A mutation in ATP11A causes autosomal-dominant auditory neuropathy type 2.

Auditory synaptopathy/neuropathy (AS/AN) is a distinct type of sensorineural hearing loss in which the cochlear sensitivity to sound (i.e. active cochlear amplification by outer hair cells) is preserved whereas sound encoding by inner hair cells and/or auditory nerve fibers is disrupted owing to genetic or environmental factors. Autosomal-dominant auditory neuropathy type 2 (AUNA2) was linked either to chromosomal bands 12q24 or 13q34 in a large German family in 2017. By whole-genome sequencing, we now detected a 5500 bp deletion in ATP11A on chromosome 13q34 segregating with the phenotype in this family. ATP11A encodes a P-type ATPase that translocates phospholipids from the exoplasmic to the cytoplasmic leaflet of the plasma membrane. The deletion affects both isoforms of ATP11A and activates a cryptic splice site leading to the formation of an alternative last exon. ATP11A carrying the altered C-terminus loses its flippase activity for phosphatidylserine. Atp11a is expressed in fibers and synaptic contacts of the auditory nerve and in the cochlear nucleus in mice, and conditional Atp11a knockout mice show a progressive reduction of the spiral ganglion neuron compound action potential, recapitulating the human phenotype of AN. By combining whole-genome sequencing, immunohistochemistry, in vitro functional assays and generation of a mouse model, we could thus identify a partial deletion of ATP11A as the genetic cause of AUNA2.

Technical Feasibility and Safety of a Snare-Less, EVAR-First Technique for Iliac Branch Endoprosthesis.

OBJECTIVE: The purpose of this study was to evaluate the technical feasibility, safety, and early outcomes of a snare-less, endovascular abdominal aortic aneurysm repair (EVAR)-first technique (SET) for iliac branch endoprosthesis (IBE) placement. METHODS: We retrospectively reviewed all patients who received IBEs between July 2018 and March 2022. Patients were divided into 2 categories based on method of IBE deployment: SET or Standard. Primary endpoints were technical success, major adverse events, mortality, reintervention, internal iliac artery (IIA) patency, and freedom from IIA branch instability. Technical success was defined by successful deployment of both the EVAR and the IBE with maintained patency of the IIA and no stent graft migration. RESULTS: There were 20 patients (90% male, median age 72 [65.4-74.5] years) who underwent IBE placement. Among these, 5 (33.3%) underwent SET to treat 5 common iliac artery (CIA)/IIA aneurysms, while the remaining 15 (66.7%) underwent standard IBE deployment with through-and-through femoral access (n=13) or trans-brachial access (n=2) to treat 19 CIA/IIA aneurysms. Overall median renal to iliac bifurcation length was 169 (152-177) mm, with 9 patients falling short of the minimum of 165 mm for on-label IBE placement. Median contrast used was 148 (120-201) mL, fluoroscopy time 42.8 (35.0-49.8) minutes, estimated blood loss 200 (100-275) mL, and procedure time 192 (167-246) minutes, with no significant differences between the 2 groups. Technical success was achieved in 100% of cases. At 30 days, there were no mortalities or major adverse events in either group; there were 100% IIA patency, no IIA instability, and no reinterventions in both groups. Median follow-up in the SET group was 5.7 (5.5-6.2) months, with 1 death at 6 months and 1 type 1B endoleak at 6 months requiring reintervention. Median follow-up for the Standard group was 1.6 (0.8-2.1) years with 2 non-aneurysm-related deaths and no reinterventions at 1 year. CONCLUSIONS: SET for IBE is a safe and effective approach that decreases technical complexity and mitigates anatomic barriers to IBE placement. CLINICAL IMPACT: SET for IBE is a safe and effective approach to IBE placement that decreases technical complexity. A critical component to this technique is a large bore sheath with a stiff steerable tip. Importantly, this approach also mitigates anatomic barriers to IBE placement, expanding applicability of IBE technology to patients who may be otherwise ineligible.

Major Adverse Limb Events Among Patients with Premature Peripheral Artery Disease Compared with Those at the Common Age Undergoing Revascularization in the Vascular Quality Initiative.

