Citations

Significance Members of the kinesin superfamily serve a wide variety of functions, and a dominant narrative for these molecular motors has been that each member of the superfamily is uniquely specialized to serve a very limited set of functions. However, it is now appreciated that many members of this group serve several distinct physiological roles, and it has been unclear how these kinesins accomplish this functional flexibility. In this report, we describe a posttranslational modification of the kinesin 5 family member Eg5 that dramatically alters its chemomechanical behavior to make it function much more efficiently under load and in ensembles. This work provides the biophysical context required to mechanistically understand the effects of modified Eg5 in dividing cells.

Background and Purpose: Management of carotid stenosis remains controversial despite several trials evaluating carotid endarterectomy (CEA) and carotid angioplasty/stenting (CAS). We compared attitudes in the management of carotid stenosis between selected experts within Europe and North America. Methods: A 3-phase Delphi survey was e-mailed to select stroke experts from Europe (n = 390) and North America (n = 289). Those completing the initial survey were shown all responses after each survey round. Consensus was defined as ≥80% agreement. Results: For phases 1, 2, and 3, response rates were 32%, 62%, and 73%, respectively. Overall, 100 (15%) of 679 participated in all 3 phases, 19% Europeans versus 9% North Americans ( P = .0007). The European group reached consensus in 6 of 15 statements; The North American group reached consensus in 4 of 15. Ninety percentage of Europeans versus 70% of North Americans ( P = .017) stated CEA is superior to CAS for symptomatic carotid stenosis. This difference was not significant in the final model (adjusted odds ratio: 3.72 [95% confidence interval: 0.95-14.5]). Sixty-nine percentage of North Americans agreed there is a stronger indication for CAS over CEA in patients younger than 65 years for symptomatic carotid stenosis, whereas 55% of Europeans ( P = .023) disagreed. For asymptomatic carotid stenosis, when asked how likely they would recommend CAS, 62% North Americans said “sometimes” versus 60% of Europeans said “never” ( P = .06). Conclusion: The majority of North American and European respondents did not consider the 2 procedures equivalent and seemed to indicate that CEA was preferred for the management of carotid stenosis. These findings need to be further explored to help establish evidence-based guidelines.

Background Mitral regurgitation is a heterogeneous disease. Determining which patients derive optimal outcomes from transcatheter edge‐to‐edge mitral valve repair (TMVR) remains challenging. We sought to determine whether baseline mitral valve anatomic characteristics are predictive of left atrial pressure (LAP) changes during TMVR with MitraClip. Methods and Results Consecutive patients with severe mitral regurgitation undergoing TMVR (n=112) underwent continuous intraprocedural LAP monitoring and retrospective echocardiographic analysis for specific mitral anatomic characteristics. Procedural success (optimal LAP reduction) was defined as ≥40% reduction in left atrial V‐wave pressure compared with baseline. Echocardiographic predictors of optimal LAP reduction and increased postprocedure mean diastolic gradient were evaluated. Mean age was 79±14 years, and 36 patients (32%) were women. Primary, mixed, and secondary mitral regurgitation were present in 78 patients (70%), 22 patients (20%), and 12 patients (10%), respectively. Baseline mean LAP and V‐wave were 22±6 and 38±13 mm Hg; after TMVR, these decreased to 19±5 and 27±10 mm Hg, respectively ( P <0.0001 for both). Independent predictors of optimal LAP reduction were the presence of a flail scallop, mitral regurgitation localized to a single scallop, and high‐quality 3‐dimensional echocardiographic imaging. Independent predictors of elevated postprocedure mean diastolic gradient were elevated preprocedure mean diastolic gradient, mitral annular calcification, and implantation of multiple clips. Conclusions Mitral valve pathoanatomic features, including a flail leaflet and single jet, are predictive of optimal LAP reduction with TMVR. High‐quality 3‐dimensional imaging may help select patients with the highest likelihood of optimal hemodynamic results with TMVR. These data expand current knowledge about patient selection for TMVR and deserve further study in larger cohorts.

Abstract The synucleinopathies—Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and pure autonomic failure—result from distinct patterns of abnormal α‐synuclein aggregation throughout the nervous system. Autonomic dysfunction in these disorders results from variable involvement of the central and peripheral autonomic networks. The major pathologic hallmark of Parkinson's disease and dementia with Lewy bodies is Lewy bodies and Lewy neurites; of multiple system atrophy, oligodendroglial cytoplasmic inclusions; and of pure autonomic failure, peripheral neuronal cytoplasmic inclusions. Clinical manifestations include orthostatic hypotension, thermoregulatory dysfunction, gastrointestinal dysmotility, and urogenital dysfunction with neurogenic bladder and sexual dysfunction. Strong evidence supports isolated idiopathic rapid eye movement sleep disorder as a significant risk factor for the eventual development of synucleinopathies with autonomic and/or motor involvement. In contrast, some neurologically normal elderly individuals have Lewy‐related pathology. Future work may reveal protective or vulnerability factors that allow some patients to harbor Lewy pathology without overt autonomic dysfunction. © 2018 International Parkinson and Movement Disorder Society

