Release of TNF-α during myocardial reperfusion depends on oxidative stress and is prevented by mast cell stabilizers

Objectives: Our study sought to elucidate the role of oxidative stress for shedding of tumor necrosis factor-α (TNF-α) and for activating TNF-α-converting enzyme (TACE). Background: TNF-α, a central inflammatory cytokine, is discussed as one of the mediators of reperfusion injury. Shedding of membrane-bound pro-TNF-α is thought to be largely due to TNF-α-converting enzyme (TACE). Methods: Release of TNF-α and TACE dependency were studied in isolated rat hearts and in the human mast cell line HMC-1. Results: In reperfused hearts, interstitial release of TNF-α occurred in two phases (2–10 and >45 min). It depended on the presence of oxygen during reperfusion and was attenuated by reduced glutathione. Infusion of the oxidants H2O2 or HOCl elicited release in non-ischemic hearts. TNF-α release was inhibited in hearts treated with degranulation inhibitors ketotifen or cromoglycate, suggesting mast cells as major source for myocardial TNF-α. This was confirmed by tissue staining. Post-ischemic release of histamine, however, did not parallel that of TNF-α. Heart tissue contained mainly mature TACE. HMC-1 expressed abundant pro-TACE and cleaved the pro-TNF-α-peptide Ac-SPLAQAVRSSSR-NH2. However, cleavage was nonspecific and only partly inhibited by TACE inhibitor TAPI-2 (10–100 μmol/l), while it was stimulated by H2O2 and HOCl and fully blocked by the nonspecific metalloprotease inhibitor o-phenanthroline. Conclusions: The mechanism underlying TNF-α release from post-ischemic myocardium is oxidation-dependent but largely independent of activation of TACE. Mast cell stabilizers may be useful in preventing TNF-α release during reperfusion

Heparinase selectively sheds heparan sulphate from the endothelial glycocalyx

A healthy vascular endothelium is coated by the endothelial glycocalyx. Its main constituents are transmembrane syndecans and bound heparan sulphates. This structure maintains the physiological endothelial permeability barrier and prevents leukocyte and platelet adhesion, thereby mitigating inflammation and tissue oedema. Heparinase, a bacteria] analogue to heparanase, is known to attack the glycocalyx. However, the exact extent and specificity of degradation is unresolved. We show by electron microscopy, immunohistological staining and quantitative measurements of the constituent parts, that heparinase selectively sheds heparan sulphate from the glycocalyx, but not the synclecans

Perspectives in Microvascular Fluid Handling: Does the Distribution of Coagulation Factors in Human Myocardium Comply with Plasma Extravasation in Venular Coronary Segments?

Background: Heterogeneity of vascular permeability has been suggested for the coronary system. Whereas arteriolar and capillary segments are tight, plasma proteins pass readily into the interstitial space at venular sites. Fittingly, lymphatic fluid is able to coagulate. However, heart tissue contains high concentrations of tissue factor, presumably enabling bleeding to be stopped immediately in this vital organ. The distribution of pro- and anti-coagulatively active factors in human heart tissue has now been determined in relation to the types of microvessels. Methods and Results: Samples of healthy explanted hearts and dilated cardiomyopathic hearts were immunohistochemically stained. Albumin was found throughout the interstitial space. Tissue factor was packed tightly around arterioles and capillaries, whereas the tissue surrounding venules and small veins was practically free of this starter of coagulation. Thrombomodulin was present at the luminal surface of all vessel segments and especially at venular endothelial cell junctions. Its product, the anticoagulant protein C, appeared only at discrete extravascular sites, mainly next to capillaries. These distribution patterns were basically identical in the healthy and diseased hearts, suggesting a general principle. Conclusions: Venular extravasation of plasma proteins probably would not bring prothrombin into intimate contact with tissue factor, avoiding interstitial coagulation in the absence of injury. Generation of activated protein C via thrombomodulin is favored in the vicinity of venular gaps, should thrombin occur inside coronary vessels. This regionalization of distribution supports the proposed physiological heterogeneity of the vascular barrier and complies with the passage of plasma proteins into the lymphatic system of the heart. Copyright (C) 2010 S. Karger AG, Base

Interatomic van der Waals potential in the presence of a magneto-electric sphere

On the basis of a general formula obtained earlier via fourth-order erturbation theory within the framework of macroscopic quantum electrodynamics, the van der Waals potential between two neutral, unpolarized, ground-state atoms in the presence of a homogeneous, dispersing and absorbing magnetoelectric sphere is studied. When the radius of the sphere becomes sufficiently large, the result asymptotically agrees with that for two atoms near a planar interface. In the opposite limit of a very small sphere, the sphere can effectively be regarded as being a third ground-state atom, and the nonadditive three-atom van der Waals potential is recovered. To illustrate the effect of a sphere of arbitrary radius, numerical results are presented for the triangular arrangement where the atoms are at equidistance from the sphere, and for the linear arrangement where the atoms and the sphere are aligned along a straight line. As demonstrated, the enhancement or reduction of the interaction potential in the presence of purely electric or magnetic spheres can be physically understood in terms of image charges.Comment: 13 pages, 7 figure

