PITX2 gain-of-function mutation associated with atrial fibrillation alters mitochondrial activity in human iPSC atrial-like cardiomyocytes.

Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide; however, the underlying causes of AF initiation are still poorly understood, particularly because currently available models do not allow in distinguishing the initial causes from maladaptive remodeling that induces and perpetuates AF. Lately, the genetic background has been proven to be important in the AF onset. iPSC-derived cardiomyocytes, being patient- and mutation-specific, may help solve this diatribe by showing the initial cell-autonomous changes underlying the development of the disease. Transcription factor paired-like homeodomain 2 (PITX2) has been identified as a key regulator of atrial development/differentiation, and the PITX2 genomic locus has the highest association with paroxysmal AF. PITX2 influences mitochondrial activity, and alterations in either its expression or function have been widely associated with AF. In this work, we investigate the activity of mitochondria in iPSC-derived atrial cardiomyocytes (aCMs) obtained from a young patient (24 years old) with paroxysmal AF, carrying a gain-of-function mutation in PITX2 (rs138163892) and from its isogenic control (CTRL) in which the heterozygous point mutation has been reverted to WT. PITX2 aCMs show a higher mitochondrial content, increased mitochondrial activity, and superoxide production under basal conditions when compared to CTRL aCMs. However, increasing mitochondrial workload by FCCP or ß-adrenergic stimulation allows us to unmask mitochondrial defects in PITX2 aCMs, which are incapable of responding efficiently to the higher energy demand, determining ATP deficiency.

Prevalence of latent tuberculosis infection among foreign students in Lübeck, Germany tested with QuantiFERON-TB Gold In-Tube and QuantiFERON-TB Gold Plus.

BACKGROUND: The tuberculosis (TB) incidence rate in foreign-born individuals has been increasing in Germany in recent years. Foreign students may be an important source of latent tuberculosis infection (LTBI) in low-incidence countries. In Germany, there are no guidelines for LTBI screening of foreign students. The aim of the study was to estimate LTBI prevalence and evaluate associated risk factors among foreign students in Germany. The second purpose of our study was to compare the results of the new generation of QuantiFERON-TB Gold Plus (QFT-Plus) to those of its predecessor QuantiFERON-TB Gold In-Tube (QFT-GIT). METHODS: This cross-sectional study was conducted between February 2016 and March 2016. Foreign students and young professionals attending the university and higher education institutes in Lübeck, Germany were tested with QFT-Plus and QFT-GIT. Participants filled out a questionnaire for the purpose of LTBI risk assessment and analysis. Variables associated with a positive test result were analyzed using logistic regression. RESULTS: One hundred thirty four students participated in the study. The overall prevalence as regards positive results from both tests, QFT-Plus and QFT-GIT, was 9.7%, and the prevalence of positive QFT-Plus results was 8.2%. The main independent variables associated with a positive QFT-Plus result were a) being born in a high-incidence country (OR = 6.7, 95% CI: 1.3-34.3) and b) previous contact with a person with active TB (OR = 4.5, 95% CI: 1.1-18.3). Higher age (OR = 2.8, 95% CI: 0.7-11.3) and male gender (OR = 1.6, 95% CI: 0.4-6.7) showed a tendency toward positive QFT-Plus results but this was not statistically significant. Agreement between QFT-Plus and QFT-GIT results was κ = 0.85, p < 0.001. CONCLUSIONS: The LTBI prevalence among foreign students was about 10%. We recommend implementing a policy whereby all foreign students are screened by means of a questionnaire about LTBI risk factors, so that only students with present risk factors are tested for LTBI. The agreement between the new QFT-Plus and the QFT-GIT (κ = 0.85) was good. QFT-Plus might be used in the same format as its predecessor.

Retinal asymmetry in children measured with optical coherence tomography.

