: Fat-to-muscle volume fraction in healthy participants was symmetric in the right and left sides (p = 0.51); in BCRL participants matched for age, sex, and BMI, fat-to-muscle volume fraction was elevated on the affected side (fraction = 0.732 ± 0.184) versus right and left side in controls (fraction = 0.545 ± 0.221, p < 0.001). Fat-to-muscle volume fraction directly correlated with muscle T2 (p = 0.046) and increased with increasing level of BCRL stage (p = 0.041). CONCLUSION: Adiposity quantified by MRI is elevated in the affected upper extremity of women with BCRL and may provide a surrogate marker of condition onset or severity. CLINICAL TRIAL: NCT02611557.

Presurgical Magnetic Resonance Imaging Indicators of Revascularization Response in Adults With Moyamoya Vasculopathy.

BACKGROUND: Moyamoya is a progressive intracranial vasculopathy, primarily affecting distal segments of the internal carotid and middle cerebral arteries. Treatment may comprise angiogenesis-inducing surgical revascularization; however, lack of randomized trials often results in subjective treatment decisions. HYPOTHESIS: Compensatory presurgical posterior vertebrobasilar artery (VBA) flow-territory reactivity, including greater cerebrovascular reactivity (CVR) and reduced vascular delay time, portends greater neoangiogenic response verified on digital subtraction angiography (DSA) at 1-year follow-up. STUDY TYPE: Prospective intervention cohort. SUBJECTS: Thirty-one patients with moyamoya (26 females; age = 45 ± 13 years; 41 revascularized hemispheres). METHODS: Anatomical MRI, hypercapnic CVR MRI, and DSA acquired presurgically in adult moyamoya participants scheduled for clinically indicated surgical revascularization. One-year postsurgery, DSA was repeated to evaluate collateralization. FIELD STRENGTH: 3 T. SEQUENCE: Hypercapnic T 2 * -weighted gradient-echo blood-oxygenation-level-dependent, T2 -weighted turbo-spin-echo fluid-attenuated-inversion-recovery, T1 -weighted magnetization-prepared-rapid-gradient-echo, and T2 -weighted diffusion-weighted-imaging. ASSESSMENT: Presurgical maximum CVR and response times were evaluated in VBA flow-territories. Revascularization success was determined using an ordinal scoring system of neoangiogenic collateralization from postsurgical DSA by two cerebrovascular neurosurgeons (R.V.C. with 8 years of experience; M.R.F. with 9 years of experience) and one neuroradiologist (L.T.D. with 8 years of experience). Stroke risk factors (age, sex, race, vasculopathy, and diabetes) were recorded. STATISTICAL TESTS: Fisher's exact and Wilcoxon rank-sum tests were applied to compare presurgical variables between cohorts with angiographically confirmed good (>1/3 middle cerebral artery [MCA] territory revascularized) vs. poor (<1/3 MCA territory revascularized) outcomes. SIGNIFICANCE: two-sided P < 0.05. Normalized odds ratios (ORs) were calculated. RESULTS: Criteria for good collateralization were met in 25 of the 41 revascularized hemispheres. Presurgical normalized VBA flow-territory CVR was significantly higher in those with good (1.12 ± 0.13 unitless) vs. poor (1.04 ± 0.05 unitless) outcomes. Younger (OR = -0.60 ± 0.67) and White (OR = -1.81 ± 1.40) participants had highest revascularization success (good outcomes: age = 42 ± 14 years, race = 84% White; poor outcomes: age = 49 ± 11 years, race = 44% White). DATA CONCLUSION: Presurgical MRI-measures of VBA flow-territory CVR are highest in moyamoya participants with better angiographic responses to surgical revascularization. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 4.

Reconstructing the heart using iPSCs: Engineering strategies and applications.

