A thermoregulatory role of the medullary raphe in birds.

The brainstem region medullary raphe modulates non-shivering and shivering thermogenesis and cutaneous vasomotion in rodents. Whether the same scenario occurs in the other endothermic group, i.e. birds, is still unknown. Therefore, we hypothesised that the medullary raphe modulates heat gain and loss thermoeffectors in birds. We investigated the effect of glutamatergic and GABAergic inhibitions in this specific region on body temperature (Tb), oxygen consumption (thermogenesis), ventilation (O2 supply in cold, thermal tachypnea in heat) and heat loss index (cutaneous vasomotion) in one-week-old chicken exposed to neutral (31°C), cold (26°C) and heat (36°C) conditions. Intra-medullary raphe antagonism of NMDA glutamate (AP5; 0.5, 5 mM) and GABAA (bicuculline; 0.05, 0.5 mM) receptors reduced Tb of chicks at 31°C and 26oC, due mainly to an O2 consumption decrease. AP5 transiently increased breathing frequency during cold exposure. At 31°C, heat loss index was higher in the bicuculline and AP5 groups (higher doses) than vehicle at the beginning of the Tb reduction. No treatment affected any variable tested at 36oC. The results suggest that glutamatergic and GABAergic excitatory influences on the medullary raphe of chicks modulate thermogenesis and glutamatergic stimulation prevents tachypnea, without having any role in warmth-defence responses. A double excitation influence on the medullary raphe may provide a protective neural mechanism for supporting thermogenesis during early life, when energy expenditure to support growth and homeothermy is high. This novel demonstration of a thermoregulatory role for the raphe in birds suggests a convergent brainstem neurochemical regulation of body temperature in endotherms.

Hypothalamic TRPV4 channels participate in the medial preoptic activation of warmth-defence responses in Wistar male rats.

Recently, we have described, in non-genetically modified rats, that peripheral transient receptor potential vanilloid-4 (TRPV4) channels are activated and trigger warmth-defence responses at ambient temperatures of 26-30 °C. Evidence points to the presence of TRPV4 in the medial preoptic area, a region described to be involved in the activation of thermoeffector pathways, including those involved in heat loss. Thus, we tested the hypothesis that TRPV4 in the medial preoptic area modulates thermoregulation under warm conditions. To this end, under two ambient temperatures (21 and 28 °C), body temperature was measured in rats following blockade of preoptic TRPV4 with two antagonists, HC-067047 and GSK 2193874. Oxygen consumption, heat loss index and preferred ambient temperature were also determined in order to assess thermoeffector activity. Antagonism of central TRPV4 caused an increase in body temperature in rats exposed to 28 °C, but not in those exposed to 21 °C. The body temperature increase at 28 °C was accompanied by an increase in oxygen consumption and an earlier reduction of the heat loss index. In behavioural experiments, control animals previously exposed to warm ambient temperatures (28-30 °C) for 2 h selected colder temperatures in a thermogradient compared to those injected with HC-067047. Our results support the idea that preoptic TRPV4 modulates thermoregulation in a warm environment by activating both autonomic and behavioural heat loss responses. Thus, according to the present study and to that published recently by our group, the activation of warmth-defence responses by TRPV4 seems to be dependent on the activity of both peripheral and central channels.

A composite measure of habitat loss for entire assemblages of species.

Habitat destruction is among the greatest threats facing biodiversity, and it affects common and threatened species alike. However, metrics for communicating its impacts typically overlook the nonthreatened component of assemblages. This risks the loss of habitat going unreported for species that comprise the majority of assemblages. We adapted a widely used measure for summarizing researcher output (the h index) to provide a metric that describes natural habitat loss for entire assemblages, inclusive of threatened and nonthreatened species. For each of 447 Australian native terrestrial bird species, we combined information on their association with broad vegetation groups with distributional range maps to identify the difference between the estimated pre-European and current extents of potential habitat, defined as vegetation groups most closely associated with each species. From this, we calculated the loss index (LI), which revealed that 30% of native birds have each lost at least 30% of their potential natural habitat (LI = 30). At the subcontinental scale, LIs ranged from 15 in arid Australia to 61 in the highly transformed southeastern part of the country. Different subcomponents of the assemblage had different LI values. For example, Australia's parrots (n = 52 species) had an LI of 38, whereas raptors (n = 32 species) had an LI of 25. The LI is simple to calculate and can be determined using readily available spatial information on species distributions, native vegetation associations, and human impacts on natural land cover. This metric, including the curves used to deduce it, could complement other biodiversity indices if it is used for regional and global biodiversity assessments that compare the status of natural habitat extent for assemblages within and among nations, monitor changes through time, and forecast future changes to guide strategic land-use planning. The LI is an intuitive tool that can be used to summarize and communicate how human actions affect whole assemblages, not just threatened species.

