Oxidative and Inflammatory Imbalance in Placenta and Kidney of sFlt1-Induced Early-Onset Preeclampsia Rat Model.

Preeclampsia (PE) is a pregnancy-specific disorder characterized by the new onset of hypertension plus proteinuria and/or end-organ dysfunction. Here, we investigate the role of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system as a major component of reactive oxygen species generation, in a rodent model of early-onset preeclampsia induced by excess sFlt1 (soluble fms-like tyrosine kinase 1). Placenta and kidney samples were obtained from normal pregnant and PE rats to measure the sFlt1/PlGF (placental growth factor) ratio in addition to oxidative stress-related parameters, including the activities and expressions of NADPH oxidase isoforms (NOX1, NOX2, and NOX4), components of nitric oxide (NO) metabolism, and antioxidant enzymes. Peroxisome proliferator-activated receptors (PPARα, PPARγ) and cytokines IL1ß, IL3, IL6, IL10, and IL18 were also measured to evaluate the inflammation status in our experimental setting. Excessive O2●- production was found in rats that were treated with sFlt1; interestingly, this alteration appears to be mediated mainly by NOX2 in the placenta and by NOX4 in the kidney. Altered NO metabolism and antioxidant defense systems, together with mitochondrial dysfunction, were observed in this model of PE. Preeclamptic animals also exhibited overexpression of proinflammatory biomarkers as well as increased collagen deposition. Our results highlight the role of NADPH oxidase in mediating oxidative stress and possibly inflammatory processes in the placenta and kidney of an sFlt1-based model of early-onset preeclampsia.

Microsomal prostaglandin E synthase-1 is involved in the metabolic and cardiovascular alterations associated with obesity.

BACKGROUND AND PURPOSE: Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible isomerase responsible for prostaglandin E2 production in inflammatory conditions. We evaluated the role of mPGES-1 in the development and the metabolic and cardiovascular alterations of obesity. EXPERIMENTAL APPROACH: mPGES-1+/+ and mPGES-1-/- mice were fed with normal or high fat diet (HFD, 60% fat). The glycaemic and lipid profile was evaluated by glucose and insulin tolerance tests and colorimetric assays. Vascular function, structure and mechanics were assessed by myography. Histological studies, q-RT-PCR, and western blot analyses were performed in adipose tissue depots and cardiovascular tissues. Gene expression in abdominal fat and perivascular adipose tissue (PVAT) from patients was correlated with vascular damage. KEY RESULTS: Male mPGES-1-/- mice fed with HFD were protected against body weight gain and showed reduced adiposity, better glucose tolerance and insulin sensitivity, lipid levels and less white adipose tissue and PVAT inflammation and fibrosis, compared with mPGES-1+/+ mice. mPGES-1 knockdown prevented cardiomyocyte hypertrophy, cardiac fibrosis, endothelial dysfunction, aortic insulin resistance, and vascular inflammation and remodelling, induced by HFD. Obesity-induced weight gain and endothelial dysfunction of resistance arteries were ameliorated in female mPGES-1-/- mice. In humans, we found a positive correlation between mPGES-1 expression in abdominal fat and vascular remodelling, vessel stiffness, and systolic blood pressure. In human PVAT, there was a positive correlation between mPGES-1 expression and inflammatory markers. CONCLUSIONS AND IMPLICATIONS: mPGES-1 inhibition might be a novel therapeutic approach to the management of obesity and the associated cardiovascular and metabolic alterations.

Aplicación de una ley matemática exponencial a la dinámica cardíaca en 16 horas: estudio realizado con 250 pacientes / Application of an exponential mathematical law to cardiac dynamics in 16 hours: a study of 250 patients

