Adolescents and adults with Fontan circulation:insights from the PREpArE-Fontan registry

The Patient Registry for Adolescents and Adults with Stable Fontan Circulation aims to describe a contemporary cohort of Fontan patients who could be eligible for a clinical trial investigating macitentan, an endothelin receptor antagonist. This international, non-interventional, multicentre, cross-sectional, observational registry enrolled patients with “stable” Fontan circulation ≥10 years following extra-cardiac conduit or lateral tunnel procedure. Main exclusion criteria were NYHA functional class IV, reoperation of Fontan circulation, or signs of disease worsening. Patient characteristics at enrolment are described; available data were collected during a single registration visit. Of the 266 screened patients, 254 were included in this analysis. At enrolment, median (interquartile range) age was 24 (20;30) years, 37%/63% of patients were from the USA/Europe, 54% were male, 54%/47% had undergone extra-cardiac conduit/lateral tunnel procedures, and 95% were in NYHA functional class I or II. History of arrhythmia was more common in older patients and patients with lateral tunnel; overall prevalence was 19%. Most laboratory values were within the normal range but mean creatinine clearance was abnormally low (87.7 ml/min). Angiotensin-converting enzyme inhibitors were used by 48% of patients and their use was associated with creatinine clearance <90 ml/min (p = 0.007), as was Fontan completion at an older age (p = 0.007). 53.4% of patients had clinical characteristics that could potentially meet an endothelin receptor antagonist trial’s eligibility criteria. The PREpArE-Fontan registry describes a cohort of patients who could potentially participate in an endothelin receptor antagonist trial and identified early subtle signs of Fontan failure, even in “stable” patients

Probe-based schemes to guarantee lightpath quality of transmission (QoT) in transparent optical networks

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Enhancing GMPLS signaling protocol for encompassing quality of transmission (QoT) in all-optical networks

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Characterization of the Molecular Determinants of Primary HIV-1 Vpr Proteins: Impact of the Q65R and R77Q Substitutions on Vpr Functions

Although HIV-1 Vpr displays several functions in vitro, limited information exists concerning their relevance during infection. Here, we characterized Vpr variants isolated from a rapid and a long-term non-progressor (LTNP). Interestingly, vpr alleles isolated from longitudinal samples of the LTNP revealed a dominant sequence that subsequently led to diversity similar to that observed in the progressor patient. Most of primary Vpr proteins accumulated at the nuclear envelope and interacted with host-cell partners of Vpr. They displayed cytostatic and proapoptotic activities, although a LTNP allele, harboring the Q65R substitution, failed to bind the DCAF1 subunit of the Cul4a/DDB1 E3 ligase and was inactive. This Q65R substitution correlated with impairment of Vpr docking at the nuclear envelope, raising the possibility of a functional link between this property and the Vpr cytostatic activity. In contradiction with published results, the R77Q substitution, found in LTNP alleles, did not influence Vpr proapoptotic activity

An integrated view on monitoring and compensation for dynamic optical networks: from management to physical layer

A vertical perspective, ranging from management and routing to physical layer options, concerning dynamic network monitoring and compensation of impairments (M&C), is given. Feasibility, reliability, and performance improvements on reconfigurable transparent networks are expected to arise from the consolidated assessment of network management and control specifications, as a more accurate evaluation of available M&C techniques. In the network layer, physical parameters aware algorithms are foreseen to pursue reliable network performance. In the physical layer, some new M&C methods were developed and rating of the state-of-the-art reported in literature is given. Optical monitoring implementation and viability is discussed.Publicad

