SIRT2 Inhibition Rescues Neurodegenerative Pathology but Increases Systemic Inflammation in a Transgenic Mouse Model of Alzheimer's Disease.

Sirtuin 2 (SIRT2) has been proposed to have a central role on aging, inflammation, cancer and neurodegenerative diseases; however, its specific function remains controversial. Recent studies propose SIRT2 pharmacological inhibition as a therapeutic strategy for several neurodegenerative diseases including Alzheimer's disease (AD). Surprisingly, none of these published studies regarding the potential interest of SIRT2 inhibition has assessed the peripheral adverse side consequences of this treatment. In this study, we demonstrate that the specific SIRT2 inhibitor, the compound 33i, does not exhibit genotoxic or mutagenic properties. Moreover, pharmacological treatment with 33i, improved cognitive dysfunction and long-term potentiation, reducing amyloid pathology and neuroinflammation in the APP/PS1 AD mouse model. However, this treatment increased peripheral levels of the inflammatory cytokines IL-1ß, TNF, IL-6 and MCP-1. Accordingly, peripheral SIRT2 inhibition with the blood brain barrier impermeable compound AGK-2, worsened the cognitive capacities and increased systemic inflammation. The analysis of human samples revealed that SIRT2 is increased in the brain but not in the serum of AD patients. These results suggest that, although SIRT2 pharmacological inhibition may have beneficial consequences in neurodegenerative diseases, its pharmacological inhibition at the periphery would not be recommended and the systemic adverse side effects should be considered. This information is essential to maximize the therapeutic potential of SIRT2 inhibition not only for AD but also for other neurodegenerative diseases.

Proton pump inhibitors and gastroprotection in patients treated with antithrombotic drugs: A cardiologic point of view.

Aspirin, other antiplatelet agents, and anticoagulant drugs are used across a wide spectrum of cardiovascular and cerebrovascular diseases. A concomitant proton pump inhibitor (PPI) treatment is often prescribed in these patients, as gastrointestinal complications are relatively frequent. On the other hand, a potential increased risk of cardiovascular events has been suggested in patients treated with PPIs; in particular, it has been discussed whether these drugs may reduce the cardiovascular protection of clopidogrel, due to pharmacodynamic and pharmacokinetic interactions through hepatic metabolism. Previously, the concomitant use of clopidogrel and omeprazole or esomeprazole has been discouraged. In contrast, it remains less known whether PPI use may affect the clinical efficacy of ticagrelor and prasugrel, new P2Y12 receptor antagonists. Current guidelines recommend PPI use in combination with antiplatelet treatment in patients with risk factors for gastrointestinal bleeding, including advanced age, concurrent use of anticoagulants, steroids, or non-steroidal anti-inflammatory drugs, and Helicobacter pylori (H. pylori) infection. In patients taking oral anticoagulant with risk factors for gastrointestinal bleeding, PPIs could be recommended, even if their usefulness deserves further data. H. pylori infection should always be investigated and treated in patients with a history of peptic ulcer disease (with or without complication) treated with antithrombotic drugs. The present review summarizes the current knowledge regarding the widespread combined use of platelet inhibitors, anticoagulants, and PPIs, discussing consequent clinical implications.

Locus coeruleus inhibition of vibrissal responses in the trigeminal subnucleus caudalis are reduced in a diabetic mouse model.

Diabetic neuropathy is the loss of sensory function beginning distally in the lower extremities, which is also characterized by pain and substantial morbidity. Furthermore, the locus coeruleus (LC) nucleus has been proposed to play an important role in descending pain control through the activation of α2-noradrenergic (NA) receptors in the spinal dorsal horn. We studied, on control and diabetic mice, the effect of electrical stimulation of the LC nucleus on the tactile responses in the caudalis division of the spinal trigeminal nucleus (Sp5C), which is involved in the relay of orofacial nociceptive information. Diabetes was induced in young adult C57BL/6J mice with one intraperitoneal injection of streptozotocin (50 mg/kg) daily for 5 days. The diabetic animals showed pain in the orofacial area because they had a decrease in the withdrawal threshold to the mechanical stimulation in the vibrissal pad. LC electrical stimulation induced the inhibition of vibrissal responses in the Sp5C neurons when applied at 50 and 100 ms before vibrissal stimulation in the control mice; however, the inhibition was reduced in the diabetic mice. These effects may be due to a reduction in the tyrosine hydroxylase positive (TH+) fibers in the Sp5C, as was observed in diabetic mice. LC-evoked inhibition was decreased by an intraperitoneal injection of the antagonist of the α2-NA receptors, yohimbine, indicating that it was due to the activation of α2-NA receptors. The decrease in the LC-evoked inhibition in the diabetic mice was partially recovered when clonidine, a non-selective α2-agonist, was injected intraperitoneally. These findings suggest that in diabetes, there is a reduction in the NA inputs from the LC in the Sp5C that may favor the development of chronic pain.

