Predictors of blood pressure and hypertension long-term after treatment of isolated coarctation of the aorta in children-a population-based study

OBJECTIVES The aim of this study was to assess predictors of BP and hypertension and relations between BP and LV mass in a population-based retrospective study of repaired isolated coarctation of aorta. METHODS We collected follow-up data until 2018 of 284/304 (93%) patients with coarctation treated by surgery (n = 235) or balloon angioplasty/stent (n = 37/12) in our unit 2000-2012. Systolic hypertension was defined as systolic BP (SBP) z-score >=+2 standard deviation (SD) or regular use of BP medication. LV hypertrophy was defined as LV mass z-score >=+2 SD or LV mass index g/m(2.7) >= 95th percentile. RESULTS The median (25-75th percentiles) follow-up time and age at follow-up were 9.7 years (6.9-13.2) and 11.8 years (7.9-16.0), respectively. Age at first procedure (P = 0.011) and systolic arm-leg-gradient (P = 0.007) were positively and transverse arch (P = 0.007) and isthmus diameter (P = 0.001) z-scores at follow-up were negatively associated with SBP z-score adjusted for age at follow-up and need for reintervention for coarctation. Systolic hypertension was present in 53/284 (18.7%) and related with increasing age at first procedure (median 33.2 vs 0.6 months; P < 0.001) and arm-leg-gradient at follow-up (mean +/- SD, -0.3 +/- 14.6 vs -6.4 +/- 11.6 mmHg; P = 0.047) adjusted for reintervention for coarctation and age at follow-up. LV hypertrophy was present in 20/227 (9.3%) and related with SBP z-score. CONCLUSIONS Higher SBP and hypertension in repaired coarctation of aorta are related with increasing age at first procedure and arm-leg-gradient at follow-up. Transverse arch and isthmus diameters at follow-up are inversely related with SBP.Peer reviewe

Reliability and Validity of The Finnish Version of The Boston Carpal Tunnel Questionnaire among Surgically Treated Carpal Tunnel Syndrome Patients

Background and Aims: The Boston Carpal Tunnel Questionnaire is the most commonly used outcome measure in the assessment of carpal tunnel syndrome. The purpose of this study was to translate the original Boston Carpal Tunnel Questionnaire into Finnish and validate its psychometric properties. Materials and Methods: We translated and culturally adapted the Boston Carpal Tunnel Questionnaire into Finnish. Subsequently, 193 patients completed the Finnish version of the Boston Carpal Tunnel Questionnaire, 6-Item CTS Symptoms Scale, and EuroQol 5 Dimensions 12 months after carpal tunnel release. The Boston Carpal Tunnel Questionnaire was re-administered after a 2-week interval. We calculated construct validity, internal consistency, test-retest reliability, and coefficient of repeatability. We also examined floor and ceiling effects. Results: The cross-cultural adaptation required only minor modifications to the questions. Both subscales of the Boston Carpal Tunnel Questionnaire (Symptom Severity Scale and Functional Status Scale) correlated significantly with the CTS-6 and EuroQol 5 Dimensions, indicating good construct validity. The Cronbach's alpha was 0.93 for both the Symptom Severity Scale and Functional Status Scale, indicating high internal consistency. Test-retest reliability was excellent, with an intraclass correlation coefficient greater than 0.8 for both scales. The coefficient of repeatability was 0.80 for the Symptom Severity Scale and 0.68 for the Functional Status Scale. We observed a floor effect in the Functional Status Scale in 28% of participants. Conclusion: Our study shows that the present Finnish version of the Boston Carpal Tunnel Questionnaire is reliable and valid for the evaluation of symptom severity and functional status among surgically treated carpal tunnel syndrome patients. However, owing to the floor effect, the Functional Status Score may have limited ability to detect differences in patients with good post-operative outcomes.Peer reviewe

The norm-1-property of a quantum observable

A normalized positive operator measure $X\mapsto E(X)$ has the norm-1-property if \no{E(X)}=1 whenever $E(X)\ne O$. This property reflects the fact that the measurement outcome probabilities for the values of such observables can be made arbitrary close to one with suitable state preparations. Some general implications of the norm-1-property are investigated. As case studies, localization observables, phase observables, and phase space observables are considered.Comment: 14 page