Abstract Background Advances in next-generation DNA sequencing technologies are now enabling detailed characterization of sequence variations in cancer genomes. With whole-genome sequencing, variations in coding and non-coding sequences can be discovered. But the cost associated with it is currently limiting its general use in research. Whole-exome sequencing is used to characterize sequence variations in coding regions, but the cost associated with capture reagents and biases in capture rate limit its full use in research. Additional limitations include uncertainty in assigning the functional significance of the mutations when these mutations are observed in the non-coding region or in genes that are not expressed in cancer tissue. Results We investigated the feasibility of uncovering mutations from expressed genes using RNA sequencing datasets with a method called Variant Detection in RNA(VaDiR) that integrates 3 variant callers, namely: SNPiR, RVBoost, and MuTect2. The combination of all 3 methods, which we called Tier 1 variants, produced the highest precision with true positive mutations from RNA-seq that could be validated at the DNA level. We also found that the integration of Tier 1 variants with those called by MuTect2 and SNPiR produced the highest recall with acceptable precision. Finally, we observed a higher rate of mutation discovery in genes that are expressed at higher levels. Conclusions Our method, VaDiR, provides a possibility of uncovering mutations from RNA sequencing datasets that could be useful in further functional analysis. In addition, our approach allows orthogonal validation of DNA-based mutation discovery by providing complementary sequence variation analysis from paired RNA/DNA sequencing datasets.

BACKGROUND Extramammary Paget's disease (EMPD) is a rare intraepithelial malignancy with high recurrence rates following standard surgical treatments, ranging from 22% to 60% in large retrospective reviews. OBJECTIVE To evaluate the local recurrence rate of Mohs micrographic surgery (MMS) supplemented with intraoperative immunohistochemistry for cytokeratin-7 (MMS + CK-7) for primary and recurrent EMPD. MATERIALS AND METHODS Retrospective, multi-center, cross-sectional study of patients treated using MMS + CK-7. Demographic, clinicopathologic, treatment, and follow-up data were obtained by chart review. RESULTS The observed local recurrence rate for MMS + CK-7 is 3.3% (2/61 tumors) with a mean follow-up of 43.5 months (1–120 months). Local recurrence occurred in 2.3% (1/43) of primary tumors and 5.6% (1/18) of recurrent tumors. Kaplan–Meier 5-year tumor-free rates are 94.6% overall, 97.1% for primary tumors, and 80.0% for recurrent tumors. The Kaplan–Meier 5-year tumor-free rates for all EMPD tumors treated with MMS + CK-7 versus a historical cohort of MMS alone are 94.6% versus 72.0% (p = .012). CONCLUSION MMS + CK-7 is an effective treatment for EMPD, demonstrating improved outcomes compared with historical controls.

ABT-263 blocks BCL-X L to induce apoptosis in human dermal fibroblasts from patients with scleroderma and in myofibroblasts in mice, reversing dermal fibrosis.

Study Design: Retrospective review. Objectives: This study investigates the prevalence of adverse postsurgical events, or osteoporosis-related complications (ORCs), following spinal fusion. Methods: Patients undergoing primary posterior thoracolumbar or lumbar fusion by 1 of 2 surgeons practicing at a single institution were analyzed from 2007 to 2014. ORCs were defined in one of the following categories: revision surgery, compression fracture, proximal junctional kyphosis, pseudarthrosis, or failure of instrumentation. Patients with a bone mineral density of the hips and/or spine performed within 1 year of the index procedure were included. Patients were stratified into normal bone density, osteopenia, and osteoporosis using WHO guidelines. Patients were excluded if they were younger than 18 years at the time of surgery, with infection, malignancy, skeletal dysplasia, neuromuscular disorders, concomitant or staged anterior-posterior procedure, or fusion performed because of trauma. Results: Out of 140 patients included, the prevalence of normal bone density was 31.4% (44/140), osteopenia 58.6% (82/140), and osteoporosis 10.0% (14/140). There were no differences between groups for gender, age, body mass index, and interbody device rate. The overall prevalence of ORCs was 32.1% (45/140). By group, there was a prevalence of 22.7% (10/44), 32.9% (27/82), and 50.0% (7/14) for normal bone density, osteopenia, and osteoporosis, respectively. These differences were significantly higher for both the osteopenia and osteoporosis groups. Conclusions: Patients with T scores below −1.0 undergoing posterior lumbar fusion have an increased prevalence of ORCs. Consideration of bone density plays a crucial role in patient selection, medical management, and counseling patient expectations.