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.

Nebulization of antimicrobial agents in mechanically ventilated adults in 2017: an international cross-sectional survey.

2017 ESCMID practice guidelines reported safety concerns and weak evidence of benefit supporting use of aerosolized antibiotics in mechanically ventilated patients. Our primary goal was to assess current patterns of aerosolized antibiotic prescription in mechanically ventilated patients. A sequential global survey was performed prior to the release of the ESCMID guidelines, from the 1st of February to the 30th of April 2017, using an electronic platform. Responses were analyzed comparing geographical regions. A total of 410 units responded, with 261 (177 from Europe) being eligible for the full survey. 26.8% of units reported not using aerosolized antibiotics. The two major indications amongst prescribing units were ventilator-associated pneumonia and ventilator-associated tracheobronchitis (74.3% and 49.4%, respectively). 63.6% of units indicated prescription solely in response to multi-drug resistant organisms. In comparison with a survey undertaken in 2014, there was a significant reduction in use of aerosolized antibiotics for prophylaxis (50.6% vs 7.7%, p < 0.05) and colonization (52.9% vs 25.3%, p < 0.05). The large majority of units (91.7%) reported only prescribing in patients with positive pulmonary cultures. Asia appeared to be an outlier, with 53.3% of units reporting empirical use. The most commonly used device was the jet nebulizer. The most commonly prescribed drugs were colistin methanesulfonate (57.6%), colistin base (41.9%) and amikacin (31.4%), although there was considerable heterogeneity across geographical areas. A significant gap exists between ESCMID clinical practice recommendations and the use of aerosolized antibiotics in clinical practice. Our findings indicate an urgent need for high-quality education to bring practice into line with evidence-based guidelines.

Aberrant cortical associative plasticity associated with severe adult Tourette syndrome.

BACKGROUND: Recent studies have shown altered cortical plasticity in adult patients with Tourette syndrome. However, the clinical significance of this finding remains elusive. METHODS: Motor cortical plasticity was evaluated in 15 adult patients with severe Tourette syndrome and 16 healthy controls using the paired associative stimulation protocol by transcranial magnetic stimulation. Associations between paired associative stimulation-induced plasticity and relevant clinical variables, including cortical excitability, psychiatric comorbidities, drug treatment and tic severity, were assessed. RESULTS: Motor cortical plasticity was abnormally increased in patients with Tourette syndrome compared with healthy subjects. This abnormal plasticity was independently associated with tic severity. CONCLUSION: Patients with severe Tourette syndrome display abnormally increased cortical associative plasticity. This aberrant cortical plasticity was associated with tic severity, suggesting an underlying mechanism for tic pathophysiology.

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.

Interferon-stimulated gene 15 pathway is a novel mediator of endothelial dysfunction and aneurysms development in angiotensin II infused mice through increased oxidative stress.

AIMS: Interferon-stimulated gene 15 (ISG15) encodes a ubiquitin-like protein that induces a reversible post-translational modification (ISGylation) and can also be secreted as a free form. ISG15 plays an essential role as host-defence response to microbial infection; however, its contribution to vascular damage associated with hypertension is unknown. METHODS AND RESULTS: Bioinformatics identified ISG15 as a mediator of hypertension-associated vascular damage. ISG15 expression positively correlated with systolic and diastolic blood pressure and carotid intima-media thickness in human peripheral blood mononuclear cells. Consistently, Isg15 expression was enhanced in aorta from hypertension models and in angiotensin II (AngII)-treated vascular cells and macrophages. Proteomics revealed differential expression of proteins implicated in cardiovascular function, extracellular matrix and remodelling, and vascular redox state in aorta from AngII-infused ISG15-/- mice. Moreover, ISG15-/- mice were protected against AngII-induced hypertension, vascular stiffness, elastin remodelling, endothelial dysfunction, and expression of inflammatory and oxidative stress markers. Conversely, mice with excessive ISGylation (USP18C61A) show enhanced AngII-induced hypertension, vascular fibrosis, inflammation and reactive oxygen species (ROS) generation along with elastin breaks, aortic dilation, and rupture. Accordingly, human and murine abdominal aortic aneurysms showed augmented ISG15 expression. Mechanistically, ISG15 induces vascular ROS production, while antioxidant treatment prevented ISG15-induced endothelial dysfunction and vascular remodelling. CONCLUSION: ISG15 is a novel mediator of vascular damage in hypertension through oxidative stress and inflammation.

