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Objective: The ideal management for ischemic stroke presenting in the very late time window, or beyond 24 hours from onset, is poorly understood. It is unknown if endovascular therapy (EVT) or best medical management (MM) is associated with superior clinical outcomes., Methods: A systematic literature and comparative meta-analysis was completed to evaluate the safety and efficacy of EVT vs. MM for stroke presenting beyond 24 hours. Outcome measures included: 90 day functional independence (mRS 0-2), 90 day mortality, and symptomatic intracranial hemorrhage (sICH) occurrence. A random effects model was used for quantitative synthesis., Results: From the five included studies, a total of 704 patients were included with 461 treated with EVT and 243 treated with MM alone. The proportion of patients achieving functional independence was significantly higher in patients treated with EVT (34.6 %) compared to MM alone (15.9 %) (OR: 4.24; CI: 2.61-6.88, P < 0.00001; I 2 =0 %). While sICH occurred more in EVT patients (6.8 %) compared to MM (2.8 %), this was not significant (OR: 1.96; CI: 0.61-6.27, P=0.26; I 2 = 67 %). Lastly, 90 day morality occurred significantly less in the EVT group (24.5 %) compared to patients treated with MM (33.1 %), and with significantly lower odds (OR: 0.51; CI: 0.35-0.73, P=0.0003; I 2 =0 %)., Conclusions: In certain patients presenting beyond 24 hours with ischemic stroke, EVT is associated with a significantly higher odds of achieving functional independence and lower odds of mortality compared with MM. While these results do not function as proof, they do encourage further research into extending the window beyond 24 hours for EVT. Randomized clinical trials are warranted to validate these findings., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Fibrin, von Willebrand factor, and extracellular DNA from neutrophil extracellular traps all contribute to acute ischemic stroke thrombus integrity., Objectives: In this study, we explored how the proteomic composition of retrieved thromboemboli relates to susceptibility to lysis with distinct thrombolytics., Methods: Twenty-six retrieved stroke thromboemboli were portioned into 4 segments, with each subjected to 1 hour of in vitro lysis at 37 °C in 1 of 4 solutions: tissue plasminogen activator (tPA), tPA + von Willebrand factor-cleaving ADAMTS-13, tPA + DNA-cleaving deoxyribonuclease (DNase) I, and all 3 enzymes. Lysis, characterized by the percent change in prelysis and postlysis weight, was compared across the solutions and related to the corresponding abundance of proteins identified on mass spectrometry for each of the thromboemboli used in lysis., Results: Solutions containing DNase resulted in approximately 3-fold greater thrombolysis than that with the standard-of-care tPA solution (post hoc Tukey, P < .01 for all). DNA content was directly related to lysis in solutions containing DNase (Spearman's ρ > 0.39 and P < .05 for all significant histones) and inversely related to lysis in solutions without DNase (Spearman's ρ < -0.40 and P < .05 for all significant histones). Functional analysis suggests distinct pathways associated with susceptibility to thrombolysis with tPA (platelet-mediated) or DNase (innate immune system-mediated)., Conclusion: This study demonstrates synergy of DNase and tPA in thrombolysis of stroke emboli and points to DNase as a potential adjunct to our currently limited selection of thrombolytics in treating acute ischemic stroke., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Perviousness is the differential attenuation on CT of an intracranial arterial occlusive thrombus before and after IV contrast administration. While perviousness/permeability has been shown to be related to various clinical outcomes and reflects histopathologic composition, it remains unclear whether perviousness is also associated with differences in proteomic composition., Materials and Methods: Retrieved clots from 59 patients were evaluated with quantitative mass spectrometry. Proteomic differences between high-perviousness (≥11 HU) and low-perviousness (<11 HU) clots were investigated. Perviousness as a continuous variable was also correlated with protein abundance. Last, an ex vivo lysis assay was performed to investigate the differential susceptibility to tPA, deoxyribonuclease, and ADAMTS13 thrombolysis as a function of perviousness., Results: In total, 2790 distinct proteins were identified. Thrombus perviousness was associated with distinct proteomic features, including depletion of the macrophage marker CD14 ( P = .039, z = 1.176) and hemoglobin subunit ζ ( P = .046, z = 1.68) in pervious clots. Additionally, proteins involved in platelet cytoskeleton remodeling (tropomyosin α-3-chain) and granule secretion/aggregation (synaptotagmin-like protein 4/FC region receptor II-a) were associated with increasing perviousness ( P < .006), among numerous other proteins. Monocyte/macrophage-associated proteins (apoptosis-associated specklike protein containing a CARD/SAMHD1) were also depleted in pervious emboli ( P < .002). Ex vivo lysis indicated that pervious clots were more susceptible to ADAMTS13-augmented tPA thrombolysis compared with impervious clots ( P < .05), though without differences in deoxyribonuclease digestion., Conclusions: Thrombus perviousness is associated with complex proteomic features, including differential abundance of platelet-related proteins in highly permeable clots with monocyte/macrophage depletion. This association may help to explain why highly pervious thrombi were also found more susceptible to ADAMTS13-augmented thrombolysis., (© 2024 by American Journal of Neuroradiology.)

