Rewiring Vascular Metabolism Prevents Sudden Death due to Aortic Ruptures-Brief Report.

BACKGROUND: The goal of this study was to determine whether boosting mitochondrial respiration prevents the development of fatal aortic ruptures triggered by atherosclerosis and hypertension. METHODS: Ang-II (angiotensin-II) was infused in ApoE (Apolipoprotein E)-deficient mice fed with a western diet to induce acute aortic aneurysms and lethal ruptures. RESULTS: We found decreased mitochondrial respiration and mitochondrial proteins in vascular smooth muscle cells from murine and human aortic aneurysms. Boosting NAD levels with nicotinamide riboside reduced the development of aortic aneurysms and sudden death by aortic ruptures. CONCLUSIONS: Targetable vascular metabolism is a new clinical strategy to prevent fatal aortic ruptures and sudden death in patients with aortic aneurysms.

Correlation Between Endoglin and Malignant Phenotype in Human Melanoma Cells: Analysis of hsa-mir-214 and hsa-mir-370 in Cells and Their Extracellular Vesicles.

Endoglin (CD105) is an auxiliary receptor of transforming growth factor (TGF)-ß family members that is expressed in human melanomas. It is heterogeneously expressed by primary and metastatic melanoma cells, and endoglin targeting as a therapeutic strategy for melanoma tumors is currently been explored. However, its involvement in tumor development and malignancy is not fully understood. Here, we find that endoglin expression correlates with malignancy of primary melanomas and cultured melanoma cell lines. Next, we have analyzed the effect of ectopic endoglin expression on two miRNAs (hsa-mir-214 and hsa-mir-370), both involved in melanoma tumor progression and endoglin regulation. We show that compared with control cells, overexpression of endoglin in the WM-164 melanoma cell line induces; (i) a significant increase of hsa-mir-214 levels in small extracellular vesicles (EVs) as well as an increased trend in cells; and (ii) significantly lower levels of hsa-mir-370 in the EVs fractions, whereas no significant differences were found in cells. As hsa-mir-214 and hsa-mir-370 are not just involved in melanoma tumor progression, but they can also target endoglin-expressing endothelial cells in the tumor vasculature, these results suggest a complex and differential regulatory mechanism involving the intracellular and extracellular signaling of hsa-mir-214 and hsa-mir-370 in melanoma development and progression.

Extracellular Tuning of Mitochondrial Respiration Leads to Aortic Aneurysm.

BACKGROUND: Marfan syndrome (MFS) is an autosomal dominant disorder of the connective tissue caused by mutations in the FBN1 (fibrillin-1) gene encoding a large glycoprotein in the extracellular matrix called fibrillin-1. The major complication of this connective disorder is the risk to develop thoracic aortic aneurysm. To date, no effective pharmacologic therapies have been identified for the management of thoracic aortic disease and the only options capable of preventing aneurysm rupture are endovascular repair or open surgery. Here, we have studied the role of mitochondrial dysfunction in the progression of thoracic aortic aneurysm and mitochondrial boosting strategies as a potential treatment to managing aortic aneurysms. METHODS: Combining transcriptomics and metabolic analysis of aortas from an MFS mouse model (Fbn1c1039g/+) and MFS patients, we have identified mitochondrial dysfunction alongside with mtDNA depletion as a new hallmark of aortic aneurysm disease in MFS. To demonstrate the importance of mitochondrial decline in the development of aneurysms, we generated a conditional mouse model with mitochondrial dysfunction specifically in vascular smooth muscle cells (VSMC) by conditional depleting Tfam (mitochondrial transcription factor A; Myh11-CreERT2Tfamflox/flox mice). We used a mouse model of MFS to test for drugs that can revert aortic disease by enhancing Tfam levels and mitochondrial respiration. RESULTS: The main canonical pathways highlighted in the transcriptomic analysis in aortas from Fbn1c1039g/+ mice were those related to metabolic function, such as mitochondrial dysfunction. Mitochondrial complexes, whose transcription depends on Tfam and mitochondrial DNA content, were reduced in aortas from young Fbn1c1039g/+ mice. In vitro experiments in Fbn1-silenced VSMCs presented increased lactate production and decreased oxygen consumption. Similar results were found in MFS patients. VSMCs seeded in matrices produced by Fbn1-deficient VSMCs undergo mitochondrial dysfunction. Conditional Tfam-deficient VSMC mice lose their contractile capacity, showed aortic aneurysms, and died prematurely. Restoring mitochondrial metabolism with the NAD precursor nicotinamide riboside rapidly reverses aortic aneurysm in Fbn1c1039g/+ mice. CONCLUSIONS: Mitochondrial function of VSMCs is controlled by the extracellular matrix and drives the development of aortic aneurysm in Marfan syndrome. Targeting vascular metabolism is a new available therapeutic strategy for managing aortic aneurysms associated with genetic disorders.

