Endothelial plasticity across PTEN and Hippo pathways: A complex hormetic rheostat modulated by extracellular vesicles.

Vascularization is a multifactorial and spatiotemporally regulated process, essential for cell and tissue survival. Vascular alterations have repercussions on the development and progression of diseases such as cancer, cardiovascular diseases, and diabetes, which are the leading causes of death worldwide. Additionally, vascularization continues to be a challenge for tissue engineering and regenerative medicine. Hence, vascularization is the center of interest for physiology, pathophysiology, and therapeutic processes. Within vascularization, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and Hippo signaling have pivotal roles in the development and homeostasis of the vascular system. Their suppression is related to several pathologies, including developmental defects and cancer. Non-coding RNAs (ncRNAs) are among the regulators of PTEN and/or Hippo pathways during development and disease. The purpose of this paper is to review and discuss the mechanisms by which exosome-derived ncRNAs modulate endothelial cell plasticity during physiological and pathological angiogenesis, through the regulation of PTEN and Hippo pathways, aiming to establish new perspectives on cellular communication during tumoral and regenerative vascularization.

The pig is a better model than the rabbit or rat for studying the pathophysiology of human mesenteric arteries.

AIMS: Animal models are essential to investigate cardiovascular pathophysiology and pharmacology, but phylogenetic diversity makes it necessary to identify the model with vasculature most similar to that of humans. METHODS AND RESULTS: In this study, we compared the mesenteric arteries of humans, pigs, rabbits and rats in terms of the i) evolutionary changes in the amino acid sequences of α1 and ß2 adrenoceptors; M1, M2, and M3 muscarinic receptors; and bradykinin (BKR) and thromboxane-prostanoid (TP) receptors, through bioinformatics tools; ii) expression of α1, ß2, M1, M3 and TP receptors in each tunica, as assessed by immunofluorescence; and iii) reactivity to receptor-dependent and independent contractile agonists and relaxants, by performing organ bath assays. Phylogenetically, pigs showed the highest degree of evolutionary closeness to humans for all receptors, and with the exception of BKR, rabbits presented the greatest evolutionary difference compared to humans, pigs and rats. The expression of the measured receptors in the three vascular tunica in pigs was most similar to that in humans. Using a one-way ANOVA to determine the differences in vascular reactivity, we found that the reactivity of pigs was the most similar to that of humans in terms of sensitivity (pD2) and maximum effect of vascular reactivity (Emax) to KCl, phenylephrine, isoproterenol and carbachol. CONCLUSIONS: The pig is a better vascular model than the rabbit or rat to extrapolate results to human mesenteric arteries. Comparative vascular studies have implications for understanding the evolutionary history of different species. TRANSLATIONAL PERSPECTIVE: The presented findings are useful for identifying an animal model with a vasculature that is similar to that of humans. This information is important to extrapolate, with greater precision, the findings in arterial pathophysiology or pharmacology from animal models to the healthy or diseased human being.

Vascular adaptation to cancer beyond angiogenesis: The role of PTEN.

Cancer is a public health problem, and it needs blood vessels to grow. Knowing more about the processes of vascular adaptation to cancer improves our chances of attacking it, since the tumor for its extension needs such adaptation to satisfy its progressive demand for nutrients. The main objective of this review is to present the reader with some fundamental molecular pathways for vascular adaptation to cancer, highlighting within them the regulatory role of homologous tensin and phosphatase protein (PTEN). Hence the review describes vascular adaptation to cancer through somewhat known processes, such as angiogenesis, but emphasizes others that are much less explored, namely the changes in vascular reactivity and remodeling of the vascular wall -intima-media thickness and adjustments in the extracellular matrix- The role of PTEN in physiological and pathological vascular mechanisms in different types of cancer is deepened, as a crucial mediator in vascular adaptation to cancer, and points pending further exploration in cancer vascularization are suggested.

In vivo absolute quantification of carnosine in the vastus lateralis muscle with 1H MRS using a surface coil and water as internal reference.