Purpose: While there is thought to be an association between spinal nerve root diverticula (NRD) and spontaneous intracranial hypotension (SIH) without a spinal longitudinal epidural collection (SLEC), it remains unclear what the overall prevalence of SLEC-negative SIH is in patients with NRD on MRI., Methods: Spine MRI imaging reports from our single institution were electronically screened for instances of NRD over a 9-year period (2016-2023). From these cases, patients with brain MRIs consistent with SIH were also identified. Subsequently, the overall proportion of SLEC-negative SIH was determined as a function of total cases with NRD based on spinal level., Results: In total, 83,843 patients with spinal MRIs were screened which identified 4174 (4.97%) with NRD. From these, there were 1203 cervical, 622 thoracic, and 2979 lumbosacral spine MRIs. In total, 16 patients (0.38%; Standard Error [SE]: 0.48%-0.28%) had a brain MRI compatible with SLEC-negative SIH and met ICHD-3 criteria. Patients with cervical NRD had SIH in 2 cases (0.16%; SE: 0.27%-0.05%). SLEC-negative SIH was present in 11 patients with lumbosacral NRD (0.34%; SE: 0.44%-0.24%). In patients with diverticula in the thoracic spine, 14 (2.3%; SE: 2.8%-1.8%) had SLEC-negative SIH. SLEC-negative SIH was significantly more prevalent in patients with thoracic diverticula compared to those with cervical ( p <.0001) or lumbosacral NRD ( p <.0001)., Conclusion: In patients with spinal NRD, concurrent SLEC-negative SIH is present in approximately 0.38% of patients, suggesting that in the vast majority of cases, they are an incidental finding. However, SIH is present in approximately 2.3% of patients with thoracic NRD and may be more specific for leak localization., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Carotid artery intraluminal thrombus (ILT), or free-floating thrombus, is an uncommon cerebrovascular entity with considerable equipoise regarding its clinical management. Likewise, in patients treated with medical management (MM), distal embolization and/or intracranial hemorrhage (ICH) may still occur., Methods: All patients with symptomatic ILT from 2016 to 2023 were identified from our tertiary care institution. Patients with MM failure (recurrent cerebral ischemia and/or symptomatic ICH) were compared with patients with MM non-failure. Differences in ILT volume and length were calculated. Receiver operator characteristic (ROC) curve analysis was used to identify the cut-off volume and length for risk of MM failure., Results: In total, 45 patients with ILT were identified with 41 treated with frontline MM. Of these 41 patients treated with MM, seven (17%) had MM failure with six (14.6%) having new embolic stroke and one (2.3%) with symptomatic ICH. Patients with MM failure had a significantly higher mean thrombus volume than MM non-failure patients (257 mm 3 vs 59.6 mm 3 , P=0.0006). Likewise, patients with MM failure had significantly longer thrombus on average (21 mm vs 6.6 mm, P=0.0009). ROC curve analysis showed that an ILT volume of 90 mm 3 resulted in a sensitivity of 71.4% and specificity of 85.3% for MM failure (AUC 0.775; CI 0.55 to 1.0, P=0.023)., Conclusions: Carotid ILTs that fail MM are significantly larger and longer. These findings suggest that a thrombus volume of 90 mm 3 may serve as a guide for intervention with good sensitivity and specificity for risk of MM failure., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