Induced pluripotent stem cells (iPSCs) have emerged as a key component of cardiac tissue engineering, enabling studies of cardiovascular disease mechanisms, drug responses, and developmental processes in human 3D tissue models assembled from isogenic cells. Since the very first engineered heart tissues were introduced more than two decades ago, a wide array of iPSC-derived cardiac spheroids, organoids, and heart-on-a-chip models have been developed incorporating the latest available technologies and materials. In this review, we will first outline the fundamental biological building blocks required to form a functional unit of cardiac muscle, including iPSC-derived cells differentiated by soluble factors (e.g., small molecules), extracellular matrix scaffolds, and exogenous biophysical maturation cues. We will then summarize the different fabrication approaches and strategies employed to reconstruct the heart in vitro at varying scales and geometries. Finally, we will discuss how these platforms, with continued improvements in scalability and tissue maturity, can contribute to both basic cardiovascular research and clinical applications in the future.

Cerebral Hemodynamics and Executive Function in Sickle Cell Anemia.

BACKGROUND AND PURPOSE: Individuals with sickle cell anemia experience cognitive deficits, even in the absence of cerebral infarcts or strokes. This study tested the hypothesis that elevated cerebral blood flow and oxygen extraction fraction are associated with lower executive function in individuals with sickle cell anemia. METHODS: Three-Tesla brain magnetic resonance imaging was performed, including anatomic, gray matter cerebral blood flow, and global oxygen extraction fraction imaging. Executive function was measured using the working memory index from an age-appropriate Wechsler battery and tasks from the National Institutes of Health Toolbox Cognition Battery. Bivariate and multivariate models were examined (significance: P<0.05). RESULTS: Fifty-four participants (age range=6-31 years) with sickle cell anemia were enrolled. Hematocrit was positively related to fluid cognition, cerebral blood flow was inversely related to working memory and inhibitory control, and oxygen extraction fraction was inversely related to processing speed. Associations remained significant in multivariate analyses controlling for age, income, and infarcts. CONCLUSIONS: Elevated cerebral blood flow and oxygen extraction fraction, markers of hemodynamic impairment, are associated with deficits in executive function in individuals with sickle cell anemia.

A cross-sectional, case-control study of intracranial arterial wall thickness and complete blood count measures in sickle cell disease.

In sickle cell disease (SCD), cerebral oxygen delivery is dependent on the cerebral vasculature's ability to increase blood flow and volume through relaxation of the smooth muscle that lines intracranial arteries. We hypothesised that anaemia extent and/or circulating markers of inflammation lead to concentric macrovascular arterial wall thickening, visible on intracranial vessel wall magnetic resonance imaging (VW-MRI). Adult and pediatric SCD (n = 69; age = 19.9 ± 8.6 years) participants and age- and sex-matched control participants (n = 38; age = 22.2 ± 8.9 years) underwent 3-Tesla VW-MRI; two raters measured basilar and bilateral supraclinoid internal carotid artery (ICA) wall thickness independently. Mean wall thickness was compared with demographic, cerebrovascular and haematological variables. Mean vessel wall thickness was elevated (P < 0·001) in SCD (1·07 ± 0·19 mm) compared to controls (0·97 ± 0·07 mm) after controlling for age and sex. Vessel wall thickness was higher in participants on chronic transfusions (P = 0·013). No significant relationship between vessel wall thickness and flow velocity, haematocrit, white blood cell count or platelet count was observed; however, trends (P < 0·10) for wall thickness increasing with decreasing haematocrit and increasing white blood cell count were noted. Findings are discussed in the context of how anaemia and circulating inflammatory markers may impact arterial wall morphology.

A Prospective, Longitudinal Magnetic Resonance Imaging Evaluation of Cerebrovascular Reactivity and Infarct Development in Patients With Intracranial Stenosis.