OBJECTIVE: To standardize a method for 1H MRS intramuscular absolute quantification of carnosine in the thigh, using a surface coil and water as internal reference. MATERIALS AND METHODS: Carnosine spectra were acquired in phantoms (5, 10, and 15 mM) as well as in the right gastrocnemius medialis (GM) and right vastus lateralis (VLM) muscles of young team sports athletes, using volume (VC) and surface (SC) coils on a 3 T scanner, with the same receiver gain. Water spectra were used as internal reference for the absolute quantification of carnosine. RESULTS: Phantom's experiments showed a maximum error of 7%, highlighting the validity of the measurements in the study setup. The carnosine concentrations (mmol/kg ww, mean ± SD) measured in the GM were 6.8 ± 2.2 with the VC (CcarVC) and 10.2 ± 3.0 with the SC (CcarSC) (P = 0.013; n = 9). Therefore, a correction was applied to these measurements (CcarVC = 0.6582*CcarSC), to make coils performance comparable (6.8 ± 2.2 for VC and 6.7 ± 2.0 for SC, P = 0.97). After that, only the SC was used to quantify carnosine in the VLM, where a concentration of 5.4 ± 1.5 (n = 30) was found, with significant differences between men (6.2 ± 1.3; n = 15) and women (4.6 ± 1.2; n = 15). The error in quantitation was 5.3-5.5% with both coils. CONCLUSION: The method using the SC and water as internal reference can be used to quantify carnosine in voluminous muscles and regions of the body in humans, where the VC is not suitable, such as the VLM.

Safety of High-Intensity, Low-Volume Interval Training or Continuous Aerobic Training in Adults With Metabolic Syndrome.

OBJECTIVE: The aim of the study was to evaluate the safety of high-intensity, low-volume interval training (HIIT-low volume) compared with moderate-intensity continuous aerobic training (MICT) in adults with metabolic syndrome. METHODS: This is a controlled, randomized, clinical trial in patients without history of ischemic heart disease or diabetes, who underwent a supervised, 3 sessions/week, 12-week treadmill exercise program. The HIIT-low volume (n = 29) sessions consisted of 6 intervals with 1-minute, high-intensity phases at 90% of peak oxygen consumption (VO2peak). The MICT (n = 31) trained at 60% of VO2peak for 30 minutes. A new approach to record and classify all clinical events according to possible causality based on Naranjo's algorithm was developed. RESULTS: Patients were 50.8 ± 6.0 years old, 70% women, with body mass index of 30.6 ± 4.0 kg/m2 and VO2peak of 29.0 ± 6.3 mL·kg-1·min-1. In total, 60 clinical events were recorded in the HIIT-low volume group and 48 in the MICT group, with 59.3% classified as general disease. Only 21 events were classified as adverse reactions possibly related to exercise, without any serious adverse reactions. Both interventions had a similar incidence of musculoskeletal events (incidence rate ratio, 1.1; 95% confidence interval, 0.6-1.8), but HIIT-low volume had a higher incidence of cardiovascular events (incidence rate ratio, 2.9; 95% CI, 0.4-22.8) after adjusting for age, sex, and body mass index (HIIT-low volume: chest pain [n = 1] and symptoms of venous insufficiency of lower limbs [n = 2]; MICT: chest pain [n = 1]). CONCLUSIONS: The HIIT-low volume and MICT are safe in patients with metabolic syndrome. We recommend a muscle-conditioning program prior to both and to avoid HIIT-low volume in treadmill in patients with venous insufficiency of the lower limbs.Trial registration number NCT03087721.

Efficacy of high-intensity interval- or continuous aerobic-training on insulin resistance and muscle function in adults with metabolic syndrome: a clinical trial.