Una Medida Compuesta de la Pérdida del Hábitat para Ensamblajes Enteros de Especies Resumen La destrucción del hábitat está entre las principales amenazas para la biodiversidad, además de que afecta tanto a especies comunes como a las especies amenazadas. Sin embargo, las medidas para comunicar los impactos de esta destrucción generalmente ignoran al componente no amenazado de los ensamblajes de especies. Esto genera el riesgo de que la pérdida del hábitat pase desapercibida en el caso de las especies que conforman a la mayoría de los ensamblajes. Adaptamos una medida de uso amplio para resumir las contribuciones de los investigadores (el índice h) y así proporcionar una medida que describa la pérdida del hábitat para ensamblajes enteros, incluyendo a las especies amenazadas y a las no amenazadas. Para cada una de las 447 especies de aves terrestres nativas a Australia, combinamos la información sobre su asociación con grupos generales de vegetación con mapas de extensión de su distribución para identificar la diferencia entre la extensión estimada previa a la llegada de los europeos y la extensión actual de los hábitats potenciales, definidos como los grupos de vegetación asociados más cercanamente con cada especie. A partir de esto, calculamos el índice de pérdida (LI, en inglés), el cual reveló que el 30% de cada una de las aves nativas ha perdido al menos el 30% de su hábitat natural potencial (LI = 30). A escala subcontinental, los LI variaron desde 15 para las partes áridas de Australia, hasta 61 en la altamente transformada parte sureste del país. Los diferentes subcomponentes del ensamblaje tuvieron diferentes valores de LI. Por ejemplo, los loros australianos (n = 52 especies) tuvieron un LI de 38, mientras que las aves rapaces (n = 32 especies) tuvieron un LI de 25. El LI es fácil de calcular y puede determinarse usando información espacial que ya se encuentra disponible, las asociaciones con la vegetación nativa y los impactos humanos sobre la cobertura natural del suelo. Esta medida, incluyendo las curvas que se usan para deducirla, podrían complementar otros índices de biodiversidad si se usa para evaluaciones de la biodiversidad regional y global, las cuales comparan el estado de la extensión del hábitat natural para ensamblajes dentro y entre las naciones, monitorean cambios a través del tiempo y pronostican cambios futuros que guíen la planeación del uso de suelo estratégico. El LI es una herramienta intuitiva que puede usarse para resumir y comunicar cómo las acciones humanas afectan a ensamblajes enteros, no sólo a las especies amenazadas.

Mu and kappa opioid receptors of the periaqueductal gray stimulate and inhibit thermogenesis, respectively, during psychological stress in rats.

The periaqueductal gray matter (PAG) is rich in mu and kappa opioid receptors, and this system is involved in thermoregulation, analgesia, and defensive behaviors. No study approached the involvement of the PAG opioids in body temperature (Tb) regulation during psychological stress such as restraint. Because activation of mu and kappa receptors increases and reduces Tb, respectively, we tested the hypothesis that they exert excitatory and inhibitory modulation, respectively, of the restraint-induced fever in rats. To this end, Tb, heat loss index (HLI, inference for peripheral vasoconstriction/vasodilation), and oxygen consumption (inference for thermogenesis) were monitored in unanesthetized rats, restrained or unrestrained, before and after intra-PAG microinjection of the selective mu opioid receptor antagonist (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 cyclic, CTAP; 1 and 10 µg/100 nL) or the selective kappa opioid receptor antagonist (nor-binaltorphimine dihydrochloride, nor-BNI; 1 and 4 µg/100 nL) or saline (100 nL). CTAP and nor-BNI did not change the Tb or HLI of euthermic animals. During restraint, Tb increased (1.0 ± 0.1 °C) in all groups; however, this effect was lower in those animals treated with CTAP and higher in animals treated with nor-BNI. The HLI decreased during restraint and increased after animals were released, but this response was not affected by any treatment. Restraint stress increased oxygen consumption (35.9 ± 3.9% elevation), but this response was diminished by CTAP and overstimulated by nor-BNI. Confirming our hypothesis, the results indicate that the mu and kappa opioid receptors in the PAG of rats play a pyrogenic and antipyretic role, respectively, during fever induced by restraint by affecting the thermogenic but not the heat conservation effector.

