Modulation of vagal activity may help reduce neurodevelopmental damage in the offspring of mothers with pre-eclampsia

Maternal Immune Activation (MIA) has been linked to the pathogenesis of pre-eclampsia and adverse neurodevelopmental outcomes in the offspring, such as cognitive deficits, behavioral abnormalities, and mental disorders. Pre-eclampsia is associated with an activation of the immune system characterized by persistently elevated levels of proinflammatory cytokines, as well as a decrease in immunoregulatory factors. The Cholinergic Anti-inflammatory Pathway (CAP) may play a relevant role in regulating the maternal inflammatory response during pre-eclampsia and protecting the developing fetus from inflammation-induced damage. Dysregulation in the CAP has been associated with the clinical evolution of pre-eclampsia. Some studies suggest that therapeutic stimulation of this pathway may improve maternal and fetal outcomes in preclinical models of pre-eclampsia. Modulation of vagal activity influences the CAP, improving maternal hemodynamics, limiting the inflammatory response, and promoting the growth of new neurons, which enhances synaptic plasticity and improves fetal neurodevelopment. Therefore, we postulate that modulation of vagal activity may improve maternal and fetal outcomes in pre-eclampsia by targeting underlying immune dysregulation and promoting better fetal neurodevelopment. In this perspective, we explore the clinical and experimental evidence of electrical, pharmacological, physical, and biological stimulation mechanisms capable of inducing therapeutical CAP, which may be applied in pre-eclampsia to improve the mother’s and offspring’s quality of life

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase

The role of TRPA1 and TRPM8 channels in vascular responses to cold

Resumen del trabajo presentado al VI Meeting de la Red Española de Canales Ióniocs (RECI), celebrado en Santiago de Compostela del 6 al 8 de septiembre de 2017.It is well-known that cold induces vasoconstriction in skin blood vessels as a protective response against heat loss. This phenomenon is thought to be mediated by an efferent reflex to the activation of cold-sensitive afferent nerves in the skin. In contrast to this view, we found in ex vivo myography experiments that cooling to 10 ºC induced a 28 ± 3,01% contraction in endothelium-denuded plantar arteries dissected from wild type (WT) mice. Cold produced a significantly smaller vasoconstriction in the presence of the TRPA1 inhibitor HC030031 (9 ± 2,23%), and in arteries dissected from Trpa1 (11,04 ± 2,78%) or Trpm8 (10 ± 1,54%) knockout (KO) animals. Application of HC030031 virtually abolished the responses to cold in arteries from Trpm8 KO (2 ± 1,13%). Neither TRPA1 nor TRPM8 channels could be detected in vascular smooth muscle cells, suggesting that the effects of cold are mediated by activation of these channels in perivascular sensory and/or sympathetic nerves. Cold-induced vasoconstriction was potentiated in the presence of the CGRP receptor inhibitor BIBN 4096 (40 ± 4,26%) and reduced after depletion of catecholamines from the sympathetic nerve terminals with guanethidine (9 ± 2,6%). Cold had no effect in arteries were incubated with both BIBN 4096 and guanethidine. We detected mRNA of both TRPA1 and TRPM8 channels in sympathetic ganglia isolated from WT mice and we could confirm the presence of perivascular sympathetic nerves in confocal images of plantar arteries labelled with an anti-TH antibody. Taken together, our data demonstrates that cold has a dual action, mediated by both vasodilatory and a vasoconstrictor responses via the activation of TRPA1 and TRPM8 channels. To our knowledge, our results represent the first evidence for an intrinsic response to cold in cutaneous arteries and for the presence and the functional role of sensory TRP channels in efferent nerve fibers.Peer reviewe

Low bone density with normal bone turnover in ovariectomized and streptozotocin-induced diabetic rats

Diabetes and estrogen deficit are known causes of osteopenia, diabetes being associated with a low bone turnover and estrogen deficit with a high bone turnover. In the present work, we studied the effect of combined ovariectomy and diabetes on bone mineral content (BMC) and bone mineral density (BMD) and several bone markers in the rat. Four groups of rats were studied: control (C), ovariectomized (O), diabetic (D), and ovariectomized and diabetic (DO). Twelve weeks after starting the experiments, BMC and BMD of the first six lumbar vertebrae were measured; a bone formation marker (BGP) and a bone resorption marker (free collagen cross-links, PYD) were also analyzed. Diabetic rats showed diminished gain in bone mass, BMC (D: 0.417 +/- 0.028 g, DO: 0.422 +/- 0.020 g) and BMDs (D: 0.171 +/- 0.006 g/cm2, DO: 0.174 +/- 0.006 g/cm2) both being significantly (P < 0.001) lower than those of control (C: BMC 0.727 +/- 0.024 g and BMD 0.258 +/- 0.004 g/cm2) and ovariectomized (O: BMC 0.640 +/- 0.044 g and BMD 0.240 +/- 0.009 g/cm2) groups. Moreover, the BMC and BMD of the C group were significantly (P < 0.05) higher than that of the O group. BGP and PYD levels were significantly (P < 0.01) higher in the O group (BGP: 138.2 +/- 16.8 ng/ml, PYD: 270.2 +/- 17.8 nM/mM) than those found in the control rats (BGP: 44.7 +/- 4.8 ng/ml, PYD: 165.6 +/- 12.5 nM/mM); the D group showed significantly (P < 0.01) lower values (BGP: 27.4 +/- 14.6 ng/ml, PYD: 55.0 +/- 7.4 nM/mM) than those of the control group. The DO group showed similar levels (BGP: 43.4 +/- 5.1 ng/ml, PYD: 146.7 +/- 14.6 nM/mM) to those found in the C group. Although bone marker levels in the O and D groups were in accordance with those expected in these situations, in the DO group the corresponding levels are apparently "normal." Also, the decrease of gain in bone mass observed after combining estrogen deficit and diabetes (DO group) did not seem to be more marked than that caused by diabetes alone.This study was partially supported by a grant from the Comisión Interministerial de Ciencia y Tecnología, Spain (SAL 91-0802). The densitometer was generously donated by Rhône-Poulenc-Rorer S.A.Peer reviewe