BACKGROUND: Patients with symptomatic atherosclerotic and non-atherosclerotic (i.e., moyamoya) intracranial steno-occlusive disease experience high 2-year infarct rates. PURPOSE: To investigate whether cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) measures may provide biomarkers of 1-to-2-year infarct risk. STUDY TYPE: Prospective, longitudinal study. SUBJECTS: Adult participants (age = 18-85 years) with symptomatic intracranial atherosclerotic disease (N = 26) or non-atherosclerotic (i.e., moyamoya; N = 43) and stenosis ≥50% of a major intracranial artery were initially scanned within 45 days of stroke. Follow-up imaging (target  = 1.5 years) was acquired for new infarct assessment. FIELD STRENGTH/SEQUENCE: 3.0 Tesla with normocapnic arterial spin labeling (ASL) and blood oxygenation level-dependent (BOLD) imaging acquired during an interleaved hypercapnic (3 minutes) and normocapnic (3 minutes) respiratory stimulus. ASSESSMENT: CBF, maximum CVR, and time-to-maximum CVR (i.e., CVRDELAY ) were calculated. Laterality indices (difference between infarcted and contralesional hemispheres divided by sum of absolute values) of metrics at enrollment were contrasted between participants with vs. without new infarcts on follow-up. STATISTICAL TESTS: Laterality indices were compared using non-parametric Wilcoxon tests (significance: two-sided P < 0.05) and effect sizes as Cohen's d. Continuous variables are presented as mean ± SD. RESULTS: New infarcts were observed on follow-up in 15.0% of participants. The laterality index of the CVRDELAY was elevated (P = 0.01) in participants with atherosclerosis with new infarcts (index = 0.13) compared to participants without new infarcts (index = 0.05). DATA CONCLUSION: Elevated CVRDELAY may indicate brain parenchyma at increased risk for new infarcts in patients with symptomatic intracranial atherosclerotic disease treated with standard-of-care medical management. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 3.

Cognitive and Attentional Function in Children with Hypoplastic Left Heart Syndrome: A Pilot Study.

While survival for children with hypoplastic left heart syndrome (HLHS) has improved, compromised cardiac output and oxygen delivery persist, and children show cognitive deficits. Most research has assessed young children on broad cognitive indices; less is known about specific indices in older youth. In this pilot study, cognitive function and attention in youth ages 8 to 16 years with HLHS (n = 20) was assessed with the Wechsler Intelligence Scale for Children - Fifth Edition (WISC-V) and NIH Toolbox Cognition Battery (NTCB); parents completed the Child Behavior Checklist. Children scored significantly lower than normative means on the WISC-V Full Scale IQ, Verbal Comprehension, Visual Spatial, Working Memory, and Processing Speed indices, and the NTCB Fluid Cognition Composite; effect sizes ranged from medium to large. Attention problems had a large significant effect. Child age corresponded to lower visual spatial scores. Findings highlight the importance of assessing multiple cognitive indices for targeted intervention and investigating age and disease factors as potential correlates in larger samples.

Magnetic resonance imaging and bioimpedance evaluation of lymphatic abnormalities in patients with breast cancer treatment-related lymphedema.

PURPOSE: Breast cancer treatment-related lymphedema (BCRL) evaluation is frequently performed using portable measures of limb volume and bioimpedance asymmetry. Here quantitative magnetic resonance imaging (MRI) is applied to evaluate deep and superficial tissue impairment, in both surgical and contralateral quadrants, to test the hypothesis that BCRL impairment is frequently bilateral and extends beyond regions commonly evaluated with portable external devices. METHODS: 3-T MRI was applied to investigate BCRL topographical impairment. Female BCRL (n = 33; age = 54.1 ± 11.2 years; stage = 1.5 ± 0.8) and healthy (n = 33; age = 49.4 ± 11.0 years) participants underwent quantitative upper limb MRI relaxometry (T2), bioimpedance asymmetry, arm volume asymmetry, and physical evaluation. Parametric tests were applied to evaluate study measurements (i) between BCRL and healthy participants, (ii) between surgical and contralateral limbs, and (iii) in relation to clinical indicators of disease severity. Two-sided p-value < 0.05 was required for significance. RESULTS: Bioimpedance asymmetry was significantly correlated with MRI-measured water relaxation (T2) in superficial tissue. Deep muscle (T2 = 37.6 ± 3.5 ms) and superficial tissue (T2 = 49.8 ± 13.2 ms) relaxation times were symmetric in healthy participants. In the surgical limbs of BCRL participants, deep muscle (T2 = 40.5 ± 4.9 ms) and superficial tissue (T2 = 56.0 ± 14.8 ms) relaxation times were elevated compared to healthy participants, consistent with an edematous micro-environment. This elevation was also observed in contralateral limbs of BCRL participants (deep muscle T2 = 40.3 ± 5.7 ms; superficial T2 = 56.6 ± 13.8 ms). CONCLUSIONS: Regional MRI measures substantiate a growing literature speculating that superficial and deep tissue, in surgical and contralateral quadrants, is affected in BCRL. The implications of these findings in the context of titrating treatment regimens and understanding malignancy recurrence are discussed.