Simultaneous Detection and Differentiation of Human Rhino- and Enteroviruses in Clinical Specimens by Real-Time PCR with Locked Nucleic Acid Probes

Abstract Human rhinoviruses (HRVs) and human enteroviruses (HEVs) are significant respiratory pathogens. While HRV infections are restricted to the respiratory tract, HEV infections may spread to secondary target organs. The method of choice for sensitive specific detection of these viruses is reverse transcription (RT)-PCR with primers targeting the conserved 5' noncoding region of the viral RNA. On the other hand, sequence similarities between HRVs and HEVs complicate their differential detection. In this study, we describe the use of locked nucleic acid (LNA) analogues in short double-dye probes which contained only two selectively HRV- or HEV-specific bases. The double-stranded DNA dye BOXTO (4-[6-(benzoxazole-2-yl-(3-methyl-)-2,3-dihydro-(benzo-1,3-thiazole)-2-methylidene)]-1-methyl-quinolinium chloride) was used with the LNA probes in a tricolor real-time PCR assay to allow specific detection of HRVs (probes labeled with 6-carboxyfluorescein [FAM] [green]) and HEVs (Cy5 [red]) with additional melting curve analysis (BOXTO [yellow]). The functionality of the probes was validated in PCR and RT-PCR assays using plasmids containing viral cDNA, quantified viral RNA transcripts, cultivated rhino- and enterovirus prototypes, and clinical specimens. Of 100 HRV and 63 HEV prototypes, the probes correctly identified all HEVs except one that produced only a BOXTO signal. Among 118 clinical specimens with sequencing results, concordant results were obtained for 116 specimens. Two specimens were reactive with both probes, but sequencing yielded only a single virus. Real-time PCR with LNA probes allowed sensitive group-specific identification of HRVs and HEVs and would enable relative copy number determination. The assay is suitable for rapid and accurate differential detection of HRVs and HEVs in a diagnostic laboratory setting. </div

Conformational adaptation of Asian macaque TRIMCyp directs lineage specific antiviral activity

TRIMCyps are anti-retroviral proteins that have arisen independently in New World and Old World primates. All TRIMCyps comprise a CypA domain fused to the tripartite domains of TRIM5α but they have distinct lentiviral specificities, conferring HIV-1 restriction in New World owl monkeys and HIV-2 restriction in Old World rhesus macaques. Here we provide evidence that Asian macaque TRIMCyps have acquired changes that switch restriction specificity between different lentiviral lineages, resulting in species-specific alleles that target different viruses. Structural, thermodynamic and viral restriction analysis suggests that a single mutation in the Cyp domain, R69H, occurred early in macaque TRIMCyp evolution, expanding restriction specificity to the lentiviral lineages found in African green monkeys, sooty mangabeys and chimpanzees. Subsequent mutations have enhanced restriction to particular viruses but at the cost of broad specificity. We reveal how specificity is altered by a scaffold mutation, E143K, that modifies surface electrostatics and propagates conformational changes into the active site. Our results suggest that lentiviruses may have been important pathogens in Asian macaques despite the fact that there are no reported lentiviral infections in current macaque populations

The predictive value of NT-proBNP and hs-TnT for risk of death in cardiac surgical patients

