Stress-induced antinociception to noxious heat requires α1A-adrenaline receptors of spinal inhibitory neurons in mice

It is well known that acute exposure to physical stress produces a transient antinociceptive effect (called stress-induced analgesia [SIA]). One proposed mechanism for SIA involves noradrenaline (NA) in the central nervous system. NA has been reported to activate inhibitory neurons in the spinal dorsal horn (SDH), but its in vivo role in SIA remains unknown. In this study, we found that an antinociceptive effect on noxious heat after acute exposure to restraint stress was impaired in mice with a conditional knockout of α1A-adrenaline receptors (α1A-ARs) in inhibitory neurons (Vgat-Cre;Adra1aflox/flox mice). A similar reduction was also observed in mice treated with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, a selective neurotoxin for NAergic neurons in the locus coeruleus (LC). Furthermore, whole-cell patch-clamp recordings using spinal cord slices revealed that NA-induced increase in the frequency of spontaneous inhibitory postsynaptic currents in the substantia gelatinosa neurons was suppressed by silodosin, an α1A-AR antagonist, and by conditional knockout of α1A-ARs in inhibitory neurons. Moreover, under unstressed conditions, the antinociceptive effects of intrathecal NA and phenylephrine on noxious heat were lost in Vgat-Cre;Adra1aflox/flox mice. Our findings suggest that activation of α1A-ARs in SDH inhibitory neurons, presumably via LC-NAergic neurons, is necessary for SIA to noxious heat.

Road Traffic Safety Development Trends in Latvia

The main focus of this article is on the road traffic safety development trends in Latvia. Soon after the regain of independence at the beginning of the 1990s, road traffic safety characteristics in Latvia were the worst in the Latvian history. The increase of car availability and affordability made the car a major road vehicle. The implementation of road safety programmes contributed to essential improvement of road traffic safety in Latvia. The number of road accident fatalities in 2020 compared to 1991 decreased more than sevenfold. Nevertheless, the current Latvian road traffic safety statistics is well below the average level of the EU member states and even the pandemics did not cause similar reduction as in most member states. This indicates that great improvement is still needed. The article shows the Latvian experience in road traffic safety enhancements and discusses the measures to improve road traffic safety.

Corrosion resistance of surface-conditioned 301 and 304 stainless steels by salt spray test

The corrosion rate of surface-conditioned 301 and 304 stainless steels (SS) was determined by salt spray test in a controlled accelerated corrosive medium (9.5 L of pure distilled water + 500 g NaCl). By surface conditioning via mechanical attrition treatment, a gradient-structured layer was firstly generated on the surface of the samples before the salt spray test. The corrosion rate was determined by the weight loss before and after the salt spray test. Compared to the untreated 301 SS sample with a weight loss of 0.15 g, the surface-conditioned samples treated for 300 s and 1200 s experienced a lower weight loss of 0.04 and 0.02 g, respectively. A similar reduction in weight loss was achieved for 304 SS sample when treated for 5, 10, and 20 mins.

Verteporfin-Loaded Mesoporous Silica Nanoparticles’ Topical Applications Inhibit Mouse Melanoma Lymphangiogenesis and Micrometastasis In Vivo

Photodynamic therapy (PDT) has been pointed out as a candidate for improving melanoma treatment. Nanotechnology application in PDT has increased its efficacy by reducing side effects. Herein, mesoporous silica nanoparticles (MSNs) conjugated with verteporfin (Ver-MSNs), in use with PDT, were administered in mice to evaluate their efficacy on lymphoangiogenesis and micrometastasis in melanoma. Melanoma was induced in mice by the subcutaneous injection of B16-F10 cells. The mice were transcutaneously treated with MSNs, Ver-MSNs, or glycerol and exposed to red light. The treatment was carried out four times until day 20. Lymphangiogenesis and micrometastasis were identified by the immunohistochemical method. Lymphoangiogenesis was halved by MSN treatment compared with the control animals, whereas the Ver-MSN treatment almost abolished it. A similar reduction was also observed in lung micrometastasis. PDT with topically administrated Ver-MSNs reduced melanoma lymphoangiogenesis and lung micrometastasis, as well as tumor mass and angiogenesis, and therefore their use could be an innovative and useful tool in melanoma clinical therapy.

