Short- and Long-Term MRI Assessed Hemodynamic Changes in Pediatric Moyamoya Patients After Revascularization.

BACKGROUND: Cerebrovascular reserve (CVR) reflects the capacity of cerebral blood flow (CBF) to change following a vasodilation challenge. Decreased CVR is associated with a higher stroke risk in patients with cerebrovascular diseases. While revascularization can improve CVR and reduce this risk in adult patients with vasculopathy such as those with Moyamoya disease, its impact on hemodynamics in pediatric patients remains to be elucidated. Arterial spin labeling (ASL) is a quantitative MRI technique that can measure CBF, CVR, and arterial transit time (ATT) non-invasively. PURPOSE: To investigate the short- and long-term changes in hemodynamics after bypass surgeries in patients with Moyamoya disease. STUDY TYPE: Longitudinal. POPULATION: Forty-six patients (11 months-18 years, 28 females) with Moyamoya disease. FIELD STRENGTH/SEQUENCE: 3-T, single- and multi-delay ASL, T1-weighted, T2-FLAIR, 3D MRA. ASSESSMENT: Imaging was performed 2 weeks before and 1 week and 6 months after surgical intervention. Acetazolamide was employed to induce vasodilation during the imaging procedure. CBF and ATT were measured by fitting the ASL data to the general kinetic model. CVR was computed as the percentage change in CBF. The mean CBF, ATT, and CVR values were measured in the regions affected by vasculopathy. STATISTICAL TESTS: Pre- and post-revascularization CVR, CBF, and ATT were compared for different regions of the brain. P-values <0.05 were considered statistically significant. RESULTS: ASL-derived CBF in flow territories affected by vasculopathy significantly increased after bypass by 41 ± 31% within a week. At 6 months, CBF significantly increased by 51 ± 34%, CVR increased by 68 ± 33%, and ATT was significantly reduced by 6.6 ± 2.9%. DATA CONCLUSION: There may be short- and long-term improvement in the hemodynamic parameters of pediatric Moyamoya patients after bypass surgery. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

A Dedicated Outpatient Pharmacy Improves Access to Discharge Medications in a Pediatric Emergency Department: A Quality Improvement Study.

STUDY OBJECTIVE: Following discharge from a pediatric emergency department (ED) or urgent care, many families do not pick up their prescribed medications. The aim of this quality improvement study was to increase the percentage of patients discharged home with medications in-hand from 6% to 30% within 6 months. METHODS: Due to the planned construction of a new ED, urgent care, and dedicated pharmacy, a multidisciplinary team was formed to increase access to discharge medications. We performed a pilot study in the urgent care to improve the discharge prescription process and expanded its scope to the ED. We evaluated the effect of our interventions on the percentage of patients discharged with medications in-hand through statistical process control charts. Process measures included the percentage of prescriptions electronically prescribed and directed to an on-site pharmacy. RESULTS: Between June 21, 2021 and March 27, 2022, 7,678 patients were discharged with at least 1 medication in-hand. The percentage of patients discharged with medications in-hand increased from 6.2% to 60.6%. The percentage of prescriptions e-prescribed and directed to an on-site pharmacy increased to 94.6% and 65.6% respectively. CONCLUSIONS: In this study, the availability of a 24-hour on-site pharmacy appears to be the most impactful intervention increasing access to discharge medications for families. Other interventions, such as a pilot study in the urgent care and implementing default electronic prescribing, may have potentiated the effect of the new pharmacy.

Psychobiography in sociocultural context: the application of culture-based theories of psychology on a culturally diverse historic subject pool.

In recent years the historical subject base in psychobiography has expanded from a traditional focus on White (Caucasian) subjects to a broader more culturally inclusive population of significant personalities throughout history. A critical component of strong multicultural psychobiography is the inclusion of anchoring theories of psychology that are rooted in socio-cultural-political context. To psychologically profile culturally diverse individuals with only traditional Western theories of psychology and psychiatry (e.g. medical models, psychodynamic, existential, cognitive-behavioral) limits the ability of the research to accurately capture the erlebnis (lived experience) of extraordinary individuals in proper cultural context. This article reviews specific psychological theories that have recently set a foundation for more nuanced and culturally contextualised psychological profiles of historic personalities who represent diverse racial/ethnic/cultural backgrounds. Among the theories covered are the Integrated African Psychology Perspective (IAPP), an Indigenous (Native American) model of psychobiography, as well as theories and models on Psychological Nigrescence (Black racial identity development), Intersectionality, Politicised Collective Identity (PCI), Queered Black Racial Identity Development (QBRID), and Adultification of Black Children, among others. Examples of applications of these culture-centered theories to psychobiography, drawn from the present authors recently completed psychobiographies, as well as from other researchers internationally, are presented.

Being and becoming: A psychobiography of James Baldwin.

