A null mutation of the neuronal sodium channel NaV1.6 disrupts action potential propagation and excitation‐contraction coupling in the mouse heart

Evidence supports the expression of brain‐type sodium channels in the heart. Their functional role, however, remains controversial. We used global NaV1.6‐null mice to test the hypothesis that NaV1.6 contributes to the maintenance of propagation in the myocardium and to excitation‐contraction (EC) coupling. We demonstrated expression of transcripts encoding full‐length NaV1.6 in isolated ventricular myocytes and confirmed the striated pattern of NaV1.6 fluorescence in myocytes. On the ECG, the PR and QRS intervals were prolonged in the null mice, and the Ca2+ transients were longer in the null cells. Under patch clamping, at holding potential (HP) = –120 mV, the peak INa was similar in both phenotypes. However, at HP = –70 mV, the peak INa was smaller in the nulls. In optical mapping, at 4 mM [K+]o, 17 null hearts showed slight (7%) reduction of ventricular conduction velocity (CV) compared to 16 wild‐type hearts. At 12 mM [K+]o, CV was 25% slower in a subset of 9 null vs. 9 wild‐type hearts. These results highlight the importance of neuronal sodium channels in the heart, whereby NaV1.6 participates in EC coupling, and represents an intrinsic depolarizing reserve that contributes to excitation.—Noujaim, S. F., Kaur, K., Milstein, M., Jones, J. M., Furspan, P., Jiang, D., Auerbach, D. S., Herron, T., Meisler, M. H., Jalife, J. A null mutation of the neuronal sodium channel NaV1.6 disrupts action potential propagation and excitation‐contraction coupling in the mouse heart. FASEB J. 26, 63–72 (2012). www.fasebj.orgPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154524/1/fsb2fj10179770.pd

Allelic mutations of the sodium channel SCN8A reveal multiple cellular and physiological functions

Allelic mutations of Scn8a in the mouse have revealed the range of neurological disorders that can result from alternations of one neuronal sodium channel. Null mutations produce the most severe phenotype, with motor neuron failure leading to paralysis and juvenile lethality. Two less severe mutations cause ataxia, tremor, muscle weakness, and dystonia. The electrophysiological effects have been studied at the cellular level by recording from neurons from the mutant mice. The data demonstrate that Scn8a is required for the complex spiking of cerebellar Purkinje cells and for persistent sodium current in several classes of neurons, including some with pacemaker roles. The mouse mutations of Scn8a have also provided insight into the mode of inheritance of channelopathies, and led to the identification of a modifier gene that affects transcript splicing. These mutations demonstrate the value of mouse models to elucidate the pathophysiology of human disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42795/1/10709_2004_Article_5381441.pd

An analysis-ready and quality controlled resource for pediatric brain white-matter research

We created a set of resources to enable research based on openly-available diffusion MRI (dMRI) data from the Healthy Brain Network (HBN) study. First, we curated the HBN dMRI data (N = 2747) into the Brain Imaging Data Structure and preprocessed it according to best-practices, including denoising and correcting for motion effects, susceptibility-related distortions, and eddy currents. Preprocessed, analysis-ready data was made openly available. Data quality plays a key role in the analysis of dMRI. To optimize QC and scale it to this large dataset, we trained a neural network through the combination of a small data subset scored by experts and a larger set scored by community scientists. The network performs QC highly concordant with that of experts on a held out set (ROC-AUC = 0.947). A further analysis of the neural network demonstrates that it relies on image features with relevance to QC. Altogether, this work both delivers resources to advance transdiagnostic research in brain connectivity and pediatric mental health, and establishes a novel paradigm for automated QC of large datasets

A device to facilitate limbal stem cell procurement from eye bank donor tissue for keratolimbal allograft procedures

To develop a device that facilitates the procurement of corneal limbal stem cell grafts for keratolimbal allograft procedures used in the treatment of ocular surface disease associated with stem cell deficiency. Description of device design and technique for use. The device is composed of a pedestal with a convex surface mounted to a flat platform. A corneoscleral button placed endothelial side down and centrally upon the convexity is secured by suction conveyed through a hollowed core in the pedestal that connects to fenestrated openings on the convex surface. A donut-shaped stainless steel ring placed on tension by springs braces the peripheral tissue. A circular corneal incision is created of a desired thickness by a suction trephine, and a crescent blade is utilized to peripherally dissect a donut-shaped keratolimbal allograft. This device facilitated the harvesting of the keratolimbal allograft tissue from four eye bank donor practice corneoscleral buttons and was then used to successfully procure grafts from six corneoscleral buttons used in three keratolimbal allograft procedures in three patients, one each with aniridia, alkali burn, and drug-induced limbal stem cell deficiency. The described device effectively facilitates procurement of corneoscleral buttons for keratolimbal allograft procedures. It appears to offer advantages over freehanded techniques and previously described devices used for the same purpose