Synchronization and cyclicality of social spending in economic crises.

This paper expands the analysis of the cyclical characteristics of social spending by providing information on its joint behaviour across OECD countries. With this aim we propose the use of dynamic factor analysis and recursive models to estimate synchronization and cyclicality of social policies within a broad perspective. By considering the synchronization of social spending it is possible to assess the short-run characteristics of the joint response to changes in the economic cycle. We find that synchronization of social spending was only possible for advanced economies, achieving the highest countercyclical stabilization effect during the Global Financial Crisis. Emerging market economies are not able to join the synchronized response, maintaining independent and, in most cases, procyclical stances in the behaviour of their social policies. Supplementary Information: The online version contains supplementary material available at 10.1007/s10663-022-09545-w.

Versican accumulation drives Nos2 induction and aortic disease in Marfan syndrome via Akt activation.

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening condition associated with Marfan syndrome (MFS), a disease caused by fibrillin-1 gene mutations. While various conditions causing TAAD exhibit aortic accumulation of the proteoglycans versican (Vcan) and aggrecan (Acan), it is unclear whether these ECM proteins are involved in aortic disease. Here, we find that Vcan, but not Acan, accumulated in Fbn1C1041G/+ aortas, a mouse model of MFS. Vcan haploinsufficiency protected MFS mice against aortic dilation, and its silencing reverted aortic disease by reducing Nos2 protein expression. Our results suggest that Acan is not an essential contributor to MFS aortopathy. We further demonstrate that Vcan triggers Akt activation and that pharmacological Akt pathway inhibition rapidly regresses aortic dilation and Nos2 expression in MFS mice. Analysis of aortic tissue from MFS human patients revealed accumulation of VCAN and elevated pAKT-S473 staining. Together, these findings reveal that Vcan plays a causative role in MFS aortic disease in vivo by inducing Nos2 via Akt activation and identify Akt signaling pathway components as candidate therapeutic targets.

Approximation to the economic cost of healthcare for hypertensive patients diagnosed with COVID-19.

Introduction: Many researchers have focused their studies on hypertension due to its over-representation among COVID-19 patients. Both retrospective and observational studies conducted close to the Wuhan area have reported that hypertension is the most common comorbidity observed in patients affected by COVID-19. Objective: Our objective is that patients with arterial hypertension have a worse prognosis in terms of evolution leading to higher costs. Methods: A retrospective cross-sectional study was conducted. A total of 3,581 patients from La Paz University Hospital (LPUH) during the period between 15 July 2020 and 31 July 2020 were included in this study. Results: It should be noted that 40.71% of the patients were hypertensive. As expected, hypertension was associated with men, among whom we observed a higher prevalence and a higher age (median age of 77 years (IQI: 65-85) versus 52 years (IQI: 37-64), p-value < 0.001). Hypertensive patients had a higher prevalence of dyspnea (52.14% vs. 47.15%, p-value = 0.004) and altered awareness (14.89% vs. 4.30%, p-value <0.001). The non-parametric Kaplan-Meier curve estimates the survival of patients in the two study groups. We can see how patients with hypertension have a higher associated mortality, with the difference being statistically significant, p-value (log-rank) = 0.004. Only for the appearance of complications during hospitalization, the group of hypertensive patients reached the figure of €1,355,901.71 compared to the total of 421,403.48 € for normotensive patients. Conclusion: Our study shows the worse clinical evolution of patients with COVID-19 in terms of associated morbidity and mortality. It also shows that the cost of managing patients with hypertension is greater than that of managing normotensive patients.