Background: European System for Cardiac Operative Risk Evaluation II (EuroSCORE II) is used for risk stratification before cardiac surgery, but whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT) may add prognostic information to EuroSCORE II is not known. Methods: Preoperative (n = 640) and postoperative (n = 629) blood samples were available from cardiac surgical patients with 961-day follow-up (FINNAKI Heart study; cohort #1). The accuracy of a parsimonious risk model with NT-proBNP measurements was also tested in 90 patients with respiratory failure after cardiac surgery (FINNALI study; cohort #2). Results: Sixty-one patients (9.5%) died during follow-up in cohort #1. Preoperative NT-proBNP and hs-TnT concentrations correlated (rho = 0.58; p <0.001) and were higher in non-survivors compared to survivors: median 2027 (Q1-3 478-5387) vs. 373 (134-1354) ng/L [NT-proBNP] and 39 (16-191) vs. 13 (8-32) ng/L [hs-TnT]; p <0.001 for both. Preoperative NT-proBNP concentrations were associated with time to death after adjustment for EuroSCORE II (HR [lnNT-proBNP] 1.33 [95% CI 1.08-1.64]), p = 0.008 and reclassified patients on top of EuroSCORE II (net reclassification index 0.39 [95% CI 0.14-0.64], p = 0.003). Pre-and postoperative NT-proBNP concentrations were closely correlated (rho = 0.80, p <0.001) and postoperative NT-proBNP concentrations were also associated with long-term mortality after adjustment for EuroSCORE II. A parsimonious risk model that included age, creatinine clearance, chronic pulmonary disease, and NT-proBNP measurements provided comparable prognostic accuracy as EuroSCORE II in cohort #1 and #2 for risk of long-term mortality. hs-TnT measurements did not add to NT-proBNP measurements Conclusion: NT-proBNP measurements could improve and simplify risk prediction in cardiac surgical patients.Peer reviewe

The RING-CH ligase K5 antagonizes restriction of KSHV and HIV-1 particle release by mediating ubiquitin-dependent endosomal degradation of tetherin

Tetherin (CD317/BST2) is an interferon-induced membrane protein that inhibits the release of diverse enveloped viral particles. Several mammalian viruses have evolved countermeasures that inactivate tetherin, with the prototype being the HIV-1 Vpu protein. Here we show that the human herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) is sensitive to tetherin restriction and its activity is counteracted by the KSHV encoded RING-CH E3 ubiquitin ligase K5. Tetherin expression in KSHV-infected cells inhibits viral particle release, as does depletion of K5 protein using RNA interference. K5 induces a species-specific downregulation of human tetherin from the cell surface followed by its endosomal degradation. We show that K5 targets a single lysine (K18) in the cytoplasmic tail of tetherin for ubiquitination, leading to relocalization of tetherin to CD63-positive endosomal compartments. Tetherin degradation is dependent on ESCRT-mediated endosomal sorting, but does not require a tyrosine-based sorting signal in the tetherin cytoplasmic tail. Importantly, we also show that the ability of K5 to substitute for Vpu in HIV-1 release is entirely dependent on K18 and the RING-CH domain of K5. By contrast, while Vpu induces ubiquitination of tetherin cytoplasmic tail lysine residues, mutation of these positions has no effect on its antagonism of tetherin function, and residual tetherin is associated with the trans-Golgi network (TGN) in Vpu-expressing cells. Taken together our results demonstrate that K5 is a mechanistically distinct viral countermeasure to tetherin-mediated restriction, and that herpesvirus particle release is sensitive to this mode of antiviral inhibition

Soluble biglycan : a potential mediator of cartilage degradation in osteoarthritis

Abstract Background Soluble biglycan (sBGN) and soluble decorin (sDCN), are two closely related essential components of extracellular matrix which both have been shown to possess proinflammatory properties. We studied whether sBGN or sDCN were present in synovial fluid (SF) of osteoarthritis (OA) or rheumatoid arthritis (RA) patients and studied sBGN or sDCN potential role in the degradation of OA cartilage. Methods SF obtained from meniscus tear, OA, and RA patients were analysed for sBGN and sDCN using enzyme-linked immunosorbent assays. OA chondrocytes and cartilage explants were stimulated for 48 h with 5 μg/ml sBGN or 1 μg/ml lipopolysaccharide. Messenger RNA (mRNA) levels of Toll-like receptors (TLRs), proteinases and cartilage matrix molecules were determined using quantitative real-time polymerase chain reaction. Protein levels of matrix metalloproteinases (MMPs) and cytokines were measured using Luminex xMap technology. Production of nitric oxide (NO), release of proteoglycans and soluble collagen were measured from conditioned culture media using biochemical assays. OA cartilage explant proteoglycans were stained for Safranin O and quantified using image analysis. TLR4 activation by sBGN and sDCN was studied in engineered HEK-293 cells with TLR4 signalling genes inserted together with a reporter gene. Results sBGN was found in meniscus tear SF (14 ± 2 ng/ml), OA SF (582 ± 307 ng/ml) and RA SF (1191 ± 482 ng/ml). Low levels of sDCN could also be detected in SF of meniscus tear (51 ± 4) ng/ml, OA (52 ± 3 ng/ml), and RA (49 ± 4 ng/ml). Stimulation of chondrocytes with sBGN increased significantly the mRNA and protein expression of catabolic MMPs, including MMP1, MMP9 and MMP13, and of inflammatory cytokines interleukin (IL)-6 and IL-8, whereas the expression of anabolic markers aggrecan and collagen type II was decreased. sBGN induced release of proteoglycans, collagen and NO from chondrocytes and cartilage explants. The catabolic response in explants was dependent of OA cartilage degradation stage. The mechanism of action of sBGN was mainly mediated through the TLR4-nuclear factor-κB pathway. Conclusions High levels of sBGN was found in advanced OA and RA SF. sBGN activates chondrocytes mainly via TLR4, which results in net loss of cartilage. Thus, sBGN can be a mediator of OA cartilage degradation and also a potential biomarker for arthritis

