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Open Access Publications from the University of California

Scholarly Works (77 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2013)

Through the use of molecular dynamics simulations, we show that fragmentation of amyloid beta (16-42) protofilaments occurs through the formation of water-conducting glycine vents surrounding the inner pore which then propagate under the increased stress due to C-terminal wrapping. We find that longer protofilaments have an increased propensity to fracture and that the stress-induced propagation of glycine vents is alleviated by thickening of the protofilament to cover exposed hydrophobic residues and reduce C-terminal wrapping. Moreover, we propose that the intrinsic flexibility of glycine-29 in the loop region plays a critical role in the fragmentation of protofilaments. We support this hypothesis by conducting a 1 ns MD simulation on a G29P-mutated 20-mer protofilament. Our results indicate that the increased rigidity of the loop region due to the proline mutation forces the C-terminal to wrap in the opposite direction and therefore prevents the opening of glycine vents, effectively inhibiting fragmentation.

    Cover page: Molecular Dynamics Study of Fragmentation in Protofilaments of Amyloid Beta (16-42)
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2018)
    White matter abnormalities are prevalent in neuropsychiatric disorders such as schizophrenia, but it is unclear whether these abnormalities represent a cause or consequence of these disorders. Reduced levels of the myelin protein 2'-3'-cyclic nucleotide 3'-phosphodiesterase (CNP) are associated with the schizophrenic symptom catatonia in both humans and mouse models. In this issue of the JCI, Janova et al. show that reduced CNP levels correlate with catatonia and white matter inflammation in human subjects. Furthermore, they demonstrate that microglial ablation prevents and alleviates catatonic signs in Cnp-/- mice, indicating that microglial-mediated inflammation causes catatonia. Together, this study identifies a cellular mechanism by which subtle myelin abnormalities cause low-grade neuroinflammation and catatonic behavior.
      Cover page: Micro(glial)-managing executive function: white matter inflammation drives catatonia
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2021)
      Myelin, multilayered lipid-rich membrane extensions formed by oligodendrocytes around neuronal axons, is essential for fast and efficient action potential propagation in the central nervous system. Initially thought to be a static and immutable process, myelination is now appreciated to be a dynamic process capable of responding to and modulating neuronal function throughout life. While the importance of this type of plasticity, called adaptive myelination, is now well accepted, we are only beginning to understand the underlying cellular and molecular mechanisms by which neurons communicate experience-driven circuit activation to oligodendroglia and precisely how changes in oligodendrocytes and their myelin refine neuronal function. Here, we review recent findings addressing this reciprocal relationship in which neurons alter oligodendroglial form and oligodendrocytes conversely modulate neuronal function.
        Cover page: Building a (w)rapport between neurons and oligodendroglia: Reciprocal interactions underlying adaptive myelination
        • Article
        • Peer Reviewed
        UC San Francisco Previously Published Works (2024)
        BACKGROUND: Preterm white matter injury (PWMI) is the most common cause of brain injury in premature neonates. PWMI involves a differentiation arrest of oligodendrocytes, the myelinating cells of the central nervous system. Clemastine was previously shown to induce oligodendrocyte differentiation and myelination in mouse models of PWMI at a dose of 10 mg/kg/day. The minimum effective dose (MED) of clemastine is unknown. Identification of the MED is essential for maximizing safety and efficacy in neonatal clinical trials. We hypothesized that the MED in neonatal mice is lower than 10 mg/kg/day. METHODS: Mouse pups were exposed to normoxia or hypoxia (10% FiO2) from postnatal day 3 (P3) through P10. Vehicle or clemastine at one of four doses (0.5, 2, 7.5 or 10 mg/kg/day) was given to hypoxia-exposed pups. Myelination was assessed at age P14 and 10 weeks to determine the MED. Clemastine pharmacokinetics were evaluated at steady-state on day 8 of treatment. RESULTS: Clemastine rescued hypoxia-induced hypomyelination with a MED of 7.5 mg/kg/day. Pharmacokinetic analysis of the MED revealed Cmax 44.0 ng/mL, t1/2 4.6 h, and AUC24 280.1 ng*hr/mL. CONCLUSIONS: Based