Citations

ABSTRACT Specialized to simulate proteins in molecular dynamics (MD) simulations with explicit solvation, FF12MC is a combination of a new protein simulation protocol employing uniformly reduced atomic masses by tenfold and a revised AMBER forcefield FF99 with (i) shortened CH bonds, (ii) removal of torsions involving a nonperipheral sp 3 atom, and (iii) reduced 1–4 interaction scaling factors of torsions ϕ and ψ . This article reports that in multiple, distinct, independent, unrestricted, unbiased, isobaric–isothermal, and classical MD simulations FF12MC can (i) simulate the experimentally observed flipping between left‐ and right‐handed configurations for C14–C38 of BPTI in solution, (ii) autonomously fold chignolin, CLN025, and Trp‐cage with folding times that agree with the experimental values, (iii) simulate subsequent unfolding and refolding of these miniproteins, and (iv) achieve a robust Z score of 1.33 for refining protein models TMR01, TMR04, and TMR07. By comparison, the latest general‐purpose AMBER forcefield FF14SB locks the C14–C38 bond to the right‐handed configuration in solution under the same protein simulation conditions. Statistical survival analysis shows that FF12MC folds chignolin and CLN025 in isobaric–isothermal MD simulations 2–4 times faster than FF14SB under the same protein simulation conditions. These results suggest that FF12MC may be used for protein simulations to study kinetics and thermodynamics of miniprotein folding as well as protein structure and dynamics. Proteins 2016; 84:1490–1516. © 2016 The Authors Proteins: Structure, Function, and Bioinformatics Published by Wiley Periodicals, Inc.

The acetylcholine receptor (AChR) from vertebrate skeletal muscle initiates voluntary movement, and its kinetics of activation are crucial for maintaining the safety margin for neuromuscular transmission. Furthermore, the kinetic mechanism of the muscle AChR serves as an archetype for understanding activation mechanisms of related receptors from the Cys-loop superfamily. Here we record currents through single muscle AChR channels with improved temporal resolution approaching half an order of magnitude over our previous best. A range of concentrations of full and partial agonists are used to elicit currents from human wild-type and gain-of-function mutant AChRs. For each agonist–receptor combination, rate constants are estimated from maximum likelihood analysis using a kinetic scheme comprised of agonist binding, priming, and channel gating steps. The kinetic scheme and rate constants are tested by stochastic simulation, followed by incorporation of the experimental step response, sampling rate, background noise, and filter bandwidth. Analyses of the simulated data confirm all rate constants except those for channel gating, which are overestimated because of the established effect of noise on the briefest dwell times. Estimates of the gating rate constants were obtained through iterative simulation followed by kinetic fitting. The results reveal that the agonist association rate constants are independent of agonist occupancy but depend on receptor state, whereas those for agonist dissociation depend on occupancy but not on state. The priming rate and equilibrium constants increase with successive agonist occupancy, and for a full agonist, the forward rate constant increases more than the equilibrium constant; for a partial agonist, the forward rate and equilibrium constants increase equally. The gating rate and equilibrium constants also increase with successive agonist occupancy, but unlike priming, the equilibrium constants increase more than the forward rate constants. As observed for a full and a partial agonist, the gain-of-function mutation affects the relationship between rate and equilibrium constants for priming but not for channel gating. Thus, resolving brief single channel currents distinguishes priming from gating steps and reveals how the corresponding rate and equilibrium constants depend on agonist occupancy.

Systematic review of experimental and clinical data on the use of curcumin in the treatment of osteosarcoma is presented. The current status of curcumin’s therapeutic potential against bone cancer is analyzed in regard to using polymeric micelles (including recently developed invertible, responsive, micelles) as a platform for curcumin delivery to treat osteosarcoma. The potential of micellar assemblies from responsive macromolecules in a controlled delivery of curcumin to osteosarcoma cells, and the release using a new inversion mechanism is revealed.

