The Exon Junction Complex Factor RBM8A in Glial Fibrillary Acid Protein-Expressing Astrocytes Modulates Locomotion Behaviors.

The role of RNA Binding Motif Protein 8a (RBM8A), an exon junction complex (EJC) component, in neurodevelopmental disorders has been increasingly studied for its crucial role in regulating multiple levels of gene expression. It regulates mRNA splicing, translation, and mRNA degradation and influences embryonic development. RBM8A protein is expressed in both neurons and astrocytes, but little is known about RBM8A's specific role in glial fibrillary acid protein (GFAP)-positive astrocytes. To address the role of RBM8A in astrocytes, we generated a conditional heterozygous knockout (KO) mouse line of Rbm8a in astrocytes using a GFAP-cre line. We confirmed a decreased expression of RBM8A in astrocytes of heterozygous conditional KO mice via RT-PCR and Sanger sequencing, as well as qRT-PCR, immunohistochemistry, and Western blot. Interestingly, these mice exhibit significantly increased movement and mobility, alongside sex-specific altered anxiety in the open field test (OFT) and elevated plus maze (OPM) tests. These tests, along with the rotarod test, suggest that these mice have normal motor coordination but hyperactive phenotypes. In addition, the haploinsufficiency of Rbm8a in astrocytes leads to a sex-specific change in astrocyte density in the dentate gyrus. This study further reveals the contribution of Rbm8a deletion to CNS pathology, generating more insights via the glial lens of an Rbm8a model of neurodevelopmental disorder.

CD98hc is a target for brain delivery of biotherapeutics.

Brain exposure of systemically administered biotherapeutics is highly restricted by the blood-brain barrier (BBB). Here, we report the engineering and characterization of a BBB transport vehicle targeting the CD98 heavy chain (CD98hc or SLC3A2) of heterodimeric amino acid transporters (TVCD98hc). The pharmacokinetic and biodistribution properties of a CD98hc antibody transport vehicle (ATVCD98hc) are assessed in humanized CD98hc knock-in mice and cynomolgus monkeys. Compared to most existing BBB platforms targeting the transferrin receptor, peripherally administered ATVCD98hc demonstrates differentiated brain delivery with markedly slower and more prolonged kinetic properties. Specific biodistribution profiles within the brain parenchyma can be modulated by introducing Fc mutations on ATVCD98hc that impact FcγR engagement, changing the valency of CD98hc binding, and by altering the extent of target engagement with Fabs. Our study establishes TVCD98hc as a modular brain delivery platform with favorable kinetic, biodistribution, and safety properties distinct from previously reported BBB platforms.

High Prevalence of Late-Onset Fabry Cardiomyopathy in a Cohort of 499 Non-Selective Patients with Left Ventricular Hypertrophy: The Asian Fabry Cardiomyopathy High-Risk Screening Study (ASIAN-FAME).

Left ventricular hypertrophy (LVH) caused by cardiac variant Fabry disease (FD) is typically late-onset and may mimic LVH caused by abnormal loading conditions. We aimed to determine the prevalence of FD in a non-selective patient population of everyday practice presenting with LVH, including those with hypertension and valve disease. We measured plasma alpha-galactosidase A activity using dried blood spot tests in 499 (age = 66 ± 13 years; 336 men) Hong Kong Chinese patients with LVH defined as maximal LV septal/posterior wall thickness ≥13 mm on echocardiography. Patients with low enzyme activity underwent mutation analysis of the GLA gene. Eight (age = 53-74 years; all men) unrelated patients (1.6%) had low plasma alpha-galactosidase A activity (0.57 ± 0.27 µmol/L wb/hr) and all were confirmed to have the GLA IVS4 + 919G > A mutation. FD patients presented with heart failure (n = 5), heart block (n = 2), ventricular tachycardia (n = 1), chest pain (n = 3), and/or murmur (n = 1). Uncontrolled hypertension (n = 4) and/or severe mitral/aortic valve pathology (n = 2) were frequent. Ethnic subgroups included Teochew (n = 5), Canton (n = 2), and Wenzhou (n = 1). Endomyocardial biopsy (n = 6) revealed hypertrophic myocytes with vacuolization and dense lamellar bodies. Late-onset IVS4 + 919G > A FD is prevalent among Chinese LVH patients, and should be considered as a cause of LVH in adult patients even when hypertension and/or valve pathology are present.

Screening for Fabry Disease in patients with unexplained left ventricular hypertrophy.