on these results, myelination-promoting exposures should be achievable with oral doses of clemastine in neonates with PWMI. IMPACT: Preterm white matter injury (PWMI) is the most common cause of brain injury and cerebral palsy in premature neonates. Clemastine, an FDA-approved antihistamine, was recently identified to strongly promote myelination in a mouse model of PWMI and is a possible treatment. The minimum effective dose in neonatal rodents is unknown and is critical for guiding dose selection and balancing efficacy with toxicity in future clinical trials. We identified the minimum effective dose of clemastine and the associated pharmacokinetics in a murine chronic hypoxia model of PWMI, paving the way for a future clinical trial in human neonates.
          Cover page: Minimum effective dose of clemastine in a mouse model of preterm white matter injury.
          • Article
          • Peer Reviewed
          UC San Diego Previously Published Works (2023)
          BACKGROUND: Catheter ablation improves outcomes in symptomatic atrial fibrillation (AF) patients. However, its safety and efficacy in the very elderly (≥80 years old) is not well described. HYPOTHESIS: Ablation of AF in the very elderly is safe and effective. METHODS: We performed a retrospective study of all patients who underwent catheter ablation enrolled in the University of California, San Diego AF Ablation Registry. The primary outcome was freedom from atrial arrhythmias on or off antiarrhythmic drugs (AADs). RESULTS: Of 847 patients, 42 (5.0%) were 80 years of age or greater with a median age of 81.5 (80-82.3) and 805 (95.0%) were less than 80 years of age with a median age of 64.4 (57.6-70.2). Among those who were ≥80 years old, 29 were undergoing de novo ablation (69.0%), whereas in the younger cohort, 518 (64.5%) were undergoing de novo ablation (p = .548). There were no statistically significant differences in fluoroscopy (p = .406) or total procedure times (p = .076), AAD use (p = .611), or procedural complications (p = .500) between groups. After multivariable adjustment, there were no statistically significant differences in recurrence of any atrial arrhythmias on or off AAD (adjusted hazard ratio [AHR]: 0.75; 95% confidence interval [CI]: 0.45-1.23; p = .252), all-cause hospitalizations (AHR: 0.86; 95% CI: 0.46-1.60; p = .626), or all-cause mortality (AHR: 4.48; 95% CI: 0.59-34.07; p = .147) between the very elderly and the younger cohort. CONCLUSION: In this registry analysis, catheter ablation of AF appears similarly effective and safe in patients 80 years or older when compared to a younger cohort.
            Cover page: Safety and efficacy of catheter ablation of atrial fibrillation in the very elderly (≥80 years old): Insights from the UC San Diego AF Ablation Registry.
            • Article
            • Peer Reviewed
            UC San Diego Previously Published Works (2019)
            Obesity and atrial fibrillation (AF) are growing epidemics with significant overlap in co-morbidities. Multiple smaller studies have evaluated the effects of weight loss and risk factor modification on recurrence of AF, reduction in AF burden and improvement in AF symptom severity. The objective of this study was to determine if a modest weight loss of ≥10% of initial body weight is enough to improve outcomes in overweight or obese patients with established AF. We performed an extensive literature search and systematic review of studies that compared weight loss of ≥10% versus weight loss of less than 10% or weight gain and assessed outcomes including recurrence of AF as determined through a Holter monitor, AF burden and improvement in AF symptom severity. Risk ratio 95% confidence intervals (CI) were measured for dichotomous variables and mean difference (MD) 95% CI were measured for continuous variables, where MD >0 favors the group with ≥10% weight loss. Five studies with a total of 548 patients were included. Patients who lost ≥10% of their initial body weight experienced less recurrence of AF (risk ratio 0.29; 95% CI 0.19 to 0.44) and a larger reduction in reported event frequency (MD 1.74; 95% CI 0.70 to 2.79), episode duration (MD 2.14; 95% CI 0.04 to 4.23), global episode severity (MD 1.89; 95% CI 1.34 to 2.45), and symptom severity (MD 5.36; 95% CI 3.75 to 6.97). In conclusion, weight loss is associated with less risk of recurrent AF, reduction in AF burden, and improvement in AF symptom severity.
              Cover page: Meta-analysis of Effect of Modest (≥10%) Weight Loss in Management of Overweight and Obese Patients With Atrial Fibrillation.
              • Article
              • Peer Reviewed
              UC San Diego Previously Published Works (2022)