Central serotonin attenuates LPS-induced systemic inflammation.

Serotonin (5-HT) is a neuromodulator involved in several central-mediated mechanisms, such as endocrine processes, behavior, and sleep. Dysfunction of the serotonergic system is mainly linked to psychiatric disorders, but emerging evidence suggests that immune system activation may also alter brain 5-HT signaling. However, whether central 5-HT modulates systemic inflammation (SI) remains unknown. For this purpose, male Wistar rats (280-350g, 8-9weeks) were submitted to the experimental protocols beginning between 9 and 10AM with the performance of injections. The animals were housed at controlled conditions [temperature (25±1°C), light (06:00-18:00) and humidity (60-65%)]. Thus, we measured 5-HT and its metabolite 5-hydroxyindole-3-acetic acid (5-HIAA) in the anteroventral preoptic region [(AVPO) - the hierarchically most important region for body temperature (Tb) control] during lipopolysaccharide (LPS)-induced SI. We also combined LPS (100µg/kg) treatment with intracerebroventricular (icv) injection of 5-HT (5, 10 and 40µg/µL) and measured Tb ("hallmark" of SI), AVPO prostaglandin E2 [(PGE2) - an essential mediator of fever] and prostaglandin D2 [(PGD2) - a cryogenic mediator], plasma corticosterone [(CORT) - a stress marker with an endogenous anti-inflammatory effect] and interleukin-6 [(IL-6) - an immune mediator] levels. Detection limits of PGE2, PGD2, CORT and IL-6 assays were 39.1-2500pg/mL, 19.5-2500pg/mL, 0.12-2000µg/dL, and 0.125-8ng/mL, respectively. We also assessed tail skin temperature [used to calculate heat loss index (HLI)] to assess a key thermoeffector mechanism. As expected we observed LPS-induced increases in Tb, AVPO PGE2 (whereas PGD2 remained unchanged), plasma CORT and IL-6 levels, as well as a decrease in HLI. These changes were accompanied by reduced levels of AVPO 5-HT and 5-HIAA. Furthermore, we also observed a negative correlation between 5-HT and plasma CORT levels. Moreover, icv 5-HT (5, 10 and 40µg/µL) microinjection caused a U-shaped dose-response curve in LPS fever, in which the intermediate dose reduced the febrile response. Icv 5-HT (10µg/µL) microinjection prevented the LPS-induced increases in AVPO PGE2 (whereas not altering PGD2), plasma CORT and IL-6 levels, as well as preventing reduced HLI. Our data are consistent with the notion that AVPO 5-HT synthesis is down-regulated during SI, favoring AVPO PGE2 synthesis and consequently potentiating the immune response. These results reveal a novel effect of central 5-HT as an anti-inflammatory neuromodulator that may take place during psychiatric disorder treatment with 5-HT reuptake inhibitors as well as suggesting that 5-HT modulation per se is a potential therapeutic approach for inflammatory diseases.

The effect of aortic area measurement site on the energy loss coefficient: a comparison between echocardiography and cardiac computed tomography angiography in patients with aortic stenosis.

AIM: The energy loss coefficient (ELCo) has been suggested as a more accurate indicator of aortic stenosis (AS) severity as compared to transthoracic echocardiography (TTE) aortic valve area (AVA). There are little data regarding the optimal location for aortic area (Aa) measurement needed for ELCo calculation and the agreement of ELCo with direct anatomical AVA measurement. The aim of this study was to determine the optimal site of Aa measurement for calculation of the ELCo, using cardiac computed tomography angiography (CCTA) AVA planimetry as the reference standard. METHODS: We analyzed 69 patients with AS who underwent both CCTA and TTE. ELCo and CCTA planimetry AVA were compared using multiple sites for CCTA Aa measurement (sinus, sinotubular junction, or ascending aorta). RESULTS: CCTA AVA was 0.96±0.46 cm2 . ELCo was 0.95±0.43 cm2 using sinotubular junction Aa, 0.92±0.41 cm2 using sinus Aa, and 0.91±0.4 cm2 using the ascending aorta (P=.84, P=.13, and P=.08 compared to CCTA AVA). There was good agreement between CCTA AVA and ELCo using all Aa locations (0.89-0.90). On subgroup analysis of 16 patients most likely to be affected by pressure recovery (aortic diameter<3 cm and AVA ≥1 cm2 ), ELCo using the sinotubular junction Aa showed the best agreement with CCTA AVA as compared to the other Aa locations (0.84 vs 0.75-0.77). CONCLUSIONS: ELCo using Aa measurement at the sinotubular junction showed the best agreement with CCTA AVA. We therefore recommend using the sinotubular junction Aa for ELCo calculation.

