Connexin43 Inhibition Prevents Human Vein Grafts Intimal Hyperplasia.

Venous bypass grafts often fail following arterial implantation due to excessive smooth muscle cells (VSMC) proliferation and consequent intimal hyperplasia (IH). Intercellular communication mediated by Connexins (Cx) regulates differentiation, growth and proliferation in various cell types. Microarray analysis of vein grafts in a model of bilateral rabbit jugular vein graft revealed Cx43 as an early upregulated gene. Additional experiments conducted using an ex-vivo human saphenous veins perfusion system (EVPS) confirmed that Cx43 was rapidly increased in human veins subjected ex-vivo to arterial hemodynamics. Cx43 knock-down by RNA interference, or adenoviral-mediated overexpression, respectively inhibited or stimulated the proliferation of primary human VSMC in vitro. Furthermore, Cx blockade with carbenoxolone or the specific Cx43 inhibitory peptide 43gap26 prevented the burst in myointimal proliferation and IH formation in human saphenous veins. Our data demonstrated that Cx43 controls proliferation and the formation of IH after arterial engraftment

Short-term pre-operative protein caloric restriction in elective vascular surgery patients: a randomized clinical trial

(1) Background: Vascular surgery operations are hampered by high failure rates and frequent occurrence of peri-operative cardiovascular complications. In pre-clinical studies, pre-operative restriction of proteins and/or calories (PCR) has been shown to limit ischemia-reperfusion damage, slow intimal hyperplasia, and improve metabolic fitness. However, whether these dietary regimens are feasible and safe in the vascular surgery patient population remains unknown. (2) Methods: We performed a randomized controlled trial in patients scheduled for any elective open vascular procedure. Participants were randomized in a 3:2 ratio to either four days of outpatient pre-operative PCR (30% calorie, 70% protein restriction) or their regular ad-libitum diet. Blood was drawn at baseline, pre-operative, and post-operative day 1 timepoints. A leukocyte subset flow cytometry panel was performed at these timepoints. Subcutaneous/perivascular adipose tissue was sampled and analyzed. Follow-up was one year post-op. (3) Results: 19 patients were enrolled, of whom 11 completed the study. No diet-related reasons for non-completion were reported, and there was no intervention group crossover. The PCR diet induced weight loss and BMI decrease without malnutrition. Insulin sensitivity was improved after four days of PCR (p = 0.05). Between diet groups, there were similar rates of re-intervention, wound infection, and cardiovascular complications. Leukocyte populations were maintained after four days of PCR. (4) Conclusions: Pre-operative PCR is safe and feasible in elective vascular surgery patients.Vascular Surger

Search for Charmless Two-body Baryonic Decays of B Mesons

We report the results of a search for the rare baryonic decays $B^0 \to p\bar{p}$, $\Lambda\bar{\Lambda}$, and $B^+ \to p\bar{\Lambda}$. The analysis is based on a data set of $31.7\times 10^6 B\bar{B}$ events collected by the Belle detector at the KEKB $e^+e^-$ collider. No statistically significant signals are found, and we set branching fraction upper limits ${\mathcal B}(B^0 \to p\bar{p}) < 1.2 \times 10^{-6}$, ${\mathcal B}(B^0 \to \Lambda\bar{\Lambda}) < 1.0 \times 10^{-6}$, and ${\mathcal B}(B^+ \to p\bar{\Lambda}) < 2.2 \times 10^{-6}$ at the 90% confidence level.Comment: 6 pages, 4 figures and 1 table. Submitted to Phys. Rev. D Rapid Communication

Search for astrophysical electron antineutrinos in Super-Kamiokande with 0.01wt% gadolinium-loaded water

We report the first search result for the flux of astrophysical electron antineutrinos for energies O(10) MeV in the gadolinium-loaded Super-Kamiokande (SK) detector. In June 2020, gadolinium was introduced to the ultra-pure water of the SK detector in order to detect neutrons more efficiently. In this new experimental phase, SK-Gd, we can search for electron antineutrinos via inverse beta decay with efficient background rejection and higher signal efficiency thanks to the high efficiency of the neutron tagging technique. In this paper, we report the result for the initial stage of SK-Gd with a $22.5\times552$ $\rm kton\cdot day$ exposure at 0.01% Gd mass concentration. No significant excess over the expected background in the observed events is found for the neutrino energies below 31.3 MeV. Thus, the flux upper limits are placed at the 90% confidence level. The limits and sensitivities are already comparable with the previous SK result with pure-water ($22.5 \times 2970 \rm kton\cdot day$) owing to the enhanced neutron tagging

Measurements of the charge ratio and polarization of cosmic-ray muons with the Super-Kamiokande detector

