ロウ症候群

Lowe syndrome is a rare, currently incurable multisystem disorder that affects the eyes, kidneys, and central nervous system. It is caused by mutations in the OCRL gene, which encodes an inositol 5-phosphatase. The disorder remains incurable, and the pathways underlying the ocular symptoms remain poorly understood, largely due to the lack of appropriate models. In this study, trabecular meshwork cell models of Lowe syndrome were generated to test two distinct gene therapy strategies: a mutation-agnostic OCRL DNA augmentation therapy and a patient-specific CRISPR-mediated gene correction strategy. The results showed that AAV2-OCRL demonstrated the highest transduction efficiency in patient iPSC-derived trabecular meshwork models (iHTM) among the three AAV-OCRL vectors evaluated, establishing it as a promising delivery vector. Targeted CRISPR-based gene therapy restored OCRL enzyme activity and corrected cellular defects in patient iPSC-derived trabecular meshwork cell models. Furthermore, RNA-sequencing analysis of these models revealed dysregulation of extracellular matrix organization, cell adhesion, focal adhesion, and cytoskeletal regulatory pathways, suggesting that disruption of interconnected ECM-adhesion-cytoskeletal networks may contribute to trabecular meshwork dysfunction in Lowe syndrome-associated glaucoma. These findings indicate the feasibility of OCRL gene augmentation and CRISPR-based gene editing in patient-derived ocular models and position AAV2-OCRL as a leading therapeutic candidate for Lowe syndrome.

BACKGROUND: Many patients with suspected acute coronary syndrome in whom myocardial infarction has been ruled out in the emergency department remain at risk for cardiovascular events. Whether further investigation reduces this risk is unknown. METHODS: In a multicenter, randomized, controlled trial, patients who presented to an emergency department in 14 hospitals across the United Kingdom were enrolled if myocardial infarction had been ruled out and high-sensitivity cardiac troponin testing indicated an intermediate risk of a cardiovascular event (maximum high-sensitivity cardiac troponin I or T concentration, >5 ng per liter). Participants were randomly assigned in a 1:1 ratio to receive either outpatient computed tomographic (CT) coronary angiography-guided care or standard care. The primary outcome was a composite of myocardial infarction or death from a cardiac cause. RESULTS: From September 18, 2019, to May 11, 2023, a total of 3170 participants (median age, 61 years; female sex, 30.2%) were assigned to undergo CT coronary angiography (1587 participants) or receive standard care (1583 participants). At 90 days after randomization, CT coronary angiography had been performed in 1462 participants (92.1%) in the CT coronary angiography group and in 35 participants (2.2%) in the standard-care group. Overall, 7 participants (0.4%) had a CT coronary angiography-related adverse event. After a median of 3.0 years, at which point the number of primary-outcome events in the standard-care group exceeded the prespecified minimum of 97, a primary-outcome event had occurred in 112 participants (7.1%) in the CT coronary angiography group and in 116 (7.3%) in the standard-care group (adjusted hazard ratio, 0.95; 95% confidence interval, 0.73 to 1.23; P = 0.71). CONCLUSIONS: In patients with suspected acute coronary syndrome in whom myocardial infarction had been ruled out, routine CT coronary angiography-guided management did not result in a lower incidence of subsequent myocardial infarction or death from a cardiac cause than standard care. (Funded by the British Heart Foundation; TARGET-CTCA ClinicalTrials.gov number, NCT03952351.).

Hemorrhage is a leading cause of preventable death after trauma, with direct pressure, appropriate tourniquet application, and volume resuscitation established as principles of hemorrhage management. In recent years, several junctional tourniquet devices have been proposed as adjuncts for groin and axillary hemorrhage control, including the Abdominal Aortic Junctional Tourniquet-Stabilized (AAJT-S), which has been marketed for non-compressible torso hemorrhage. To date, evidence supporting its use has been primarily limited to studies on cadavers, porcine models, healthy human subjects, and a few case reports. We present the case of a young adult male with multiple gunshot wounds to the pelvis and lower extremities who presented to a level I trauma center with an AAJT-S in place. Device removal in the trauma bay was followed by cardiac arrest and subsequent complications to include metabolic acidosis, compartment syndrome, rhabdomyolysis, renal and liver infarcts, pulmonary emboli, and stroke. This case highlights the potential harm of the device. We review and contrast these outcomes with the limited available literature and present our recommendation for future evaluation and caution with application of this device.