The platelet-derived growth factor-BB (PDGF-BB) pathway provides critical regulation of cerebrovascular pericytes, orchestrating their investment and retention within the brain microcirculation. Dysregulated PDGF Receptor-beta (PDGFRβ) signaling can lead to pericyte defects that compromise blood-brain barrier (BBB) integrity and cerebral perfusion, impairing neuronal activity and viability, which fuels cognitive and memory deficits. Receptor tyrosine kinases such as PDGF-BB and vascular endothelial growth factor-A (VEGF-A) are often modulated by soluble isoforms of cognate receptors that establish signaling activity within a physiological range. Soluble PDGFRβ (sPDGFRβ) isoforms have been reported to form by enzymatic cleavage from cerebrovascular mural cells, and pericytes in particular, largely under pathological conditions. However, pre-mRNA alternative splicing has not been widely explored as a possible mechanism for generating sPDGFRβ variants, and specifically during tissue homeostasis. Here, we found sPDGFRβ protein in the murine brain and other tissues under normal, physiological conditions. Utilizing brain samples for follow-on analysis, we identified mRNA sequences corresponding to sPDGFRβ isoforms, which facilitated construction of predicted protein structures and related amino acid sequences. Human cell lines yielded comparable sequences and protein model predictions. Retention of ligand binding capacity was confirmed for sPDGFRβ by co-immunoprecipitation. Visualizing fluorescently labeled sPDGFRβ transcripts revealed a spatial distribution corresponding to murine brain pericytes alongside cerebrovascular endothelium. Soluble PDGFRβ protein was detected throughout the brain parenchyma in distinct regions, such as along the lateral ventricles, with signals also found more broadly adjacent to cerebral microvessels consistent with pericyte labeling. To better understand how sPDGFRβ variants might be regulated, we found elevated transcript and protein levels in the murine brain with age, and acute hypoxia increased sPDGFRβ variant transcripts in a cell-based model of intact vessels. Our findings indicate that soluble isoforms of PDGFRβ likely arise from pre-mRNA alternative splicing, in addition to enzymatic cleavage mechanisms, and these variants exist under normal physiological conditions. Follow-on studies will be needed to establish potential roles for sPDGFRβ in regulating PDGF-BB signaling to maintain pericyte quiescence, BBB integrity, and cerebral perfusion-critical processes underlying neuronal health and function, and in turn, memory and cognition.

Microvascular networks are vital components of the cardiovascular system, performing many key roles in maintaining the health and homeostasis of the tissues and organs in which they develop. As discussed in this review, the molecular and cellular components within the microcirculation orchestrate critical processes to establish functional capillary beds, including organization of endothelial cell (EC) polarity, guiding investment of vascular pericytes (PCs), and building the specialized extracellular matrix (ECM) that comprises the vascular basement membrane (vBM). Herein, we further discuss the unique features of the microvasculature in the central nervous system (CNS), focusing on the cells contributing to the neurovascular unit (NVU) that form and maintain the blood-brain barrier (BBB). With a focus on vascular PCs, we offer basic and clinical perspectives on neurovascular-related pathologies that involve defects within the cerebral microvasculature. Specifically, we present microvascular anomalies associated with glioblastoma multiforme (GBM) including defects in vascular-immune cell interactions and associated clinical therapies targeting microvessels (ie, vascular-disrupting/anti-angiogenic agents and focused ultrasound). We also discuss the involvement of the microcirculation in stroke responses and potential therapeutic approaches. Our goal was to compare the cellular and molecular changes that occur in the microvasculature and NVU, and to provide a commentary on factors driving disease progression in GBM and stroke. We conclude with a forward-looking perspective on the importance of microcirculation research in developing clinical treatments for these devastating conditions., (© 2020 John Wiley & Sons Ltd.)