Fabry Disease (FD) is a systemic disorder that can result in cardiovascular, renal, and neurovascular disease leading to reduced life expectancy. FD should be considered in the differential of all patients with unexplained left ventricular hypertrophy (LVH). We therefore performed a prospective screening study in Edmonton and Hong Kong using Dried Blood Spot (DBS) testing on patients with undiagnosed LVH. Participants found to have unexplained LVH on echocardiography were invited to participate and subsequently subjected to DBS testing. DBS testing was used to measure α-galactosidase (α-GAL) enzyme activity and for mutation analysis of the α-galactosidase (GLA) gene, both of which are required to make a diagnosis of FD. DBS testing was performed as a screening tool on patients (n = 266) in Edmonton and Hong Kong, allowing for detection of five patients with FD (2% prevalence of FD) and one patient with hydroxychloroquine-induced phenocopy. Left ventricular mass index (LVMI) by GLA genotype showed a higher LVMI in patients with IVS4 + 919G > A mutations compared to those without the mutation. Two patients were initiated on ERT and hydroxychloroquine was discontinued in the patient with a phenocopy of FD. Overall, we detected FD in 2% of our screening cohort using DBS testing as an effective and easy to administer screening tool in patients with unexplained LVH. Utilizing DBS testing to screen for FD in patients with otherwise undiagnosed LVH is clinically important due to the availability of effective therapies and the value of cascade screening in extended families.

Safety and efficacy of sonographically guided high-intensity focused ultrasound for symptomatic uterine fibroids: preliminary study of a modified protocol.

OBJECTIVES: We aimed to assess the safety and efficacy of sonographically guided high-intensity focused ultrasound for treating patients with symptomatic uterine fibroids using a modified protocol. METHODS: This work was part of an ongoing prospective phase 1 study. Twenty patients with 22 symptomatic fibroids were treated with sonographically guided high-intensity focused ultrasound under no anesthesia. The modified protocol consisted of repeated and shortened (<25 minutes) treatment sessions of high-input acoustic intensity (1000-1500 W/cm(2)) and intensified sonication pulses (1500-2000) at each spot. The primary end points were periprocedural complications. The secondary end points were symptomatic improvement and radiologic evidence of treatment responses, including the degree of fibroid infarction and volume shrinkage 3 months after treatment. Symptomatic improvement was assessed by a pain score, a pictorial chart menstrual score, the Urogenital Distress Inventory short form, and the Incontinence Impact Questionnaire short form. The degree of fibroid infarction was assessed by the nonperfused ratio on contrast-enhanced magnetic resonance imaging, defined as the ratio of the nonperfused fibroid volume to the total fibroid volume. RESULTS: Nineteen patients tolerated the treatment well, with no major adverse events. One patient who received treatment for a fibroid located within 6 cm from the skin had third-degree skin burns at 2 sites of 1 cm in diameter. Fibroid-related abdominal pain, pictorial chart, Urogenital Distress Inventory, and Incontinence Impact Questionnaire scores were significantly improved (P < .05). The median nonperfused ratio at 3 months was 20% (95% confidence interval, 5%-32.5%). Median volume shrinkage at 3 months was 17.2% (95% confidence interval, 4.3%-26.6%). CONCLUSIONS: Sonographically guided high-intensity focused ultrasound using a modified protocol may be safe and effective for symptomatic uterine fibroids in selected patients to avoid skin burns.

Glenoid bone loss: assessment with MR imaging.

PURPOSE: To investigate the agreement among magnetic resonance (MR) imaging, computed tomography (CT), and arthroscopy in the measurement of glenoid bone loss. MATERIALS AND METHODS: This study was approved by the institutional ethics committee. One hundred seventy-six patients (158 male and 18 female patients; mean age, 26.8 years ± 12.3) with anterior shoulder dislocation underwent both shoulder MR imaging and CT examination. Anterior straight line length, glenoid width, and best-fit bone loss were measured with MR imaging and CT. Sixty-five patients also underwent arthroscopy, which was used as the standard of reference. Assessment of glenoid bone loss at MR imaging was compared with that at CT and arthroscopy. Inter- and intrareader reproducibility of MR imaging-derived measurements of glenoid bone loss was evaluated. RESULTS: There was excellent correlation between CT and MR imaging with regard to anterior straight line length (r = 0.97, P < .0001), glenoid width (r = 0.95, P < .0001), and severity of glenoid bone loss-particularly with use of best-fit circle width (r = 0.83, P < .0001) rather than best-fit circle area (r = 0.82, P < .0001). In the assessment of glenoid bone loss, the correlation between CT and arthroscopy (r = 0.91, P < .0001) was marginally better than that between MR imaging and arthroscopy (r = 0.84, P < .0001). The inter- and intrareader correlations of MR imaging-derived measurements of glenoid bone loss were excellent (R = 0.90-0.95). CONCLUSION: MR imaging assessment of glenoid bone loss, particularly with use of glenoid width, is almost as accurate as CT assessment.

Comparison of clinical outcomes of tris-acryl microspheres versus polyvinyl alcohol microspheres for uterine artery embolization for leiomyomas: results of a randomized trial.