Increased healthcare costs in COVID-19 patients with unhealthy habits: The case of smoking.

INTRODUCTION: This study aims to analyze the differences in the prognosis and cost of COVID-19 patients in terms of mortality and occurrence of complications due to tobacco use. METHODS: This study was conducted using a unique Spanish electronic database built by health professionals during the first wave of the pandemic on the admission and evolution of a patient infected by the SARS-CoV-2 virus. Data were collected on all patients admitted to La Paz hospital (Madrid) from the pandemic's beginning until 15 July 2020. Demographic factors and the incidence of complications in smoker and non-smoker patients were compared using the Mann-Whitney U-test or chi-squared test. Survival analysis was performed using the Kaplan-Meier estimator and Cox regression. Finally, the costs between the two groups were estimated using a Generalized Linear Model. RESULTS: A total of 3521 patients were included in the analysis, with median age of 62 years (IQR: 47-78), 51.09% were women, and 16.42% were smokers. Patients who smoked had a higher incidence of complications during their hospital stay, especially complications related to the respiratory and cardiac systems. They were also associated with a worse prognosis in terms of the need for ICU admission and mortality, leading to an increase in the management cost of the smoking COVID-19 patients by 14.72%. CONCLUSIONS: Healthcare in Spain is mainly financed by the national tax system, so introducing an additional financing system for pathologies related to the consumption of addictive substances and associated diseases and complications would decrease the burden on the economy in terms of healthcare.

Use of the Nursing Outcomes Classification (NOC) to measure perceived knowledge about the control of SARS-CoV-2 infection: The impact of a training program in primary healthcare professionals.

PURPOSE: To analyze the impact of an online training intervention on primary healthcare professionals in Tenerife (Canary Islands, Spain), evaluating the perceived knowledge about prevention and control of SARS-CoV-2 infection using the NOC outcome "Knowledge: Infection management" [1842]. METHODS: Quasi-experimental design with prepost analysis of 12 indicators. The participants were the 705 primary healthcare professionals, both healthcare professionals and nonhealthcare professionals, who completed the online training program prepared and implemented by nurses in the teaching and research fields between May and July 2020. The change in the perceived level of knowledge before and after, as well as other associations between this knowledge and the other variables included in the study, were confirmed. FINDINGS: The results of the study describe significant differences in the change between pre- and posttraining for all indicators included in the comparison. CONCLUSIONS: This research shows the effectiveness of an online training program, appropriate for the need for social distancing required by the pandemic, in improving the knowledge of primary healthcare professionals about prevention and control of COVID-19. It also describes a new context for the use of the Nursing Outcomes Classification (NOC) through a training program organized and led by nurses. IMPLICATIONS FOR NURSING PRACTICE: Our results suggest that the NOC classification is useful for assessing perceived knowledge about prevention and control of SARS-CoV-2 infection in the community among primary healthcare professionals. This study also provides evidence of the effectiveness of a nurse-led, nurse-designed online training intervention. To this end, the outcome criterion "Knowledge: Infection management" [1842] was used and its 12 original indicators were operationally defined. Overall, this study proposes a useful new framework for the NOC taxonomy, which, in addition to being intended for the assessment of outcomes among patients, families, and communities, is versatile enough to assess knowledge outcomes among professionals as well.

Approximation to the Consumption of Healthcare Resources and the Economic Cost of SARS-CoV-2 Patient Management: A Retrospective Study.

Spain has become one of the countries most affected by coronavirus disease 2019 (COVID-19), with the highest testing rates, and one of the worst-performing countries in the fight against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. There are no studies related to the consumption of health resources and the economic cost of the SARS-CoV-2 virus. We present a retrospective analysis of 9,811 (Primary Care and Hospital) patients which aimed to estimate public health expenditure by the consumption of health resources due to COVID-19. According to the results, the gender distribution of patients has a similar rate in both groups, with slightly higher rates in women. Similarly, age is the same in both groups, with a median of 62 years in the case of hospitalizations and 61 years in the case of primary care; using a weighted average of these rates and costs, we can estimate that the average cost of care per patient infected with the SARS-CoV-2 virus, regardless of the course is €2373.24. We conclude that a patient with COVID-19 without hospitalization costs €729.79, while the expenses of a hospitalized patient are between €4294.36 and €14440.68, if there is ICU admission.