Purpose of Review: Pericytes are essential components of capillaries in many tissues and organs, contributing to vessel stability and integrity, with additional contributions to microvascular function still being discovered. We review current and foundational studies identifying pericyte differentiation mechanics and their roles in the earliest stages of vessel formation., Recent Findings: Recent advances in pericyte-focused tools and models have illuminated critical aspects of pericyte biology including their roles in vascular development.Pericytes likely collaborate with endothelial cells undergoing vasculogenesis, initiating direct interactions during sprouting and intussusceptive angiogenesis. Pericytes also provide important regulation of vascular growth including mechanisms underlying vessel pruning, rarefaction, and subsequent regrowth., Competing Interests: Conflict of Interest None of the authors have any conflicts of interest to disclose. This work was supported in part by funding from the National Institutes of Health (R01-HL146596 to J.C.C.), the National Science Foundation (CAREER Award 1752339 to J.C.C.), and the American Heart Association (19TPA34910121 to J.C.C. and 19POST34380560 to L.B.P.).

SINC, a new type III secreted protein of the avian and human pathogen Chlamydia psittaci, uniquely targets the nuclear envelope of C. psittaci-infected cells and uninfected neighboring cells. Digitonin-permeabilization studies of SINC-GFP-transfected HeLa cells indicate that SINC targets the inner nuclear membrane. SINC localization at the nuclear envelope was blocked by importazole, confirming SINC import into the nucleus. Candidate partners were identified by proximity to biotin ligase-fused SINC in HEK293 cells and mass spectrometry (BioID). This strategy identified 22 candidates with high confidence, including the nucleoporin ELYS, lamin B1, and four proteins (emerin, MAN1, LAP1, and LBR) of the inner nuclear membrane, suggesting that SINC interacts with host proteins that control nuclear structure, signaling, chromatin organization, and gene silencing. GFP-SINC association with the native LEM-domain protein emerin, a conserved component of nuclear "lamina" structure, or with a complex containing emerin was confirmed by GFP pull down. Our findings identify SINC as a novel bacterial protein that targets the nuclear envelope with the capability of globally altering nuclear envelope functions in the infected host cell and neighboring uninfected cells. These properties may contribute to the aggressive virulence of C. psittaci., (© 2015 Mojica et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).)

Background/aims: Outcome information regarding females with classical congenital adrenal hyperplasia (CAH) have generally suggested poor quality of life (QoL), general maladjustment, problems regarding sexuality, and decreased fertility. The aim of this study was to assess QoL, psychosocial adaptation, and psychosexual characteristics, includingchildhood gender role behavior, gender identity, and sexual orientation in females with CAH., Methods: Female patients with 21-hydroxylase deficiency CAH were evaluated using a questionnaire with items relating to knowledge of their condition and its therapy; consistency of medical, surgical, and psychological care; childhood friends and play behavior; and genital, pubertal, and sexual development. The subjects' perception of outcome was compared with family support and adolescent and adult QoL perspectives, including social relationships, self and body image, and gender and sexual issues., Results: Childhood play and gender characteristics, childhood and adult genital perception, and sexual identity and orientation varied as previously reported. However, most patients indicated good family support, understanding of their condition, good quality medical care, positive self-satisfaction, indices of happiness and body image perception, and satisfaction with their sex lives., Conclusion: The data reported here suggest that overall outcome can be very good for females with CAH and that good outcome appears to relate to quality of care and positive social support.

