Abstract
In the 16 years since the first pioneering procedure, transcatheter aortic valve implantation (TAVI) has come of age and become a routine strategy for aortic valve replacement, increasingly ...performed under conscious sedation via transfemoral access. Simplification of the procedure, accumulation of clinical experience, and improvements in valve design and delivery systems have led to a dramatic reduction in complication rates. These advances have allowed transition to lower risk populations, and outcome data from the PARTNER 2A and SURTAVI trials have established a clear evidence base for use in intermediate risk patients. Ongoing studies with an expanding portfolio of devices seem destined to expand indications for TAVI towards lower risk, younger and asymptomatic populations. In this article, we outline recent advances, new devices and current guidelines informing the use of TAVI, and describe remaining uncertainties that need to be addressed.
Background and Purpose
Nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor agonists display a promising analgesic profile in preclinical studies. However, supraspinal N/OFQ produced hyperalgesia in ...rodents and such effects have not been addressed in primates. Thus, the aim of this study was to investigate the effects of centrally administered ligands on regulating pain and itch in non‐human primates. In particular, nociceptive thresholds affected by intracisternal N/OFQ were compared with those of morphine and substance P, known to provide analgesia and mediate hyperalgesia, respectively, in humans.
Experimental Approach
Intrathecal catheters were installed to allow intracisternal and lumbar intrathecal administration in awake and unanaesthetized rhesus monkeys. Nociceptive responses were measured using the warm water tail‐withdrawal assay. Itch scratching responses were scored from videotapes recording behavioural activities of monkeys in their home cages. Antagonist studies were conducted to validate the receptor mechanisms underlying intracisternally elicited behavioural responses.
Key Results
Intracisternal morphine (100 nmol) elicited more head scratches than those after intrathecal morphine. Distinct dermatomal scratching locations between the two routes suggest a corresponding activation of supraspinal and spinal μ receptors. Unlike intracisternal substance P, which induced hyperalgesia, intracisternal N/OFQ (100 nmol) produced antinociceptive effects mediated by NOP receptors. Neither peptide increased scratching responses.
Conclusions and Implications
Taken together, these results demonstrated differential actions of ligands in the primate supraspinal region in regulating pain and itch. This study not only improves scientific understanding of the N/OFQ‐NOP receptor system in pain processing but also supports the therapeutic potential of NOP‐related ligands as analgesics.
XL-Calibur is a hard X-ray (15-80 keV) polarimetry mission operating from a stabilised balloon-borne platform in the stratosphere. It builds on heritage from the X-Calibur mission, which observed the ...accreting neutron star GX 301 - 2 from Antarctica, between December 29th 2018 and January 1st 2019. The XL-Calibur design incorporates an X-ray mirror, which focusses X-rays onto a polarimeter comprising a beryllium rod surrounded by Cadmium Zinc Telluride (CZT) detectors. The polarimeter is housed in an anticoincidence shield to mitigate background from particles present in the stratosphere. The mirror and polarimeter-shield assembly are mounted at opposite ends of a 12 m long lightweight truss, which is pointed with arcsecond precision by WASP – the Wallops Arc Second Pointer. The XL-Calibur mission will achieve a substantially improved sensitivity over X-Calibur by using a larger effective area X-ray mirror, reducing background through thinner CZT detectors, and improved anticoincidence shielding. When observing a 1 Crab source for tdaydays, the Minimum Detectable Polarisation (at 99% confidence level) is ∼2%·tday−1/2. The energy resolution at 40 keV is ∼5.9 keV. The aim of this paper is to describe the design and performance of the XL-Caliburmission, as well as the foreseen science programme.
Background
The aim of this study was to evaluate the use of intestinal fatty acid binding protein (I‐FABP) and traditional biomarkers in the early diagnosis of acute intestinal ischaemia of different ...causes.
Methods
I‐FABP, white blood cell (WBC) count, C‐reactive protein, base deficit, lactate, lactate dehydrogenase, aspartate aminotransferase, creatine kinase and D‐dimer were measured prospectively in consecutive patients suspected of having acute intestinal ischaemia. Biomarker levels were compared in patients with vascular and non‐vascular ischaemia.
Results
Two hundred and eight patients with a clinical suspicion of acute intestinal ischaemia were enrolled. Vascular intestinal ischaemia was diagnosed in 24 patients (11·5 per cent), non‐vascular ischaemia in 62 (29·8 per cent) and non‐ischaemic disease in 122 (58·7 per cent). The levels of most biomarkers (except WBC count and creatine kinase) were significantly higher in the vascular ischaemia group than in the other groups (P < 0·010). However, none of the biomarker levels differed between patients with non‐vascular intestinal ischaemia and those with non‐ischaemic disease. Receiver operating characteristic (ROC) curve analysis suggested that I‐FABP was best at diagnosing vascular intestinal ischaemia (area under the curve 0·88).
Conclusion
Serum biomarkers may be useful in the diagnosis of vascular, but not non‐vascular, intestinal ischaemia. Among them, I‐FABP shows promise for detecting vascular ischaemia.