Pediatric Acute Stroke Protocol Implementation and Utilization Over 7 Years.

OBJECTIVE: To examine the implementation and utilization of a pediatric acute stroke protocol over a 7-year period, hypothesizing improvements in protocol implementation and increased protocol use over time. STUDY DESIGN: Clinical and demographic data for this retrospective observational study from 2011 through 2018 were obtained from a quality improvement database and medical records of children for whom the acute stroke protocol was activated. The initial 43 months of the protocol (period 1) were compared with the subsequent 43 months (period 2). RESULTS: Over the 7-year period, a total of 385 stroke alerts were activated, in 150 children (39%) in period 1 and 235 (61%) in period 2, representing a 56% increase in protocol activation. Stroke was the final diagnosis in 80 children overall (21%), including 38 (25%) in period 1 and 42 (19%) in period 2 (P = .078). The combined frequency of diagnosed stroke, transient ischemic attack (TIA), and other neurologic emergencies remained stable across the 2 time periods at 39% and 37%, respectively (P = .745). Pediatric National Institutes of Health Stroke Scale (PedNIHSS) documentation increased from 42% in period 1 to 82% in period 2 (P < .001). Magnetic resonance imaging (MRI) was the first neuroimaging study for 68% of the children in period 1 vs 78% in period 2 (P = .038). All children with acute stroke received immediate supportive care. CONCLUSIONS: Pediatric stroke protocol implementation improved over time with increased use of the PedNIHSS and use of MRI as the first imaging study. However, with increased utilization, the frequency of confirmed strokes and other neurologic emergencies remained stable. The frequency of stroke and other neurologic emergencies in these children affirms the importance of implementing and maintaining a pediatric acute stroke protocol.

Differential cerebral hemometabolic responses to blood transfusions in adults and children with sickle cell anemia.

BACKGROUND: Blood transfusions are administered to children and adults with sickle cell anemia (SCA) for secondary stroke prevention, or as treatment for recurrent pain crises or acute anemia, but transfusion effects on cerebral hemodynamics and metabolism are not well-characterized. PURPOSE: To compare blood transfusion-induced changes in hemometabolic parameters, including oxygen extraction fraction (OEF) and cerebral blood flow (CBF), within and between adults and children with SCA. STUDY TYPE: Prospective, longitudinal study. SUBJECTS: Adults with SCA (n = 16) receiving simple (n = 7) or exchange (n = 9) transfusions and children with SCA (n = 11) receiving exchange transfusions were scanned once when hematocrit was near nadir and again within 7 days of transfusion. Adult controls without SCA or sickle trait (n = 7) were scanned twice on separate days. FIELD STRENGTH/SEQUENCE: 3.0T T1 -weighted, T2 -weighted, and T2 -relaxation-under-spin-tagging (TRUST) imaging, and phase contrast angiography. ASSESSMENT: Global OEF was computed as the relative difference between venous oxygenation (from TRUST) and arterial oxygenation (from pulse oximetry). Global CBF was computed as total blood flow to the brain normalized by intracranial tissue volume. STATISTICAL TESTS: Hemometabolic variables were compared using two-sided Wilcoxon signed-rank tests; associations were analyzed using two-sided Spearman's correlation testing. RESULTS: In adults with SCA, posttransfusion OEF = 0.38 ± 0.05 was lower (P = 0.001) than pretransfusion OEF = 0.45 ± 0.09. A change in OEF was correlated with increases in hematocrit (P = 0.02; rho = -0.62) and with pretransfusion hematocrit (P = 0.02; rho = 0.65). OEF changes after transfusion were greater (P = 0.002) in adults receiving simple versus exchange transfusions. Posttransfusion CBF = 77.7 ± 26.4 ml/100g/min was not different (P = 0.27) from pretransfusion CBF = 82.3 ± 30.2 ml/100g/min. In children with SCA, both posttransfusion OEF = 0.28 ± 0.04 and CBF = 76.4 ± 26.4 were lower than pretransfusion OEF = 0.36 ± 0.06 (P = 0.004) and CBF = 96.4 ± 16.5 (P = 0.004). DATA CONCLUSION: Cerebral OEF reduces following transfusions in adults and children with SCA. CBF reduces following transfusions more often in children compared to adults, indicating that vascular reserve capacity may remain near exhaustion posttransfusion in many adults. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage 5 J. Magn. Reson. Imaging 2019;49:466-477.