Tomographic reconstruction of quantum states in N spatial dimensions

Most quantum tomographic methods can only be used for one-dimensional problems. We show how to infer the quantum state of a non-relativistic N-dimensional harmonic oscillator system by simple inverse Radon transforms. The procedure is equally applicable to finding the joint quantum state of several distinguishable particles in different harmonic oscillator potentials. A requirement of the procedure is that the angular frequencies of the N harmonic potentials are incommensurable. We discuss what kind of information can be found if the requirement of incommensurability is not fulfilled and also under what conditions the state can be reconstructed from finite time measurements. As a further example of quantum state reconstruction in N dimensions we consider the two related cases of an N-dimensional free particle with periodic boundary conditions and a particle in an N-dimensional box, where we find a similar condition of incommensurability and finite recurrence time for the one-dimensional system.Comment: 8 pages, 1 figur

Molecular Seesaw: How Increased Hydrogen Bonding Can Hinder Excited-State Proton Transfer

A previously unexplained effect in the relative rate of excited-state intramolecular proton transfer (ESIPT) in related indole derivatives is investigated using both theory and experiment. Ultrafast spectroscopy [J. Phys. Chem. A, 2015, 119, 5618–5625] found that although the diol 1,3-bis(2-pyridylimino)-4,7-dihydroxyisoindole exhibits two equivalent intramolecular hydrogen bonds, the ESIPT rate associated with tautomerization of either hydrogen bond is a factor of 2 slower than that of the single intramolecular hydrogen bond in the ethoxy-ol 1,3-bis(2-pyridylimino)-4-ethoxy-7-hydroxyisoindole. Excited-state electronic structure calculations suggest a resolution to this puzzle by revealing a seesaw effect in which the two hydrogen bonds of the diol are both longer than the single hydrogen bond in the ethoxy-ol. Semiclassical rate theory recovers the previously unexplained trends and leads to clear predictions regarding the relative H/D kinetic isotope effect (KIE) for ESIPT in the two systems. The theoretical KIE predictions are tested using ultrafast spectroscopy, confirming the seesaw effect

Non-equilibrium dynamics from RPMD and CMD

We investigate the calculation of approximate non-equilibrium quantum time correlation functions (TCFs) using two popular path-integral-based molecular dynamics methods, ring-polymer molecular dynamics (RPMD) and centroid molecular dynamics (CMD). It is shown that for the cases of a sudden vertical excitation and an initial momentum impulse, both RPMD and CMD yield non-equilibrium TCFs for linear operators that are exact for high temperatures, in the t = 0 limit, and for harmonic potentials; the subset of these conditions that are preserved for non-equilibrium TCFs of non-linear operators is also discussed. Furthermore, it is shown that for these non-equilibrium initial conditions, both methods retain the connection to Matsubara dynamics that has previously been established for equilibrium initial conditions. Comparison of non-equilibrium TCFs from RPMD and CMD to Matsubara dynamics at short times reveals the orders in time to which the methods agree. Specifically, for the position-autocorrelation function associated with sudden vertical excitation, RPMD and CMD agree with Matsubara dynamics up to O(t^4) and O(t^1), respectively; for the position-autocorrelation function associated with an initial momentum impulse, RPMD and CMD agree with Matsubara dynamics up to O(t^5) and O(t^2), respectively. Numerical tests using model potentials for a wide range of non-equilibrium initial conditions show that RPMD and CMD yield non-equilibrium TCFs with an accuracy that is comparable to that for equilibrium TCFs. RPMD is also used to investigate excited-state proton transfer in a system-bath model, and it is compared to numerically exact calculations performed using a recently developed version of the Liouville space hierarchical equation of motion approach; again, similar accuracy is observed for non-equilibrium and equilibrium initial conditions