Aortic valve replacement reduces valvuloarterial impedance but does not affect systemic arterial compliance in elderly men with degenerative calcific trileaflet aortic valve stenosis.

OBJECTIVE: Standard methods of quantifying aortic valve stenosis (AS), which focus entirely on the valve itself, do not adequately characterize the magnitude, predict the onset, progression, and severity of symptoms, or identify the incidence of subsequent adverse events. Valvuloarterial impedance (Z(va)) is an index of global left ventricular (LV) afterload that incorporates valvular and arterial loads. The authors tested the hypothesis that aortic valve replacement (AVR) reduces Z(va) but does not affect the arterial component of LV afterload in elderly patients with degenerative calcific trileaflet AS. DESIGN: Observational study. SETTING: Veterans affairs medical center. PARTICIPANTS: Eight elderly (age, 79 ± 4 years) men with moderate-to-severe AS and normal preoperative LV function (ejection fraction, 61% ± 9%) scheduled for AVR with or without coronary artery bypass graft surgery were studied after institutional review board approval. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A comprehensive TEE examination was performed during isoflurane-fentanyl-rocuronium anesthesia. Doppler echocardiography was used to measure pressure gradients across the aortic valve, stroke volume (continuity equation), and aortic valve area using standard techniques. Z(va) was determined as (systolic arterial pressure+mean gradient)/stroke volume index. Energy loss index was calculated as (aortic area × aortic valve area)/([aortic area--aortic valve area]× body surface area). The stroke work loss was obtained as (mean gradient × 100/[systolic arterial pressure+mean gradient]). The ratio of stroke volume index to pulse pressure was used to measure systemic arterial compliance. Z(va), energy loss index, stroke work loss, and systemic arterial compliance were assessed before and 15 minutes after cardiopulmonary bypass. Systemic and pulmonary hemodynamics (invasive catheters) were similar after versus before AVR. Aortic valve area increased significantly (p<0.05) with AVR (0.92 ± 0.26 cm(2) to 1.94 ± 0.35 cm(2)), concomitant with decreases in peak and mean gradients (60 ± 17 mmHg to 15 ± 8 mmHg and 38 ± 11 mmHg to 8 ± 5 mmHg, respectively) and peak blood flow velocity (3.9 ± 0.5 m · s(-1) to 1.9 ± 0.5 m · s(-1)). AVR reduced Z(va) (4.6 ± 1.0 mmHg · mL(-1) · m(-2) to 3.5 ± 0.3 mmHg · mL(-1) · m(-2)) and improved energy loss index (0.55 ± 0.16 cm(2) · m(-2) to 1.58 ± 0.48 cm(2) · m(-2)) concomitant with a decline in stroke work loss (25% ± 6% to 7% ± 4%), but systemic arterial compliance remained unchanged (0.63 ± 0.13 compared with 0.70 ± 0.12 mL · mmHg(-1)· m(-2)). CONCLUSION: The current results showed that AVR acutely reduced Zva, improved energy loss index, and decreased stroke work loss, but did not affect systemic arterial compliance in elderly men with degenerative calcific trileaflet AS.

Energy Loss Index and Dimensionless Index Outperform Direct Valve Planimetry in Low-Gradient Aortic Stenosis.

Background/Objectives: Among patients with suspected severe aortic stenosis (AS), discordance between effective orifice area (EOA) and transvalvular gradients is frequent and requires a multiparametric workup including flow assessment and calcium-scoring to confirm true severe AS. The aim of this study was to assess direct planimetry, energy loss index (Eli) and dimensionless index (DI) as stand-alone parameters to identify non-severe AS in discordant cases. Methods: In this prospective cohort study, we included consecutive AS patients > 70 years with EOA < 1.0 cm2 referred for valve replacement between 2014 and 2017. AS severity was retrospectively reassessed using the multiparametric work-up recommended in the 2021 ESC/EACTS guidelines. DI and ELi were calculated, and valve area was measured by direct planimetry on transesophageal echocardiography. Results: A total of 101 patients (mean age 82 y; 57% male) were included. Discordance between EOA and gradients was observed in 46% and non-severe AS found in 24% despite an EOA < 1 cm2. Valve planimetry performed poorly, with an area under the ROC curve (AUC) of 0.64. At a cut-off value of >0.82 cm2, sensitivity and specificity to identify non-severe AS were 67 and 66%, respectively. DI and ELi showed a higher diagnostic accuracy, with an AUC of 0.77 and 0.76, respectively. Cut-off values of >0.24 and >0.6 cm2/m2 identified non-severe AS, with a high specificity of 79% and 91%, respectively. Conclusions: Almost one in four patients with EOA < 1 cm2 had non-severe AS according to guideline-recommended multiparametric assessment. Direct valve planimetry revealed poor diagnostic accuracy and should be interpreted with caution. Usual prognostic cut-off values for DI > 0.24 and ELI > 0.6 cm2/m2 identified non-severe AS with high specificity and should therefore be included in the assessment of low-gradient AS.