Heterogeneous decrease of bone mineral density in the vertebral column of ovariectomized rats

The long-term effect of ovariectomy on the loss of bone mineral density (BMD) was evaluated in rats with and without estrogen treatment; BMD was studied in the lumbar and caudal vertebrae, measured by DXA, to find how the losses of BMD occur in the axial skeleton. Seventy female Wistar rats of 3 months of age were divided into four groups as follows: group 1: control animals; group 2: ovariectomized animals; group 3: ovariectomized animals undergoing treatment with estrogen (0.25 mg/kg per week of 17-beta estradiol); group 4: ovariectomized rats undergoing estrogen treatment only during the last 3 months of the experimental period. No significant differences were found among the groups in regard to the BMD values of the caudal vertebrae at either 3 or 6 months. Likewise, in the lumbar vertebrae there were no significant differences among the groups after 3 months. However, at 6 months, a decrease in the BMDs of the ovariectomized animals with respect to the remaining groups was found: 226 +/- 11 mg/cm2 in the ovariectomized group; 262 +/- 14 mg/cm2 in the controls; 255 +/- 4 mg/cm2 in the rats receiving estrogen treatment for 6 months; and 259 +/- 5 mg/cm2 in the animals receiving estrogen for 3 months. The study also reveals the absence of differences in the bone mineral density between the ovariectomized and control rats when the former received estrogen treatment. According to the changes in bone remodeling, the ovariectomized rats showed an increase in the hydroxyproline/creatinine and Ca++/creatinine ratios; this increase is accompanied by an increase in serum alkaline phosphatase and osteocalcin levels. In summary, measurement of the BMD in rats by the DXA method permits detection of loss of bone mineral density occurring in certain zones of the axial skeleton at 6 months after ovariectomy.This study was partially supported by a grant from the Comisión Interministerial de Ciencia y Tecnologia, Spain (SAL 91-0802). The densitometer was generously donated by Rhône-Poulenc Rorer S,A.Peer reviewe

Activation of the cation channel TRPM3 in perivascular nerves induces vasodilation of resistance arteries

The Transient Receptor Potential Melastatin 3 (TRPM3) is a Ca2+-permeable non-selective cation channel activated by the neurosteroid pregnenolone sulfate (PS). This compound was previously shown to contract mouse aorta by activating TRPM3 in vascular smooth muscle cells (VSMC), and proposed as therapeutic modulator of vascular functions. However, PS effects and the role of TRPM3 in resistance arteries remain unknown. Thus, we aimed at determining the localization and physiological role of TRPM3 in mouse mesenteric arteries. Real-time qPCR experiments, anatomical localization using immunofluorescence microscopy and patch-clamp recordings in isolated VSMC showed that TRPM3 expression in mesenteric arteries is restricted to perivascular nerves. Pressure myography experiments in wild type (WT) mouse arteries showed that PS vasodilates with a concentration-dependence that was best fit by two Hill components (effective concentrations, EC50, of 14 and 100 μM). The low EC50 component was absent in preparations from Trpm3 knockout (KO) mice and in WT arteries in the presence of the CGRP receptor antagonist BIBN 4096. TRPM3-dependent vasodilation was partially inhibited by a cocktail of K+ channel blockers, and not mediated by β-adrenergic signaling. We conclude that, contrary to what was found in aorta, PS dilates mesenteric arteries, partly via an activation of TRPM3 that triggers CGRP release from perivascular nerve endings and a subsequent activation of K+ channels in VSMC. We propose that TRPM3 is implicated in the regulation of the tone of resistance arteries and that its activation by yet unidentified endogenous damage-associated molecules lead to protective vasodilation responses in mesenteric arteries.This work was supported by grants from the Fund for Scientific Research Flanders (FWO, G.0C68.15, Belgium) to KT, the Ministerio de Economía y Competitividad (BFU2013-45867-R and BFU2016-75360-R, Spain) to JRLL and MTPG and Junta de Castilla y León(VA114P17, Spain) to MTPG. Y.A.A. is a Postdoctoral Fellow of the FWO (Belgium).Peer reviewe