Conserved Linkage of Early Growth Response 4, Annexin 4, and Transforming Growth Factor [alpha] on Mouse Chromosome 6

The mouse genes encoding early growth response 4 (Egr4), annexin IV (Anx4), and transforming growth factor a (Tgfa) have been mapped to a linkage group on mouse chromosome 6 that is conserved on human chromosome 2p11-p13. The genes are closely linked, with 0/215 recombinants between Anx4 and Tgfa and 1/215 recombinants between these genes and Egr4 . The genes are located approximately 2 cM distal to mnd2, a mouse mutation causing neuromuscular disease. The results demonstrate that mnd2 is located at an internal position within this conserved linkage group.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31832/1/0000779.pd

Treatment strategies and visual acuity outcomes in chronic postoperative propionibacterium acnes endophthalmitis

To report the treatment strategies and visual acuity outcomes of chronic postoperative endophthalmitis caused by Propionibacterium acnes. Retrospective noncomparative case series. All patients presenting 8 or more weeks after cataract surgery with intraocular inflammation caused by culture-proven P. acnes infection and treated at two institutions from 1974 through 1996 were included. Patients underwent three different initial treatment strategies. The study did not have a defined treatment protocol, but all patients received intraocular antibiotics. Patients were not randomly assigned to the various treatment strategies. Final visual acuity and effectiveness of various treatment procedures either as initial or follow-up therapy were assessed. Using the 3 initial strategies, 36 patients were treated: (1) intraocular antibiotic injection alone (IOAB; n = 12); (2) pars plana vitrectomy and IOAB injection (PPV; n = 10); and (3) PPV with subtotal capsulectomy and IOAB injection (PPV-PC; n = 14). The number of patients with recurrent or persistent inflammation after one of the three initial treatment strategies were as follows: (1) IOAB alone, 12 (100%); (2) PPV, 5 (50%); and (3) PPV-PC, 2 (14%). None of the patients that underwent subsequent PPV, total capsular bag removal, IOAB injection, and either intraocular lens (IOL) exchange or removal had persistent or recurrent intraocular inflammation. Overall, final visual acuity was 20/40 or better in 18 patients (50%), and a total of 28 patients (78%) retained 20/400 or better vision. The mean follow-up after the last treatment was 2.9 years. In this series of chronic P. acnes endophthalmitis, initial treatment with IOAB injection alone or vitrectomy without capsulectomy was associated with high rates of recurrent or persistent intraocular inflammation. Pars plana vitrectomy, partial capsulectomy, and IOAB injection without IOL exchange was usually successful on long-term follow-up. In patients with recurrent intraocular inflammation, pars plana vitrectomy, total capsular bag removal, IOAB injection, and IOL exchange or removal was a uniformly successful strategy. In contrast to other types of postoperative endophthalmitis, IOL exchange can be considered in these patients after total capsular bag removal

Minimum bactericidal concentrations of Propionibacterium acnes isolates from cases of chronic endophthalmitis

Six isolates of Propionibacterium acnes recovered from cases of chronic infectious endophthalmitis following extracapsular cataract extraction were tested for antibiotic susceptibility. All isolates were susceptible to penicillin, cefazolin, and vancomycin with a macrobroth dilution method, Minimum bactericidal concentrations testing at 72 h revealed that six of six isolates were killed by ⩽1.0 μg of vancomycin/ml, one of six isolates by ⩽1.0 μg of penicillin/ml, and zero of six isolates by ⩽1.0 μg cefazolin/ml

Growth curve for Propionibacterium acnes

We established growth curves for Propionibacterium acnes isolates recovered from eyes with chronic postoperative endophthalmitis. The growth curve plotted the average of the duplicate bacterial concentration against time. The generation time for P. acnes calculated from the growth curves was approximately 5.1 hours. The growth of P. acnes is slower than other anaerobic bacteria. This may account for its delayed appearance in culture of ocular specimens. It may also explain treatment failure if the concentration of an antibiotic injected into the vitreous does not remain at an effective level during the critical replicative phase of the organism