State guarantees to counteract the financial effects of the COVID-19 pandemic on industrial supply chains.

As the recent COVID-19 pandemic has clearly demonstrated, appropriate state support policies are crucial for supporting industrial supply chains during crises to prevent viable businesses from defaulting. In this context, this study proposes a hybrid credit risk model to appropriately size public interventions for viable (worthy) businesses through systematic risk assessment during a period of turmoil. This study discusses the effects of the credit crunch-based economic downturn and proposes a methodology to assist policymakers in managing limited public resources to effectively support industrial supply chains. The proposed approach initially focuses on the dynamics of credit risk during economic recession periods, identifying the conditions that may justify a public intervention strategy based on public guarantees. Subsequently, a hybrid credit risk model is developed to appropriately size public interventions by quantifying systematic risk. Finally, a numerical application is presented to demonstrate the effectiveness of the proposed approach.

Time trends in antithrombotic therapy prescription patterns: Real-world monocentric study in hospitalized patients with atrial fibrillation.

BACKGROUND: Since 2010, the European Society of Cardiology has extended prescription criteria for oral antithrombotic therapy (OAT) in atrial fibrillation (AF). Direct oral anticoagulants (DOACs) were upgraded from an IIAa recommendation in 2012 to an IA in 2016. In real-world scenarios, however, OAC prescription is still suboptimal, mainly for DOACs. AIM: To evaluate OAT temporal prescription patterns in a cohort of patients hospitalized with AF in a Cardiology Department. METHODS: A retrospective observational study was conducted on a cohort of hospitalized patients in a secondary setting (Trapani, Italy) from 2010 to 2021 with AF as the main or secondary diagnosis. For 4089 consecutive patients, the variables extracted from the Cardiology department database were: Sex, age, time of hospitalization, antithrombotic therapy (warfarin, acenocoumarol, apixaban, dabigatran, edoxaban, rivaroxaban, aspirin, clopidogrel, other antiplatelet agents, low molecular weight heparin, and fondaparinux), diagnosis at discharge and used resources. Basal features are presented as percentage values for categorized variables and as mean +/- SD for categorized once. RESULTS: From January 1st, 2010 to October 6th, 2021, 25132 patients were hospitalized in our department; 4089 (16.27%, mean age 75.59+/-10.82) were discharged with AF diagnosis; of them, 2245 were males (54.81%, mean age 73.56+/-11.45) and 1851 females (45.19%, mean age 78.06+/-9.47). Average length of stay was 5.76+/-4.88 days; 154 patients died and 88 were moved to other Departments/Structures. AF was the main diagnosis in 899 patients (21.94%). The most frequent main diagnosis in patients with AF was acute myocardial infarction (1973 discharges, 48.19%). The most frequent secondary cardiac diagnosis was chronic coronary syndrome (1864 discharges, 45.51%), and the most frequent secondary associated condition was arterial hypertension (1010 discharges, 24.66%). For the analysis of antithrombotic treatments, the final sample included 3067 patients, after excluding in-hospital deaths, transferred out or self-discharged patients, as well as discharges lacking indications for prescribed treatments. OAC treatment increased significantly (35.63% in 2010-2012 vs 61.18% in 2019-2021, +25.55%, P < 0.0001), in spite of any antiplatelet agent use. This rise was due to increasing use of DOACs, with or without antiplatelet agents, from 3.04% in 2013-2015 to 50.06% in 2019-2021 (+47.02%, P < 0.0001) and was greater for factor Xa inhibitors, especially apixaban. In addition, treatment with a vitamin K antagonist, in spite of any antiplatelet agent use, decreased from 35.63% in 2010-2012 to 11.12% in 2019-2021 (-24.48%, P < 0.0001), as well as any antiplatelet therapy, alone or in double combination, (49.18% in 2010-2012 vs 34.18% in 2019-2021, -15.00%, P < 0.0001); and patients not receiving antithrombotic therapy declined with time (14.58% in 2010-2012 vs 1.97% in 2021, P < 0.0001). CONCLUSION: Real-world patients with AF are elderly and affected by cardiovascular and non-cardiovascular diseases. The percentage of patients on OAT and DOACs increased. These data suggest a slow, gradual guidelines implementation process.

Climatic influences on cardiovascular diseases.