Fermi LAT Observations of the Supernova Remnant W28 (G6.4-0.1)

We present detailed analysis of the two gamma-ray sources,1FGL J1801.3-2322c and 1FGL J1800.5-2359c,that have been found toward the supernova remnant(SNR) W28 with the Large Area Telescope(LAT) on board the Fermi Gamma-ray Space Telescope.1FGL J1801.3-2322c is found to be an extended source within the boundary of SNR W28,and to extensively overlap with the TeV gamma-ray source HESS J1801-233,which is associated with a dense molecular cloud interacting with the supernova remnant.The gamma-ray spectrum measured with LAT from 0.2--100 GeV can be described by a broken power-law function with a break of ~1GeV,and photon indices of 2.09$\pm$0.08(stat)$\pm$0.28(sys) below the break and 2.74$\pm$0.06(stat)$\pm$0.09(sys) above the break.Given the clear association between HESS J1801-233 and the shocked molecular cloud and a smoothly connected spectrum in the GeV--TeV band,we consider the origin of the gamma-ray emission in both GeV and TeV ranges to be the interaction between particles accelerated in the SNR and the molecular cloud.The decay of neutral pions produced in interactions between accelerated hadrons and dense molecular gas provide a reasonable explanation for the broadband gamma-ray spectrum. 1FGL J1800.5-2359c, located outside the southern boundary of SNR W28, cannot be resolved.An upper limit on the size of the gamma-ray emission was estimated to be ~16$'$ using events above ~2GeV under the assumption of a circular shape with uniform surface brightness. It appears to coincide with the TeV source HESS J1800-240B,which is considered to be associated with a dense molecular cloud that contains the ultra compact HII region W28A2(G5.89-0.39).We found no significant gamma-ray emission in the LAT energy band at the positions of TeV sources HESS J1800-230A and HESS J1800-230C.The LAT data for HESS J1800-230A combined with the TeV data points indicate a spectral break between 10GeV and 100GeV.Comment: 23 pages, 6 figures. Accepted for publication in the Astrophysical Journal. Corresponding authors: H. Katagiri, H. Tajima, T. Tanaka, and Y. Uchiyam

Network synchronization landscape reveals compensatory structures, quantization, and the positive effect of negative interactions

Synchronization, in which individual dynamical units keep in pace with each other in a decentralized fashion, depends both on the dynamical units and on the properties of the interaction network. Yet, the role played by the network has resisted comprehensive characterization within the prevailing paradigm that interactions facilitating pair-wise synchronization also facilitate collective synchronization. Here we challenge this paradigm and show that networks with best complete synchronization, least coupling cost, and maximum dynamical robustness, have arbitrary complexity but quantized total interaction strength that constrains the allowed number of connections. It stems from this characterization that negative interactions as well as link removals can be used to systematically improve and optimize synchronization properties in both directed and undirected networks. These results extend the recently discovered compensatory perturbations in metabolic networks to the realm of oscillator networks and demonstrate why "less can be more" in network synchronization.Comment: 11 pages and 8 figures (including Supporting Information), Supporting video available at http://www.youtube.com/watch?v=3dMI1Yyxmb