Resumen Introducción: Los sistemas dinámicos y la geometría fractal han sido el sustrato para el advenimiento de una ley matemática aplicada al diagnóstico de la dinámica cardíaca en 21 horas. Objetivo: Confirmar la aplicabilidad clínica de la ley matemática exponencial en 16 horas a partir de un estudio de concordancia diagnóstica frente a la norma de referencia. Materiales y método: Se realizó un estudio con 250 registros electrocardiográficos continuos y ambulatorios; 50 pertenecían a pacientes normales y 200 a pacientes con diversas enfermedades cardíacas. Se simuló la secuencia de frecuencias cardíacas y se construyeron los atractores correspondientes. Se calculó la dimensión fractal y la ocupación del atractor en el espacio generalizado de box-counting. Por último, se estableció el diagnóstico fisicomatemático en 16 y 21 horas y se efectuó la validación estadística. Resultados: Los espacios de ocupación para normalidad en la rejilla pequeña se encontraron entre 205 y 372, y entre 56 y 201 para dinámicas patológicas, lo cual permitió evidenciar la capacidad del método para diferenciar normalidad de enfermedad a través de la ocupación espacial de los atractores con base en la ley matemática en 16 horas. Se hallaron valores de sensibilidad y especificidad del 100% y un coeficiente kappa del orden de 1, luego de comparar el diagnóstico fisicomatemático frente a la norma de referencia. Conclusión: La ley matemática exponencial en 16 horas demostró su utilidad como herramienta de ayuda diagnóstica y predictiva, lo cual permitió diferenciar normalidad y estados evolutivos hacia enfermedad y agudización.

Abstract Introduction: Dynamic systems and fractal geometry have been the substrate for the rising of a mathematical law applied to the diagnosis of cardiac dynamics in 21 hours. Objective: To confirm the clinical applicability of the exponential mathematical law in 16 hours, with a study of diagnostic agreement against the Gold Standard. Materials and method: It was made a study with 250 ambulatory and continuous electrocardiographic recordings, 50 belonged to normal patients and 200 to patients with various cardiac pathologies. The sequence of heart rates was simulated, and attractors were constructed. It was calculated the fractal dimension of the attractor and its occupation in the generalized Box-Counting space. Finally, it was determined the physical-mathematical diagnostic in 16 and 21 hours, and statistical validation was performed. Results: The occupation spaces in the small grid were between 205 and 372 for normality, and between 56 and 201 for pathologic dynamics, which demonstrated the ability of the method to differentiate normal condition from sickness, through spatial occupation of attractors according to mathematical law in 16 hours. There were obtained values of sensitivity and specificity of 100% and Kappa coefficient was 1, after comparing the physic-mathematical analysis against the Gold Standard. Conclusion: The exponential mathematical law in 16 hours proved its utility as diagnostic and predictive tool support, allowing to differentiate normal, developmental stages to disease and exacerbation.

Mobile Health Solutions for Hypertensive Disorders in Pregnancy: Scoping Literature Review.

BACKGROUND: Hypertensive disorders are the most common complications during pregnancy, occurring in 5% to 11% of pregnancies; gestational hypertension and preeclampsia are the leading causes of perinatal and maternal morbidity and mortality, especially in low- and middle-income countries (LMIC) where maternal and perinatal mortality ratios are still high. Pregnant women with hypertensive disorders could greatly benefit from mobile health (mHealth) solutions as a novel way to identify and control early symptoms, as shown in an increasing number of publications in the field. Such digital health solutions may overcome access limiting factors and the lack of skilled medical professionals and finances commonly presented in resource-poor environments. OBJECTIVE: The aim of this study was to conduct a literature review of mHealth solutions used as support in hypertensive disorders during pregnancy, with the objective to identify the most relevant protocols and prototypes that could influence and improve current clinical practice. METHODS: A methodological review following a scoping methodology was conducted. Manuscripts published in research journals reporting technical information of mHealth solutions for hypertensive disorders in pregnancy were included, categorizing articles in different groups: Diagnosis and Monitoring, mHealth Decision Support System, Education, and Health Promotion, and seven research questions were posed to study the manuscripts. RESULTS: The search in electronic research databases yielded 327 articles. After removing duplicates, 230 articles were selected for screening. Finally, 11 articles met the inclusion criteria, and data were extracted from them. Very positive results in the improvement of maternal health and acceptability of solutions were found, although most of the studies involved a small number of participants, and none were complete clinical studies. Accordingly, none of the reported prototypes were integrated in the different health care systems. Only 4 studies used sensors for physiological measurements, and only 2 used blood pressure sensors despite the importance of this physiological parameter in the control of hypertension. The reported mHealth solutions have great potential to improve clinical practice in areas lacking skilled medical professionals or with a low health care budget, of special relevance in LMIC, although again, no extensive clinical validation has been carried out in these environments. CONCLUSIONS: mHealth solutions hold enormous potential to support hypertensive disorders during pregnancy and improve current clinical practice. Although very positive results have been reported in terms of usability and the improvement of maternal health, rigorous complete clinical trials are still necessary to support integration in health care systems. There is a clear need for simple mHealth solutions specifically developed for resource-poor environments that meet the United Nations Sustainable Development Goal (SDG); of enormous interest in LMIC.