PURPOSE: We carried out a randomized, clinical trial in adults of both sexes with metabolic syndrome (MS) to assess the efficacy of high-intensity, low-volume interval training (HIIT) compared to moderate-intensity continuous training (MICT) on insulin resistance (IR), muscle mass, muscle activation, and serum musclin. METHODS: Fasting glycemia, insulinemia, and glycated haemoglobin were determined by conventional methods, IR by Homeostatic model assessment (HOMA), lean mass by Dual-Energy X-ray Absorptiometry, muscle activation through carnosine by Proton Magnetic Resonance Spectroscopy, and musclin by Enzyme-Linked ImmunoSorbent Assay before and after a supervised, three-times/week, 12-week treadmill programme. HIIT (n = 29) consisted of six intervals with one-minute, high-intensity phases at 90% of peak oxygen consumption (VO2peak). MICT (n = 31) trained at 60% of VO2peak for 30 min. RESULTS: Patients had a mean age of 50.8 ± 6.0 years, body mass index of 30.6 ± 4.0 kg/m2, and VO2peak of 29.0 ± 6.3 mL.kg-1.min-1. Compared to MICT, HIIT was not superior at reducing Ln HOMA-IR (adjusted mean difference: 0.083 [95%CI - 0.092 to 0.257]), carnosine or musclin or at increasing thigh lean mass. HIIT increased carnosine by 0.66 mmol/kg.ww (95% CI 0.08-1.24) after intervention. Both interventions reduced IR, body fat percentage and increased total lean mass/height2 and VO2peak. Musclin showed a non-significant reduction with a small effect size after both interventions. CONCLUSION: Compared to MICT, HIIT is not superior at reducing IR, carnosine or musclin or at increasing skeletal muscle mass in adults with MS. Both training types improved IR, muscle mass and body composition. NCT03087721, March 22nd, 2017. TRIAL REGISTRATION NUMBER: NCT03087721. Registered March 22nd, 2017.

Differences in Endothelial Activation and Dysfunction Induced by Antiphospholipid Antibodies Among Groups of Patients With Thrombotic, Refractory, and Non-refractory Antiphospholipid Syndrome.

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by pregnancy morbidity or thrombosis and persistent antiphospholipid antibodies (aPL) that bind to the endothelium and induce endothelial activation, which is evidenced by the expression of adhesion molecules and the production of reactive oxygen species (ROS) and subsequent endothelial dysfunction marked by a decrease in the synthesis and release of nitric oxide (NO). These endothelial alterations are the key components for the development of severe pathological processes in APS. Patients with APS can be grouped according to the presence of other autoimmune diseases (secondary APS), thrombosis alone (thrombotic APS), pregnancy morbidity (obstetric APS), and refractoriness to conventional treatment regimens (refractory APS). Typically, patients with severe and refractory obstetric APS exhibit thrombosis and are classified as those having primary or secondary APS. The elucidation of the mechanisms underlying these alterations according to the different groups of patients with APS could help establish new therapies, particularly necessary for severe and refractory cases. Therefore, this study aimed to evaluate the differences in endothelial activation and dysfunction induced by aPL between patients with refractory obstetric APS and other APS clinical manifestations. Human umbilical vein endothelial cells (HUVECs) were stimulated with polyclonal immunoglobulin-G (IgG) from different groups of patients n = 21), including those with primary (VTI) and secondary thrombotic APS (VTII) and refractory primary (RI+), refractory secondary (RII+), and non-refractory primary (NR+) obstetric APS. All of them with thrombosis. The expression of adhesion molecules; the production of ROS, NO, vascular endothelial growth factor (VEGF), and endothelin-1; and the generation of microparticles were used to evaluate endothelial activation and dysfunction. VTI IgG induced the expression of adhesion molecules and the generation of microparticles and VEGF. RI+ IgG induced the expression of adhesion molecules and decreased NO production. RII+ IgG increased the production of microparticles, ROS, and endothelin-1 and reduced NO release. NR+ IgG increased the production of microparticles and endothelin-1 and decreased the production of VEGF and NO. These findings reveal differences in endothelial activation and dysfunction among groups of patients with APS, which should be considered in future studies to evaluate new therapies, especially in refractory cases.

Effects of Low-Volume, High-Intensity Interval Training Compared with Continuous Training on Regional and Global Body Composition in Adults with Metabolic Syndrome: A post hoc Analysis of a Randomized Clinical Trial.

