Traces, CSLBS Newsletter Summer 2023

With contributions from Matthew J. Smith, O.D. Jones, Sean Cham, Ella Sinclair, and Tacita Quinn

Bmi1+ Progenitor Cell Dynamics in Murine Cornea During Homeostasis and Wound Healing

The outermost layer of the eye, the cornea, is renewed continuously throughout life. Stem cells of the corneal epithelium reside in the limbus at the corneal periphery and ensure homeostasis of the central epithelium. However, in young mice, homeostasis relies on cells located in the basal layer of the central corneal epithelium. Here, we first studied corneal growth during the transition from newborn to adult and assessed Keratin 19 (Krt19) expression as a hallmark of corneal maturation. Next, we set out to identify a novel marker of murine corneal epithelial progenitor cells before, during and after maturation, and we found that Bmi1 is expressed in the basal epithelium of the central cornea and limbus. Furthermore, we demonstrated that Bmi1+ cells participated in tissue replenishment in the central cornea. These Bmi1+ cells did not maintain homeostasis of the cornea for more than 3 months, reflecting their status as progenitor rather than stem cells. Finally, after injury, Bmi1+ cells fueled homeostatic maintenance, whereas wound closure occurred via epithelial reorganization. Stem Cells 2018

Population pharmacokinetics of NNZ-2566 in healthy subjects

NNZ-2566 is a novel, small molecule being developed as a treatment for cognitive impairment in different CNS conditions, including Rett and Fragile-X syndrome, both of which are associated with moderate to severe neurodevelopmental disorder. In current study we characterise the population pharmacokinetics of NNZ-2566 after administration of single and repeated ascending doses to healthy subjects. A meta-analytical approach was used to analyse pharmacokinetic data from 3 different studies, in which a total of 61 healthy subjects (median age 23years, range 19 to 38) were treated with NNZ-2566. Doses of NNZ-2566 ranged from 6.0 to 100mg/kg after oral administration and from 0.1 to 30mg/kg after intravenous administration. A two-compartment model with first order absorption and elimination was found to best describe the pharmacokinetics of NNZ-2566. Inter-individual variability was identified in clearance, absorption rate, central volume of distribution, peripheral volume of distribution and inter-compartmental clearance. Population predicted clearance and central volume of distribution were 10.35L/h and 20.23L, respectively. No accumulation, metabolic inhibition or induction was observed during the course of treatment. Dose proportionality was observed across the dose range evaluated in healthy subjects. In addition, oral bioavailability appeared to vary with food intake. The relatively short half-life of 1.4h suggests the need for a twice or three times daily regimen to maintain relevant systemic levels of NNZ-2566 in plasma

Incidence of Atrial Fibrillation in Patients with either Heart Failure or Acute Myocardial Infarction and Left Ventricular Dysfunction: A Cohort Study

<p>Abstract</p> <p>Background</p> <p>We examined the incidence of new-onset atrial fibrillation in patients with left ventricular dysfunction. Patients either had a recent myocardial infarction (with or without clinical heart failure) or symptomatic heart failure (without a recent MI). Patients were with and without treatment with the class III antiarrhythmic drug dofetilide over 36 months.</p> <p>Methods</p> <p>The Danish Investigations of Arrhythmia and Mortality ON Dofetilide (DIAMOND) studies included 2627 patients without atrial fibrillation at baseline, who were randomised to treatment with either dofetilide or placebo.</p> <p>Results</p> <p>The competing risk analyses estimated the cumulative incidences of atrial fibrillation during the 42 months of follow-up to be 9.6% in the placebo-treated heart failure-group, and 2.9% in the placebo-treated myocardial infarction-group.</p> <p>Cox proportional hazard regression found a 42% significant reduction in the incidence of new-onset AF when assigned to dofetilide compared to placebo (hazard ratio 0.58, 95% confidence interval 0.40-0.82) and there was no interaction with study (p = 0.89).</p> <p>In the heart failure-group, the incidence of atrial fibrillation was significantly reduced to 5.6% in the dofetilide-treated patients (hazard ratio 0.57, 95% confidence interval 0.38-0.86).</p> <p>In the myocardial infarction-group the incidence of atrial fibrillation was reduced to 1.7% with the administration of dofetilide. This reduction was however not significant (hazard ratio 0.61, 95% confidence interval 0.30-1.24).</p> <p>Conclusion</p> <p>In patients with left ventricular dysfunction the incidence of AF in 42 months was 9.6% in patients with heart failure and 2.9% in patients with a recent MI. Dofetilide significantly reduced the risk of developing atrial fibrillation compared to placebo in the entire study group and in the subgroup of patients with heart failure. The reduction in the subgroup with recent MI was not statistically significant, but the hazard ratio was similar to the hazard ratio for the heart failure patients, and there was no difference between the effect in the two studies (p = 0.89 for interaction).</p

Sudden cardiac death in childhood RASopathy-associated hypertrophic cardiomyopathy: Validation of the HCM risk-kids model and predictors of events