O-B06 The Impact of Covid-19 on Bariatric surgery in England during 2020

Background The Covid-19 pandemic had a significant impact on NHS services across England. Due to the significant rise in demand for beds in both ward and ITU environments, trusts were forced to reduce the number of operations carried out to help reduced the burden on secondary care services. Whilst efforts were made to preserve operations where possible, the Covid-19 burden has had a significant impact on bariatric surgery throughout 2020. The following research looks at the true impact of Covid-19 on bariatric surgery in England and analyses this in relation to the Covid-19 burden. Methods Data relating to operation numbers was taken from The Surgical Workload Outcomes Audit (SWORD) database. The SWORD database was interrogated for the years 2017 – 2020. A mean number of operations was calculated using the 2017-2019 data and compared to data from 2020 for gastric bypass, sleeve gastrectomy, gastric banding and biliopancreatic diversion. Operations performed and other demographic data was analysed regionally and compared to Covid-19 deaths throughout England. Covid-19 data was obtained from the national government dashboards. Results The results of the study show that Nationally there was a significant decline in bariatric surgery operations carried out throughout 2020 due to the Covid-19 pandemic. Overall there was a 53.5% reduction in bariatric surgery operations carried out in 2020. Looking at the individual operation types, there was a 50.7% reduction in gastric bypass surgery, a 50% reduction in biliopancreatic diversion and a 51.9% reduction in sleeve gastrectomy. There was a greater reduction in gastric bands, with a 78.1 % reduction in procedures which may also reflect changes in current practice with regards to the use of gastric bands. On reviewing data at a local level, all trusts were significantly impacted by the pandemic with the reduction in services ranging from 50% to 100% reduction in operations performed. Conclusions Overall, despite national efforts to preserve as many operations as possible, there was a significant reduction in the delivery of bariatric surgery services throughout England during the Covid-19 pandemic. Due to this reduction in service provision, it is likely that there are now much larger waiting lists which will need to be addressed as we recover from the Covid-19 pandemic. Whilst there was a similar reduction in services across most trusts due to the elective nature of the operations, variation should be further analysed to allow for better planning and resource allocation for futor future waves or future pandemics.

Effects of forages, dust exposure and proresolving lipids on airway inflammation in horses

OBJECTIVE To investigate the role of omega-3 polyunsaturated fatty acids (Ω-3)–derived proresolving lipid mediators (PRLM) in the resolution of mild airway inflammation in horses. ANIMALS 20 horses with mild airway inflammation. PROCEDURES Horses previously eating hay were fed hay pellets (low Ω-3 content; n = 10) or haylage (high Ω-3 content; 9) for 6 weeks. Dust exposure was measured in the breathing zone with a real-time particulate monitor. Bronchoalveolar lavage (BAL) was performed at baseline, week 3, and week 6. The effect of PRLM on neutrophil apoptosis and efferocytosis was examined in vitro. BAL fluid inflammatory cell proportions, apoptosis of circulating neutrophils, efferocytosis displayed by alveolar macrophages, and plasma lipid concentrations were compared between groups fed low and high amounts of Ω-3 by use of repeated measures of generalized linear models. RESULTS Dust exposure was significantly higher with hay feeding, compared to haylage and pellets, and equivalent between haylage and pellets. BAL fluid neutrophil proportions decreased significantly in horses fed haylage (baseline, 11.8 ± 2.4%; week 6, 2.5 ± 1.1%) but not pellets (baseline, 12.1 ± 2.3%; week 6, 8.5% ± 1.7%). At week 6, horses eating haylage had significantly lower BAL neutrophil proportions than those eating pellets, and a significantly lower concentration of stearic acid than at baseline. PRLM treatments did not affect neutrophil apoptosis or efferocytosis. CLINICAL RELEVANCE Despite similar reduction in dust exposure, horses fed haylage displayed greater resolution of airway inflammation than those fed pellets. This improvement was not associated with increased plasma Ω-3 concentrations. Feeding haylage improves airway inflammation beyond that due to reduced dust exposure, though the mechanism remains unclear.

Therapeutic Benefit of Galectin-1: Beyond Membrane Repair, a Multifaceted Approach to LGMD2B

Two of the main pathologies characterizing dysferlinopathies are disrupted muscle membrane repair and chronic inflammation, which lead to symptoms of muscle weakness and wasting. Here, we used recombinant human Galectin-1 (rHsGal-1) as a therapeutic for LGMD2B mouse and human models. Various redox and multimerization states of Gal-1 show that rHsGal-1 is the most effective form in both increasing muscle repair and decreasing inflammation, due to its monomer-dimer equilibrium. Dose-response testing shows an effective 25-fold safety profile between 0.54 and 13.5 mg/kg rHsGal-1 in Bla/J mice. Mice treated weekly with rHsGal-1 showed downregulation of canonical NF-κB inflammation markers, decreased muscle fat deposition, upregulated anti-inflammatory cytokines, increased membrane repair, and increased functional movement compared to non-treated mice. Gal-1 treatment also resulted in a positive self-upregulation loop of increased endogenous Gal-1 expression independent of NF-κB activation. A similar reduction in disease pathologies in patient-derived human cells demonstrates the therapeutic potential of Gal-1 in LGMD2B patients.