Classical risk factors only partially account for variations in cardiovascular disease incidence; therefore, also other so far unknown features, among which meteorological factors, may influence heart diseases (mainly coronary heart diseases, but also heart failure, arrhythmias, aortic dissection and stroke) rates. The most studied phenomenon is ambient temperature. The relation between mortality, as well as cardiovascular diseases incidence, and temperature appears graphically as a ''U'' shape. Exposure to cold, heat and heat waves is associated with an increased risk of acute coronary syndromes. Other climatic variables, such as humidity, atmospheric pressure, sunlight hours, wind strength and direction and rain/snow precipitations have been hypothesized as related to fatal and non-fatal cardiovascular diseases incidence. Main limitation of these studies is the unavailability of data on individual exposure to weather parameters. Effects of weather may vary depending on other factors, such as population disease profile and age structure. Climatic stress may increase direct and indirect risks to human health via different, complex pathophysiological pathways and exogenous and endogenous mechanisms. These data have attracted growing interest because of the recent earth's climate change, with consequent increasing ambient temperatures and climatic fluctuations. This review evaluates the evidence base for cardiac health consequences of climate conditions, and it also explores potential further implications.

Do Grapholita funebrana Infestation Rely on Specific Plum Fruit Features?

The effective control of the plum fruit moth, Grapholita funebrana (Lepidoptera: Tortricidae) still represents a difficult challenge for organic plum farming. Little information is available on the susceptibility of plum cultivars to this moth pest. We investigated the roles of several fruit parameters (i.e., shape, volume, hardness, fruit colour, and physiochemical properties) on the susceptibility of four different plum cultivars (Angeleno, Friar, President and Stanley) to G. funebrana attack. Field data demonstrated the importance of some fruit parameters (i.e., elongation index, sugar degree, titratable acidity, cover colour percentage) on susceptibility to G. funebrana infestation. Under laboratory conditions, colour and shape had a significant role in determining the time spent on false fruits, i.e., female moths preferred yellow and rounded fruits over elongated red or green fruits. Angeleno (yellow and rounded fruits) and Stanley (green and elongated fruits) were the most and least susceptible cultivars, respectively. Overall, this study adds useful knowledge about plum cultivar susceptibility to G. funebrana. Information reported here may be useful to improve integrated pest management strategies both in conventional and organic orchards because the use of less susceptible cultivars may reduce insecticidal treatments, limiting the development of resistance in target insects and the harmful side effects on beneficial species.

Influence of Distance from the Host on Parasitisation by Psyttalia concolor (Szépligeti) (Hymenoptera: Braconidae).

The olive fruit fly, Bactrocera oleae, is considered the main olive pest worldwide, and has been the target of biological control programmes through the release of the braconid parasitoid Psyttalia concolor. Laboratory tests were performed to evaluate the influence of distance from the host on parasitisation, placing larvae of the substitute host Ceratitis capitata at seven distances (0, 0.5, 1, 1.5, 2, 2.5, 3 mm) and four different time periods (7, 15, 30, 60 min). Moreover, field collected olives of Ogliarola Barese cultivar infested by B. oleae were exposed to P. concolor females to confirm its ability to parasitise B. oleae in small olives. Psyttalia concolor oviposition was inhibited at 2.5 and 3 mm due to the ovipositor length of the parasitoid females (2.7 mm). Hosts were easily parasitised at distances between 0 and 1.5 mm. The thin fruit pulp (up to 3.5 mm) of field collected olives allowed the parasitisation to occur also in mature fruits. At the best combination distance/time (0 mm, 30 min), tests performed with different larvae/parasitoid female ratio showed an increasing emergence of P. concolor (from 20% to 57%) with larvae/parasitoid ratio increasing from 0.11 to 0.74. The results of the present study might optimise the mass rearing of P. concolor, through a proper setting of its parameters, such as the host/parasitoid ratio, exposure distances, and interaction time.

Age- and Gender-Specific Prognostic Cutoff Values of Coronary Flow Velocity Reserve in Vasodilator Stress Echocardiography.