Objectives To investigate the effect of the number and type of comorbid conditions on death and hospitalizations in individuals with incident heart failure ( HF ). Design Population‐based cohort study. Setting Olmsted County, Minnesota. Participants Olmsted County, Minnesota, residents with incident HF from 2000 to 2010 (mean age 76 ± 14, 56% female) (N = 1,714). Measurements The prevalence of 16 chronic conditions obtained at HF diagnosis classified into three groups: cardiovascular ( CV ) related, other physical, and mental. Results The mean number of conditions per participant was 2.6 ± 1.5 for CV ‐related conditions, 1.3 ± 1.1 for other physical conditions, and 0.30 ± 0.61 for mental conditions. After a mean follow‐up of 4.2 years, 1,073 deaths and 6,306 hospitalizations had occurred. After adjustment for age, sex, ejection fraction, in‐ or outpatient status, and number of other conditions, an increase of one other physical condition was associated with a 14% ( HR = 1.14, 95% CI = 1.08–1.20) greater risk of death and a 26% ( HR = 1.26, 95% CI = 1.20–1.32) greater risk of hospitalization, and an increase of one mental condition was associated with a 31% ( HR = 1.31, 95% CI = 1.19–1.44) greater risk of death and an 18% ( HR = 1.18, 95% CI = 1.07–1.29) greater risk of hospitalization. In contrast, an increase of one CV ‐related condition was not associated with greater risk of death and was associated with a 10% ( HR = 1.10, 95% CI = 1.06–1.15) greater risk of hospitalization. Conclusion CV ‐related conditions are the most common type of comorbid conditions in individuals with HF , but other physical and mental conditions are more strongly associated with death and hospitalizations. This underscores the effect of non‐ CV conditions on outcomes in HF .

SummaryBackgroundMalignant hyperthermia (MH) is a rare anesthetic pharmacogenetic disorder that can be difficult to detect in its earliest phases. Prompt treatment is known to improve outcomes. The modern anesthesia information management systems (AIMS) collect enormous amounts of data. However, data lack context and are not able to provide real‐time guidance. Utilizing our AIMS, we developed the capacity to incorporate decision support.AimsWe describe the creation and evaluation of a real‐time detection tool for MH.MethodsCases of MH from 2003 to 2013 were retrospectively reviewed to confirm the diagnosis of MH and to calculate a MH clinical grading scale score. The index cases were utilized to develop four electronic data Rules, based on endtidal CO2 (ETCO2) and temperature criteria. The Rules were then applied retrospectively to the index cases and to a full cohort of general operating room (OR) patients from January 2012 to June 2012. If criteria for possible MH was met, the detection tool generated an alert on the monitor at the patient's bedside.ResultsWe identified seven patients with confirmed MH with MH Scores ranging from 28 to 70. Using four data Rules, all of our seven index cases were captured and generated an appropriate alert. Median time from MH computer alert time to dantrolene administration time among our index cases was 23 min (IQR 17–77). There were 938 false‐positive alerts for possible MH (1.8%) when the Rules were applied to a general OR cohort of 51 579 total cases from January 2012 to June 2012.ConclusionsWe demonstrated a real‐time MH detection tool based on established physiologic criteria that is sensitive enough to capture cases suspicious for MH, while limiting false positives to prevent alarm fatigue. This has the potential to notify the provider of possible MH such that treatment may be rapidly initiated.

Objectives/HypothesisTo report the preliminary outcomes of patients with single‐sided deafness and asymmetric hearing loss undergoing cochlear implantation at two centers.Study DesignRetrospective review and prospective data collection.MethodsPatients with single‐sided deafness who underwent cochlear implantation at two centers were included. Pre‐ and postoperative measures included monosyllabic word and sentence recognition in quiet for the ear implanted, and sentence recognition in noise in the best‐aided bilateral condition.ResultsAverage monosyllabic word recognition scores in quiet improved significantly from 11.3% (standard deviation [SD] 15.6%) preoperatively to 48.7% (SD 24.2%) at the 3‐month postactivation interval, although they did not increase significantly between the 3‐month and 6‐month intervals. Sentence recognition scores in quiet increased significantly from 18.4% (SD 28.5%) preoperatively to 65.9% (SD 17.9%) at the 3‐month postactivation interval, but not between the 3‐month and 6‐month intervals. Sentence recognition in noise in the best‐aided bilateral condition increased from 59% (SD 16.3%) preoperatively to 72% (SD 16.0%) at 6‐months postactivation, though the difference was not statistically significant. Thirteen of the participants reported tinnitus prior to surgery. Of those, 12 reported that tinnitus was improved after implantation, and one reported that tinnitus was unchanged.ConclusionPreliminary results suggest that speech recognition in a singly deafened ear is significantly improved after cochlear implantation, although speech recognition in noise measured in the bilateral condition remains the same at 6‐months postactivation.Level of Evidence4. Laryngoscope, 127:223–228, 2017

