Altered central nervous system processing of baroreceptor input following hindlimb unloading in rats

NASA Technical Reports Server (NTRS)

Moffitt, J. A.; Schadt, J. C.; Hasser, E. M.

1999-01-01

The effect of cardiovascular deconditioning on central nervous system processing of baroreceptor afferent activity was evaluated following 14 days of hindlimb unloading (HU). Inactin-anesthetized rats were instrumented with catheters, renal sympathetic nerve electrodes, and aortic depressor nerve electrodes for measurement of mean arterial pressure, heart rate, renal sympathetic nerve activity (RSNA), and aortic depressor nerve activity (ADNA). Baroreceptor and baroreflex functions were assessed during infusion of phenylephrine and sodium nitroprusside. Central processing of baroreceptor afferent input was evaluated by linear regression relating RSNA to ADNA. The maximum baroreflex-elicited increase in RSNA was significantly reduced in HU rats (122 +/- 3.8 vs. 144 +/- 4.9% of baseline RSNA), whereas ADNA was not altered. The slope (-0.18 +/- 0.04 vs. -0.40 +/- 0.04) and y-intercept (121 +/- 3.2 vs. 146 +/- 4.3) of the linear regression relating increases in efferent RSNA to decreases in afferent ADNA during hypotension were significantly reduced in HU rats. There were no differences during increases in arterial pressure. Results demonstrate that the attenuation in baroreflex-mediated increases in RSNA following HU is due to changes in central processing of baroreceptor afferent information rather than aortic baroreceptor function.

Cardiopulmonary baroreceptor control of muscle sympathetic nerve activity in heat-stressed humans

NASA Technical Reports Server (NTRS)

Crandall, C. G.; Etzel, R. A.; Farr, D. B.

1999-01-01

Whole body heating decreases central venous pressure (CVP) while increasing muscle sympathetic nerve activity (MSNA). In normothermia, similar decreases in CVP elevate MSNA, presumably via cardiopulmonary baroreceptor unloading. The purpose of this project was to identify whether increases in MSNA during whole body heating could be attributed to cardiopulmonary baroreceptor unloading coincident with the thermal challenge. Seven subjects were exposed to whole body heating while sublingual temperature, skin blood flow, heart rate, arterial blood pressure, and MSNA were monitored. During the heat stress, 15 ml/kg warmed saline was infused intravenously over 7-10 min to increase CVP and load the cardiopulmonary baroreceptors. We reported previously that this amount of saline was sufficient to return CVP to pre-heat stress levels. Whole body heating increased MSNA from 25 +/- 3 to 39 +/- 3 bursts/min (P < 0. 05). Central blood volume expansion via rapid saline infusion did not significantly decrease MSNA (44 +/- 4 bursts/min, P > 0.05 relative to heat stress period) and did not alter mean arterial blood pressure (MAP) or pulse pressure. To identify whether arterial baroreceptor loading decreases MSNA during heat stress, in a separate protocol MAP was elevated via steady-state infusion of phenylephrine during whole body heating. Increasing MAP from 82 +/- 3 to 93 +/- 4 mmHg (P < 0.05) caused MSNA to decrease from 36 +/- 3 to 15 +/- 4 bursts/min (P < 0.05). These data suggest that cardiopulmonary baroreceptor unloading during passive heating is not the primary mechanism resulting in elevations in MSNA. Moreover, arterial baroreceptors remain capable of modulating MSNA during heat stress.

[Comparative study on the reflex responses of carotid and aortic baroreceptors in the rabbit].

PubMed

Li, Z; Ho, S Y

1989-08-01

In 81 anesthetized rabbits, the baroreflex control of heart rate (HR), hind-limb vascular resistance (HVR) and renal sympathetic nerve activity (RSNA) was observed during arterial baroreceptor loading and unloading by intravenously injecting phenylephrine (PE) and nitroprusside (NP). The results were as follows: (1) An increase of arterial pressure with PE caused reduction in HR, HVR and RSNA, while a decrease of arterial pressure with NP evoked opposite responses. These reflex responses were reproducible. (2) By either carotid baroreceptor denervation (CBRX) or aortic baroreceptor denervation (ABRX), the reflex changes of HR induced by injecting PE and NP were impaired (P less than 0.01), while the reflex responses in HVP remained unchanged. Despite of the enhanced basal RSNA following ABRX or CBRX, the magnitude of reflex inhibition in RSNA during injecting NP was similar to that before denervation, whereas that of the reflex excitation in RSNA during injecting NP was reduced (P less than 0.05). (3) After complete sino-aortic denervation (SAD), the change of arterial pressure following PE or NP injection was enhanced, but the reflex changes in HR, HVR and RSNA were significantly diminished (P less than 0.001). (4) Vagotomy abolished the residual reflex changes observed after SAD. The results indicate that the aortic and carotid baroreceptors may regulate HR in a simple additive manner, while the aortic baroreceptor seems to be more important. Furthermore, both the aortic and carotid baroreceptors may play important roles for the reflex control of HVR and RSNA, and operate mutually by the way of inhibitory summation.