Cannabis-based medicines and medical cannabis for adults with cancer pain

Background: Pain is a common symptom in people with cancer; 30% to 50% of people with cancer will experience moderate‐to‐severe pain. This can have a major negative impact on their quality of life. Opioid (morphine‐like) medications are commonly used to treat moderate or severe cancer pain, and are recommended for this purpose in the World Health Organization (WHO) pain treatment ladder. Pain is not sufficiently relieved by opioid medications in 10% to 15% of people with cancer. In people with insufficient relief of cancer pain, new analgesics are needed to effectively and safely supplement or replace opioids.Objectives: To evaluate the benefits and harms of cannabis‐based medicines, including medical cannabis, for treating pain and other symptoms in adults with cancer compared to placebo or any other established analgesic for cancer pain.Search methods: We used standard, extensive Cochrane search methods. The latest search date was 26 January 2023.Selection criteria: We selected double‐blind randomised, controlled trials (RCT) of medical cannabis, plant‐derived and synthetic cannabis‐based medicines against placebo or any other active treatment for cancer pain in adults, with any treatment duration and at least 10 participants per treatment arm.Data collection and analysis: We used standard Cochrane methods. The primary outcomes were 1. proportions of participants reporting no worse than mild pain; 2. Patient Global Impression of Change (PGIC) of much improved or very much improved and 3. withdrawals due to adverse events. Secondary outcomes were 4. number of participants who reported pain relief of 30% or greater and overall opioid use reduced or stable; 5. number of participants who reported pain relief of 30% or greater, or 50% or greater; 6. pain intensity; 7. sleep problems; 8. depression and anxiety; 9. daily maintenance and breakthrough opioid dosage; 10. dropouts due to lack of efficacy; 11. all central nervous system adverse events. We used GRADE to assess certainty of evidence for each outcome.Main results: We identified 14 studies involving 1823 participants. No study assessed the proportions of participants reporting no worse than mild pain on treatment by 14 days after start of treatment.We found five RCTs assessing oromucosal nabiximols (tetrahydrocannabinol (THC) and cannabidiol (CBD)) or THC alone involving 1539 participants with moderate or severe pain despite opioid therapy. The double‐blind periods of the RCTs ranged between two and five weeks. Four studies with a parallel design and 1333 participants were available for meta‐analysis.There was moderate‐certainty evidence that there was no clinically relevant benefit for proportions of PGIC much or very much improved (risk difference (RD) 0.06, 95% confidence interval (CI) 0.01 to 0.12; number needed to treat for an additional beneficial outcome (NNTB) 16, 95% CI 8 to 100). There was moderate‐certainty evidence for no clinically relevant difference in the proportion of withdrawals due to adverse events (RD 0.04, 95% CI 0 to 0.08; number needed to treat for an additional harmful outcome (NNTH) 25, 95% CI 16 to endless). There was moderate‐certainty evidence for no difference between nabiximols or THC and placebo in the frequency of serious adverse events (RD 0.02, 95% CI −0.03 to 0.07). There was moderate‐certainty evidence that nabiximols and THC used as add‐on treatment for opioid‐refractory cancer pain did not differ from placebo in reducing mean pain intensity (standardised mean difference (SMD) −0.19, 95% CI −0.40 to 0.02).There was low‐certainty evidence that a synthetic THC analogue (nabilone) delivered over eight weeks was not superior to placebo in reducing pain associated with chemotherapy or radiochemotherapy in people with head and neck cancer and non‐small cell lung cancer (2 studies, 89 participants, qualitative analysis). Analyses of tolerability and safety were not possible for these studies.There was low‐certainty evidence that synthetic THC analogues were superior to placebo (SMD −0.98, 95% CI −1.36 to −0.60), but not superior to low‐dose codeine (SMD 0.03, 95% CI −0.25 to 0.32; 5 single‐dose trials; 126 participants) in reducing moderate‐to‐severe cancer pain after cessation of previous analgesic treatment for three to four and a half hours (2 single‐dose trials; 66 participants). Analyses of tolerability and safety were not possible for these studies.There was low‐certainty evidence that CBD oil did not add value to specialist palliative care alone in the reduction of pain intensity in people with advanced cancer. There was no difference in the number of dropouts due to adverse events and serious adverse events (1 study, 144 participants, qualitative analysis).We found no studies using herbal cannabis.Authors' conclusions: There is moderate‐certainty evidence that oromucosal nabiximols and THC are ineffective in relieving moderate‐to‐severe opioid‐refractory cancer pain. There is low‐certainty evidence that nabilone is ineffective in reducing pain associated with (radio‐) chemotherapy in people with head and neck cancer and non‐small cell lung cancer. There is low‐certainty evidence that a single dose of synthetic THC analogues is not superior to a single low‐dose morphine equivalent in reducing moderate‐to‐severe cancer pain. There is low‐certainty evidence that CBD does not add value to specialist palliative care alone in the reduction of pain in people with advanced cancer