AbstractIntroductionThis study combined data across four independent cohorts to examine the positive and negative predictive values of an Alzheimer's disease (AD) blood test if implemented in primary care.MethodsBlood samples from 1329 subjects from multiple independent, multiethnic, community‐based, and clinic‐based cohorts were analyzed. A “locked‐down” referent group of 1128 samples was generated with 201 samples randomly selected for validation purposes. Random forest analyses were used to create the AD blood screen. Positive (PPV) and negative (NPV) predictive values were calculated.ResultsIn detecting AD, PPV was 0.81, and NPV was 0.95 while using the full AD blood test. When detecting mild cognitive impairment, PPV and NPV were 0.74 and 0.93, respectively. Preliminary analyses were conducted to detect any “neurodegenerative disease”. The full 21‐protein AD blood test yielded a PPV of 0.85 and NPV of 0.94.DiscussionThe present study creates the first‐ever multiethnic referent sample that spans community‐based and clinic‐based populations for implementation of an AD blood screen.

As ventricular-assist devices (VADs) are increasingly employed in heart failure management, a leading cause of mortality, new literature is consistently published on less-invasive implantation techniques. Although early perioperative outcomes have been shown to be favorable with minimally invasive left thoracotomy (LT) approaches compared with conventional sternotomy (CS), studies comparing long-term outcomes are lacking. We set out to evaluate long-term follow up between LT and CS approach. In a single center, retrospective review, data on patients with similar demographic profiles were collected. HeartWare (HVAD) implantation was performed by either CS or LT. Analysis was performed on perioperative adverse outcomes, and 6 month postoperative adverse events. Primary objectives of the study included comparative outcomes of morbidity and mortality between both groups at 180 days postimplantation. Eighty-one (n = 81) bridge to transplant (BTT) patients underwent CS or LT HVAD implantation. Perioperative transfusion (p = 0.04) favored the LT cohort compared with CS, with a median of 6 units and 8 units transfused for each group, respectively. No survival difference was observed between both groups at 6 months postimplantation (p = 0.52). Clinical outcomes at an average of 6 month follow up showed no difference in adverse events, including common postoperative VAD complications such as infection and right heart failure. Miniaturization of LVAD size and improvement in technology has allowed expansion of interest in alternative surgical approaches for HVAD implantation. For BTT patients, no difference in early outcome was observed 6 months after implantation using a left LT versus CS technique.

Background/Purpose: To describe the findings and clinical course of a patient with scleromyxedema complicated by retinal vasculitis and macular edema. Methods: Interventional case report. Results: A 64-year old Caucasian woman with recently diagnosed, biopsy proven scleromyxedema presented with decreased visual acuity (20/50 OD; 20/100 OS) due to retinal vasculitis and macular edema. She received intravitreal bevacizumab and subtenon's triamcinolone acetonide for the macular edema, and bilateral pars plana vitrectomies were required for vitreous hemorrhages. Monthly intravenous infusions of immunoglobulins (IVIG) resulted in resolution of the macular edema and vasculitis, and stabilization of the VA (20/40 OD; counting fingers at 6 feet OS). Conclusion: Scleromyxedema may be complicated by retinal vasculitis and macular edema. Treatment with corticosteroids and vascular endothelial growth factor inhibitors may be minimally effective but IVIG should be considered for both the ocular and systemic findings.