INTRODUCTION: James Baldwin (1924-1987) was a prolific African American author and activist whose writing centered primarily on race, sexuality, and religion. Baldwin's lived experiences and breadth of knowledge provided him with a unique perspective of the Black experience in America, a theme he frequently revisited in his work and the impetus for his involvement in the Civil Rights Movement METHOD: This article presents a psychobiographical application of Queering Black Racial Identity Development to conceptualize the life story of James Baldwin. RESULTS: This study explores the life of James Baldwin, highlights his influence as a historical figure and agent of social change, and explores the "why" of his life and behavior. Specifically, his decision to return to the United States during the Civil Rights Movement and possible reasons he avoided politicizing his sexuality in the same way he did his racial identity. CONCLUSION: As an African American, nonheterosexual, male author and Civil Rights activist, Baldwin's intersectional identities played a significant role in his decision to dedicate his life to writing and activism. Limitations of the study are discussed.

Med25 Limits Master Regulators That Govern Adipogenesis.

Mediator 25 (Med25) is a member of the mediator complex that relays signals from transcription factors to the RNA polymerase II machinery. Multiple transcription factors, particularly those involved in lipid metabolism, utilize the mediator complex, but how Med25 is involved in this context is unclear. We previously identified Med25 in a translatome screen of adult cardiomyocytes (CMs) in a novel cell type-specific model of LMNA cardiomyopathy. In this study, we show that Med25 upregulation is coincident with myocardial lipid accumulation. To ascertain the role of Med25 in lipid accumulation, we utilized iPSC-derived and neonatal CMs to recapitulate the in vivo phenotype by depleting lamins A and C (lamin A/C) in vitro. Although lamin A/C depletion elicits lipid accumulation, this effect appears to be mediated by divergent mechanisms dependent on the CM developmental state. To directly investigate Med25 in lipid accumulation, we induced adipogenesis in Med25-silenced 3T3-L1 preadipocytes and detected enhanced lipid accumulation. Assessment of pertinent mediators driving adipogenesis revealed that C/EBPα and PPARγ are super-induced by Med25 silencing. Our results indicate that Med25 limits adipogenic potential by suppressing the levels of master regulators that govern adipogenesis. Furthermore, we caution the use of early-developmental-stage cardiomyocytes to model adult-stage cells, particularly for dissecting metabolic perturbations emanating from LMNA mutations.

Elevated dual specificity protein phosphatase 4 in cardiomyopathy caused by lamin A/C gene mutation is primarily ERK1/2-dependent and its depletion improves cardiac function and survival.

Mutations in the lamin A/C gene (LMNA) encoding the nuclear intermediate filament proteins lamins A and C cause a group of tissue-selective diseases, the most common of which is dilated cardiomyopathy (herein referred to as LMNA cardiomyopathy) with variable skeletal muscle involvement. We previously showed that cardiomyocyte-specific overexpression of dual specificity protein phosphatase 4 (DUSP4) is involved in the pathogenesis of LMNA cardiomyopathy. However, how mutations in LMNA activate Dusp4 expression and whether it is necessary for the development of LMNA cardiomyopathy are currently unknown. We now show that female LmnaH222P/H222P mice, a model for LMNA cardiomyopathy, have increased Dusp4 expression and hyperactivation of extracellular signal-regulated kinase (ERK) 1/2 with delayed kinetics relative to male mice, consistent with the sex-dependent delay in the onset and progression of disease. Mechanistically, we show that the H222P amino acid substitution in lamin A enhances its binding to ERK1/2 and increases sequestration at the nuclear envelope. Finally, we show that genetic deletion of Dusp4 has beneficial effects on heart function and prolongs survival in LmnaH222P/H222P mice. These results further establish Dusp4 as a key contributor to the pathogenesis of LMNA cardiomyopathy and a potential target for drug therapy.

Stereotactic EEG-guided laser interstitial thermal therapy for mesial temporal lobe epilepsy.

OBJECTIVE: To determine the outcomes of combined stereo-electroencephalography-guided and MRI-guided stereotactic laser interstitial thermal therapy (LITT) in the treatment of patients with drug-resistant mesial temporal lobe epilepsy (mTLE). METHODS: We prospectively assessed the surgical and neuropsychological outcomes in 21 patients with medically refractory mTLE who underwent LITT at the University of Chicago Medical Center. We further compared the surgical outcomes in patients with and without mesial temporal sclerosis (MTS). RESULTS: Of the 21 patients, 19 (90%) underwent Invasive EEG study and 11 (52%) achieved freedom from disabling seizures with a mean duration of postoperative follow-up of 24±11 months after LITT. Eight (73%) of 11 patients with MTS achieved freedom from disabling seizures, whereas 3 (30 %) of 10 patients without MTS achieved freedom from disabling seizures. Patients with MTS were significantly more likely to become seizure-free, as compared with those without MTS (P=0.002). There was no significant difference in total ablation volume and the percentage of the ablated amygdalohippocampal complex between seizure-free and non-seizure-free patients. Presurgical and postsurgical neuropsychological assessments were obtained in 10 of 21 patients. While there was no group decline in any neuropsychological assessment, a significant postoperative decline in verbal memory and confrontational naming was observed in individual patients. CONCLUSIONS: MRI-guided LITT is a safe and effective alternative to selective amygdalohippocampectomy and anterior temporal lobectomy for mTLE with MTS. Nevertheless, its efficacy in those without MTS seems modest. Large multicentre and prospective studies are warranted to further determine the efficacy and safety of LITT.

