Citations

Background— Type 2 long QT syndrome involves mutations in the human ether a-go-go–related gene ( hERG or KCNH2 ). T421M, an S1 domain mutation in the Kv11.1 channel protein, was identified in a resuscitated patient. We assessed its biophysical, protein trafficking, and pharmacological mechanisms in adult rat ventricular myocytes. Methods and Results— Isolated adult rat ventricular myocytes were infected with wild-type (WT)–Kv11.1– and T421M-Kv11.1–expressing adenovirus and analyzed with the use of patch clamp, Western blot, and confocal imaging techniques. Expression of WT-Kv11.1 or T421M-Kv11.1 produced peak tail current ( I Kv11.1 ) of 8.78±1.18 and 1.91±0.22 pA/pF, respectively. Loss of mutant I Kv11.1 resulted from (1) a partially trafficking-deficient channel protein with reduced cell surface expression and (2) altered channel gating with a positive shift in the voltage dependence of activation and altered kinetics of activation and deactivation. Coexpression of WT+T421M-Kv11.1 resulted in heterotetrameric channels that remained partially trafficking deficient with only a minimal increase in peak I Kv11.1 density, whereas the voltage dependence of channel gating became WT-like. In the adult rat ventricular myocyte model, both WT-Kv11.1 and T421M-Kv11.1 channels responded to β-adrenergic stimulation by increasing I Kv11.1 . Conclusions— The T421M-Kv11.1 mutation caused a loss of I Kv11.1 through interactions of abnormal protein trafficking and channel gating. Furthermore, for coexpressed WT+T421M-Kv11.1 channels, different dominant-negative interactions govern protein trafficking and ion channel gating, and these are likely to be reflected in the clinical phenotype. Our results also show that WT and mutant Kv11.1 channels responded to β-adrenergic stimulation.

Background and Purpose— Minorities in the United States have less access to healthcare system resources, especially preventative treatments. We sought to determine whether racial and sex disparities existed in the treatment of unruptured intracranial aneurysms. Methods— Using the Nationwide Inpatient Sample, hospitalizations for clipping and coiling of intracranial aneurysms from 2001 to 2009 were identified by cross-matching International Classification of Diseases, 9th Revision codes for diagnosis of unruptured aneurysm and subarachnoid hemorrhage (SAH) with procedure codes for clipping or coiling of cerebral aneurysms. Demographic information analyzed included age (<50, 50–64, 65–79, and ≥80 years), race (white, black, Hispanic, Asian/Pacific Islander), sex, income quartile, primary payer (Medicare, Medicaid, private insurance, self-pay, no charge, other), and Charlson comorbidity index. Results— When compared with patients treated for SAH, those treated for unruptured intracranial aneurysm were significantly more likely to be women (75.0% versus 69.0%; P <0.0001). In all, 9.7% of patients receiving treatment for SAH were self-payers versus 3.0% of patients being treated for unruptured intracranial aneurysm ( P <0.0001). In all, 62.2% of patients receiving treatment for SAH were white compared with 76.4% of patients being treated for unruptured intracranial aneurysm ( P <0.0001). There was a higher proportion of black, Hispanic, and Asian patients in the SAH treatment group when compared with the unruptured aneurysm treatment group ( P <0.0001 for all groups). Conclusions— When compared with patients undergoing treatment for SAH, patients undergoing surgical and endovascular treatment for unruptured intracranial aneurysm are generally from higher socioeconomic strata and are more likely to be insured, women, and white. Future studies are needed to determine the underlying causes and solutions for this disparity.