Study of the Falling Friction Effect on Rolling Contact Parameters

[EN] The existence of a wheel rail friction coefficient that depends on the slip velocity has been associated in the literature with important railway problems like the curving squeal and certain corrugation problems in rails. Rolling contact models that take into account this effect were carried out through the so-called Exact Theories adopting an exact elastic model of the solids in contact, and Simplified Theories which assume simplified elastic models such as Winkler. The former ones, based on Kalker s Variational Theory, give rise to numerical problems; the latter ones need to adopt hypotheses that significantly deviate from actual conditions, leading to unrealistic solutions of the contact problem. In this paper, a methodology based on Kalker s Variational Theory is presented, in which a local slip velocity-dependent friction law is considered. A formulation to get steady-state conditions of rolling contact by means of regularisation of the Coulomb s law is proposed. The model allows establishing relationships in order to estimate the global properties (creepage velocities vs. total longitudinal forces) through local properties (local slip velocity vs. coefficient of friction) or vice versa. The proposed model shows a good agreement with experimental tests while solving the numerical problems previously mentioned.The authors acknowledge the financial contribution of the Spanish Ministry of Economy and Competitiveness through the Project TRA2013-45596-C2-1-R.Giner Navarro, J.; Baeza González, LM.; Vila Tortosa, MP.; Alonso Pazos, A. (2017). Study of the Falling Friction Effect on Rolling Contact Parameters. Tribology Letters. 65(1). https://doi.org/10.1007/s11249-016-0810-8S651Grassie, S.L., Elkins, J.A.: Rail corrugation on North American transit systems. Veh. Syst. Dyn. 28, 5–17 (1998)Hsu, S.S., Huang, Z., Iwnicki, S.D., Thompson, D.J., Jones, C.J.C., Xie, G., Allen, P.D.: Experimental and theoretical investigation of railway wheel squeal. Proc. Inst. Mech. Eng. F J. Rail Rapid Transit 221, 59–73 (2007)Kalker, J.J.: Three-Dimensional Elastic Bodies in Rolling Contact. Kluwer, Dordrecht (1990)Polach, O.: Influence of locomotive tractive effort on the forces between wheel and rail. Veh. Syst. Dyn. 35, 7–22 (2001)Giménez, J.G., Alonso, A., Gómez, E.: Introduction of a friction coefficient dependent on the slip in the FastSim algorithm. Veh. Syst. Dyn. 43, 233–244 (2005)Baeza, L., Vila, P., Roda, A., Fayos, J.: Prediction of corrugation in rails using a non-stationary wheel–rail contact model. Wear 265, 1156–1162 (2008)Vollebregt, E.A.H., Schuttelaars, H.M.: Quasi-static analysis of two-dimensional rolling contact with slip-velocity dependent friction. J. Sound Vib. 331, 2141–2155 (2012)Avlonitis, M., Kalaitzidou, K., Streator, J.: Investigation of friction statics and real contact area by means a modified OFC model. Tribol. Int. 69, 168–175 (2014)Berger, E.J., Mackin, T.J.: On the walking stick–slip problem. Tribol. Int. 75, 51–60 (2014)Alonso, A., Guiral, A., Baeza, B., Iwnicki, S.D.: Wheel–rail contact: experimental study of the creep forces–creepage relationships. Veh. Syst. Dyn. 52(S1), 469–487 (2014)Spiryagin, M., Polach, O., Cole, C.: Creep force modelling for rail traction vehicles based on the Fastsim algorithm. Veh. Syst. Dyn. 51, 1765–1783 (2013)Vollebregt, E.A.H.: Numerical modeling of measured railway creep versus creep-force curves with CONTACT. Wear 314, 87–95 (2014)Kalker, J.J.: On the Rolling Contact of Two Elastic Bodies in the Presence of Dry Friction. PhD Thesis, Technical University of Delft (Holland) (1967)Baeza, L., Fuenmayor, F.J., Carballeira, J., Roda, A.: Influence of the wheel–rail contact instationary process on contact parameters. J. Strain Anal. Eng. 42, 377–387 (2007)Le Rouzic, J., Le Bot, A., Perret-Liaudet, J., Guibert, M., Rusanov, A., Douminge, L., Bretagnol, F., Mazuyer, D.: Friction-induced vibration by Stribeck’s law: application to wiper blade squeal noise. Tribol. Lett. 49, 563–572 (2013)Rabinowicz, E.: The nature of the static and kinetic coefficients of friction. J. Appl. Phys. 22, 1373–1379 (1951)Carter, F.W.: On the action of locomotive driving wheel. Proc. R. Soc. Lon. Ser. A 112, 151–157 (1926)Kalker, J.J.: A fast algorithm for the simplified theory of rolling contact. Veh. Syst. Dyn. 11, 1–13 (1982

Risk of requiring a wheelchair in primary progressive multiple sclerosis: Data from the ORATORIO trial and the MSBase registry