PURPOSE: To determinate the physiological asymmetry of retinal measurements in the pediatric population with Fourier-domain optical coherence tomography (Cirrus HD-OCT). DESIGN: Prospective cross-sectional study. METHODS: Three hundred and fifty-seven healthy children were recruited. All subjects underwent a comprehensive ophthalmologic examination and an evaluation of the retinal nerve fiber layer (RNFL), optic nerve head, and macula with Cirrus OCT. Differences between right and left eyes were calculated and values were compared by means of a paired t test. Normal ranges of interocular differences were established as the 2.5th and the 97.5th percentiles. The correlations between right and left eyes were assessed by the intraclass correlation coefficients. RESULTS: Mean best-corrected visual acuity (logMAR) was -0.01. Differences in the average RNFL between right and left eyes were not statistically significant. The RNFL in the right eyes was thicker in the temporal and nasal quadrants, whereas the left eyes showed thicker RNFL in the superior quadrant. The interocular difference tolerance limits for average RNFL and macular thicknesses were 13.00 µm and 23.20 µm, respectively. There was a strong correlation for all the parameters between the right and the left eyes. CONCLUSIONS: The asymmetry of retinal parameters might be more valuable than the absolute values in assessing certain early diseases. The interocular differences in average RNFL and macular thickness of normal individuals should not exceed 13 µm and 23 µm, respectively, if measured with Cirrus HD-OCT.

Reproducibility of optical coherence tomography measurements in children.

PURPOSE: To determine the interobserver and intraobserver reproducibility of a Fourier-domain optical coherence tomography device (Cirrus HD OCT; Carl Zeiss Meditec, Dublin, California, USA) in normal pediatric eyes. DESIGN: Prospective cross-sectional study. METHODS: One hundred healthy children were recruited prospectively and consecutively. Only 1 randomly chosen eye per subject was included in the study. The eye underwent 3 scans centered on the optic disc and another 3 scans centered on the macula that were acquired by a single operator. A fourth examination was performed by a second operator. Interobserver and intraobserver reproducibility were described by intraclass correlation coefficients (ICCs) and coefficients of variation (COVs). RESULTS: The mean age was 9.15 years (range, 6.22 to 11.31 years; standard deviation, 1.05 years). Mean retinal nerve fiber layer thickness was 99.53 µm (standard deviation, 10.10 µm), and mean macular thickness was 282.91 µm (standard deviation, 11.83 µm). All the parameters evaluated were highly reproducible. Intraobserver COVs of the retinal nerve fiber layer measurements ranged from 2.24% to 5.52%, and the COV of macular thickness was 0.97%. The intraclass correlation coefficient was greater than 0.8 for all the parameters. The interobserver COV ranged from 2.23% to 5.18%, and the COV of macular thickness was 0.82%. In all the evaluated parameters, the intraclass correlation coefficient was more than 0.75. Repeatability was slightly better in children older than 10 years than in children younger than 9 years. CONCLUSIONS: Retinal nerve fiber layer and macular measurements obtained by Fourier-domain optical coherence tomography showed good repeatability for healthy eyes in the pediatric population. Cirrus HD OCT examinations of the retina are reliable in children.

Normal reference ranges of optical coherence tomography parameters in childhood.

OBJECTIVE: To report normal reference values for peripapillary retinal nerve fibre layer (RNFL) thickness and optic disc parameters in children from a community population. METHODS: The authors performed a cross-sectional study examining RNFL and optic nerve head (ONH) properties in 358 children aged between 6 and 13 years with no ocular disease. All children underwent an ophthalmic examination that included visual acuity (logMAR), stereopsis assessment (TNO) and optical coherence tomography (Cirrus OCT Zeiss, 'Optic Disc Cube 200×200' protocol). One eye from each subject selected at random was finally analysed. The authors evaluated the influence of height, gender and age on measurements. RESULTS: High-quality scan data were obtained from 357 children and 344 were finally included. The mean age (SD) was 9.16 (1.7) years and the mean (SD) RNFL average thickness was 98.46 (10.79) µm. The temporal quadrant showed the thinnest RNFL (69.35±11.28 µm), followed by the nasal (71.30±13.45 µm), superior (123.65±19.49 µm) and inferior (130.18±18.13 µm) quadrants. The mean rim area (SD) and disc area (SD) were 1.59 (0.33) and 2.05 (0.39) mm(2), respectively. The average cup to disc (C:D) ratio (SD) was 0.43 (0.19). The authors found no differences in any of the parameters with regard to weight, height and gender. CONCLUSIONS: This study demonstrates normative values of RNFL thickness and ONH parameters in a sample of Caucasian children from the general population.