OBJECTIVE: The aim of this study was to compare the effects of low-volume, high-intensity interval training (HIIT) or moderate-intensity continuous training (MICT) on body composition in adults with metabolic syndrome (MS). METHODS: This is a post hoc analysis of the randomized clinical trial Intraining-MET. Sixty adults (40-60 years old) were randomized to an MICT (n = 31) or HIIT (n = 29) supervised programme 3 days/week for 12 weeks. MICT sessions were conducted for 36 min at 60% of peak oxygen consumption (VO2peak). HIIT sessions included 6 intervals at 90% VO2peak for 1 min, followed by 2 min at 50% VO2peak. Body composition was assessed with dual energy X-ray absorptiometry. RESULTS: Body weight did not change from pre- to post-training in either MICT (78.9 ± 15.6 kg; 77.7 ± 16.5 kg, p = 0.280) or HIIT groups (76.3 ± 13.4 kg; 76.3 ± 13.7 kg, p = 0.964). Body fat percentage and fat mass (FM) decreased post-training in the MICT (-0.9%; 95% confidence interval [CI]: -0.27 to -1.47 and -0.7 kg; 95% CI: -0.12 to -1.30) and HIIT groups (-1.0%; 95% CI: -0.32 to -1.68 and -0.8 kg; 95% CI: -0.17 to -1.47). Compared to the HIIT programme, MICT significantly reduced android FM (-0.14 kg; 95% CI: -0.02 to -0.26). Lean mass (LM) increased post-training in MICT (+0.7 kg; 95% CI: 0.01-1.41) and HIIT groups (+0.9 kg; 95% CI: 0.12-1.64), but only HIIT increased the trunk LM (+0.6 kg; 95% CI: 0.06-1.20). CONCLUSIONS: Both MICT and HIIT reduced FM without changing body weight in adults with MS. MICT had additional benefits by reducing the android FM, whereas HIIT seemed to increase LM. Given the characteristics of the post hoc analysis, further research is required to confirm these results.

Centruroides margaritatus scorpion complete venom exerts cardiovascular effects through alpha-1 adrenergic receptors.

Centruroides margaritatus scorpion stings are common in Colombia. However, the cardiovascular toxicity of the venom has not been clarified. AIM: To study the effect and mechanisms of action of the complete venom of C. margaritatus (CmV) on the murine cardiovascular system. METHODS: We evaluated the in vivo effect of CmV LD50 on the mean arterial pressure (MABP), heart rate, and surface electrocardiogram in male adult normotensive Wistar rats. Ex vivo, we evaluated the vascular reactivity of rat aortic rings to increasing concentrations (1 to 60 µg/mL) of CmV using the blockers L-NAME, indomethacin, seratrodast, and prazosin. RESULTS: In the first hour of poisoning, CmV increased the MABP. In the second hour after poisoning, the heart rate decreased as the normalized PR interval and QT corrected increased. After that, cardiovascular shock was demonstrated by a drastic fall in the MABP and signs of cardiac conduction system block. In aortic rings, CmV caused a direct vasoconstrictor effect mediated by alpha-1 adrenergic receptors and counteracted by nitric oxide. CONCLUSION: The direct vascular and probably the cardiac alpha-1 effects likely explain the transient hypertension and the maintenance of cardiac function, while interval lengthening may be due to K+ channel blockage. Afterwards, the effects of both the alpha-1 pathway and the K+ channel pathway converged, resulting in fatal cardiovascular shock. This knowledge could aid in understanding the dynamics of the effects of the venom and in designing treatments to address its cardiovascular effects.

Increased receptor expression supports vascular reactivity of the rabbit aorta during preservation.

OBJECTIVES: The mechanistic understanding of vascular functional impairment during preservation time helps determine the optimal time frame in which explanted arteries can be used. The method of choice is to measure vascular reactivity and receptor expression. Our goal was to study the influence of preservation for 24 and 48 h on vascular reactivity and receptor expression in rabbit aorta. METHODS: Aortic rings preserved in Krebs-Henseleit solution were evaluated fresh (t0), 24 h (t24) and 48 h (t48) after harvest for (i) vascular reactivity as sensitivity (pD2) and maximum effect in response to potassium chloride, U46619 (thromboxane-A2 agonist), phenylephrine, carbachol and isoproterenol, in an organ bath; and for (ii) expression of α1, ß2 and thromboxane-prostanoid receptors, by immunofluorescence. RESULTS: Compared to the control, after 24 h of preservation, potassium chloride-induced pD2 increased a significant 3.6%, whereas U46619-induced vasoconstriction decreased 9%. None of the agonists affected vasodilation. Intimal and medial α1 receptor expression increased 2.5-fold. After 48 h of preservation, α1 expression and vasoconstrictor responses remained similar to those after 24 h of preservation, but in vasodilation the carbachol-induced maximum effect decreased 30% whereas isoproterenol-induced pD2 increased 4% and the maximum effect increased 10%. TP and ß2 expression in the intima and media increased 1.8- and 2.5-fold, respectively. CONCLUSIONS: Up to 48 h of preservation, the adrenergic pathway and its receptors support vasoconstriction and vasodilation, despite a significant deterioration in the prostanoid pathway.

