Citations

ABSTRACT Background Depression, parkinsonism, and hypoventilation (Perry syndrome) or familial motor neuron disease have been linked to mutations in dynactin P150 Glued ( DCTN1 ). Methods We employed genealogic, clinical, neurologic, and MRI investigations, as well as analysis of genes implicated in parkinsonism. Cellular transfection, immunocytochemistry, and immunoprecipitation analysis of wild‐type (WT) and mutant DCTN1 were also performed. Results A novel heterozygous mutation, DCTN1 c.156T>G, encoding p.Phe52Leu, segregates with parkinsonism in a Japanese family. The substitution was not observed in affected probands with familial parkinsonism or control subjects and is evolutionarily conserved. In contrast to Perry syndrome, affected carriers have late‐onset disease and slower progression, with frontotemporal atrophy revealed by MRI. In vitro studies suggest the mutant protein has impaired microtubule binding, compared to WT dynactin p150 Glued . Conclusions DCTN1 mutations may contribute to disparate neurodegenerative diagnoses, including familial motor neuron disease, parkinsonism, and frontotemporal atrophy, and further studies of dynactin‐mediated cargo transport may prove insightful. © 2014 International Parkinson and Movement Disorder Society

Summary Objective To demonstrate the safety and effectiveness of responsive stimulation at the seizure focus as an adjunctive therapy to reduce the frequency of seizures in adults with medically intractable partial onset seizures arising from one or two seizure foci. Methods Randomized multicenter double‐blinded controlled trial of responsive focal cortical stimulation (RNS System). Subjects with medically intractable partial onset seizures from one or two foci were implanted, and 1 month postimplant were randomized 1:1 to active or sham stimulation. After the fifth postimplant month, all subjects received responsive stimulation in an open label period ( OLP ) to complete 2 years of postimplant follow‐up. Results All 191 subjects were randomized. The percent change in seizures at the end of the blinded period was −37.9% in the active and −17.3% in the sham stimulation group (p = 0.012, Generalized Estimating Equations). The median percent reduction in seizures in the OLP was 44% at 1 year and 53% at 2 years, which represents a progressive and significant improvement with time (p < 0.0001). The serious adverse event rate was not different between subjects receiving active and sham stimulation. Adverse events were consistent with the known risks of an implanted medical device, seizures, and of other epilepsy treatments. There were no adverse effects on neuropsychological function or mood. Significance Responsive stimulation to the seizure focus reduced the frequency of partial‐onset seizures acutely, showed improving seizure reduction over time, was well tolerated, and was acceptably safe. The RNS System provides an additional treatment option for patients with medically intractable partial‐onset seizures.

The purpose of the RAZOR (randomized open vs robotic cystectomy) study is to compare open radical cystectomy ( ORC ) vs robot‐assisted RC ( RARC ), pelvic lymph node dissection ( PLND ) and urinary diversion for oncological outcomes, complications and health‐related quality of life ( HRQL ) measures with a primary endpoint of 2‐year progression‐free survival ( PFS ). RAZOR is a multi‐institutional, randomized, non‐inferior, phase III trial that will enrol at least 320 patients with T 1– T 4, N 0– N 1, M 0 bladder cancer with ≈160 patients in both the RARC and ORC arms at 15 participating institutions. Data will be collected prospectively at each institution for cancer outcomes, complications of surgery and HRQL measures, and then submitted to trial data management services Cancer Research and Biostatistics ( CRAB ) for final analyses. To date, 306 patients have been randomized and accrual to the RAZOR trial is expected to conclude in 2014. In this study, we report the RAZOR trial experimental design, objectives, data safety, and monitoring, and accrual update. The RAZOR trial is a landmark study in urological oncology, randomizing T 1– T 4, N 0– N 1, M 0 patients with bladder cancer to ORC vs RARC , PLND and urinary diversion. RAZOR is a multi‐institutional, non‐inferiority trial evaluating cancer outcomes, surgical complications and HRQL measures of ORC vs RARC with a primary endpoint of 2‐year PFS . Full data from the RAZOR trial are not expected until 2016–2017.

Background: Multiple markers are used to assess glycemic control in patients with diabetes mellitus (DM). New technology that permits simultaneous detection of multiple biomarkers combined with those used at the point of care indicative of glycemic control, including glycemic variability determined from 1,5-anhydroglucitol measurement, could provide better management and further insight into the disease. Methods: This platform was based on previous research involving glucose detection and uses electrochemical impedance spectroscopy to detect a range of 1,5-anhydroglucitol concentrations at an optimal binding frequency. The enzyme pyranose oxidase was fixed to gold electrodes while a sine wave of sweeping frequencies was induced in purified solutions and in variable presence of whole blood. Results: The optimal binding frequency for the detection of 1,5-anhydroglucitol was found to be 3.71 kHz. The impedance response compared to the concentration of target present was found to have a logarithmic slope of 7.04 with an R-squared value of 0.96. This response includes 2 experimental sets, a single test of a low concentration range and a high concentration range with 5 replicates. The relative standard deviation of the high range varied from 28% to 27% from lowest to highest concentrations. Best detection in complex solutions was found in lower blood concentrations of 0.5% and 1%, but maintained relatively high accuracy in concentrations 5% and 10%. Conclusions: The sensor platform was successfully evaluated at a high dynamic range of 1,5-AG in purified solutions. In the presence of whole blood, lowest percentages yielded the best results indicating that filtering interferents may be necessary in final device architecture.