Telodendrimers for Physical Encapsulation and Covalent Linking of Individual or Combined Therapeutics.

New therapeutics for glioblastoma multiforme and our ability to deliver them using efficient nanocarriers constitute topical areas of research. We report a comparative study of temozolomide and quercetin in the treatment of glioblastoma (GBM) in three-dimensions, and their incorporation into micelles obtained from synthetically articulated architectural copolymers, and a commercially available linear polymer poly(ethylene glycol)-poly(lactic-co-glycolic acid) (PEG-PLGA). A versatile synthetic methodology to telodendrimers, which can be easily adapted to the needs of other therapeutic interventions, is presented. These dendritic block copolymers self-assemble into micelles and offer a platform for single or combination drug therapy. Telodendrimer micelles loaded with quercetin did not exhibit superior cell killing effect over the free drug, but acetazolamide, an inhibitor carbonic anhydrase IX, significantly reduced GBM cell viability in 3D spheroids. Results from these studies show that high loading of drugs into telodendrimer micelles requires a physical fit between the biologically active agent and telodendrimer nanocarrier, and points toward new possibilities for incorporation of chemotherapeutic and other agents to enhance their effectiveness.

miR-149 and miR-29c as candidates for bipolar disorder biomarkers.

Bipolar disorder (BD) is a common, recurring psychiatric illness with unknown pathogenesis. Recent studies suggest that microRNA (miRNA) levels in brains of BD patients are significantly altered, and these changes may offer insight into BD pathology or etiology. Previously, we observed significant alterations of miR-29c levels in extracellular vesicles (EVs) extracted from prefrontal cortex (Brodmann area 9, BA9) of BD patients. In this study, we show that EVs extracted from the anterior cingulate cortex (BA24), a crucial area for modulating emotional expression and affect, have increased levels of miR-149 in BD patients compared to controls. Because miR-149 has been shown to inhibit glial proliferation, increased miR-149 expression in BA24-derived EVs is consistent with the previously reported reduced glial cell numbers in BA24 of patients diagnosed with either familial BD or familial major depressive disorder. qPCR analysis of laser-microdissected neuronal and glial cells from BA24 cortical samples of BD patients verified that the glial, but not neuronal, population exhibits significantly increased miR-149 expression. Finally, we report altered expression of both miR-149 and miR-29c in EVs extracted from brains of Flinders Sensitive Line rats, a well-validated animal model exhibiting depressive-like behaviors and glial (astrocytic) dysfunction. These findings warrant future investigations into the potential of using EV miRNA signatures as biomarkers to further enhance the biological definition of BD. © 2017 Wiley Periodicals, Inc.

Abnormal p38α mitogen-activated protein kinase signaling in dilated cardiomyopathy caused by lamin A/C gene mutation.

We previously interrogated the transcriptome in heart tissue from Lmna(H222P/H222P) mice, a mouse model of cardiomyopathy caused by lamin A/C gene (LMNA) mutation, and found that the extracellular signal-regulated kinase 1/2 and Jun N-terminal kinase branches of the mitogen-activated protein (MAP) kinase signaling pathway were abnormally hyperactivated prior to the onset of significant cardiac impairment. We have now used an alternative gene expression analysis tool to reanalyze this transcriptome and identify hyperactivation of a third branch of the MAP kinase cascade, p38α signaling. Biochemical analysis of hearts from Lmna(H222P/H222P) mice showed enhanced p38α activation prior to and after the onset of heart disease as well as in hearts from human subjects with cardiomyopathy caused by LMNA mutations. Treatment of Lmna(H222P/H222P) mice with the p38α inhibitor ARRY-371797 prevented left ventricular dilatation and deterioration of fractional shortening compared with placebo-treated mice but did not block the expression of collagen genes involved in cardiac fibrosis. These results demonstrate that three different branches of the MAP kinase signaling pathway with overlapping consequences are involved in the pathogenesis of cardiomyopathy caused by LMNA mutations. They further suggest that pharmacological inhibition of p38α may be useful in the treatment of this disease.