              Purpose

              Mitral annular flutter (MAF) is a common arrhythmia after atrial fibrillation ablation. We sought to compare the efficacy and safety of catheter ablation utilizing either a left atrial anterior wall (LAAW) line or a lateral mitral isthmus (LMI) line.

              Methods

              We performed a systematic review for all studies that compared LAAW versus LMI lines. Risk ratio (RR) and mean difference (MD) 95% confidence intervals were measured for dichotomous and continuous variables, respectively.

              Results

              Four studies with a total of 594 patients were included, one of which was a randomized control trial. In the LMI ablation group, 40% of patients required CS ablation. There were no significant differences in bidirectional block (RR 1.26; 95% CI, 0.94-1.69) or ablation time (MD -1.5; 95% CI, -6.11-3.11), but LAAW ablation was associated with longer ablation line length (MD 11.42; 95% CI, 10.69-12.14) and longer LAA activation delay (MD 67.68; 95% CI, 33.47-101.89.14) when compared to LMI. There was no significant difference in pericardial effusions (RR 0.36; 95% CI, 0.39-20.75) between groups and more patients were maintained sinus rhythm (RR 1.19; 95% CI, 1.03-1.37, p = 0.02) who underwent LAAW compared to LMI.

              Conclusion

              Ablation of mitral annular flutter with a LAAW line compared to a LMI line showed no difference in rates of acute bidirectional block, ablation time, or pericardial effusion. However, LAAW ablation required a longer ablation line length, resulted in greater LAA activation delayed and was associated with more sinus rhythm maintenance, with the added advantage of avoiding ablation in the CS.
                Cover page: Ablation of mitral annular flutter ablation utilizing a left atrial anterior line versus a lateral mitral isthmus line: a systematic review and meta-analysis
                • Article
                • Peer Reviewed
                UC San Diego Previously Published Works (2022)
                BACKGROUND: The accuracy of noninvasive arrhythmia source localization using a forward-solution computational mapping system has not yet been evaluated in blinded, multicenter analysis. This study tested the hypothesis that a computational mapping system incorporating a comprehensive arrhythmia simulation library would provide accurate localization of the site-of-origin for atrial and ventricular arrhythmias and pacing using 12-lead ECG data when compared with the gold standard of invasive electrophysiology study and ablation. METHODS: The VMAP study (Vectorcardiographic Mapping of Arrhythmogenic Probability) was a blinded, multicenter evaluation with final data analysis performed by an independent core laboratory. Eligible episodes included atrial and ventricular: tachycardia, fibrillation, pacing, premature atrial and ventricular complexes, and orthodromic atrioventricular reentrant tachycardia. Mapping system results were compared with the gold standard site of successful ablation or pacing during electrophysiology study and ablation. Mapping time was assessed from time-stamped logs. Prespecified performance goals were used for statistical comparisons. RESULTS: A total of 255 episodes from 225 patients were enrolled from 4 centers. Regional accuracy for ventricular tachycardia and premature ventricular complexes in patients without significant structural heart disease (n=75, primary end point) was 98.7% (95% CI, 96.0%-100%; P<0.001 to reject predefined H0 <0.80). Regional accuracy for all episodes (secondary end point 1) was 96.9% (95% CI, 94.7%-99.0%; P<0.001 to reject predefined H0 <0.75). Accuracy for the exact or neighboring segment for all episodes (secondary end point 2) was 97.3% (95% CI, 95.2%-99.3%; P<0.001 to reject predefined H0 <0.70). Median spatial accuracy was 15 mm (n=255, interquartile range, 7-25 mm). The mapping process was completed in a median of 0.8 minutes (interquartile range, 0.4-1.4 minutes). CONCLUSIONS: Computational ECG mapping using a forward-solution approach exceeded prespecified accuracy goals for arrhythmia and pacing localization. Spatial accuracy analysis demonstrated clinically actionable results. This rapid, noninvasive mapping technology may facilitate catheter-based and noninvasive targeted arrhythmia therapies. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04559061.
                  Cover page: Forward-Solution Noninvasive Computational Arrhythmia Mapping: The VMAP Study.
                  • Article
                  • Peer Reviewed
                  UC San Diego Previously Published Works (2023)