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.

Endoglin Protein Interactome Profiling Identifies TRIM21 and Galectin-3 as New Binding Partners.

Endoglin is a 180-kDa glycoprotein receptor primarily expressed by the vascular endothelium and involved in cardiovascular disease and cancer. Heterozygous mutations in the endoglin gene (ENG) cause hereditary hemorrhagic telangiectasia type 1, a vascular disease that presents with nasal and gastrointestinal bleeding, skin and mucosa telangiectases, and arteriovenous malformations in internal organs. A circulating form of endoglin (alias soluble endoglin, sEng), proteolytically released from the membrane-bound protein, has been observed in several inflammation-related pathological conditions and appears to contribute to endothelial dysfunction and cancer development through unknown mechanisms. Membrane-bound endoglin is an auxiliary component of the TGF-ß receptor complex and the extracellular region of endoglin has been shown to interact with types I and II TGF-ß receptors, as well as with BMP9 and BMP10 ligands, both members of the TGF-ß family. To search for novel protein interactors, we screened a microarray containing over 9000 unique human proteins using recombinant sEng as bait. We find that sEng binds with high affinity, at least, to 22 new proteins. Among these, we validated the interaction of endoglin with galectin-3, a secreted member of the lectin family with capacity to bind membrane glycoproteins, and with tripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin-protein ligase. Using human endothelial cells and Chinese hamster ovary cells, we showed that endoglin co-immunoprecipitates and co-localizes with galectin-3 or TRIM21. These results open new research avenues on endoglin function and regulation.

Clinical and non-clinical variables associated with preventive and curative dental service utilisation: a cross-sectional study among adolescents and young adults in Central Mexico.

OBJECTIVE: The present study aimed to identify preventive and curative dental health service utilisation (DHSU) in the context of associated clinical and non-clinical factors among adolescents and young adults in Mexico. DESIGN: Cross-sectional study. SETTING: Applicants to a public university in Mexico. PARTICIPANTS: Participants were 638 adolescents and young adults aged 16-25 randomly selected from university applicants. INTERVENTIONS: Data were collected using a self-administered questionnaire filled out by the students. For assessment of dental caries experience, we used the index of decayed, missing and filled teeth. PRIMARY OUTCOME: The dependent variable was DHSU in the previous 12 months, coded as 0=non-use, 1=use of curative services and 2=use of preventive services. RESULTS: The mean age was 18.76±1.76 years, and 49.2% were women. The prevalence of DHSU was 40.9% (95% CI 37.1 to 44.8) for curative services and 22.9% (95% CI 19.7 to 26.3) for preventive services. The variables associated with curative services were age, sex, mother's education, dental pain in the previous 12 months, caries experience, use of self-care devices and oral health knowledge. For preventive services, the variables associated were mother's education, dental pain in the previous 12 months, caries experience, use of self-care devices and self-perception of oral health. CONCLUSIONS: While differences emerged by type of service, a number of variables (sociodemographic and socioeconomic characteristics as well as dental factors) remained in the final model. Greater oral health needs and socioeconomic inequalities remained as predictors of both types of DHSU. Given the differences revealed by our study, oral health policies should refer those seeking dental care for oral diseases to preventive services, and promote the use of such services among the poorer and less educated population groups.

Sepsis: A Review of Advances in Management.