We present the results of the charge ratio (R) and polarization (Pμ0) measurements using the decay electron events collected from 2008 September to 2022 June by the Super-Kamiokande detector. Because of its underground location and long operation, we performed high precision measurements by accumulating cosmic-ray muons. We measured the muon charge ratio to be R=1.32±0.02 (stat.+syst.) at EμcosθZenith=0.7+0.3−0.2 TeV, where Eμ is the muon energy and θZenith is the zenith angle of incoming cosmic-ray muons. This result is consistent with the Honda flux model while this suggests a tension with the πK model of 1.9σ. We also measured the muon polarization at the production location to be Pμ0=0.52±0.02 (stat.+syst.) at the muon momentum of 0.9+0.6−0.1 TeV/c at the surface of the mountain; this also suggests a tension with the Honda flux model of 1.5σ. This is the most precise measurement ever to experimentally determine the cosmic-ray muon polarization near 1 TeV/c. These measurement results are useful to improve the atmospheric neutrino simulations

Is Overnight Fasting before Surgery Too Much or Not Enough? How Basic Aging Research Can Guide Preoperative Nutritional Recommendations to Improve Surgical Outcomes: A Mini-Review.

Dietary restriction (DR) is best known for extending lifespan in experimental model organisms, but also increases resistance to a variety of clinically relevant stressors, including those associated with surgery. Extended periods of DR, lasting months to years, are required for optimal longevity benefits in rodents, but short-term dietary preconditioning (less than 1 week) remarkably protects from acute injury. Here, we discuss recent advances in our understanding of the mechanistic basis of short-term DR and fasting in the context of surgical stress resistance, including upstream amino acid sensing by the GCN2 and mTORC1 pathways, and downstream effector mechanisms including increased insulin-dependent prosurvival signaling and elevated endogenous hydrogen sulfide production. We also review the current trend in preoperative nutrition away from preoperative fasting and towards carbohydrate loading. Finally, we discuss the rationale for the nonmutually exclusive use of brief DR or pharmacological DR mimetics to precondition against the stress and potential complications of surgery

Hydrogen Sulphide Release via the Angiotensin Converting Enzyme Inhibitor Zofenopril Prevents Intimal Hyperplasia in Human Vein Segments and in a Mouse Model of Carotid Artery Stenosis.

Hypertension is a major risk factor for intimal hyperplasia (IH) and re-stenosis following vascular and endovascular interventions. Preclinical studies suggest that hydrogen sulphide (H &lt;sub&gt;2&lt;/sub&gt; S), an endogenous gasotransmitter, limits re-stenosis. While there is no clinically available pure H &lt;sub&gt;2&lt;/sub&gt; S releasing compound, the sulfhydryl containing angiotensin converting enzyme inhibitor zofenopril is a source of H &lt;sub&gt;2&lt;/sub&gt; S. Here, it was hypothesised that zofenopril, due to H &lt;sub&gt;2&lt;/sub&gt; S release, would be superior to other non-sulfhydryl containing angiotensin converting enzyme inhibitors (ACEi) in reducing intimal hyperplasia. Spontaneously hypertensive male Cx40 deleted mice (Cx40 &lt;sup&gt;-/-&lt;/sup&gt; ) or wild type (WT) littermates were randomly treated with enalapril 20 mg or zofenopril 30 mg. Discarded human vein segments and primary human smooth muscle cells (SMCs) were treated with the active compound enalaprilat or zofenoprilat. IH was evaluated in mice 28 days after focal carotid artery stenosis surgery and in human vein segments cultured for seven days ex vivo. Human primary smooth muscle cell (SMC) proliferation and migration were studied in vitro. Compared with control animals (intima/media thickness 2.3 ± 0.33 μm), enalapril reduced IH in Cx40 &lt;sup&gt;-/-&lt;/sup&gt; hypertensive mice by 30% (1.7 ± 0.35 μm; p = .037), while zofenopril abrogated IH (0.4 ± 0.16 μm; p &lt; .002 vs. control and p &gt; .99 vs. sham operated Cx40 &lt;sup&gt;-/-&lt;/sup&gt; mice). In WT normotensive mice, enalapril had no effect (0.9665 ± 0.2 μm in control vs. 1.140 ± 0.27 μm; p &gt; .99), while zofenopril also abrogated IH (0.1623 ± 0.07 μm; p &lt; .008 vs. control and p &gt; .99 vs. sham operated WT mice). Zofenoprilat, but not enalaprilat, also prevented IH in human vein segments ex vivo. The effect of zofenopril on carotid and SMCs correlated with reduced SMC proliferation and migration. Zofenoprilat inhibited the mitogen activated protein kinase and mammalian target of rapamycin pathways in SMCs and human vein segments. Zofenopril provides extra beneficial effects compared with non-sulfhydryl ACEi in reducing SMC proliferation and re-stenosis, even in normotensive animals. These findings may hold broad clinical implications for patients suffering from vascular occlusive diseases and hypertension