Impact of functional studies on exome sequence variant interpretation in early-onset cardiac conduction system diseases

Aims The genetic cause of cardiac conduction system disease (CCSD) has not been fully elucidated. Whole-exome sequencing (WES) can detect various genetic variants; however, the identification of pathogenic variants remains a challenge. We aimed to identify pathogenic or likely pathogenic variants in CCSD patients by using WES and 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines as well as evaluating the usefulness of functional studies for determining them. Methods and Results We performed WES of 23 probands diagnosed with early-onset (<65 years) CCSD and analyzed 117 genes linked to arrhythmogenic diseases or cardiomyopathies. We focused on rare variants (minor allele frequency < 0.1%) that were absent from population databases. Five probands had protein truncating variants in EMD and LMNA which were classified as “pathogenic” by 2015 ACMG standards and guidelines. To evaluate the functional changes brought about by these variants, we generated a knock-out zebrafish with CRISPR-mediated insertions or deletions of the EMD or LMNA homologs in zebrafish. The mean heart rate and conduction velocities in the CRISPR/Cas9-injected embryos and F2 generation embryos with homozygous deletions were significantly decreased. Twenty-one variants of uncertain significance were identified in 11 probands. Cellular electrophysiological study and in vivo zebrafish cardiac assay showed that 2 variants in KCNH2 and SCN5A, 4 variants in SCN10A, and 1 variant in MYH6 damaged each gene, which resulted in the change of the clinical significance of them from “Uncertain significance” to “Likely pathogenic” in 6 probands. Conclusions Of 23 CCSD probands, we successfully identified pathogenic or likely pathogenic variants in 11 probands (48%). Functional analyses of a cellular electrophysiological study and in vivo zebrafish cardiac assay might be useful for determining the pathogenicity of rare variants in patients with CCSD. SCN10A may be one of the major genes responsible for CCSD. Translational Perspective Whole-exome sequencing (WES) may be helpful in determining the causes of cardiac conduction system disease (CCSD), however, the identification of pathogenic variants remains a challenge. We performed WES of 23 probands diagnosed with early-onset CCSD, and identified 12 pathogenic or likely pathogenic variants in 11 of these probands (48%) according to the 2015 ACMG standards and guidelines. In this context, functional analyses of a cellular electrophysiological study and in vivo zebrafish cardiac assay might be useful for determining the pathogenicity of rare variants, and SCN10A may be one of the major development factors in CCSD

Coincidence analysis to search for inspiraling compact binaries using TAMA300 and LISM data

Japanese laser interferometric gravitational wave detectors, TAMA300 and LISM, performed a coincident observation during 2001. We perform a coincidence analysis to search for inspiraling compact binaries. The length of data used for the coincidence analysis is 275 hours when both TAMA300 and LISM detectors are operated simultaneously. TAMA300 and LISM data are analyzed by matched filtering, and candidates for gravitational wave events are obtained. If there is a true gravitational wave signal, it should appear in both data of detectors with consistent waveforms characterized by masses of stars, amplitude of the signal, the coalescence time and so on. We introduce a set of coincidence conditions of the parameters, and search for coincident events. This procedure reduces the number of fake events considerably, by a factor $\sim 10^{-4}$ compared with the number of fake events in single detector analysis. We find that the number of events after imposing the coincidence conditions is consistent with the number of accidental coincidences produced purely by noise. We thus find no evidence of gravitational wave signals. We obtain an upper limit of 0.046 /hours (CL $= 90$) to the Galactic event rate within 1kpc from the Earth. The method used in this paper can be applied straightforwardly to the case of coincidence observations with more than two detectors with arbitrary arm directions.Comment: 28 pages, 17 figures, Replaced with the version to be published in Physical Review

Results of the search for inspiraling compact star binaries from TAMA300's observation in 2000-2004

We analyze the data of TAMA300 detector to search for gravitational waves from inspiraling compact star binaries with masses of the component stars in the range 1-3Msolar. In this analysis, 2705 hours of data, taken during the years 2000-2004, are used for the event search. We combine the results of different observation runs, and obtained a single upper limit on the rate of the coalescence of compact binaries in our Galaxy of 20 per year at a 90% confidence level. In this upper limit, the effect of various systematic errors such like the uncertainty of the background estimation and the calibration of the detector's sensitivity are included.Comment: 8 pages, 4 Postscript figures, uses revtex4.sty The author list was correcte

Patency of separate tube grafts for intercostal artery reconstruction: Size and length matter

Objectives. Low patency is a major concern when using separate tube grafts for intercostal artery reconstruction. We aimed to elucidate the optimal size and length of grafts from the patency and computational fluid dynamics. Methods. The patency, size, and length of separate tube grafts were evaluated in 41 patients. Computational fluid dynamics simulation was performed in a model derived from a patient with a patent 12-mm graft of 15mm in length, with 2 simulation models with a smaller (8-mm) or longer (30-mm) graft. Results. A total of 49 grafts were used for intercostal artery reconstruction. There was 1 in-hospital death and 2 spinal cord injuries. The patency rate, which could be evaluated in 46 grafts, was 63% (29/46). It was 71% (24/34) in thoracoabdominal aortic replacement and 42% (5/12) in descending aortic replacement. Among 14 patients in whom all grafts were occluded, no patients developed spinal cord injury. All grafts longer than 25mm were occluded (n=5). Eight- and 10-mm grafts showed better patency than 12-mm grafts in thoracoabdominal aortic replacement (p=0.008), when grafts were shorter than 25mm. Computational fluid dynamics simulation revealed vortical flow within the 12-mm graft, which did not reach the intercostal orifice, while helical flow was maintained throughout the cardiac cycle within the 8-mm graft. Conclusions. Eight- and 10-mm grafts seemed better than 12-mm grafts, and grafts should be kept shorter than 25mm. Computational fluid dynamics simulation may shed light on the issue of optimal intercostal artery reconstruction technique.journal articl