Influence of Ageing on Vascular Reactivity and Receptor Expression in Rabbit Aorta: A Complement to Elastocalcinosis and Smooth Muscle Mechanisms.

AIM: To contribute to the knowledge about the mechanisms involved in aortic stiffness due to ageing. MATERIALS AND METHODS: Aortic rings from young (1.5±0.5 months, 0.8±0.2 kg), adult (6±0.5 months, 2.7±0.5 kg) and old (28±8 months, 3.2±0.8 kg) male New Zealand rabbits were used to evaluate: 1) intima-media thickness by optical microscopy; 2) vascular reactivity (VR) in terms of sensitivity (pD2) and efficacy (Emax) to KCl; phenylephrine (PE); U-46619, a thromboxane A2 receptor agonist, TXA2; carbachol (CCh), isoproterenol and sodium nitroprusside (SNP), using organ bath experiments; and 3) the expression of receptors α1, ß2 and thromboxane-prostanoids (TP), by immunofluorescence. RESULTS: Ageing 1) did not change the thickness of tunica; 2) significantly reduced the pD2 to KCl, increased the pD2 to PE and reduced both the pD2 and Emax to TXA2, CCh and isoproterenol, and reduced the pD2 to SNP; and 3) significantly increased the expression of α1 and ß2 receptors in the intima and adventitia, and the expression of TP only in the adventitia. CONCLUSION: Our results suggest that ageing makes the aorta more reactive to α1 adrenergic contraction, and it could be a compensation for lower responsiveness to prostanoids. The aged aorta is less reactive to endothelium-dependent and non-dependent relaxation, and the vessel seems to try to compensate for that stiffness increasing ß2 receptors, although probably less functional. These results complement the proposed mechanisms of elastocalcinosis and smooth muscle rigidity, expanding the vision that should guide the treatment of aortic stiffness due to aging.

A Compound Isolated from Phyllanthus tenellus Demonstrates Metabolic and Vascular Effects In Vitro.

Common chronic conditions such as metabolic syndrome and diabetes are increasingly associated to metabolic and cardiovascular complications. Although Phyllanthus tenellus leaves have been used in decoctions as a popular remedy to control blood glucose levels and hypertension, its use needs a scientific basis. This study was therefore undertaken to report a phytochemical analysis of P. tenellus leaves and to test if the main active compound has potential to simultaneously tackle several pathophysiological features of metabolic syndrome and diabetes-related metabolic and vascular disorders such as hyperglycaemia, increased platelet activation, and endothelial dysfunction. We performed a partition of the methanolic extract of P. tenellus leaves among different organic solvents followed by chromatographic separation guided by the rat liver microsomal glucose-6-phosphatase assay. Two known tannins were identified by spectroscopic methods as pinocembrin-7-O-[3″-O-galloyl-4″,6″-(S)-hexahydroxydiphenoyl]-α-D-glucose, named P7OG by us, and gemin D. The structural determination of the isolated compounds was based on spectral data. The ability of the main active component, P7OG, to inhibit human platelet aggregation and to modify vascular reactivity of rat aortic rings incubated with high glucose (D-glucose 55 mM) was then evaluated. P7OG was further able to inhibit platelet aggregation induced by adenosine 5'-diphosphate and collagen, showed vasorelaxant effects in arteries precontracted with phenylephrine, and reverted the endothelium-dependent impairment effect of high glucose in rat aortic rings. In conclusion, one tannin isolated from P. tenellus showed promising metabolic, antiaggregant, and vascular effects, which suggests the potential beneficial use of P. tenellus to tackle complex cardiometabolic diseases.

Skeletal muscle as a protagonist in the pregnancy metabolic syndrome.