BACKGROUND: Premature peripheral artery disease (PAD), defined as ≤ 50 years of age, is associated with poor outcomes following lower extremity revascularization (LER). However, the specific characteristics and outcomes of this group of patients compared to those at the common age undergoing revascularization have not been examined. The aim of this study is to compare patients with early versus late onset premature PAD undergoing LER focusing on major adverse limb events (MALEs). METHODS: All LER procedures (open and endovascular) in the Vascular Quality Initiative (VQI) were reviewed. A histogram of patient age at the time of initial LER (no prior LER) was used to define the common age, which included all patients within one standard deviation of the mean. Characteristics and outcomes of patients with premature PAD were compared to patients treated at the common age of presentation undergoing LER. RESULTS: A histogram of all patients undergoing LER was used to define 60 to 80 years as the common age. Patients with premature PAD were more likely to be female, African American, and Hispanic compared to patients at the common age. Patients with premature PAD were also more likely to have insulin-dependent diabetes, be current smokers, on dialysis, and be treated for claudication. Patients with premature PAD were less likely to have Transatlantic Intersociety Consensus (TASC II) C or D disease and were less likely to be on antiplatelets and statins. These differences were more pronounced in patients with chronic limb-threatening ischemia (CLTI). Cox proportional hazards regression demonstrated that premature PAD was independently associated with major adverse limb events (MALEs) at 1-year for patients with claudication (HR:1.7, 95% CI:1.4-2.0) and CLTI (HR:1.3, 95% CI:1.2-1.5) compared to patients 60 to 80 years of age. CONCLUSIONS: Patients with premature PAD have significant differences in characteristics compared to patients treated at the common age. Vascular providers should emphasize medical therapy prior to LER given the lower rates of medical optimization and worse 1-year MALEs in patients with premature PAD.

Glomerular endothelial cell maturation depends on ADAM10, a key regulator of Notch signaling.

The principal function of glomeruli is to filter blood through a highly specialized filtration barrier consisting of a fenestrated endothelium, the glomerular basement membrane and podocyte foot processes. Previous studies have uncovered a crucial role of endothelial a disintegrin and metalloprotease 10 (ADAM10) and Notch signaling in the development of glomeruli, yet the resulting defects have not been further characterized nor understood in the context of kidney development. Here, we used several different experimental approaches to analyze the kidneys and glomeruli from mice lacking ADAM10 in endothelial cells (A10ΔEC mice). Scanning electron microscopy of glomerular casts demonstrated enlarged vascular diameter and increased intussusceptive events in A10ΔEC glomeruli compared to controls. Consistent with these findings, genes known to regulate vessel caliber (Apln, AplnR and Vegfr3) are significantly upregulated in A10ΔEC glomeruli. Moreover, transmission electron microscopy revealed the persistence of diaphragms in the fenestrae of A10ΔEC glomerular endothelial cells, which was corroborated by the elevated expression of the protein PLVAP/PV-1, an integral component of fenestral diaphragms. Analysis of gross renal vasculature by light sheet microscopy showed no major alteration of the branching pattern, indicating a localized importance of ADAM10 in the glomerular endothelium. Since intussusceptions and fenestrae with diaphragms are normally found in developing, but not mature glomeruli, our results provide the first evidence for a crucial role of endothelial ADAM10, a key regulator of Notch signaling, in promoting the development and maturation of the glomerular vasculature.

PREPULSE INHIBITION DEFICITS ONLY IN FEMALES WITH OBSESSIVE-COMPULSIVE DISORDER.

BACKGROUND: Deficits in sensorimotor gating have been hypothesized to underlie the inability to inhibit repetitive thoughts and behaviors. To test this hypothesis, this study assessed prepulse inhibition (PPI), a measure of sensorimotor gating, across three psychiatric disorders (obsessive-compulsive disorder [OCD], social anxiety disorder [SAD], and anorexia nervosa [AN]) whose clinical presentations include repetitive thoughts and behaviors METHODS: We tested acoustic PPI in unmedicated individuals with OCD (n = 45), SAD (n = 37), and AN (n = 26), and compared their results to matched healthy volunteers (n = 62). All participants completed a structured clinical interview and a clinical assessment of psychiatric symptom severity. RESULTS: Percent PPI was significantly diminished in females with OCD compared to healthy female volunteers (P = .039). No other differences between healthy volunteers and participants with disorders (male or female) were observed. Percent PPI was not correlated with severity of obsessions and compulsions, as measured by the Yale-Brown Obsessive Compulsive Scale. CONCLUSIONS: This is the first study to assess PPI in participants with SAD or AN, and the largest study to assess PPI in participants with OCD. We found PPI deficits only in females with OCD, which suggests that the cortico-striato-pallido-thalamic and pontine circuitry (believed to underlie PPI) differs between males and females with OCD. Given that PPI deficits were only present in females with OCD and not related to repetitive thoughts and behaviors, our results do not support the hypothesis that sensorimotor gating deficits, as measured by PPI, underlie the inability to inhibit repetitive thoughts and behaviors in individuals with OCD, SAD, and AN.