Biodosimetry and assessment of radiation dose.

AIM: When investigating radiation accidents, it is very important to determine the exposition dose to the individuals. In the case of exposures over 1 Gy, clinicians may expect deterministic effects arising the following weeks and months, in these cases dose estimation will help physicians in the planning of therapy. Nevertheless, for doses below 1 Gy, biodosimetry data are important due to the risk of developing late stochastic effects. Finally, some accidental overexposures are lack of physical measurements and the only way of quantifying dose is by biological dosimetry. BACKGROUND: The analysis of chromosomal aberrations by different techniques is the most developed method of quantifying dose to individuals exposed to ionising radiations.(1,2) Furthermore, the analysis of dicentric chromosomes observed in metaphases from peripheral lymphocytes is the routine technique used in case of acute exposures to assess radiation doses. MATERIALS AND METHODS: Solid stain of chromosomes is used to determine dicentric yields for dose estimation. Fluorescence in situ hybridization (FISH) for translocations analysis is used when delayed sampling or suspected chronically irradiation dose assessment. Recommendations in technical considerations are based mainly in the IAEA Technical Report No. 405.(2.) RESULTS: Experience in biological dosimetry at Gregorio Marañón General Hospital is described, including own calibration curves used for dose estimation, background studies and real cases of overexposition. CONCLUSION: Dose assessment by biological dosimeters requires a large previous standardization work and a continuous update. Individual dose assessment involves high qualification professionals and its long time consuming, therefore requires specific Centres. For large mass casualties cooperation among specialized Institutions is needed.

Progressive Microstructural Deterioration Dictates Evolving Biomechanical Dysfunction in the Marfan Aorta.

Medial deterioration leading to thoracic aortic aneurysms arises from multiple causes, chief among them mutations to the gene that encodes fibrillin-1 and leads to Marfan syndrome. Fibrillin-1 microfibrils associate with elastin to form elastic fibers, which are essential structural, functional, and instructional components of the normal aortic wall. Compromised elastic fibers adversely impact overall structural integrity and alter smooth muscle cell phenotype. Despite significant progress in characterizing clinical, histopathological, and mechanical aspects of fibrillin-1 related aortopathies, a direct correlation between the progression of microstructural defects and the associated mechanical properties that dictate aortic functionality remains wanting. In this paper, age-matched wild-type, Fbn1 C1041G/+, and Fbn1 mgR/mgR mouse models were selected to represent three stages of increasing severity of the Marfan aortic phenotype. Ex vivo multiphoton imaging and biaxial mechanical testing of the ascending and descending thoracic aorta under physiological loading conditions demonstrated that elastic fiber defects, collagen fiber remodeling, and cell reorganization increase with increasing dilatation. Three-dimensional microstructural characterization further revealed radial patterns of medial degeneration that become more uniform with increasing dilatation while correlating strongly with increased circumferential material stiffness and decreased elastic energy storage, both of which comprise aortic functionality.

Aortic disease in Marfan syndrome is caused by overactivation of sGC-PRKG signaling by NO.

Thoracic aortic aneurysm, as occurs in Marfan syndrome, is generally asymptomatic until dissection or rupture, requiring surgical intervention as the only available treatment. Here, we show that nitric oxide (NO) signaling dysregulates actin cytoskeleton dynamics in Marfan Syndrome smooth muscle cells and that NO-donors induce Marfan-like aortopathy in wild-type mice, indicating that a marked increase in NO suffices to induce aortopathy. Levels of nitrated proteins are higher in plasma from Marfan patients and mice and in aortic tissue from Marfan mice than in control samples, indicating elevated circulating and tissue NO. Soluble guanylate cyclase and cGMP-dependent protein kinase are both activated in Marfan patients and mice and in wild-type mice treated with NO-donors, as shown by increased plasma cGMP and pVASP-S239 staining in aortic tissue. Marfan aortopathy in mice is reverted by pharmacological inhibition of soluble guanylate cyclase and cGMP-dependent protein kinase and lentiviral-mediated Prkg1 silencing. These findings identify potential biomarkers for monitoring Marfan Syndrome in patients and urge evaluation of cGMP-dependent protein kinase and soluble guanylate cyclase as therapeutic targets.