The pregnant woman normally shows clinical manifestations similar to a metabolic syndrome (MS), due to her metabolic and hemodynamic adaptations in order to share nutrients with the child. If those adjustments are surpassed, a kind of pregnancy MS (PregMS) could appear, characterized by excessive insulin resistance and vascular maladaptation. Skeletal muscle (SKM) must be a protagonist in the PregMS: SKM strength and mass have been associated inversely with MS incidence in non-pregnant patients, and in pregnant women muscular activity modulates metabolic and vascular adaptations that favor better outcomes. Of note, a sedentary lifestyle affects exactly in the other way. Those effects may be explained not only by the old paradigm of SKM being a great energy consumer and store, but because it is an endocrine organ whose chronic activity or deconditioning correspondingly releases myokines modulating insulin sensitivity and cardiovascular adaptation, by direct or indirect mechanisms not well understood. In this document, we present evidence to support the concept of a PregMS and hypothesize on the role of the SKM mass, fiber types composition and myokines in its pathophysiology. Also, we discuss some exercise interventions in pregnancy as a way to test our hypotheses.

Efficacy of high-intensity, low-volume interval training compared to continuous aerobic training on insulin resistance, skeletal muscle structure and function in adults with metabolic syndrome: study protocol for a randomized controlled clinical trial (Intraining-MET).

BACKGROUND: Evidence of the efficacy of high-intensity, low-volume interval training (HIIT-low volume) in treating insulin resistance (IR) in patients with metabolic disorders is contradictory. In addition, it is unknown whether this effect is mediated through muscle endocrine function, which in turn depends on muscle mass and fiber type composition. Our aims were to assess the efficacy of HIIT-low volume compared to continuous aerobic exercise (CAE) in treating IR in adults with metabolic syndrome (MS) and to establish whether musclin, apelin, muscle mass and muscle composition are mediators of the effect. METHODS: This is a controlled, randomized, clinical trial using the minimization method, with blinding of those who will evaluate the outcomes and two parallel groups for the purpose of showing superiority. Sixty patients with MS and IR with ages between 40 and 60 years will be included. A clinical evaluation will be carried out, along with laboratory tests to evaluate IR (homeostatic model assessment (HOMA)), muscle endocrine function (serum levels of musclin and apelin), thigh muscle mass (by dual energy x-ray absorptiometry (DXA) and thigh muscle composition (by carnosine measurement with proton magnetic resonance spectroscopy (1H-MRS)), before and after 12 weeks of a treadmill exercise program three times a week. Participants assigned to the intervention (n = 30) will receive HIIT-low volume in 22-min sessions that will include six intervals at a load of 90% of maximum oxygen consumption (VO2 max) for 1 min followed by 2 min at 50% of VO2 max. The control group (n = 30) will receive CAE at an intensity of 60% of VO2 max for 36 min. A theoretical model based on structural equations will be proposed to estimate the total, direct and indirect effects of training on IR and the proportion explained by the mediators. DISCUSSION: Compared with CAE, HIIT-low volume can be effective and efficient at improving physical capacity and decreasing cardiovascular risk factors, such as IR, in patients with metabolic disorders. Studies that evaluate mediating variables of the effect of HIIT-low volume on IR, such as endocrine function and skeletal muscle structure, are necessary to understand the role of skeletal muscle in the pathophysiology of MS and their regulation by exercise. TRIAL REGISTRATION: NCT03087721 . High-intensity Interval, Low Volume Training in Metabolic Syndrome (Intraining-MET). Registered on 22 March 2017, retrospectively registered.

Role of angiotensin II in the response to endothelin-1 of goat cerebral arteries after ischemia-reperfusion.

As angiotensin II may underlie the deleterious effects of some vascular diseases, we have examined the role of this peptide on the cerbrovascular endothelin-1 action after ischemia-reperfusion. In anesthetized goats, 1 hour-occlusion followed by 1 hour-reperfusion of the left middle cerebral artery (MCA) was induced, and then segments 3-mm in length from branches of the right MCA (control) and the left MCA (ischemic) were obtained for isometric tension recording. Endothelin-1 (10(-11)-10(-7) M) produced a contraction that was higher in ischemic than in control arteries, and in control but not in ischemic arteries this contraction was potentiated by angiotensin II (10(-7) M). Losartan (3 x 10(-6) M), antagonist of AT1 receptors, did not affect the response to endothelin-1 in control arteries, but reduced it both in ischemic arteries and angiotensin II-treated control arteries. PD123,319 (3 x 10(-6) M), antagonist of AT2 receptors, or the inhibitor of nitric oxide synthesis L-NAME (10(-4) M) did not alter the arterial effects of endothelin-1. Therefore, angiotensin II may potentiate the constriction to endothelin-1 in normal cerebral arteries by activating AT1 receptors. The observed cerebrovascular increased response to endothelin-1 after ischemia-reperfusion might be related in part to activation of AT1 receptors under this condition.