Objective: It is generally recognized that obesity and cardiometabolic risk are more prevalent in African Americans. Kallistatin, a novel tissue kallikrein inhibitor, has anti-inflammatory and anti-oxidant properties. Thus, the goal of this study was to examine the relationships among plasma kallistatin levels, adiposity and cardiometabolic risk factors in African American adolescents., Materials/methods: Plasma kallistatin levels were determined in 318 apparently healthy African American adolescents (aged 14-19 years, 48.1% females) by enzyme-linked immunosorbent assay., Results: Plasma kallistatin levels did not differ between males (27.9±11.2 μg/mL) and females (26.8±11.0 μg/mL) (p=0.47). Plasma kallistatin levels were inversely correlated with percent body fat (% BF, r=-0.13, p=0.04), total cholesterol (r=-0.28, p<0.01), low density lipoprotein cholesterol (LDL, r=-0.30, p<0.01) and interleukin-6 (r=-0.14, p=0.05), but positively correlated with adiponectin (r=0.16, p=0.03) and high density lipoprotein (HDL, r=0.17, p=0.02). These correlations remained significant after adjustment for age, sex and body mass index percentiles. Stepwise multiple linear regression analysis showed that LDL cholesterol alone explained 14.2% of the variance in kallistatin, while % BF and adiponectin explained an additional 3.6% and 2.8% of the variance, respectively., Conclusions: The present study demonstrates that plasma kallistatin levels are inversely associated with adiposity, adverse lipid profiles and inflammation in apparently healthy African American adolescents. As a potent antioxidant and anti-inflammation agent, kallistatin may also hold therapeutic promise in cardiometabolic disorders., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Existing outcomes for DSD individuals are inadequate because reports are based upon information collected retrospectively. This paper is presented to review existing data emphasizing information needed to lead to better future care, is based on presentations and discussions at a multi-disciplinary meeting on DSD held in Annecy in 2012, and is not intended to define the present status of management of each of the various DSD diagnoses. Rather it is intended to provide information needed to do studies regarding outcome data from the treatment of children with DSD by providing a summary of recommendations of 'patient-centered' topics that need investigation. The hope is that by being concerned with what is not known, new protocols will be developed for improving both early management and transition to adult life., (Copyright © 2012. Published by Elsevier Ltd.)

This paper is a review of some of the recent publications regarding outcome of DSD patients, with an emphasis upon surgical and sexual outcomes. Currently available outcome studies of patients with DSDs have limitations because of multiple factors, including lack of representative patient sampling, and lack of adequate information concerning both medical and surgical care, and psychological, social and family support. The most frequent reports involve females with 21-α-hydroxylase deficiency congenital adrenal hyperplasia (CAH). This most common form of DSD, if one excludes hypospadias and cryptorchidism, is an excellent example of a form of DSD in which all aspects of outcome, regarding surgery, sexual functionality and sensitivity, psychological input and endocrine hormonal therapy, carry a major role. The goals of therapy include a surgical outcome with a good cosmetic appearance and functionality with potential for sexual intercourse with sufficient sensitivity for satisfactory responsiveness. Endocrine replacement therapy should provide a normal adrenal hormonal milieu, while sex steroid therapy may be indicated. Psychological care should be provided from birth with gradual transition primarily to the patient, including basic counseling with full disclosure, although adjustment depends upon the patient's personality and parents' abilities and acceptance. Among forms of DSD involving gonadal insufficiency, hormonal replacement therapy should provide physiologic levels. Among females, estrogen therapy enhances healing after feminizing surgery and is required from puberty throughout adult life to maintain femininity, sexual organs and bone health, and enhance gender and sexuality. Among males, appropriate testosterone therapy maintains stamina, muscle tone, bone health, libido, sexual potency and general well-being, while benefit for healing after genital surgery is unclear. Further, outcome is clearly related to predominant cultural factors. Outcome studies should include evaluation of all of these factors., (Copyright © 2012. Published by Elsevier Ltd.)