Modelling the interaction among several mechanisms in the short-term arterial pressure control.

PubMed

Ursino, M

2000-01-01

A Mathematical model of the short-term arterial pressure control in humans is presented. It includes a six-compartment description of the vascular system, an elastance variable model of the pulsating heart, two groups of baroreceptors (high-pressure or sinoaortic baroreceptors and low-pressure or cardiopulmonary baroreceptors), the efferent activity in the sympathetic nerves and in the vagus, and the response of four distinct effectors (heart period, systemic peripheral resistance, systemic venous unstressed volume and heart contractility). Several experimental results reported in the physiological literature can be reproduced with the model quite well. The examples presented in this work include the effect of combined sympathetic and vagal stimulation on heart rate, the baroreflex response to mild and severe acute haemorrhages, and the baroreflex response to ventricular pacing at different rates performed during atrioventricular block. The results suggest that: i) The sympathetic nerves and the vagus interact linearly in regulating heart period. The apparent negative interaction observed experimentally can be ascribed merely to the hyperbolic relationship which links heart rate to heart period. ii) The cardiopulmonary baroafferents play a significant role in the control of systemic arterial pressure during mild haemorrhages (lower than 3-4% of the overall blood volume). In this range, they may allow arterial pressure to be maintained at its normal level without the intervention of the sinoaortic baroreceptors. In contrast, the sinoaortic baroreceptors become the major responsible of the observed cardiovascular adjustments during more severe haemorrhages, when the role of cardiopulmonary baroreceptors becomes progressively exhausted. iii) The stability margin of the closed-loop system is quite low. Increasing the static gain of the baroreceptors or reducing the rate-dependent component may result in self-sustained oscillations similar to Mayer waves.

From supine to standing: in vivo segregation of myogenic and baroreceptor vasoconstriction in humans.

PubMed

Estañol, Bruno; Rivera, Ana Leonor; Martínez Memije, Raúl; Fossion, Ruben; Gómez, Fermín; Bernal, Katherine; Murúa Beltrán, Sofía; Delgado-García, Guillermo; Frank, Alejandro

2016-12-01

Myogenic vascular response is a form of systemic and regional vasoconstriction produced increasing the intra-arterial pressure by gravity. Here, the vasoconstriction due to the myogenic response, induced by the gravitational action in a dependent limb, is separated from that caused by the baroreceptor reflex. Regional changes of skin blood flow (SBF), total blood volume of the finger (TBVF), pulse pressure (PP), heart rate (HR), systolic, and diastolic blood pressure (BP) were analyzed in 10 healthy young subjects in supine and upright positions. By lowering the arm in supine position, SBF decreased compared to its basal measurement, PR increased, and PP contracted, indicating arterial vasoconstriction that rise BP TBVF increased, demonstrating an increment in venous volume. HR did not change, reflecting no action of the baroreceptor reflex. In upright position with lowered arm, there was an additional increase in BP variables, demonstrating vasoconstriction. Moreover, BP and HR showed oscillations at 0.1 Hz reflecting the entrance of the baroreceptor reflex. The action of gravity in a dependent limb in supine position induces a regional vasoconstriction and an increase of BP due to activation of the myogenic response, while the baroreceptor reflex or other neural factors do not appear to operate. In the upright position with the arm dependent, there is a further increase in regional vasoconstriction and BP with reciprocal changes in HR, indicating the entrance of the baroreceptor superimposed to the myogenic response. This study demonstrates that the myogenic and baroreceptor vasoconstriction can be separated in vivo. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Cardiovascular reflexes during rest and exercise modified by gravitational stresses

NASA Astrophysics Data System (ADS)

Bonde-petersen, Flemming

The hypotheses tested were whether variations in central venous pressure via the low pressure baroreceptors would take over or modify the arterial baroreceptor function, and further to which extent local and "whole body" hydrostatic stresses influence blood flow distribution. We investigated total forearm and skin blood flow (venous occlusion plethysmography and 133-Xe clearance) and cardiac output (rebreathing method) among other parameters. Hypo-and hypergravitational stresses were simulated by LBNP, LBPP, water immersion and lowering of the arm. The changes in flow distribution in the arm were ascribed to arterial baroreceptor function and not to low pressure baroreceptor activity. The enhancement of venous return during water immersion increased exercise tolerance during heat stress presumably due both to increased stroke volume and decreased venous pooling. The response to sustained handgrip exercise during LBNP and LBPP was not different from control measurements and the effects explained by arterial baroreceptor function. Application of exercise and local hydrostatic stresses in combination with gravitational stresses represent an interesting model for further study of the mechanisms behind the distribution of cardiac output to the peripheral organs.