Cognitive Function in Pediatric Hypoplastic Left Heart Syndrome: Systematic Review and Meta-Analysis.

OBJECTIVE: Despite surgical palliation, children with hypoplastic left heart syndrome (HLHS) have compromised cardiac functioning and increased risk for cognitive deficits. We quantitatively reviewed the empirical data from this literature. METHODS: The present meta-analysis included 13 studies reporting cognitive function for children with HLHS between the ages of 2 years and 6 months and 17 years that used standardized assessments of Full Scale IQ (FSIQ), Verbal IQ (VIQ), and Performance IQ (PIQ). Differences in cognitive function were assessed relative to normative data, and we examined sample mean age and publication year as moderators. RESULTS: Large effects were found for FSIQ (g = -.87, 95% CI [-1.10, -.65], M = 86.88) and PIQ (g = -.89, 95% CI [-1.11, -.68], M = 86.56), and a medium effect was found for VIQ (g = -.61, 95% CI [-.84, -.38], M = 90.82). All models demonstrated significant heterogeneity. Meta-regression analyses of effect size via Hedges' g on child age revealed a significant effect on FSIQ (coefficient = -.07, 95% CI [-.12, -.01], p < .01, R2 = .40) indicating a loss of 1.1 FSIQ points across studies with each increased year of mean sample age. CONCLUSIONS: Deficits in FSIQ may reflect chronic brain injury or failure to make expected gains as children age. This review highlights the importance of early intervention in this population, and the need for longitudinal studies analyzing more specific domains of cognitive function and potential moderators.

Enriched Astaxanthin Extract from Haematococcus pluvialis Augments Growth Factor Secretions to Increase Cell Proliferation and Induces MMP1 Degradation to Enhance Collagen Production in Human Dermal Fibroblasts.

Among many antioxidants that are used for the repairing of oxidative stress induced skin damages, we identified the enriched astaxanthin extract (EAE) from Haematococcus pluvialis as a viable ingredient. EAE was extracted from the red microalgae through supercritical fluid carbon dioxide extraction. To compare the effectiveness, EAE wastreated on human dermal fibroblasts with other components, phorbol 12-myristate 13-acetate (PMA), and doxycycline. With sirius red staining and quantitative real-time polymerase chain reaction (qRT-PCR), we found that PMA decreased the collagen concentration and production while overall the addition of doxycycline and EAE increased the collagen concentration in a trial experiments. EAE increased collagen contents through inhibited MMP1 and MMP3 mRNA expression and induced TIMP1, the antagonists of MMPs protein, gene expression. As for when tested for various proteins through western blotting, it was seen that the addition of EAE increased the expression of certain proteins that promote cell proliferation. Testing those previous solutions using growth factor assay, it was noticeable that EAE had a positive impact on cell proliferation and vascular endothelial growth factor (VEGF) than doxycycline, indicating that it was a better alternative treatment for collagen production. To sum up, the data confirmed the possible applications as medical cosmetology agentsand food supplements.