PURPOSE: To compare tris-acryl microspheres and polyvinyl alcohol (PVA) microspheres as embolic agents in uterine artery embolization (UAE) for uterine leiomyomas in terms of clinical outcome, inflammatory response, and adverse reactions. MATERIALS AND METHODS: A double-blinded randomized controlled trial was performed, with 27 patients in the tris-acryl microsphere group and 29 in the PVA microsphere group. The primary endpoint was clinical success, defined as a 2-year freedom from subsequent surgery as a result of persistent or deteriorated symptoms. Secondary endpoints included (i) posttreatment leiomyoma enlargement, (ii) leiomyoma volume reduction at 3 and 9 months, (iii) significant residual intratumoral perfusion, (iv) increase in inflammatory and stress markers, (v) incidence of complications, and (vi) duration of hospital stay. RESULTS: There was no statistically significant difference between the two groups in patient demographics, clinical presentation, initial tumor findings, change in inflammatory and stress markers after treatment, incidence of complications, and duration of hospital stay. Tris-acryl microspheres were associated with a higher rate of clinical success than PVA microspheres (96.3% [26 of 27] vs 69% [20 of 29]; P = .012), a lower incidence of posttreatment leiomyoma enlargement (P = .030), and a lower incidence of significant residual intratumoral perfusion (P = .030). CONCLUSIONS: In the treatment of uterine leiomyomas, UAE with tris-acryl microspheres was associated with a higher clinical success rate, a lower incidence of tumor enlargement, and no significant differences in adverse reactions and inflammatory response compared with the use of PVA microspheres. Tris-acryl microspheres therefore represent the preferred agent for UAE of uterine leiomyomas.

The long-term impact of severe acute respiratory syndrome on pulmonary function, exercise capacity and health status.

BACKGROUND AND OBJECTIVE: Severe acute respiratory syndrome (SARS) emerged in 2003 and its long-term sequelae remain largely unclear. This study examined the long-term outcome of pulmonary function, exercise capacity, health and work status among SARS survivors. METHODS: A prospective cohort study of SARS patients at the Prince of Wales Hospital, Hong Kong was conducted, with serial assessments of lung function, 6MWD and 36 item Short Form General Health Survey at 3, 6, 12, 18 and 24 months after disease onset. The work status was also recorded. RESULTS: Serial assessments were completed by 55 of the 123 (39.9%) subjects, of whom 27 were health-care workers (HCW). The mean age of the group was 44.4 (SD 13.2) years and 19 (34.5%) were males. At 24 months, 10 (18.2%), 9 (16.4%), 6 (10.9%) and 29 (52.7%) subjects had FEV(1), FVC, TLC and DL(CO) < 80% of predicted values, respectively. The mean (SD) 6MWD increased significantly from 439.0 (89.1) m at 3 months to 460.1 (102.8) m at 6 months (P 0.016) and became steady after 6 months. However, 6MWD and 36 item Short Form General Health Survey scores were lower than the normal population throughout the study. Moreover, 29.6% of HCW and 7.1% of non-HCW had not returned to work 2 years after illness onset. CONCLUSIONS: This 2-year study of a selected population of SARS survivors, showed significant impairment of DL(CO), exercise capacity and health status persisted, with a more marked adverse impact among HCW.

Sonographic measurement of lateral parapharyngeal wall thickness in patients with obstructive sleep apnea.

INTRODUCTION: Lateral parapharyngeal wall (LPW) thickness may be a predominant anatomic factor causing airway narrowing in apneic subjects. In this study, we explored sonographic measurement of the LPW thickness and compared the results with LPW thickness measured by magnetic resonance imaging (MRI). We also investigated the association between sonographic measurement of LPW thickness and apnea-hypopnea index (AHI). METHOD: Seventy-six patients with suspected obstructive sleep apnea (OSA) underwent ultrasound examination of LPW thickness after overnight polysomnography. Fifteen out of 76 subjects also participated in correlation and reliability studies of sonographic and MRI measurements of LPW thickness. RESULTS: There was good correlation between measurements of LPW thickness on ultrasound and MRI (r = 0.78, P = 0.001), although Bland-Altman analysis indicated overestimation of LPW thickness by ultrasound, when compared with the LPW as measured by MRI. The sonographic measurement of LPW thickness had high reproducibility, with intraclass correlation coefficients of 0.90 and 0.97 for intraoperator and interoperator reliability, respectively. Fifty-eight subjects with significant OSA (AHI > or = 10/h) had a higher body mass index, larger neck circumference, and greater LPW thickness measured by ultrasound than those (n = 18) with an AHI of less than 10 per hour. LPW thickness had a positive correlation with AHI on univariate analysis (r = 0.37, P = 0.001). On multivariate analysis, LPW thickness had a positive independent association with AHI after adjustment for age, sex, neck circumference, and body mass index. The positive association of LPW thickness with AHI remained significant in both univariate and multivariate analyses of men only (n = 62). CONCLUSIONS: Sonographic measurement of LPW thickness is a novel and reliable technique and had good correlations with measurement by MRI and the severity of OSA. Ultrasound may provide an alternative imaging modality with easy accessibility and lower cost in OSA research.