Impact of pressure recovery on the assessment of pulmonary homograft function using Doppler ultrasound.

Relevant pressure recovery (PR) has been shown to increase functional stenotic aortic valve orifice area and reduce left ventricular load. However, little is known about the relevance of PR in the pulmonary artery. The study examined the impact of PR using 2D-echocardiography in the pulmonary artery distal to the degenerated homograft in patients after Ross surgery. Ninety-two patients with pulmonary homograft were investigated by Doppler echocardiography (mean time interval after surgery 31 ± 26 months). PR was measured as a function of pulmonary artery diameter determined by computed tomography angiography. Homograft orifice area, valve resistance, and transvalvular stroke work were calculated with and without considering PR. PR decreased as the pulmonary artery diameter increased (r = -0.69, p < 0.001). Mean PR was 41.5 ± 7.1% of the Doppler-derived pressure gradient (Pmax ), which resulted in a markedly increased homograft orifice area (energy loss coefficient index [ELCOI] vs. effective orifice area index [EOAI], 1.3 ± 0.4 cm2 /m2 vs. 0.9 ± 0.4 cm2 /m2 , p < 0.001). PR significantly reduced homograft resistance and transvalvular stroke work (822 ± 433 vs. 349 ± 220 mmHg × ml, p < 0.0001). When PR was considered, the correlations of the parameters used were significantly better, and 11 of 18 patients (61%) in the group with severe homograft stenosis (EOAI <0.6 cm2 /m2 ) could be reclassified as moderate stenosis. Our results showed that the Doppler measurements overestimated the degree of homograft stenosis and thus the right ventricular load, when PR was neglected in the pulmonary artery. Therefore, Doppler measurements that ignore PR can misclassify homograft stenosis and may lead to premature surgery.

Clinical significance of energy loss index in patients with low-gradient severe aortic stenosis and preserved ejection fraction.

AIMS: We hypothesized that among patients with low-gradient severe aortic stenosis (AS) and preserved left ventricular ejection fraction (LVEF), reclassification of AS severity as moderate by pressure recovery adjusted indexed aortic valve area (AVAi) = energy loss index (ELI), may identify a subgroup of patients with a better outcome. METHODS AND RESULTS: Three hundred and seventy-nine patients with low-gradient AS (defined by AVAi ≤ 0.6 cm2/m2 and mean aortic pressure gradient < 40 mmHg) and preserved LVEF ≥50% were studied. Reclassification as moderate AS by ELI was defined as AVAi ≤0.6 cm2/m2 but with an ELI >0.6 cm2/m2. Cardiac events [cardiac mortality and/or need for aortic valve replacement (AVR)] during follow-up were studied. One hundred and forty-eight patients (39%) were reclassified as moderate AS by ELI. Reclassification as moderate AS was independently associated with decreased body surface area, normal flow status, decreased left ventricular mass index, and left atrial volume index (all P < 0.05). After adjustment for variables of prognostic interest, reclassification as moderate AS by ELI was associated with a considerable reduction of risk of cardiac events {adjusted hazard ratio (HR) 0.49 [95% confidence interval (CI) 0.33-0.72]; P < 0.001}, need for AVR [adjusted HR 0.52 (95% CI 0.34-0.81); P = 0.004], and cardiac mortality [adjusted HR 0.46 (95% CI 0.22-0.98); P = 0.044]. CONCLUSION: In patients with low-gradient severe AS and preserved LVEF, calculation of ELI permits to reclassify almost 40% of patients as having moderate AS. These reclassified patients have a considerable reduction of the risk of cardiac events during follow-up. Calculation of ELI is useful for decision-making in patients with low-gradient severe AS and preserved ejection fraction.