PURPOSE: Coronary flow velocity reserve (CFVR) of the left anterior descending artery is useful for risk stratification during stress echocardiography (SE) as an add-on to regional wall motion abnormalities (RWMA). We sought to provide sex- and age-specific prognostic cutoff values for CFVR. METHODS: A total of 5,577 patients (2,284 women; 110 age ≥ 85 years) who underwent dipyridamole SE with evaluation of RWMA and CFVR were enrolled in a multicenter prospective SE registry. Death and myocardial infarction were the clinical end points. RESULTS: During 20 months' median follow-up, 649 events (236 deaths, 413 infarctions) occurred: 288 in women and 38 in patients ≥85 years. At receiver operating characteristics analysis, the best prognostic cutoff value for CFVR was similar for men (2.03) and women (2.02) and consistent across all age strata (<45 years: 2.03; 45-54 years: 2.04; 45-64 years: 2.03; 65-74 and 75-84 years: 2.0) except for patients >85 years, who showed 1.90 as the optimal value. Independent predictors of mortality or myocardial infarction were RWMA (hazard ratio [HR] = 5.42), reduced CFVR (HR = 3.26), resting ejection fraction (HR = 0.98), smoking habit (HR = 1.41), age (HR = 1.02), and prior percutaneous coronary intervention (HR = 1.20) in patients age <85 years; and RWMA (HR = 5.42), smoking habit (HR = 3.24), and resting ejection fraction (HR = 0.97) in those age ≥85 years. CFVR added a prognostic contribution over clinical parameters, resting ejection fraction, and stress-induced RWMA in all age and sex groups except men >85 years. CONCLUSIONS: A sex-independent value of CFVR ≤2.0 provides the optimal prognostication across all age groups, except for those ≥85 years in whom a cutoff ≤1.90 is needed. Risk stratification is more effective for all age groups when CFVR is combined with RWMA.

Echo-derived peak cardiac power output-to-left ventricular mass with cardiopulmonary exercise testing predicts outcome in patients with heart failure and depressed systolic function.

AIMS: Peak cardiac power output-to-mass (CPOM) represents a measure of the rate at which cardiac work is delivered respect to the potential energy stored in left ventricular (LV) mass. We studied the value of CPOM and cardiopulmonary exercise test (CPET) in risk stratification of patients with heart failure (HF). MATERIALS AND RESULTS: We studied 159 patients with chronic HF (mean rest LV ejection fraction 30%) undergoing CPET and exercise stress echocardiography. CPOM was calculated as the product of a constant (K = 2.22 × 10-1) with cardiac output (CO) and the mean blood pressure (MBP), divided by LV mass (M), and expressed in the unit of W/100 g: CPOM = [K × CO (L/min) × MBP (mmHg)]/LVM(g). Patients were followed-up for the primary endpoint, including all-cause death, ventricular assist device implantation, and heart transplantation, and the secondary endpoint that comprised hospitalization for HF. In multivariate Cox regression analyses, peak CPOM was selected as the most powerful independent predictor of both primary and secondary endpoint [hazard ratio (HR) 0.004, 95% confidence interval (CI) 0.004-0.3; P = 0.002 and HR 0.09, 95% CI 0.02-0.55; P = 0.009]. Sixty-month survival free from the combined endpoint was 85% in those exhibiting oxygen consumption (VO2) > 14 mL/min/kg and peak CPOM > 0.6 W/100 g. Peak VO2 ≤ 14 mL/min/kg provided incremental prognostic value over demographic and clinical variables, brain natriuretic peptide, and resting echocardiographic parameters (χ2 from 58 to 64; P = 0.04), that was further increased by peak CPOM ≤ 0.6 W/100 g (χ2 77; P < 0.001). CONCLUSION: Peak CPOM and peak VO2 showed independent and incremental prognostic values in patients with chronic HF.

Biological and life table parameters of Typhlodromus laurentii and Iphiseius degenerans (Acari, Phytoseiidae) fed on Panonychus citri and pollen of Oxalis pes-caprae under laboratory conditions.

Typhlodromus laurentii and Iphiseius degenerans are two generalist phytoseiid mites, broadly spread in the Mediterranean area, especially in citrus orchards. In the present work we report results on various biological and life table parameters of the two phytoseiids, fed on pollen of Oxalis pes-caprae and various stages of the tetranychid Panonychus citri. Iphiseius degenerans had the shortest post embryonic development (6.53 days), the highest oviposition rate (1.83 eggs/female/day) and the shortest mean time between eggs laid (0.55 day) on Oxalis pollen, whereas the two food types did not influence these parameters in T. laurentii. However, Oxalis pollen showed a positive effect on the survivorship of the latter phytoseiid, with a median life time (LT50) of 44.51 days, which was two times longer than that registered on prey with the same phytoseiid, and on both food types with I. degenerans. This latter species had a better performance on the pollen (rm = 0.243, λ = 1.275, Ro = 22.88, DT = 2.85) than on prey (rm = 0.182, λ = 1.199, Ro = 17.43, DT = 3.81). On the other hand, the pollen influenced the net reproductive rate (25.43 females/female) of T. laurentii positively but showed the same effect as the prey on the other demographic parameters. Our results improve knowledge on the feeding behaviour of the above mentioned phytoseiids on two food sources that could represent the main possibility to maintain a consistent population of these predators during winter. Moreover, both phytoseiids were shown to be good biocontrol candidates of P. citri populations.