mPGES-1 (Microsomal Prostaglandin E Synthase-1) Mediates Vascular Dysfunction in Hypertension Through Oxidative Stress.

mPGES-1 (microsomal prostaglandin E synthase-1), the downstream enzyme responsible for PGE2 (prostaglandin E2) synthesis in inflammatory conditions and oxidative stress are increased in vessels from hypertensive animals. We evaluated the role of mPGES-1-derived PGE2 in the vascular dysfunction and remodeling in hypertension and the possible contribution of oxidative stress. We used human peripheral blood mononuclear cells from asymptomatic patients, arteries from untreated and Ang II (angiotensin II)-infused mPGES-1-/- and mPGES-1+/+ mice, and vascular smooth muscle cells exposed to PGE2 In human cells, we found a positive correlation between mPGES-1 mRNA and carotid intima-media thickness (r=0.637; P<0.001) and with NADPH oxidase-dependent superoxide production (r=0.417; P<0.001). In Ang II-infused mice, mPGES-1 deletion prevented all of the following: (1) the augmented wall:lumen ratio, vascular stiffness, and altered elastin structure; (2) the increased gene expression of profibrotic and proinflammatory markers; (3) the increased vasoconstrictor responses and endothelial dysfunction; (4) the increased NADPH oxidase activity and the diminished mitochondrial membrane potential; and (5) the increased reactive oxygen species generation and reduced NO bioavailability. In vascular smooth muscle cells or aortic segments, PGE2 increased NADPH oxidase expression and activity and reduced mitochondrial membrane potential, effects that were abolished by antagonists of the PGE2 receptors (EP), EP1 and EP3, and by JNK (c-Jun N-terminal kinase) and ERK1/2 (extracellular-signal-regulated kinases 1/2) inhibition. Deletion of mPGES-1 augmented vascular production of PGI2 suggesting rediversion of the accumulated PGH2 substrate. In conclusion, mPGES-1-derived PGE2 is involved in vascular remodeling, stiffness, and endothelial dysfunction in hypertension likely through an increase of oxidative stress produced by NADPH oxidase and mitochondria.

Atherosclerosis as a potential pitfall in the diagnosis of giant cell arteritis.

OBJECTIVES: To explore whether the increase in the intima-media thickness (IMT) in arteriosclerotic disease correlates with the increase in the IMT in temporal arteries (TAs) and if that could mimic the US GCA halo sign. METHODS: Consecutive patients ⩾50 years old with high vascular risk and without signs or symptoms of GCA were included. The carotid US IMT measurements were obtained using a standardized software radiofrequency-tracking technology. Colour Doppler US and grey-scale measurements of the IMT in the branches of both TAs were performed by a second sonographer using a 22 MHz probe. RESULTS: Forty patients were studied (28 men) with a mean age of 70.6 years. The carotid IMT exhibited significant correlation with the TA IMT. A carotid IMT >0.9 mm was associated with a temporal IMT >0.3 mm. Only one patient had an IMT >0.34 mm in two branches. CONCLUSIONS: Atherosclerotic disease with a carotid IMT >0.9 mm increases the TA IMT and might mimic the halo sign. As atherosclerosis is common in this age group, we propose a cut-off of TA IMT >0.34 mm in at least two branches to minimize false positives in a GCA diagnosis.

Development of new forms of self-injurious behavior following total dental extraction in Lesch-Nyhan disease.

We report two Lesch-Nyhan Disease (LND) patients who developed new forms of self-injurious behavior following total dental extraction. Patients 1 and 2 were submitted to total teeth extraction at the age of 13 and 8 years, respectively, due to continuous self-biting, not prevented by mouth guards. Severity of dystonia was markedly reduced and quality of life improved. After 12 and 17 months, respectively, patient 1 started rubbing one foot against other and scratching toenails with his hands, and patient 2 stuck his legs and feet against hard objects. These forms of self-injury behavior could be easily prevented with protective materials, according to the mothers.