Objective: Low vitamin D status is common among healthy black and white adolescents residing at southern U.S. latitudes with a year-round sunny climate. Thus we aimed to study the relationships between circulating 25-hydroxyvitamin D [25(OH)D] and cardiometabolic risk factors in this population., Research Design and Methods: 25(OH)D concentrations were measured with liquid chromatography tandem mass spectroscopy in 701 girls and boys (14-18 years old, 54% blacks, 49% females). Cardiometabolic risk was indexed by adipokines, inflammatory markers, fasting glucose, homeostatic model assessment-insulin resistance (HOMA-IR), lipid profile, and blood pressure (BP)., Results: Controlling for age, sex, race, sexual maturation, season, physical activity, and percent body fat, 25(OH)D concentrations were significantly correlated with adiponectin (r = 0.06, P = 0.05), leptin (r = -0.32, P < 0.01), fibrinogen (r = -0.05, P = 0.03), glucose (r = -0.16, P = 0.02), HOMA-IR (r = -0.17, P < 0.01), HDL cholesterol (r = 0.14, P = 0.02), systolic BP (r = -0.10, P = 0.02), and diastolic BP (r = -0.21, P < 0.01). When 25(OH)D concentrations were stratified into increasing tertiles, there were significant linear upward trends for adiponectin (P = 0.01) and HDL cholesterol (P = 0.04), but significant linear down trends for glucose (P < 0.01), HOMA-IR (P < 0.01), and systolic BP (P < 0.01), after adjusting for the above covariates., Conclusions: Circulating 25(OH)D concentrations are associated with various adverse cardiometabolic risk factors, independent of adiposity. Clinical trials addressing the effects of vitamin D supplementation on cardiometabolic risk are warranted in adolescents irrespective of their geographical regions.

The recent consensus conference addressed several aspects of the care of patients with Disorders of Sex Development (DSD). Among these were proposals regarding a new terminology to classify patients, medical, surgical and psychological care and the decision regarding sex of rearing or gender assignment for those with the most severe forms of genital ambiguity. However, a basis was found to be lacking for the assignment of sex of rearing for many diagnoses as well as for some for whom no diagnosis could be made. Also, no consensus could be made concerning genital surgery, particularly in response to the call to defer all genital surgery until the age a child could decide. This in part involved the lack of a clear indication of the point when a person has arrived at a state of maturity enabling such a decision. However, consensus was reached that genital surgery should be performed for the infant with significant ambiguity, in spite of the lack of outcome data, when the parents unequivocally desire. It was clear that desired outcome data will not be available for decades, if ever. Also, blatantly lacking are adequate data concerning the impact of prenatal androgen on the fetal central nervous system regarding subsequent development of gender and sexual issues., ((c) 2008 S. Karger AG, Basel.)

Background: The Sorry Works! Coalition, an organization of doctors, lawyers, insurers, and patient advocates, is dedicated to promoting full disclosure and apologies for medical errors as a "middle-ground solution" in the medical liability crisis. If a standard of care was not met (as shown by a root cause analysis) in a bad outcome or adverse event, the providers (and their insurer) should apologize to the patient/family, admit fault, provide an explanation of what happened and how the hospital will ensure that the error is not repeated, and offer compensation. The Sorry Works! protocol is based on the disclosure program developed at the Department of Veterans Affairs Hospital in Lexington, Kentucky., Goals: The coalition's goals are to (1) educate all stakeholders in the medical liability debate, (2) serve as an organizing force for the full-disclosure movement, and (3) advocate for legislative incentives, including pilot programs. OVERCOMING CULTURAL AND LEGAL OBSTACLES: In large part, the coalition's educational efforts are intended to overcome cultural and legal barriers to full disclosure, which often represent emotional, knee-jerk responses within the medical, insurance, and legal communities. Perhaps the greatest hurdle of all is the culture of the medical profession; considerable changes are needed if doctors are to enjoy the benefits of Sorry Works! and other full-disclosure programs., Conclusion: Sorry Works! entails changing the culture of medicine, medical risk management, and the associated insurance and legal support structure.