Midlife metabolic syndrome and neurocognitive function in a mixed Asian sample.

BACKGROUND: An association between metabolic syndrome (MetS) and disturbances in neurocognitive function has been identified in Caucasians but the nature and extent of impaired cognition in Asian MetS patients, who may be at greater risk of degenerative cognitive decline, remains unspecified. METHODS: A cross-sectional study was conducted at the National University Hospital of Singapore. Participants were recruited from a diabetes clinic at the National University Hospital. Fifty-three patients who met MetS criteria and 44 clinical controls were recruited. All participants were 55 years and above and community ambulant. Neurocognitive function was assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB). CANTAB performances between MetS and control groups were examined with analysis of variance (ANOVA) and the relative contributions of vascular risk, and intrademographic factors on CANTAB scores were dilineated with stepwise regression analyses. RESULTS: Participants with MetS consistently performed significantly worse than controls across all CANTAB subtests. Education and Chinese race were found to be potential protective factors. CONCLUSIONS: Executive and memory impairment is present in Asian patients with midlife MetS who may be particularly vulnerable to the detrimental impact of MetS in midlife.

The infraclavicular approach for venous thoracic outlet syndrome.

Venous thoracic outlet syndrome (vTOS) is an esoteric condition that presents in young, healthy adults. Treatment includes catheter-directed thrombolysis, followed by first-rib resection for decompression of the thoracic outlet. Various techniques for first-rib resection have been described with successful outcomes. The infraclavicular approach is well-suited to treat the most medial structures that are anatomically relevant for vTOS. A narrative review was conducted to specifically examine the literature on infraclavicular exposure for vTOS. The technique for this operation is described, as well as the advantages and disadvantages of this approach. The infraclavicular approach is a reasonable choice for definitive treatment of uncomplicated vTOS.

An optimized step-by-step protocol for isolation of nucleus pulposus, annulus fibrosus, and end plate cells from the mouse intervertebral discs and subsequent preparation of high-quality intact total RNA.

Intervertebral disc degeneration is the most significant, and least understood, cause of chronic back pain, affecting almost one in seven individuals at some point of time. Each intervertebral disc has three components; central nucleus pulposus (NP), concentric layers of annulus fibrosus (AF), and a pair of end plate (EP) that connects the disc to the vertebral bodies. Understanding the molecular and cellular basis of intervertebral disc growth, health, and aging will generate significant information for developing therapeutic approaches. Rapid and efficient preparations of homogeneous and pure cells are crucial for meaningful and rigorous downstream analysis at the cellular, molecular, and biochemical level. Cross-sample contamination may influence the interpretation of the results. In addition to altering gene expression, slow or delayed isolation procedures will also cause the degradation of cells and biomolecules that create a bias in the outcomes of the study. The mouse model system is extensively used to understand the intervertebral disc biology. Here we describe two protocols: (a) for efficient isolation of pure NP, AF, and EP cells from mouse lumbar intervertebral disc. We validated the purity of the NP and AF cells using Shh Cre/+ ; R26 mT/mG/+ dual-fluorescent reporter mice where all NP cells are GPF+ve, and by the sensitive approach of qPCR analysis using TaqMan probes for Shh, and Brachyury as NP-specific markers, Tenomodulin as AF-specific marker, and Osteocalcin as bone-specific marker. (b) For isolation of high-quality intact RNA with RIN of 9.3 to 10 from disc cells. These methods will be useful for the rigorous analysis of NP and AF cells, and improve our understanding of intervertebral disc biology.