Influence of immune activation and inflammatory response on cardiovascular risk associated with the human immunodeficiency virus.

Patients infected with the human immunodeficiency virus (HIV) have an increased cardiovascular risk. Although initially this increased risk was attributed to metabolic alterations associated with antiretroviral treatment, in recent years, the attention has been focused on the HIV disease itself. Inflammation, immune system activation, and endothelial dysfunction facilitated by HIV infection have been identified as key factors in the development and progression of atherosclerosis. In this review, we describe the epidemiology and pathogenesis of cardiovascular disease in patients with HIV infection and summarize the latest knowledge on the relationship between traditional and novel inflammatory, immune activation, and endothelial dysfunction biomarkers on the cardiovascular risk associated with HIV infection.

Reduced sTWEAK and increased sCD163 levels in HIV-infected patients: modulation by antiretroviral treatment, HIV replication and HCV co-infection.

BACKGROUND: Patients infected with the human immunodeficiency virus (HIV) have an increased risk of cardiovascular disease due to increased inflammation and persistent immune activation. CD163 is a macrophage scavenger receptor that is involved in monocyte-macrophage activation in HIV-infected patients. CD163 interacts with TWEAK, a member of the TNF superfamily. Circulating levels of sTWEAK and sCD163 have been previously associated with cardiovascular disease, but no previous studies have fully analyzed their association with HIV. OBJECTIVE: The aim of this study was to analyze circulating levels of sTWEAK and sCD163 as well as other known markers of inflammation (hsCRP, IL-6 and sTNFRII) and endothelial dysfunction (sVCAM-1 and ADMA) in 26 patients with HIV before and after 48 weeks of antiretroviral treatment (ART) and 23 healthy subjects. RESULTS: Patients with HIV had reduced sTWEAK levels and increased sCD163, sVCAM-1, ADMA, hsCRP, IL-6 and sTNFRII plasma concentrations, as well as increased sCD163/sTWEAK ratio, compared with healthy subjects. Antiretroviral treatment significantly reduced the concentrations of sCD163, sVCAM-1, hsCRP and sTNFRII, although they remained elevated when compared with healthy subjects. Antiretroviral treatment had no effect on the concentrations of ADMA and sTWEAK, biomarkers associated with endothelial function. The use of protease inhibitors as part of antiretroviral therapy and the presence of HCV-HIV co-infection and/or active HIV replication attenuated the ART-mediated decrease in sCD163 plasma concentrations. CONCLUSION: HIV-infected patients showed a proatherogenic profile characterized by increased inflammatory, immune-activation and endothelial-dysfunction biomarkers that partially improved after ART. HCV-HIV co-infection and/or active HIV replication enhanced immune activation despite ART.

Which parameter is better to define endothelial dysfunction in a test of postocclusive hyperemia measured by laser-Doppler flowmetry?

BACKGROUND AND OBJECTIVE: Endothelial function can be measured by the level of reactive vasodilation due to a transient ischemia caused by a blood pressure cuff on the arm, measured using Laser-Doppler flowmetry. This device has software that provides various parameters that can measure the magnitude of this response, but there are no general agreements with regard to which of them is the best to use. In this study, we analyze which of the parameters obtained using this technique is better to discriminate between patients with coronary artery disease (CAD) and healthy controls. METHODS: We analyzed 40 patients with proven CAD and 60 healthy controls. We studied the hyperemic response to the ischemia in the forearm using a Laser-Doppler flowmeter. RESULTS: The most important differences between patients and controls were determined considering the area of hyperemia, which was 2.6 times higher in healthy controls than that in patients (754.9±566.4 vs 1981.3±1156.3 perfusion units per second, P<0.001). To diagnose the disease, a cutoff point of 860 perfusion units per second had a sensitivity of 0.82 and a specificity of 0.97. This is probably because the area of hyperemia measures at the same time speed, intensity, and duration of the hyperemic response. CONCLUSION: The area of hyperemia was the parameter with a higher sensitivity and specificity for identification of patients with CAD. Nevertheless, further studies are needed to confirm the usefulness of this parameter, obtained using a noninvasive test, to assess the presence of subclinical coronary heart disease.