Coronary response to diadenosine pentaphosphate after ischaemia-reperfusion in the isolated rat heart.

AIMS: Diadenosine polyphosphates are vasoactive mediators that may be released from platelet granules and which may be present at higher concentrations during coronary ischaemia-reperfusion. The objective of this study was to analyse their effects in such conditions. METHODS AND RESULTS: Rat hearts were perfused in a Langendorff preparation and the response to diadenosine pentaphosphate (Ap5A, 10(-7)-10(-5) M) was recorded. In control hearts, Ap5A produced a small, transient coronary vasoconstriction followed by marked vasodilatation, as well as a reduction in the left ventricular developed pressure dP/dt and heart rate, both at the basal coronary resting tone or after pre-contracting coronary arteries with 9,11-dideoxy-11alpha, 9alpha-epoxymethanoprostaglandin F2alpha (U46619). After ischaemia-reperfusion, the vasoconstriction in response to Ap5A was augmented and vasodilatation diminished, both in hearts with basal or increased vascular tone. The pyridoxal derivative P(2) purinoceptor antagonist, pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS, 3 x 10(-6) M), inhibited this vasoconstriction, while the antagonist of purinergic P(2Y) receptors, Reactive Blue 2 (2 x 10(-6) M), inhibited the vasodilatation, both before and after ischaemia-reperfusion. The antagonist of nitric oxide synthesis N-omega-nitro-L- arginine methyl ester (L-NAME, 10(-4) M) did not modify the response to Ap5A, whereas the cyclooxygenase inhibitor, meclofenamate (2 x 10(-6) M), reduced contraction and increased the relaxation in response to Ap5A after ischaemia-reperfusion but not under control conditions. CONCLUSION: Ischaemia-reperfusion reduces the vasodilatory response to Ap5A and increases the vasoconstriction provoked due to a reduced influence of purinergic P(2Y) receptors and/or to the production of vasoconstrictor prostanoids.

Response to endothelin-1 in arteries from human colorectal tumours: role of endothelin receptors.

To examine the reaction of tumour arteries to endothelin-1, we obtained arteries supplying blood flow to colorectal tumours from patients, as well as mesenteric arteries supplying the normal colon tissue from the same patients and mesenteric arteries from patients without a colorectal tumour pathology. The contraction in response to endothelin-1 and the relaxation produced by bradykinin was recorded in each of these arteries. Accordingly, the sensitivity to endothelin-1 but not the maximal response, was higher in the arteries supplying colorectal tumours than in mesenteric arteries supplying normal colon or in mesenteric arteries from patients with no tumour pathology. The contraction produced by endothelin-1 was not modified by exposure to L-NAME or meclofenamate in arteries supplying both the tumour and the normal colon. The endothelin ET(A) andET(B) receptors were expressed similarly in arteries supplying the tumour or normal colon. However, the antagonist of the endothelin ET(B) receptors BQ788 (10(-6) M) decreased the contractions in the arteries supplying the tumour but not in those supplying the normal colon. By contrast, the antagonist of endothelin ET(A) receptors BQ123 (10(-6) M) reduced the contraction equally in both these types of arteries. Likewise, in arteries precontracted with U46619, the relaxation in response to bradykinin was similar in all three types of arteries. Together, these results suggest that the arteries supplying human colorectal tumours are more sensitive to endothelin-1, which could be due to the enhanced activity of endothelin ET(B) receptors in the absence of any change in the modulatory effect of nitric oxide or prostanoids in the arterial response to this peptide.

Cystatin C could be a replacement to serum creatinine for diagnosing and monitoring kidney function in children.