Background and purpose: Reaching Expanded Disability Status Scale (EDSS) ≥7.0 represents the requirement for a wheelchair. Here we (i) assess the effect of ocrelizumab on time to EDSS ≥7.0 over the ORATORIO (NCT01194570) double-blind and extended controlled periods (DBP+ECP), (ii) quantify likely long-term benefits by extrapolating results, and (iii) assess the plausibility of extrapolations using an independent real-world cohort (MSBase registry; ACTRN12605000455662). Methods: Post hoc analyses assessing time to 24-week confirmed EDSS ≥7.0 in two cohorts of patients with primary progressive multiple sclerosis (baseline EDSS 3.0–6.5) were investigated in ORATORIO and MSBase. Results: In the ORATORIO DBP+ECP, ocrelizumab reduced the risk of 24-week confirmed EDSS ≥7.0 (hazard ratio = 0.54, 95% confidence interval [CI]: 0.31–0.92; p = 0.022). Extrapolated median time to 24-week confirmed EDSS ≥7.0 was 12.1 and 19.2 years for placebo and ocrelizumab, respectively (7.1-year delay [95% CI: −4.3 to 18.4]). In MSBase, the median time to 24-week confirmed EDSS ≥7.0 was 12.4 years. Conclusions: Compared with placebo, ocrelizumab significantly delayed time to 24-week confirmed wheelchair requirement in ORATORIO. The plausibility of the extrapolated median time to reach this milestone in the placebo group was supported by observed real-world data from MSBase. Extrapolated benefits for ocrelizumab over placebo could represent a truly meaningful delay in loss of ambulation and independence

Iron is neurotoxic in retinal detachment and transferrin confers neuroprotection.

In retinal detachment (RD), photoreceptor death and permanent vision loss are caused by neurosensory retina separating from the retinal pigment epithelium because of subretinal fluid (SRF), and successful surgical reattachment is not predictive of total visual recovery. As retinal iron overload exacerbates cell death in retinal diseases, we assessed iron as a predictive marker and therapeutic target for RD. In the vitreous and SRF from patients with RD, we measured increased iron and transferrin (TF) saturation that is correlated with poor visual recovery. In ex vivo and in vivo RD models, iron induces immediate necrosis and delayed apoptosis. We demonstrate that TF decreases both apoptosis and necroptosis induced by RD, and using RNA sequencing, pathways mediating the neuroprotective effects of TF are identified. Since toxic iron accumulates in RD, we propose TF supplementation as an adjunctive therapy to surgery for improving the visual outcomes of patients with RD

Lentiviral Vpx Accessory Factor Targets VprBP/DCAF1 Substrate Adaptor for Cullin 4 E3 Ubiquitin Ligase to Enable Macrophage Infection

Vpx is a small virion-associated adaptor protein encoded by viruses of the HIV-2/SIVsm lineage of primate lentiviruses that enables these viruses to transduce monocyte-derived cells. This probably reflects the ability of Vpx to overcome an as yet uncharacterized block to an early event in the virus life cycle in these cells, but the underlying mechanism has remained elusive. Using biochemical and proteomic approaches, we have found that Vpx protein of the pathogenic SIVmac 239 strain associates with a ternary protein complex comprising DDB1 and VprBP subunits of Cullin 4–based E3 ubiquitin ligase, and DDA1, which has been implicated in the regulation of E3 catalytic activity, and that Vpx participates in the Cullin 4 E3 complex comprising VprBP. We further demonstrate that the ability of SIVmac as well as HIV-2 Vpx to interact with VprBP and its associated Cullin 4 complex is required for efficient reverse transcription of SIVmac RNA genome in primary macrophages. Strikingly, macrophages in which VprBP levels are depleted by RNA interference resist SIVmac infection. Thus, our observations reveal that Vpx interacts with both catalytic and regulatory components of the ubiquitin proteasome system and demonstrate that these interactions are critical for Vpx ability to enable efficient SIVmac replication in primary macrophages. Furthermore, they identify VprBP/DCAF1 substrate receptor for Cullin 4 E3 ubiquitin ligase and its associated protein complex as immediate downstream effector of Vpx for this function. Together, our findings suggest a model in which Vpx usurps VprBP-associated Cullin 4 ubiquitin ligase to enable efficient reverse transcription and thereby overcome a block to lentivirus replication in monocyte-derived cells, and thus provide novel insights into the underlying molecular mechanism