A human Tau expressing zebrafish model of progressive supranuclear palsy identifies Brd4 as a regulator of microglial synaptic elimination.

Progressive supranuclear palsy (PSP) is an incurable neurodegenerative disease characterized by 4-repeat (0N/4R)-Tau protein accumulation in CNS neurons. We generated transgenic zebrafish expressing human 0N/4R-Tau to investigate PSP pathophysiology. Tau zebrafish replicated multiple features of PSP, including: decreased survival; hypokinesia; impaired optokinetic responses; neurodegeneration; neuroinflammation; synapse loss; and Tau hyperphosphorylation, misfolding, mislocalization, insolubility, truncation, and oligomerization. Using automated assays, we screened 147 small molecules for activity in rescuing neurological deficits in Tau zebrafish. (+)JQ1, a bromodomain inhibitor, improved hypokinesia, survival, microgliosis, and brain synapse elimination. A heterozygous brd4+/- mutant reducing expression of the bromodomain protein Brd4 similarly rescued these phenotypes. Microglial phagocytosis of synaptic material was decreased by (+)JQ1 in both Tau zebrafish and rat primary cortical cultures. Microglia in human PSP brains expressed Brd4. Our findings implicate Brd4 as a regulator of microglial synaptic elimination in tauopathy and provide an unbiased approach for identifying mechanisms and therapeutic targets in PSP.

Physiologic Pacing Targeting the His Bundle and Left Bundle Branch: a Review of the Literature.

PURPOSE OF REVIEW: Conduction system pacing (CSP) has emerged as a means to preserve or restore physiological ventricular activation via pacing at the His bundle or at more distal targets in the conduction system, including the left bundle branch area. This review examines strengths, weaknesses, and clinical applications of CSP performed via these approaches. RECENT FINDINGS: His bundle pacing (HBP) has been successfully utilized for standard bradyarrhythmia indications and for QRS correction among patients receiving devices for cardiac resynchronization therapy (CRT). Limitations of HBP pacing have included implant complexity and rising pacing thresholds over time. Left bundle branch area pacing (LBBAP) appears to deliver similar physiological benefits with shorter implant times and more stable thresholds. More recently, hybrid systems utilizing HBP or LBBAP in combination with left ventricular leads have been used to treat heart failure (HF) patients, and may be useful in multilevel or mixed conduction blocks. There is growing interest in CSP for bradycardia and HF indications, although high quality data with randomized controlled trials are needed to help guide future treatment paradigms.

Retrospective Analysis of Perioperative Variables Associated With Postoperative Delirium and Other Adverse Outcomes in Older Patients After Spine Surgery.

BACKGROUND: The aim of this retrospective study was to identify perioperative variables predictive of the development of delirium in older surgical patients after spine surgery. MATERIALS AND METHODS: We collected preoperative, intraoperative, and postoperative data on patients 65 years of age and above having spine surgery between July 1, 2015 and March 15, 2017. The primary outcome was the development of postoperative delirium. Data were analyzed using univariate and multivariable analysis. RESULTS: Among the 716 patients included in this study 127 (18%) developed postoperative delirium. On multivariable analysis, independent predictors of postoperative delirium included older age (odds ratio [OR]=1.04; 95% confidence interval [CI], 1.00-1.09; P=0.048), American Society of Anesthesiologists physical status >2 (OR=1.89 [95% CI, 1.04-3.59]; P=0.042), metabolic equivalents of task <4 (OR=1.84 [95% CI, 1.10-3.07]; P=0.019), depression (OR=2.01 [95% CI, 1.21-3.32]; P=0.006), nonelective surgery (OR=4.81 [95% CI, 1.75-12.79]; P=0.002), invasive surgical procedures (OR=1.97 [95% CI, 1.10-3.69]; P=0.028) and higher mean pain scores on postoperative day 1 (OR=1.28 [95% CI, 1.11-1.48]; P<0.001). CONCLUSIONS: Postoperative delirium is a common complication in older patients after spine surgery, and there are several perioperative risk factors associated with its development.

Modulation of the zebrafish optokinetic reflex by pharmacologic agents targeting GABAA receptors.

Optokinetic reflex (OKR) responses provide a convenient means to evaluate visual, integrative and oculomotor function in larval zebrafish. We measured multiple aspects of the OKR response in zebrafish exposed systemically to compounds altering signaling at GABAA receptors in order to derive quantitative concentration-response relationships. The GABAA antagonist picrotoxin caused concentration-dependent decreases in reflex gain, saccade velocity, saccade amplitude, interocular concordance and interocular gain. Conversely, the GABAA agonist gaboxadol provoked increases in reflex gain, saccade velocity, saccade amplitude and ocular range at low concentrations, and decreases in some of these parameters at higher concentrations. These data show that GABAA signaling influences multiple aspects of the OKR (including gain, generation of saccades, and coordination between the two eyes) and provide proof of concept that quantitative OKR analysis can be used as a tool for chemical biology and neuropharmacology applications.

An open-source method to analyze optokinetic reflex responses in larval zebrafish.

BACKGROUND: Optokinetic reflex (OKR) responses provide a convenient means to evaluate oculomotor, integrative and afferent visual function in larval zebrafish models, which are commonly used to elucidate molecular mechanisms underlying development, disease and repair of the vertebrate nervous system. NEW METHOD: We developed an open-source MATLAB-based solution for automated quantitative analysis of OKR responses in larval zebrafish. The package includes applications to: (i) generate sinusoidally-transformed animated grating patterns suitable for projection onto a cylindrical screen to elicit the OKR; (ii) determine and record the angular orientations of the eyes in each frame of a video recording showing the OKR response; and (iii) analyze angular orientation data from the tracking program to yield a set of parameters that quantify essential elements of the OKR. The method can be employed without modification using the operating manual provided. In addition, annotated source code is included, allowing users to modify or adapt the software for other applications. RESULTS: We validated the algorithms and measured OKR responses in normal larval zebrafish, showing good agreement with published quantitative data, where available. COMPARISON WITH EXISTING METHOD(S): We provide the first open-source method to elicit and analyze the OKR in larval zebrafish. The wide range of parameters that are automatically quantified by our algorithms significantly expands the scope of quantitative analysis previously reported. CONCLUSIONS: Our method for quantifying OKR responses will be useful for numerous applications in neuroscience using the genetically- and chemically-tractable zebrafish model.