Intestinal fatty acid binding protein shows promise
We report on the results of a Suzaku observation of the plasma in the filament located between the two massive clusters of galaxies, Abell 399 and Abell 401. Abell 399 (z = 0.0724) and Abell 401 (z = ...0.0737) are expected to be in the initial phase of a cluster merger. In the region between the two clusters, we find a clear enhancement in the temperature of the filament plasma from 4 keV (expected value of a typical cluster temperature profile) to kT ~ 6.5 keV. Our analysis also shows that filament plasma is present out to a radial distance of 15′ (1.3 Mpc) from a line connecting the two clusters. The temperature profile is characterized by an almost flat radial shape with kT ~ 6–7 keV within 10′ or ~0.8 Mpc. Across r = 8′ from the axis, the temperature of the filament plasma shows a drop from 6.3 keV to 5.1 keV, indicating the presence of a shock front. The Mach number based on the temperature drop is estimated to be ℳ ~ 1.3. We also successfully determined the abundance profile up to 15′ (1.3 Mpc), showing an almost constant value (Z = 0.3 solar) at the cluster outskirts. We estimated the Compton y parameter to be ~ 14.5 ± 1.3 × 10-6, which is in agreement with the Planck results (14–17 × 10-6 on the filament). The line-of-sight depth of the filament is l ~ 1.1 Mpc, which indicates that the geometry of filament is likely a pancake shape rather than cylindrical. The total mass of the filamentary structure is ~7.7 × 1013M⊙. We discuss a possible interpretation of the drop of X-ray emission at the rim of the filament, which was pushed out by the merging activity and formed by the accretion flow induced by the gravitational force of the filament.
Background and purpose
Using an innovative chemical approach, peptide welding technology (PWT), a tetrabranched derivative of nociceptin/orphanin FQ (N/OFQ) has been generated and pharmacologically ...characterized. Both in vitro and in vivo PWT2‐N/OFQ displayed the same pharmacological profile to the natural ligand. It was more potent and produced longer‐lasting effects. The aim of the present study was to investigate the spinal effects of PWT2‐N/OFQ in nociceptive and neuropathic pain models in mice and non‐human primates.
Experimental Approach
Tail withdrawal assay in mice and monkeys was used as a nociceptive pain model and mechanical threshold in mice subjected to chronic constriction injury was used as a neuropathic pain model. The antinociceptive effects of spinally administered N/OFQ and PWT2‐N/OFQ were assessed in these models.
Key Results
PWT2‐N/OFQ mimicked the spinal antinociceptive effects of N/OFQ both in nociceptive and neuropathic pain models in mice as well as in non‐human primates displaying 40‐fold higher potency and a markedly prolonged duration of action. The effects of N/OFQ and PWT2‐N/OFQ were sensitive to the N/OFQ receptor (NOP) antagonist SB‐612111, but not to opioid receptor antagonists.
Conclusions and Implications
The present study has demonstrated that PWT2‐N/OFQ mimicked the antinociceptive effects of the natural peptide in rodents and non‐human primates acting as a potent and longer‐lasting NOP‐selective agonist. More generally, PWT derivatives of biologically active peptides can be viewed as innovative pharmacological tools for investigating those conditions and states in which selective and prolonged receptor stimulation promotes beneficial effects.
•Intrathecal (IT) pDNA IL-10 reverses spinally-mediated measures of neuropathic pain.•Development of TARS, a new 2-arm choice task to assess supraspinal pain processing.•Spinal and supraspinal ...indices of neuropathic pain developed in parallel over time.•Both indices of pain were reversed in parallel after IT pDNA-IL10 gene therapy.•Details for construction and use of the TARS operant behavior task are provided.
Intrathecal delivery of interleukin-10 (IL-10) gene therapy has been reported to be effective in suppressing pain enhancement in a variety of rodent models. However, all publications that have tested this treatment have relied upon measures of static allodynia (von Frey test) and thermal hyperalgesia (Hargreaves test). As this plasmid DNA IL-10 (pDNA-IL10) therapeutic approach is now in human clinical trials for multiple pain indications, including intrathecal delivery for human neuropathic pain, it is important to consider the recent concerns raised in the pain field that such tests reflect spinal rather than supraspinal processing of, and responsivity to, noxious stimuli. Consequently, this raises the question of whether intrathecal pDNA-IL10 can reverse established neuropathic pain when assessed by a test requiring supraspinal, rather than solely spinal, mediation of the behavioral response. The present study utilizes the rat sciatic chronic constriction injury (CCI) model of neuropathic pain to compare the expression of static allodynia with that of cognitively controlled choice behavior in a two-arm maze, adapted from Hayashida et al. (2019). This modification, termed the Two-Arm Rodent Somatosensory (TARS) task, provides rats free choice to reach a desired goal box via a short “arm” of the maze with tactile probes as flooring versus a longer “arm” of the maze with a smooth surface. Here we demonstrate that static allodynia and avoidance of the nociceptive flooring in TARS develop in parallel over time, and that both behaviors also resolve in parallel following intrathecal pDNA-IL10 gene therapy. Details for the construction and use of this new maze design are also provided. Together, this study documents both: (a) the important finding that intrathecal IL-10 gene therapy does indeed resolve neuropathic pain as measured by a supraspinally-mediated behavioral task, and (b) a new, supraspinally-mediated task that allows behavioral assessments across weeks and allows the analysis of both development and resolution of neuropathic pain by therapeutic interventions. As such, the TARS operant behavior task is an improvement over other approaches such as the mechanical conflict-avoidance system which have difficulties demonstrating development and reversal of pain behavior in a within-subject design.