Background: RASopathies account for nearly 20% of cases of childhood hypertrophic cardiomyopathy (HCM). Sudden cardiac death (SCD) occurs in patients with RASopathy-associated HCM, but the risk factors for SCD have not been systematically evaluated. Aim: To validate the HCM Risk-Kids SCD risk prediction model in children with RASopathy-associated HCM and investigate potential specific SCD predictors in this population. Methods: Validation of HCM Risk-Kids was performed in a retrospective cohort of 169 patients with a RASopathy-associated HCM from 15 international paediatric cardiology centres. Multiple imputation by chained equations was used for missing values related to the HCM Risk-Kids parameters. Results: Eleven patients (6.5%) experienced a SCD or equivalent event at a median age of 12.5 months (IQR 7.7–28.64). The calculated SCD/equivalent event incidence was 0.78 (95% CI 0.43–1.41) per 100 patient years. Six patients (54.54%) with an event were in the low-risk category according to the HCM Risk-Kids model. Harrell's C index was 0.60, with a sensitivity of 9.09%, specificity of 63.92%, positive predictive value of 1.72%, and negative predictive value of 91%; with a poor distinction between the different risk groups. Unexplained syncope (HR 42.17, 95% CI 10.49–169.56, p < 0.001) and non-sustained ventricular tachycardia (HR 5.48, 95% CI 1.58–19.03, p < 0.007) were predictors of SCD on univariate analysis. Conclusion: Unexplained syncope and the presence of NSVT emerge as predictors for SCD in children with RASopathy-associated HCM. The HCM Risk-Kids model may not be appropriate to use in this population, but larger multicentre collaborative studies are required to investigate this further

Azimuthal anisotropy and correlations at large transverse momenta in p+pp+p and Au+Au collisions at sNN\sqrt{s_{_{NN}}}= 200 GeV

Results on high transverse momentum charged particle emission with respect to the reaction plane are presented for Au+Au collisions at $\sqrt{s_{_{NN}}}$= 200 GeV. Two- and four-particle correlations results are presented as well as a comparison of azimuthal correlations in Au+Au collisions to those in $p+p$ at the same energy. Elliptic anisotropy, $v_2$, is found to reach its maximum at $p_t \sim 3$ GeV/c, then decrease slowly and remain significant up to $p_t\approx 7$ -- 10 GeV/c. Stronger suppression is found in the back-to-back high-$p_t$ particle correlations for particles emitted out-of-plane compared to those emitted in-plane. The centrality dependence of $v_2$ at intermediate $p_t$ is compared to simple models based on jet quenching.Comment: 4 figures. Published version as PRL 93, 252301 (2004

Azimuthal anisotropy in Au+Au collisions at sqrtsNN = 200 GeV

The results from the STAR Collaboration on directed flow (v_1), elliptic flow (v_2), and the fourth harmonic (v_4) in the anisotropic azimuthal distribution of particles from Au+Au collisions at sqrtsNN = 200 GeV are summarized and compared with results from other experiments and theoretical models. Results for identified particles are presented and fit with a Blast Wave model. Different anisotropic flow analysis methods are compared and nonflow effects are extracted from the data. For v_2, scaling with the number of constituent quarks and parton coalescence is discussed. For v_4, scaling with v_2^2 and quark coalescence is discussed.Comment: 26 pages. As accepted by Phys. Rev. C. Text rearranged, figures modified, but data the same. However, in Fig. 35 the hydro calculations are corrected in this version. The data tables are available at http://www.star.bnl.gov/central/publications/ by searching for "flow" and then this pape

Effects of Hylan G-F 20 supplementation on cartilage preservation detected by magnetic resonance imaging in osteoarthritis of the knee: a two-year single-blind clinical trial

<p>Abstract</p> <p>Background</p> <p>Although viscosupplementation is an effective symptomatic treatment for knee osteoarthritis (OA), the effect of longer term administration on articular cartilage has not been fully explored. We examined the effect of viscosupplementation with Hylan G-F 20 on knee cartilage over 2 years in patients with knee OA.</p> <p>Methods</p> <p>In this prospective, single-blind, parallel control group pilot study, 78 patients with symptomatic knee OA (Kellgren-Lawrence grade II and III) were assigned to either intervention group (n = 39 receiving 4 courses of 3 × 2.0 ml of intra-articular Hylan G-F 20 injections at 6 month intervals) or control group (n = 39 receiving usual care for knee OA without injections). Magnetic resonance imaging of the study knee was performed at baseline, 12 and 24 months. Cartilage volume and defects were assessed using validated methods.</p> <p>Results</p> <p>Fifty-five subjects (71%) completed 24 month follow up. Over 24 months, the intervention group had a reduced annual percentage rate of medial and lateral tibial cartilage volume loss (mean ± SD, -0.3 ± 2.7% and -1.4 ± 4.3%) compared with the control group (2.3 ± 2.6% and 1.4 ± 2.6%, P = 0.001 and 0.005 for difference, respectively). The intervention group also showed reduced cartilage defect score increment in the medial tibiofemoral compartment (0.1 ± 1.3) compared with the control group (0.8 ± 1.5, P = 0.05).</p> <p>Conclusions</p> <p>Six monthly intra-articular injections of Hylan G-F 20 administered to patients with symptomatic knee OA have a beneficial effect on knee cartilage preservation measured by both cartilage volume and cartilage defects. Hylan G-F 20 warrants further evaluation in larger clinical trials as a possible disease-modifying agent in the treatment of knee OA.</p> <p>Trial Registration</p> <p>The study was registered with ClinicalTrials.gov (<a href="http://www.clinicaltrials.gov/ct2/show/NCT00393393">NCT00393393</a>).</p