18-fluorodeoxyglucose positron emission tomography in the diagnosis of prosthetic aortic graft infection; difference between open and endovascular repair

雑誌掲載タイトル：18-Fluorodeoxyglucose positron emission tomography in the diagnosis of prosthetic aortic graft infection: the difference between open and endovascular repair[Objective] 18F-FDG PET/CT has been reported useful for diagnosing aortic graft infection. However, 18F-FDG uptake may depend upon various factors including open vs endovascular repair and time from surgery. We aimed to elucidate the factors influencing its uptake and the diagnostic value of 18F-FDG PET/CT after open and endovascular repair. [Methods] Hospital database of PET/CT (N=14490) and our departmental database were cross-checked to identify those who underwent 18F-FDG PET/CT after aortic repair. Patient’s data were retrieved from the chart. Images were reviewed by two nuclear medicine specialists in consensus, and the presence of increased 18F-FDG uptake was recorded. The maximum standardized uptake value (SUV max) was measured. [Results] Among the 1112 patients who underwent aortic repair between 2011 and 2022, 71 patients were identified. Eighteen patients underwent 18F-FDG PET/CT for suspected graft infection and the remaining 53 patients for other purposes (malignancy etc.). Fourteen patients were treated as aortic graft infection. They had significantly higher SUV max than those without graft infection (mean 8.64 (SD2.78) vs 3.40 (SD0.84); p<0.01). In the non-infected grafts, SUV max was higher early after open surgical repair, while it remained low after endovascular repair. [Conclusion] After endovascular aortic repair, a constant cut-off value of “SUV max=4.5” seems appropriate for diagnosing graft infection, since it remains low and stable from the early postoperative period. After open surgical repair, it seems acceptable to have “stepwise cut-off value” depending on the time from surgery.journal articl

PK20, a new opioid-neurotensin hybrid peptide that exhibits central and peripheral antinociceptive effects

<p>Abstract</p> <p>Background</p> <p>The clinical treatment of various types of pain relies upon the use of opioid analgesics. However most of them produce, in addition to the analgesic effect, several side effects such as the development of dependence and addiction as well as sedation, dysphoria, and constipation. One solution to these problems are chimeric compounds in which the opioid pharmacophore is hybridized with another type of compound to incease antinociceptive effects. Neurotensin-induced antinociception is not mediated through the opioid system. Therefore, hybridizing neurotensin with opioid elements may result in a potent synergistic antinociceptor.</p> <p>Results</p> <p>Using the known structure-activity relationships of neurotensin we have synthesized a new chimeric opioid-neurotensin compound PK20 which is characterized by a very strong antinociceptive potency. The observation that the opioid antagonist naltrexone did not completely reverse the antinociceptive effect, indicates the partial involvement of the nonopioid component in PK20 in the produced analgesia.</p> <p>Conclusions</p> <p>The opioid-neurotensin hybrid analogue PK20, in which opioid and neurotensin pharmacophores overlap partially, expresses high antinociceptive tail-flick effects after central as well as peripheral applications.</p

Characteristics of Community-living Elderly People with a Slight Decline in Higher-level Functional Capacity

departmental bulletin pape

Observation results by the TAMA300 detector on gravitational wave bursts from stellar-core collapses

We present data-analysis schemes and results of observations with the TAMA300 gravitational-wave detector, targeting burst signals from stellar-core collapse events. In analyses for burst gravitational waves, the detection and fake-reduction schemes are different from well-investigated ones for a chirp-wave analysis, because precise waveform templates are not available. We used an excess-power filter for the extraction of gravitational-wave candidates, and developed two methods for the reduction of fake events caused by non-stationary noises of the detector. These analysis schemes were applied to real data from the TAMA300 interferometric gravitational wave detector. As a result, fake events were reduced by a factor of about 1000 in the best cases. The resultant event candidates were interpreted from an astronomical viewpoint. We set an upper limit of 2.2x10^3 events/sec on the burst gravitational-wave event rate in our Galaxy with a confidence level of 90%. This work sets a milestone and prospects on the search for burst gravitational waves, by establishing an analysis scheme for the observation data from an interferometric gravitational wave detector

Factors associated with mortality among patients with culture-positive pulmonary tuberculosis in the urban poor population of Osaka City, Japan

Objective: To determine the characteristics associated with mortality in patients with culture-positive pulmonary tuberculosis (PTB) in Airin, Osaka City, Japan. Methods: The characteristics of patients with culture-positive PTB registered between 2015 and 2018 in Airin, Osaka City, Japan, were compared between those who died of all causes before or during treatment and those who completed treatment. Results: Of the 241 culture-positive PTB patients eligible for this study, 170 completed treatment, with negative sputum culture tests, and 62 died. The all-cause case fatality rate was 26.7% (62/232). Multivariate analysis showed that mortality was associated with age >70 years, having a positive sputum smear, a body mass index of <18.5 and serious comorbidities such as cancer and heart and renal disease. Detection of tuberculosis (TB) by screening or in an outpatient department (OPD) for other diseases was inversely associated with mortality. Discussion: Detection of PTB by chest X-ray screening and during regular visits to OPDs for other diseases was associated with non-fatal TB and might contribute to early case finding. Therefore, current active TB case finding and health education on regular visits to physicians for other diseases should be strengthened further for the urban poor population of Osaka City, Japan

Usefulness of the Timed up-and-go (TUG) Test as an Indicator for Care Prevention Among Community-dwelling Elderly

departmental bulletin pape