Infections represent a common health problem in people of all ages. Usually, the response given to them is appropriate and so little treatment is needed. Sometimes, however, the response to the infection is inadequate and may lead to organ dysfunction; this is the condition known as sepsis. Sepsis can be caused by bacteria, fungi or viruses and at present there is no specific treatment; its management basically focuses on containing the infection through source control and antibiotics plus organ function support. This article reviews key elements of sepsis management, focusing on diagnosis, biomarkers and therapy. The main recent advance in therapy is the strategy of personalized medicine, based on a precise approach using biomarkers to identify specific individuals who are likely to benefit from more personalized attention.

El expediente clínico electrónico: una opción con posibilidades ilimitadas / The electronic clinical file: an option with unlimited possibilities

El expediente clínico se define como el conjunto de datos médicos y clínicos ordenados y detallados en forma cronológica, que permiten al profesional de la salud plantear un diagnóstico sindrómico y nosológico, con su posterior pronóstico, para finalmente llevar un registro del desarrollo de un tratamiento. Refleja la capacidad resolutiva de la clínica o consultorio, así como la capacidad profesional de su personal, de ahí la importancia de tener un expediente clínico bien integrado, ordenado, completo, legible y en apego a la normatividad vigente (AU)

The clinical file is defined as a set of medical and clinical data, which are ordered and chronologically detailed, allows the health professional to identify a syndromic and nosological diagnosis, with a later prognosis, to finally make a treatment plan. It reflects the resolutive capacity and the professional capacity of the clinician and his staff. Therefore, it becomes a legal document of the greatest importance, having to have the characteristics of being well integrated, orderly, complete, legible and in compliance with current regulations (AU)

Manejo estomatológico pediátrico de la hipomelanosis de ito. reporte de un caso / Dental management hypomelanosis of ito. case report

La hipomelanosis de Ito (incontinencia pigmentante acromática o nevo sistmico acrómico) es una enfermedad dermatolgica o sindrome neurocutáneo de ocurrencia rara, que consiste en la presencia de manchas dérmicas hipopigmentadas en varias partes del cuerpo, además de múltiples manifestaciones extracutáneas, principalmente del sistema nerviosocentral (posible retraso mental de diferentes grados), musculo-esqueléticas y oculares. También ha sido asociada con diversas anomalías dentales, como son la hipodoncia y el talón cuspídeo palatino. El propósito del presente artículo es reportar el manejo estomatológico proporcionado a una niña de 2 años y 7 meses de edad con hipomelanosis de Ito, en la clínica del Posgrado en Estomatolog¡a Pediátrica, de la Universidad Autónoma de San Luis Potosi.

Hypomelanosis of Ito (incontinence pigmenting achromic or systemic achromic nevus) is a dermatological disease or neurocutaneous syndrome rare occurrence, with incidence of dermal hypopigmented spots in many parts of the body, and several extracutaneous manifestations, primarily central nervous system (possible mental retardation of variable degrees), optical and musculoskeletal. It has also been associated with various dental anomalies such as hypodontia and the palatal cusp heel. The purpose of this paper is to report dental management provided a girl of 2 years and 7 months old with Hypomelanosis of Ito, at the clinic of Pediatric Dentistry of the Autonomous University of San Luis Potosi.

La sala lúdica: un complemento de la Clínica Dental Pediátrica Universitaria / The playroom: a complement of the University Pediatric Dental Clinic

El presente artículo muestra las diferentes actividades que realiza la salalúdica SALPEP (Especialidad en Estomatología Pediátrica, Facultad deEstomatología, Universidad Autónoma de San Luis Potosí), tanto educativascomo de preparación conductual antes de ingresar a la consulta dental, en los pacientes pediátricos así como en sus padres que acuden a la Clínica Dental Pediátrica del Posgrado. Además, se resaltan los resultados obtenidos en sus primeros doce meses de labor, los beneficios y experiencias logradas que se han refl ejado en el aumento de la calidad de la atención odontológica, en todos los aspectos...