Association between SGLT2 Inhibitors vs DPP-4 Inhibitors and Risk of Pneumonia Among Patients with Type 2 Diabetes

Context Patients with diabetes are at a higher risk of pneumonia and pneumonia mortality. Sodium-glucose co-transporter 2 inhibitors (SGLT2is), the latest class of glucose-lowering agents, were shown to reduce the risk of pneumonia in clinical trials. However, the real-world effectiveness of SGLT2is on the risk of pneumonia is largely unknown. Objective To investigate the associations between SGLT2is use and the risk of pneumonia and pneumonia mortality compared to dipeptidyl peptidase-4 inhibitors (DPP4is) using an electronic medical database in Hong Kong. Design A retrospective cohort study. The “prevalent new-user” design was adopted to account for the previous exposure to the study drugs being compared. Propensity score (PS) matching (1:4) was used to balance the baseline characteristics of the two groups. Setting and participants Electronic health data of type 2 diabetes patients using SGLT2is and DPP4is between 2015 and 2018 was collected from the Clinical Data Analysis and Reporting System (CDARS). Main Outcome Measures Pneumonia incidence and mortality. Results The PS-matched cohort consisted of 6,664 users of SGLT2is and 26,656 users of DPP4is, with a mean follow-up of 3.8 years. Poisson regression showed that SGLT2is use was associated with lower risk of pneumonia compared to DPP4is with an absolute rate difference of 4.05 per 1000 person-years (95% CI: 2.61-5.51). The corresponding IRR was 0.71 (95% CI: 0.62-0.81). Similar reduction in risk of pneumonia death was observed (HR: 0.57; 95% CI: 0.42-0.77). Conclusion Compared to DPP4is, SGLT2is use was associated with a reduced risk of pneumonia and pneumonia mortality in a real-world setting.

The R346K Mutation in the Mu Variant of SARS-CoV-2 Alter the Interactions with Monoclonal Antibodies from Class 2: A Free Energy of Perturbation Study

The Mu variant of SARS-CoV-2 has been recently classified as a variant of interest (VOI) by the world health organization (WHO) but limited data are available at the moment. In particular, a special attention was given to the R346K mutation located in the receptor binding domain (RBD). In the current study we performed Free energy of perturbation (FEP) calculations to elucidate it possible impact on a set of neutralizing monoclonal antibodies (mAbs) which have been shown to be strong inhibitors of the most other known COVID-19 variants. Our results show that R346K affects the class 2 antibodies but its effect is not so significant (0.66 kcal/mol); i.e. reduces the binding with RBD about 3 times. An identical value was calculated also in the presence of both class 1 and class 2 antibodies (BD-812/836). Further, a similar reduction in the binding (0.4 kcal/mol) was obtained for BD-821/771 pair of mAbs. For comparison, the addition of K417N mutation, present in the newly registered Mu variant in July 2021 in UK, affected the class 1 mAbs by 1.29 kcal/mol reducing stronger the binding by about 10 times. Thus, the resistance effect of R346K mutation in the Mu variant is possible but not so significant and is due to the additional decrease of antibody neutralization based on the reduced binding of class 2 antibodies.

Curcumin and Carnosic Acid Cooperate to Inhibit Proliferation and Alter Mitochondrial Function of Metastatic Prostate Cancer Cells

Anticancer activities of plant polyphenols have been demonstrated in various models of neoplasia. However, evidence obtained in numerous in vitro studies indicates that proliferation arrest and/or killing of cancer cells require quite high micromolar concentrations of polyphenols that are difficult to reach in vivo and can also be (geno)toxic to at least some types of normal cells. The ability of certain polyphenols to synergize with one another at low concentrations can be used as a promising strategy to effectively treat human malignancies. We have recently reported that curcumin and carnosic acid applied at non-cytotoxic concentrations synergistically cooperate to induce massive apoptosis in acute myeloid leukemia cells, but not in normal hematopoietic and non-hematopoietic cells, via sustained cytosolic calcium overload. Here, we show that the two polyphenols can also synergistically suppress the growth of DU145 and PC-3 metastatic prostate cancer cell cultures. However, instead of cell killing, the combined treatment induced a marked inhibition of cell proliferation associated with G0/G1 cell cycle arrest. This was preceded by transient elevation of cytosolic calcium levels and prolonged dissipation of the mitochondrial membrane potential, without generating oxidative stress, and was associated with defective oxidative phosphorylation encompassing mitochondrial dysfunction. The above effects were concomitant with a significant downregulation of mRNA and protein expression of the oncogenic kinase SGK1, the mitochondria-hosted mTOR component. In addition, a moderate decrease in SGK1 phosphorylation at Ser422 was observed in polyphenol-treated cells. The mTOR inhibitor rapamycin produced a similar reduction in SGK1 mRNA and protein levels as well as phosphorylation. Collectively, our findings suggest that the combination of curcumin and carnosic acid at potentially bioavailable concentrations may effectively target different types of cancer cells by distinct modes of action. This and similar combinations merit further exploration as an anticancer modality.