PURPOSE: The purpose of this study was to provide a comprehensive, quantitative dataset of anterior segment (AS) parameters obtained from ultrasound biomicroscopy (UBM) images to support research in ocular development, disease characterization, and image-based analysis. METHODS: UBM images were prospectively collected from 185 eyes of 138 participants aged 3 weeks to 26 years (median = 17 months), encompassing diagnoses such as healthy controls, primary congenital glaucoma (PCG), glaucoma following cataract surgery (GFCS), congenital cataract, traumatic cataract, Lowe syndrome, and Sturge-Weber syndrome (SWS)-associated glaucoma. Twenty-seven quantitative AS parameters were measured from deidentified images using ImageJ software following a standardized protocol. RESULTS: The resulting dataset includes demographic and diagnostic metadata paired with quantitative UBM-derived parameters for each eye. The dataset is provided in comma-separated value (CSV) format with an accompanying data dictionary. CONCLUSIONS: This dataset provides one of the most extensive collections of quantitative pediatric AS measurements obtained by UBM, enabling characterization of age- and disease-related anatomic variation and facilitating reproducible secondary analyses. TRANSLATIONAL RELEVANCE: This open-source pediatric UBM dataset establishes a foundation for studies of ocular growth, disease mechanisms, and surgical planning, and provides a valuable resource for the development and validation of automated image analysis and machine learning models in pediatric AS imaging.

BACKGROUND: Corticobasal syndrome (CBS) is a neurodegenerative syndrome that often results from a 4-repeat tauopathy. Abnormalities on tau PET, structural MRI, and diffusion MRI (dMRI) have been observed in CBS, although no prior work has systematically compared the relative sensitivity of these modalities. In addition, the relationships between tau uptake, volume loss, and white matter degeneration remain incompletely understood. OBJECTIVE: To compare the sensitivity of tau PET, structural volume, and dMRI metrics to differentiate CBS from controls, and to characterize relationships between regional tau uptake, volume loss, and white matter tract abnormalities. METHODS: Thirty-two participants meeting criteria for possible or probable CBS and 35 healthy controls underwent standardized 3T dMRI, 18 F-flortaucipir tau PET, and detailed neurologic assessment. Diffusion data were processed using complementary diffusion tensor, free-water, and Neurite Orientation Dispersion and Density Imaging (NODDI) pipelines, with tract-level metrics extracted using the Johns Hopkins University-Eve (JHU EVE) White Matter atlas. Regional gray matter volumes and flortaucipir standardized uptake value ratios (SUVRs) were calculated. Global tau PET uptake, represented by the first principal component (PC1), was removed in a secondary tau analysis. Modality-level discrimination was assessed using area under the curve (AUC) analyses. Cross-modality relationships were evaluated using regional correlations and covariate-adjusted models comparing volume- and tau-related predictors of white matter abnormalities. RESULTS: Relative to controls, CBS showed widespread higher mean diffusivity (MD) and lower intracellular volume fraction (ICVF), especially in sensorimotor and projection white matter pathways. Structural volume reductions were most prominent in precentral cortex and subcortical regions including putamen, thalamus, and pallidum, whereas tau PET abnormalities were weaker and less spatially extensive. MD showed the strongest overall discrimination between CBS and controls, followed by ICVF, structural volume, PC1-removed tau PET, and original tau PET. In targeted sensorimotor analyses, higher DTI-MD was most strongly associated with lower gray matter volume. PC1-removed sensorimotor tau uptake was also associated with higher sensorimotor DTI-MD, whereas original tau uptake and broader cortical or subcortical tau measures were not significant predictors. CONCLUSIONS: White matter microstructural disruption is a dominant imaging signature of CBS and is more closely linked to gray matter volume loss than to measurable uptake on tau PET. dMRI, particularly MD and ICVF, may provide greatest sensitivity for detecting disease-related changes in CBS.