Primary cilia serve as cellular antenna for various sensory signaling pathways. However, how the sensory receptors are properly targeted to the ciliary surface remains poorly understood. Here, we show that UBC-9, the sole E2 small ubiquitin-like modifier (SUMO)-conjugating enzyme, physically interacts with and SUMOylates the C terminus of small GTPase ARL-13, the worm orthologue of ARL13B that mutated in ciliopathy Joubert syndrome. Mutations that totally abolish the SUMOylation of ARL-13 do not affect its established role in ciliogenesis, but fail to regulate the proper ciliary targeting of various sensory receptors and consequently compromise the corresponding sensory functions. Conversely, constitutively SUMOylated ARL-13 fully rescues all ciliary defects of arl-13–null animals. Furthermore, SUMOylation modification of human ARL13B is required for the ciliary entry of polycystin-2, the protein mutated in autosomal dominant polycystic kidney disease. Our data reveal a novel but conserved role for the SUMOylation modification of ciliary small GTPase ARL13B in specifically regulating the proper ciliary targeting of various sensory receptors.

Objective To report a retrospective analysis of patients with migraine headaches treated with rimabotulinumtoxin B as preventive treatment, investigating an association between clinical responsiveness with migraine directionality and migrainous aura. Background The P hase III R esearch E valuating M igraine P rophylaxis T herapy studies demonstrated onabotulinumtoxin A is effective in the preventive management of chronic migraine headaches. J akubowski et al reported greater response to onabotulinumtoxin A in migraine patients reporting inward‐directed head pain (imploding or ocular) compared with outward‐directed head pain (exploding), suggesting subpopulations of patients may be better candidates for its use. No correlation was found between those reporting migrainous aura and onabotulinumtoxin A responsiveness. Methods One hundred twenty‐eight migraine patients were identified who had received rimabotulinumtoxin B injections over an average of 22 months, or 7 injection cycles. Migraine directionality was reported as inward directed (imploding, n = 72), eye centered (ocular, n = 28), outward directed (exploding, n = 16), and mixed (n = 12). Results One hundred two out of one hundred twenty‐eight patients (80%) improved; of these, 58 (57%) demonstrated a >75% reduction in monthly headache frequency (“>75%‐responders”), 76% of which noted sustained benefits >12 months with repeated injections every 10‐12 weeks. Those reporting ocular‐ and imploding‐directed headaches were significantly more likely to be >75%‐responders, compared with exploding‐ and mixed‐directed headaches ( P < .0025). Patients with ocular‐directed headaches were most likely to be sustained >75%‐responders. Patients reporting migrainous aura were more likely to be >75%‐responders ( P = .0007). Those reporting exploding‐ and mixed‐directed headaches were more likely to be nonresponders ( P < .0001). Conclusions Reported migraine directionality and presence of migrainous aura predict migraine headache responsiveness to rimabotulinumtoxin B injections.

Objective Emerging off-pump beating heart valve repair techniques offer patients less invasive alternatives for mitral valve (MV) repair. However, most of these techniques rely on the limited spatial and temporal resolution of transesophageal echocardiography (TEE) alone, which can make tool visualization and guidance challenging. Methods Using a magnetic tracking system and integrated sensors, we created an augmented reality (AR) environment displaying virtual representations of important intracardiac landmarks registered to biplane TEE imaging. In a porcine model, we evaluated the AR guidance system versus TEE alone using the transapically delivered NeoChord DS1000 system to perform MV repair with chordal reconstruction. Results Successful tool navigation from left ventricular apex to MV leaflet was achieved in 12 of 12 and 9 of 12 (P = 0.2) attempts with AR imaging and TEE alone, respectively. The distance errors of the tracked tool tip from the intended midline trajectory (5.2 ± 2.4 mm vs 16.8 ± 10.9 mm, P = 0.003), navigation times (16.7 ± 8.0 seconds vs 92.0 ± 84.5 seconds, P = 0.004), and total path lengths (225.2 ± 120.3 mm vs 1128.9 ± 931.1 mm, P = 0.003) were significantly shorter in the AR-guided trials compared with navigation with TEE alone. Furthermore, the potential for injury to other intracardiac structures was nearly 40-fold lower when using the AR imaging for tool navigation. The AR guidance also seemed to shorten the learning curve for novice surgeons. Conclusions Augmented reality–enhanced TEE facilitates more direct and safe intracardiac navigation of the NeoChord DS tool from left ventricular apex to MV leaflet. Tracked tool path results demonstrate fourfold improved accuracy, fivefold shorter navigation times, and overall improved safety with AR imaging guidance.