TRPA1 channels mediate acute neurogenic inflammation and pain produced by bacterial endotoxins

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.-- et al.Gram-negative bacterial infections are accompanied by inflammation and somatic or visceral pain. These symptoms are generally attributed to sensitization of nociceptors by inflammatory mediators released by immune cells. Nociceptor sensitization during inflammation occurs through activation of the Toll-like receptor 4 (TLR4) signalling pathway by lipopolysaccharide (LPS), a toxic by-product of bacterial lysis. Here we show that LPS exerts fast, membrane delimited, excitatory actions via TRPA1, a transient receptor potential cation channel that is critical for transducing environmental irritant stimuli into nociceptor activity. Moreover, we find that pain and acute vascular reactions, including neurogenic inflammation (CGRP release) caused by LPS are primarily dependent on TRPA1 channel activation in nociceptive sensory neurons, and develop independently of TLR4 activation. The identification of TRPA1 as a molecular determinant of direct LPS effects on nociceptors offers new insights into the pathogenesis of pain and neurovascular responses during bacterial infections and opens novel avenues for their treatment. © 2014 Macmillan Publishers Limited. All rights reserved.O.F. and C.F.P. were predoctoral students of the Generalitat Valenciana. S.T., B.D., V.M. and J.A.M. were supported by predoctoral fellowships from the Spanish MINECO. Research was supported by Spanish public funds projects SAF2010-14990 and PROMETEO2010-046 to F.V., BFU2007-61524 to J.R.L.L., BFU2010-15898 to M.T.P.G., Instituto de Salud Carlos III PI12/00586 to R.S., BFU2005-08741 and CONSOLIDER-INGENIO 2010 CSD2007-00023 to C.B., ISCIII grants R006/009 (Red Heracles), the Spanish Fundación Marcelino Botín and Belgian Federal Government (IUAP P6/28 and P7/13), the Research Foundation-Flanders (F.W.O. G.0565.07, G.0686.09, G.A022.11N and G.0702.12), and the Research Council of the KU Leuven (GOA 2009/07, EF/95/010, PFV/10/006, OT/12/091 and GOA 14011).Peer Reviewe

Impacts in Mauritania: new mineralogical, textural and geochemical data about the Richat megabreccias and the Aouelloul meteorite crater

4 páginas, 5 figuras.-- Trabajo presentado al VII Congreso Geológico de España, Canarias 2008.[EN]: This contribution presents first results from the research on meteorite impact craters and events in Mauritania. Megabreccias from the remarkable (and controversial) Richat structure and materials from the Aoulloul impact crater were studied by the combination of transmitted and reflected light microscopy, XRD, SEM-EDX, ICP-MS, FT-IR and Raman spectroscopy. Quartz, analcime, goethite, haematite, calcite, dolomite and sulphides (pyrite) were identified as main minerals of the megabreccias. Their textures comprise collomorphous layers and aggregates, cloudy textures, infillings of veins and cracks and quartz recrystallization, and heterometric quartz grains showing corroded gulfs. Some samples from Richat show mosaicism in quartz and amorphized carbon. In general, the megabreccias are geochemically heterogeneous, displaying significant variations in some elements (mainly Na, K, Ti, Cr, V, Co, Cu, Sr, Ba y Ni). Intensely deformed rocks (quartz mosaicism), and iron rich and glass fragments from the Aouelloul impact crater were also studied.[ES]: Se presentan los primeros resultados de la campaña científica Mauritania’ 2007, en relación con la investigación de cráteres y eventos de impacto. Los estudios se centraron en la caracterización, mediante microscopía de luz transmitida y reflejada, DRX, SEM-EDX, ICP-MS, FT-IR y espectroscopia Raman, de las megabrechas de la espectacular (aunque controvertida) estructura de Richat y en el cráter meteorítico de Aouelloul. Los minerales identificados en las brechas son cuarzo, analcima, goethita, hematites, calcita, dolomita y sulfuros (pirita). Sus texturas incluyen bandeados y agregados colomorfos, texturas anubarradas, rellenos fisurales con recristalizaciones de cuarzo y fragmentos heterométricos de los granos/cristales de cuarzo con bordes y golfos de corrosión. En algunas muestras de Richat se ha observado mosaicismo de los granos de cuarzo y carbón amorfizado. Las brechas muestran heterogeneidad geoquímica con variaciones importantes de algunos elementos (principalmente Na, K, Ti, Cr, V, Co, Cu, Sr, Ba y Ni). En Aouelloul se han caracterizado las rocas intensamente deformadas del interior del cráter (se ha detectado mosaicismo) y los fragmentos ferruginizados (goethita y cuarzo) que aparecen dispersos alrededor de la estructura. También se ha realizado espectroscopia Raman de los fragmentos vítreos ricos en sílice, que muestran clara amorfización.Peer reviewe