Object The clinical success rates of anterior cervical discectomy and fusion (ACDF) procedures are substantially reduced as more cervical levels are included in the fusion procedure. One method that has been proposed as an adjunctive technique for multilevel ACDF is the placement of screws across the facet joints (“transfacet screws”). However, the biomechanical stability imparted by transfacet screw placement (either unilaterally or bilaterally) has not been reported. Therefore, the purpose of this study was to determine the acute stability conferred by implementation of unilateral and bilateral transfacet screws to an ACDF construct. Methods Eight C2–T1 fresh-frozen human cadaveric spines (3 female and 5 male; mean age 50 years) were tested. Three different instrumentation variants were performed on cadaveric cervical spines across C4–7: 1) ACDF with an intervertebral spacer and standard plate/screw instrumentation; 2) ACDF with an intervertebral spacer and standard plate/screw instrumentation with unilateral facet screw placement; and 3) ACDF with an intervertebral spacer and standard plate/screw instrumentation with bilateral facet screw placement. Kinetic ranges of motion in flexion-extension, lateral bending, and axial rotation at 1.5 Nm were captured after each of these procedures and were statistically analyzed for significance. Results All 3 fixation scenarios produced statistically significant reductions (p < 0.05) in all 3 bending planes compared with the intact condition. The addition of a unilateral facet screw to the ACDF construct produced significant reductions at the C4–5 and C6–7 levels in lateral bending and axial rotation but not in flexion-extension motion. Bilateral facet screw fixation did not produce any statistically significant decreases in flexion-extension motion compared with unilateral facet screw fixation. However, in lateral bending, significant reductions at the C4–5 and C5–6 levels were observed with the addition of a second facet screw. The untreated, adjacent levels (C2–3, C3–4, and C7–1) did not demonstrate significant differences in range of motion. Conclusions The data demonstrated that adjunctive unilateral facet screw fixation to an ACDF construct provides significant gains in stability and should be considered a potential option for increasing the likelihood for obtaining a successful arthrodesis for multilevel ACDF procedures.

Object Choline acetyltransferase (ChAT) is an enzyme synthesized within the body of a motor neuron whose role is to form the neurotransmitter acetylcholine. Quantification of ChAT levels in motor or mixed nerves has been proposed to provide information regarding the viability of a proximal nerve stump for motor neurotization following brachial plexus injury. To do so requires information regarding normal ChAT levels and those in injured nerves, as well as the correlation of ChAT level determined at surgery with eventual motor recovery. The purpose of this study was to determine ChAT activity in the normal and injured sciatic/peroneal nerve in a rat model, evaluate the correlation between ChAT and motor recovery, find the relationship between ChAT activity and isometric muscle force, and elucidate the parallel between ChAT activity and acetylcholinesterase (AChE) activity. Methods Sixty animals were divided into 3 groups. The sciatic nerves in Group 1 were transected without repair. Nerves in Group 2 were transected and repaired. Nerves in Group 3 sustained a crush injury followed by transection and reconstruction. All animals were allowed 12 weeks of recovery followed by evaluation of ChAT levels in the peroneal nerve, correlated with measures of maximal isometric tibialis anterior muscle force and muscle weight (the operated side normalized to the control side). Karnovsky AChE staining of peroneal nerve segments was also compared with radiochemical assay of ChAT activity in the same nerve. Results A significant difference in the tibialis anterior isometric tetanic force and the tibialis anterior muscle weight index (TAMI) was noted between Group 1 and Groups 2 and 3 (p < 0.0001); no significant difference was found comparing Group 2 with Group 3. The correlation between the force measurement and the TAMI was 0.382. Both AChE measurement and ChAT activity demonstrated significantly fewer fibers in the operated nerve compared with the contralateral nerve. Intergroup variability could also be illustrated using these tests. The correlation coefficient between the isometric tetanic force measurement and the ChAT analysis in Groups 1 and 2 was 0.468. The correlation for the AChE staining and the isometric tetanic force measurement was 0.111. The correlation between the TAMI and the ChAT levels was 0.773. The correlation between the TAMI and the AChE-stained fibers was 0.640. Correlating AChE staining to the ChAT analysis produced a correlation of 0.712. Conclusions The great variability in all groups and weak correlations to the functional muscle assessments and the ChAT radiochemical assay made this technique an unreliable method of determining motor nerve viability.

Inhibitors of human DNA methyltransferases (DNMT) are of increasing interest to develop novel epi-drugs for the treatment of cancer and other diseases. As the number of compounds with reported DNMT inhibition is increasing, molecular docking is shedding light to elucidate their mechanism of action and further interpret structure–activity relationships. Herein, we present a structure-based rationalization of the activity of SW155246, a distinct sulfonamide compound recently reported as an inhibitor of human DNMT1 obtained from high-throughput screening. We used flexible and induce-fit docking to develop a binding model of SW155246 with a crystallographic structure of human DNMT1. Results were in excellent agreement with experimental information providing a three-dimensional structural interpretation of ‘activity cliffs’, e.g., analogues of SW155246 with a high structural similarity to the sulfonamide compound, but with no activity in the enzymatic assay.