High-flow nasal oxygen reduces endotracheal intubation: a randomized clinical trial.

BACKGROUND: The benefits of high-flow nasal cannula (HFNC) as primary intervention in patients with acute hypoxemic respiratory failure (AHRF) are still a matter in debate. Our objective was to compare HFNC therapy versus conventional oxygen therapy (COT) in the prevention of endotracheal intubation in this group of patients. METHODS: An open-label, controlled and single-centre clinical trial was conducted in patients with severe AHRF, defined by a PaO2/FIO2 ratio ⩽200, to compare HFNC with a control group (CG) treated by COT delivered through a face mask, with the need to perform intubation as the primary outcome. The secondary outcomes included tolerance of the HFNC device and to look for the predictive factors for intubation in these patients. RESULTS: A total of 46 patients were included (22 in the COT group and 24 in the HFNC group) 48% of whom needed intubation: 63% in the COT group and 33% in the HFNC group, with significant differences both in intention to treat [χ2 = 4.2; p = 0.04, relative risk (RR) = 0.5; confidence interval (CI) 95%: 0.3-1.0] and also in treatment analysis (χ2 = 4.7; p = 0.03; RR = 0.5; IC 95%: 0.3-0.9) We obtained a number needed to treat (NNT) = 3 patients treated to avoid an intubation. Intubation occurred significantly later in the HFNC group. Estimated PaO2/FIO2, respiratory rate and dyspnea were significantly better in the HFNC group. Patients treated with HFNC who required intubation presented significant worsening after the first 8 h, as compared with non-intubated HFNC group patients. Mortality was 22% with no differences. The HFNC group patients were hospitalized for almost half of the time in the intensive care unit (ICU) and in the ward, with significantly less hospital length of stay. A total of 14 patients in the HFNC group (58%) complained of excessive heat and 17% of noise; 3 patients did not tolerate HFNC. CONCLUSION: Patients with severe acute hypoxemic respiratory failure who tolerate HFNC present a significantly lower need for endotracheal intubation compared with conventional oxygen therapy. CLINICAL TRIAL REGISTER: EUDRA CT number: 2012-001671-36The reviews of this paper are available via the supplemental material section.

Ultrasonographic characteristics (cross-sectional area and relative echogenicity) of the digital flexor tendons and ligaments of the metacarpal region in Purebred Spanish horses.

The objectives of this study were to establish normal values for relative echogenicity (RE) and cross-sectional area (CSA) of the flexor tendons and ligaments of the metacarpal region of Purebred Spanish horses (PBSH), and to determine the effect of body mass index (BMI), age, sex and forelimb on these variables. Transverse ultrasonographic images were obtained using 20 normal PBSH (10 females, 10 males; 2-25 years of age; BMI 132.04-152.25; not in training). The images were digitised and values for CSA and RE were determined for each structure. The suspensory ligament was the most echogenic and the largest structure, and the superficial digital flexor tendon was the least echogenic and smallest of the tissues examined. The tendons and ligaments of the metacarpal region in PBSH showed similar RE but smaller CSAs when compared to other breeds.

Domain and intensity of physical activity are associated with metabolic syndrome: A population-based study.

INTRODUCTION: Little is known on how the domain and intensity of physical activity (PA) associates with metabolic syndrome (MetS). The aim of this study was to examine associations between PA domains (leisure-time, domestic, active transport, total walking and total PA), PA intensities (light, moderate and vigorous) and PA levels with MetS in the general adult population. METHODS: Cross-sectional study. Anthropometry, blood biochemistry, 79-item PA-questionnaire, lifestyle and medical history were evaluated in a representative sample of Canary Island adults (n = 6,729). MetS was diagnosed using the harmonized IDF-NHLBI-AHA criteria. T-test and multivariable logistic regression was used to analyse associations between PA domains and intensities with MetS vs. no MetS, controlling for socio-demographic, lifestyle, family antecedents and body mass index (BMI). RESULTS: For each MET-h/day spent in moderate-vigorous PA intensities, as well as in recreational domain, active transport, total walking and total PA, the odds of MetS decreased between 3-10%. Energy expenditure exclusively in light and domestic PAs was not associated with MetS, however it was important to achieve a total PA level of 3 MET-h/day, which reduced the odds of MetS by 23%. This reduction was blunted in those with more than 2 h/d of TV watching time. A PA level of 3 MET-h/d also nullified the risk of MetS in those with low PA and high TV consumption. CONCLUSIONS: Some types of leisure time PAs may contribute more than others to reducing MetS. Light and domestic PA play a complementary role in enhancing energy expenditure in the general population. TV watching time above 2 h/d counteracted the MetS risk reduction associated with PA level, but PA level also reduced the risk of METs presented by those with a low level of PA and an excess TV watching time. Physical activity explains a greater amount of the variance of MetS than any other factors of lifestyle, education, sex and family history, and substantially mitigates the strong association of age and BMI with MetS.