SUMMARY
Gastric pull-up is a common procedure to reconstruct the continuity of the upper digestive tract after esophageal resection. However, this technique sometimes causes postoperative anastomotic ...leakage or stricture, resulting from insufficient blood flow at the distal end. To overcome this problem, additional microvascular venous anastomoses were performed. The purpose of this study was to compare the outcomes of post-surgical anastomotic leakage and stricture in patients with and without additional microvascular venous superdrainage after cervical esophageal and hypopharyngeal resection and gastric tube reconstruction. A total of 29 consecutive patients with esophageal or hypopharyngeal cancer who underwent total esophagectomy and hypopharyngectomy with gastric tube reconstruction in the National Organization Nagasaki Medical Center between April 2014 and May 2016 were analyzed in this study. Of these patients, 20 underwent additional venous anastomoses (superdrainage group), and 9 did not undergo additional procedures (standard group). We compared the frequency of post-surgical stricture and leakage in the two groups retrospectively. Three of nine patients (33.3%) developed postoperative leakage in the standard group, and 1 of 20 (5.0%) did so in the superdrainage group. Six of nine patients (66.7%) showed postoperative anastomotic stricture in the standard group, but none did so in the superdrainage group. Patients who did not undergo additional venous superdrainage were significantly more likely to develop postsurgical leakage (P < 0.05, Chi-square test) and anastomotic stricture (P < 0.001, Chi-square test). Our study revealed that only additional venous anastomoses could reduce the incidence of postoperative anastomotic leakage and stricture. This procedure is of merit to perform after total esophagectomy and hypopharyngectomy with gastric tube reconstruction.
Strongly magnetized isolated neutron stars (NSs) are categorized into two families according, mainly, to their magnetic field strength. The one with a higher magnetic field of 1014–1015 Gauss is ...called “magnetar,” and the other is the X‐ray isolated neutron star (XINS) with 1013 Gauss. Both magnetars and XINSs show thermal emission in X‐rays, whose spectra are different. The soft X‐ray spectrum (below 10 keV) of a magnetar is reproduced with a two‐temperature blackbody (2BB), whereas that of an XINS shows only a single‐temperature blackbody (1BB), and its temperature is even lower than that of magnetars. On the basis of the magnetic field and temperature, it is often speculated that XINSs may be old and cooled magnetars. However, no other strong observational evidence has yet been reported to support the speculation. Here, we report that all the seven known XINSs show high‐temperature emission, which should have a similar origin to that of magnetars. Analyzing all the XMM‐Newton data of the XINSs with the highest statistics ever achieved, we find that their X‐ray spectra are all reproduced with a 2BB model, similar to magnetars, as opposed to the traditional 1BB model. Their emission radii and temperature ratios are also similar to those of magnetars except for two XINSs, which show significantly smaller radii than the others. The remarkable similarity in the X‐ray spectra between XINSs and magnetars suggests that the origins of their emitting regions are also the same. The lower temperature in XINSs can be explained if XINSs are older than magnetars. Therefore, this result is another observational indication that supports the standard hypothesis of classification of highly magnetized NSs. This article is based on our paper Yoneyama et al. (2019; accepted to PASJ).
•Characteristics of OFC and 304 stainless steel friction welded joints were investigated.•Relationship between the weldability and weld faying surface properties of those was clarified.•Some ...characteristics were affected to the weld faying surface properties of OFC side.•Good joint could make at a low friction pressure so that the central area of the weld interface joined.•It should be made with the polishing of the weld faying surface to OFC side just before welding.
This paper reported the effects of tensile strength on friction welding condition and weld faying surface properties of friction welded joints between pure copper (OFC) and austenitic stainless steel (AISI 304). The joining phenomena and the joint tensile strength at various friction welding conditions were investigated. The maximum temperature of the joint at a friction pressure of 90 MPa was lower than that of 30 MPa. Also, the central portion of the weld interface of the joint with high friction pressure was not joined completely. Hence, it was showed that the joint should be made with a low friction pressure. In addition, the friction torque curve, joint appearance, flash quantity, and axial shortening of joints differed by virtue of the polishing timing at the weld faying surface, and they were influenced by the surface condition of the OFC side before welding. As a conclusion, the good joint with the fracture in the OFC side should be made with a low friction pressure such as 30 MPa, a friction time after the friction torque reached the initial peak such as 3.6 s, and a high forge pressure such as 270 MPa. Furthermore, the weld faying surface of the OFC side should be polished just before welding, and it was suggested.
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