Cannabis-based medicines and medical cannabis for adults with cancer pain

Background: Pain is a common symptom in people with cancer; 30% to 50% of people with cancer will experience moderate‐to‐severe pain. This can have a major negative impact on their quality of life. Opioid (morphine‐like) medications are commonly used to treat moderate or severe cancer pain, and are recommended for this purpose in the World Health Organization (WHO) pain treatment ladder. Pain is not sufficiently relieved by opioid medications in 10% to 15% of people with cancer. In people with insufficient relief of cancer pain, new analgesics are needed to effectively and safely supplement or replace opioids.Objectives: To evaluate the benefits and harms of cannabis‐based medicines, including medical cannabis, for treating pain and other symptoms in adults with cancer compared to placebo or any other established analgesic for cancer pain.Search methods: We used standard, extensive Cochrane search methods. The latest search date was 26 January 2023.Selection criteria: We selected double‐blind randomised, controlled trials (RCT) of medical cannabis, plant‐derived and synthetic cannabis‐based medicines against placebo or any other active treatment for cancer pain in adults, with any treatment duration and at least 10 participants per treatment arm.Data collection and analysis: We used standard Cochrane methods. The primary outcomes were 1. proportions of participants reporting no worse than mild pain; 2. Patient Global Impression of Change (PGIC) of much improved or very much improved and 3. withdrawals due to adverse events. Secondary outcomes were 4. number of participants who reported pain relief of 30% or greater and overall opioid use reduced or stable; 5. number of participants who reported pain relief of 30% or greater, or 50% or greater; 6. pain intensity; 7. sleep problems; 8. depression and anxiety; 9. daily maintenance and breakthrough opioid dosage; 10. dropouts due to lack of efficacy; 11. all central nervous system adverse events. We used GRADE to assess certainty of evidence for each outcome.Main results: We identified 14 studies involving 1823 participants. No study assessed the proportions of participants reporting no worse than mild pain on treatment by 14 days after start of treatment.We found five RCTs assessing oromucosal nabiximols (tetrahydrocannabinol (THC) and cannabidiol (CBD)) or THC alone involving 1539 participants with moderate or severe pain despite opioid therapy. The double‐blind periods of the RCTs ranged between two and five weeks. Four studies with a parallel design and 1333 participants were available for meta‐analysis.There was moderate‐certainty evidence that there was no clinically relevant benefit for proportions of PGIC much or very much improved (risk difference (RD) 0.06, 95% confidence interval (CI) 0.01 to 0.12; number needed to treat for an additional beneficial outcome (NNTB) 16, 95% CI 8 to 100). There was moderate‐certainty evidence for no clinically relevant difference in the proportion of withdrawals due to adverse events (RD 0.04, 95% CI 0 to 0.08; number needed to treat for an additional harmful outcome (NNTH) 25, 95% CI 16 to endless). There was moderate‐certainty evidence for no difference between nabiximols or THC and placebo in the frequency of serious adverse events (RD 0.02, 95% CI −0.03 to 0.07). There was moderate‐certainty evidence that nabiximols and THC used as add‐on treatment for opioid‐refractory cancer pain did not differ from placebo in reducing mean pain intensity (standardised mean difference (SMD) −0.19, 95% CI −0.40 to 0.02).There was low‐certainty evidence that a synthetic THC analogue (nabilone) delivered over eight weeks was not superior to placebo in reducing pain associated with chemotherapy or radiochemotherapy in people with head and neck cancer and non‐small cell lung cancer (2 studies, 89 participants, qualitative analysis). Analyses of tolerability and safety were not possible for these studies.There was low‐certainty evidence that synthetic THC analogues were superior to placebo (SMD −0.98, 95% CI −1.36 to −0.60), but not superior to low‐dose codeine (SMD 0.03, 95% CI −0.25 to 0.32; 5 single‐dose trials; 126 participants) in reducing moderate‐to‐severe cancer pain after cessation of previous analgesic treatment for three to four and a half hours (2 single‐dose trials; 66 participants). Analyses of tolerability and safety were not possible for these studies.There was low‐certainty evidence that CBD oil did not add value to specialist palliative care alone in the reduction of pain intensity in people with advanced cancer. There was no difference in the number of dropouts due to adverse events and serious adverse events (1 study, 144 participants, qualitative analysis).We found no studies using herbal cannabis.Authors' conclusions: There is moderate‐certainty evidence that oromucosal nabiximols and THC are ineffective in relieving moderate‐to‐severe opioid‐refractory cancer pain. There is low‐certainty evidence that nabilone is ineffective in reducing pain associated with (radio‐) chemotherapy in people with head and neck cancer and non‐small cell lung cancer. There is low‐certainty evidence that a single dose of synthetic THC analogues is not superior to a single low‐dose morphine equivalent in reducing moderate‐to‐severe cancer pain. There is low‐certainty evidence that CBD does not add value to specialist palliative care alone in the reduction of pain in people with advanced cancer