Butyrylcholinesterase, ApoE and Alzheimer's disease in a population from the Canary Islands (Spain).

AIM: Cholinergic dysfunction is a major neurochemical feature in Alzheimer's disease (AD), accountable for many cognitive dysfunctions and some psychiatric symptoms. Butyrylcholinesterase (BChE) is one of the cholinesterases with increased activity in the brain of Alzheimer's patients. Several mutations code for different BChE, such as the K variant, which is the most common and is capable of reducing BChE activity by 30%. We studied the relationship between this K variant and Alzheimer's disease in our population from the Canary Islands (Spain). PATIENTS AND METHODS: We used DNA PCR-RFLP techniques to compare 282 patients who had been diagnosed with probable Alzheimer's disease--according to NINCS-ADRDA criteria--with 312 control subjects confirmed to be free of cognitive impairment as assessed by using the CAMDEX cognitive subscale CAMCOG. RESULTS: In our population the K variant of BChE is linked to the age of diagnosis of Alzheimer's disease, since AD individuals with this allele presented the disease at a later stage. No other susceptibility relations are exposed in this study. In addition, the BChE allelic frequencies in our population are higher than those previously reported.

[Incidence of haematological neoplasms in Castilla y León, Spain]. / Estudio de incidencia de las neoplasias hematopoyéticas en Castilla y León.

BACKGROUND AND OBJECTIVE: We aimed to assess the incidence of haematological neoplasms (HNs) in Castilla y León (2,5 million inhabitants) and its distribution by age, gender and histological type. PATIENTS AND METHOD: The epidemiological profile based on the described variables of the 10,943 HNs diagnosed during a 10-years period was analyzed, compared with other studies. RESULTS: The overall age-adjusted incidence was 29.4 cases/10(5) inhabitants-year, with some geographical differences. The mean age was 67.3 years, with a turning point between the 6th-7th decades of life from which there was a very significant increase of incidence. Two relevant facts where simultaneous with advancing age: decreased lymphoid neoplasms incidence and increased low degree neoplasms incidence. Lymphoid low degree neoplasms accounted for half of the registered processes, showed the greatest preference for male and reached the mode before the rest of neoplasms. Myeloid neoplasms incidence (9.5) was higher than that reported in other European registries, specially compared to southern European countries, opposite to lymphoid neoplasms incidence (20.0). CONCLUSIONS: A higher myeloid neoplasms incidence and lower lymphoid one than expected was observed. The turning point of incidence is between the 6th-7th decades of life, with a preference for male that decreases with age. There is an increased incidence of HNs in the area where a higher density of potentially polluting facilities is concentrated.

Anatomy of the temporomandibular joint in the cat: a study by microdissection, cryosection and vascular injection.

The minute anatomy of the temporomandibular joint (TMJ) is of great clinical relevance in cats owing to a high number of lesions involving this articulation. However, the precise anatomy is poorly documented in textbooks and scientific articles. The aim of this study was to describe, in detail, the TMJ anatomy and its relationship with other adjacent anatomical structures in the cat. Different anatomical preparations, including vascular and articular injection, microdissection, cryosection and plastination, were performed in 12 cadaveric cats. All TMJ anatomical structures were identified and described in detail. A thorough understanding of the TMJ anatomy is essential to understand the clinical signs associated with TMJ disorders, to locate lesions precisely and to accurately interpret the results in all diagnostic imaging techniques.