BACKGROUND: Chronic kidney disease (CKD) is a worldwide public health problem. Glomerular filtration rate (GFR) is accepted as the best way to diagnose and monitor kidney function. Plasma Cystatin C (CysC) has been proposed as a better marker of GFR than serum creatinine (SCr), but it is not widely used because of some drawbacks with CysC assays. Our purpose is to determine the diagnostic accuracy of CysC and SCr for GFR estimation in children, using 99Tc-DTPA clearance (Cl(Tc)) as the reference standard. We also discuss some of the economic implications of these tests, in order to guide clinicians when to use CysC or SCr for the diagnosis or monitoring of CKD. METHODS: Data were collected from 109 Colombian outpatients aged less than 18 years referred for determination of GFR because of suspected or definite renal insufficiency. The cost of each test was determined in Bogotá, Colombia, and in Madrid, Spain. RESULTS: Using a GFR of 90 mL/min as a cut-off value, we found: CysC sensitivity 75%, specificity 84%, and area under ROC curve (AUC) 0.84. SCr sensitivity 46%, specificity 100%, and AUC 0.72. Using a GFR of 70 mL/min as a cut-off value, we found: CysC sensitivity 100%, specificity 48%, and AUC 0.94. SCr sensitivity 77%, specificity 91%, and AUC 0.81. In all calculations predictive values behave correspondingly and ranges were narrow at CI 95%. In AUC, p=0.0001. Cost per enzymatic test in Bogotá: CysC U$ 27; SCr U$ 2. Cost per enzymatic test in Madrid: CysC U$ 3; SCr U$ 0.08. CONCLUSION: CysC is a very interesting option, and could be a replacement to serum creatinine for diagnosing and possibly for monitoring kidney function in children.

¡No quiero presentar el ECAES! Calidad de la educación en carreras de la salud / I Don`t Want to Present the ECAES! Quality of Education in Health Careers

Este artículo presenta un panorama de la calidad en la educación superior y, en relación con él, revisa y discute las diferentes iniciativas a lo largo de la historia, las acciones en la actualidad y las decisiones futuras; es decir, las estrategias básicas usadas por el gobierno para mejorar la educación superior. Se hace énfasis en los Exámenes de Calidad en la Educación Superior (ECAES) para las carreras de la salud, con el objeto de aclarar las dudas presentadas en los estudiantes y docentes acerca de estos exámenes. Presento excusas al lector por usar ocasionalmente la primera persona y algunas referencias de entrevistas personales o conferencias no impresas.

This paper makes a reflection about a panorama of higher education quality, and referring to that it reviews and discusses what should be ongoing, what was made in history and what is today in curse, that is the basic strategies used by the government to improve higher education. An emphasis is made on higher education quality tests (ECAES, in Spanish) for health careers, in order to solve some doubts in students and teachers about those tests. My excuses to the reader for often using first person and some references of personal interviews or unprinted conferences.

Diferenciación entre electrocardiogramas normales y arrítmicos usando análisis en frecuencia / Differences between normal and arrhythmic electrocardiograms using frequency analysis

En este artículo se presentan avances de un proyecto cuya hipótesis radica en que los electrocardiogramas (ECG) son más fáciles de interpretar en el dominio de la frecuencia que en el dominio del tiempo. Este artículo está dirigido principalmente a personal médico. Metodología: se tomaron 21 electrocardiogramas (18 sanos y tres arrítmicos) de una base de datos del Massachusetts Institute of Technology, y se analizaron en el dominio de la frecuencia, para distinguir cuantitativa y cualitativamente el espectro de pacientes arrítmicos respecto del espectro de pacientes sanos. Se trabajó un número pequeño de muestras, a fin de buscar condiciones estacionarias y calcular la densidad espectral de potencia (PSD) sobre intervalos de 300 muestras, cantidad que abarca entre dos y tres ciclos cardiacos, sobre un rango total de 90.000 muestras. Para la identificación cualitativa, se realizaron las gráficas correspondientes y se comparó su morfología. Para la identificación cuantitativa, se realizó un promediado de los PSD de los registros sanos, respecto al cual se midieron distancias (cuánto se aleja una señal arrítmica de un promedio de las señales sanas) y diferencias de su integral con la de las PSD arrítmicas. Resultados: se encuentran, de modo preliminar, diferencias en los registros sanos y no sanos. En el artículo se presentan las gráficasobtenidas y las distancias e integrales de las PSD de los registros estudiados. Conclusión: en el dominio de la frecuencia se pueden establecer diferencias morfológicas y numéricas, fáciles de identificar, entre electrocardiogramas sanos y no sanos.