                  Background

                  High-dose isoproterenol infusion is a useful provocative maneuver to elicit triggers of atrial fibrillation (AF) during ablation. We evaluated whether the use of isoproterenol infusion to elicit triggers of AF after ablation is associated with differential outcomes.

                  Methods

                  We performed a retrospective study of all patients who underwent de novo radiofrequency catheter ablation of AF enrolled in the University of California, San Diego AF Ablation Registry. The primary outcome was freedom from atrial arrhythmias on or off antiarrhythmic drugs (AAD).

                  Results

                  Of 314 patients undergoing AF ablation, 235 (74.8%) received isoproterenol while 79 (25.2%) did not. Among those who received isoproterenol, 11 (4.7%) had additional triggers identified. There were no statistically significant differences in procedure time (p = 0.432), antiarrhythmic drug use (p = 0.289), procedural complications (p = 0.279), recurrences of atrial arrhythmias on or off AAD [adjusted hazard ratio (AHR) 0.92 (95% CI 0.58-1.46); p = 0.714], all-cause hospitalizations [AHR 1.00 (95% CI 0.60-1.67); p = 0.986], or all-cause mortality [AHR 0.14 (95% CI 0.01-3.52); p = 0.229] between groups.

                  Conclusions

                  In this registry analysis, use of isoproterenol is safe but was not associated with a reduction in recurrence of atrial arrhythmias.
                    Cover page: Association of isoproterenol infusion during catheter ablation of atrial fibrillation with outcomes: insights from the UC San Diego AF Ablation Registry
                    • Article
                    • Peer Reviewed
                    UC San Diego Previously Published Works (2019)

                    Obesity and atrial fibrillation (AF) are growing epidemics with significant overlap in co-morbidities. Multiple smaller studies have evaluated the effects of weight loss and risk factor modification on recurrence of AF, reduction in AF burden and improvement in AF symptom severity. The objective of this study was to determine if a modest weight loss of ≥10% of initial body weight is enough to improve outcomes in overweight or obese patients with established AF. We performed an extensive literature search and systematic review of studies that compared weight loss of ≥10% versus weight loss of less than 10% or weight gain and assessed outcomes including recurrence of AF as determined through a Holter monitor, AF burden and improvement in AF symptom severity. Risk ratio 95% confidence intervals (CI) were measured for dichotomous variables and mean difference (MD) 95% CI were measured for continuous variables, where MD >0 favors the group with ≥10% weight loss. Five studies with a total of 548 patients were included. Patients who lost ≥10% of their initial body weight experienced less recurrence of AF (risk ratio 0.29; 95% CI 0.19 to 0.44) and a larger reduction in reported event frequency (MD 1.74; 95% CI 0.70 to 2.79), episode duration (MD 2.14; 95% CI 0.04 to 4.23), global episode severity (MD 1.89; 95% CI 1.34 to 2.45), and symptom severity (MD 5.36; 95% CI 3.75 to 6.97). In conclusion, weight loss is associated with less risk of recurrent AF, reduction in AF burden, and improvement in AF symptom severity.

                      Cover page: Meta-analysis of Effect of Modest (≥10%) Weight Loss in Management of Overweight and Obese Patients With Atrial Fibrillation.
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