Reflex vascular responses to alterations in abdominal arterial pressure and flow in anaesthetized dogs.

PubMed

Drinkhill, M J; Doe, C P; Myers, D S; Self, D A; Hainsworth, R

1997-11-01

The existence of abdominal arterial baroreceptors has long been controversial. Previously difficulties have been encountered in localizing a stimulus to abdominal arteries without affecting reflexogenic areas elsewhere. In these experiments, using anaesthetized dogs, the abdomen was vascularly isolated at the level of the diaphragm, perfused through the aorta, and drained from the inferior vena cava to a reservoir. Changes in abdominal arterial pressure were effected by changing the perfusion pump speed. During this procedure the flow back to the animal from the venous outflow reservoir was held constant. Increases and decreases in abdominal arterial pressure resulted, respectively, in decreases and increases in perfusion pressure to a vascularly isolated hind-limb and in some dogs also a forelimb. Responses were significantly larger when carotid sinus pressure was high (120-180 mmHg) than when it was low (60 mmHg). Responses were still obtained after cutting vagus, phrenic and splanchnic nerves, but were abolished by spinal cord lesion at T12. These experiments provide evidence for the existence of abdominal arterial baroreceptors. The afferent pathway for the reflex vasodilatation appears to run in the spinal cord.

Chaotic behavior of renal sympathetic nerve activity: effect of baroreceptor denervation and cardiac failure.

PubMed

DiBona, G F; Jones, S Y; Sawin, L L

2000-09-01

Nonlinear dynamic analysis was used to examine the chaotic behavior of renal sympathetic nerve activity in conscious rats subjected to either complete baroreceptor denervation (sinoaortic and cardiac baroreceptor denervation) or induction of congestive heart failure (CHF). The peak interval sequence of synchronized renal sympathetic nerve discharge was extracted and used for analysis. In control rats, this yielded a system whose correlation dimension converged to a low value over the embedding dimension range of 10-15 and whose greatest Lyapunov exponent was positive. Complete baroreceptor denervation was associated with a decrease in the correlation dimension of the system (before 2.65 +/- 0.27, after 1.64 +/- 0.17; P < 0.01) and a reduction in chaotic behavior (greatest Lyapunov exponent: 0.201 +/- 0.008 bits/data point before, 0.177 +/- 0.004 bits/data point after, P < 0.02). CHF, a state characterized by impaired sinoaortic and cardiac baroreceptor regulation of renal sympathetic nerve activity, was associated with a similar decrease in the correlation dimension (control 3.41 +/- 0.23, CHF 2.62 +/- 0.26; P < 0.01) and a reduction in chaotic behavior (greatest Lyapunov exponent: 0.205 +/- 0.048 bits/data point control, 0.136 +/- 0.033 bits/data point CHF, P < 0.02). These results indicate that removal of sinoaortic and cardiac baroreceptor regulation of renal sympathetic nerve activity, occurring either physiologically or pathophysiologically, is associated with a decrease in the correlation dimensions of the system and a reduction in chaotic behavior.

Arterial baroreceptors in the management of systemic hypertension

PubMed Central

Kougias, Panagiotis; Weakley, Sarah M.; Yao, Qizhi; Lin, Peter H.; Chen, Changyi

2010-01-01

Summary Hypertension is a multifactorial disease associated with significant morbidity. Increased sympathetic nervous system activity has been noted as an important etiologic factor and is, in part, regulated by afferent input arising from arterial and cardiopulmonary baroreceptors, activation of which causes inhibition of sympathetic output. It was thought for many years that baroreceptors control only short-term blood pressure changes, a conclusion stemming from observations in sinoaortic denervation (SAD) animal models and the phenomenon of rapid baroreceptor resetting, also seen in animal models. Newer observations, however, indicate that SAD is rather imperfect and resetting is rarely complete. Recent studies reveal that baroreceptors control sympathetic output on a more long-term basis and participate in fluid volume regulation by the kidney, and thus have the potential to adjust blood pressure chronically. Importantly, these findings are consistent with studies and observations in humans. Meanwhile, a model of electrical stimulation of the carotid sinus has been developed and successfully tested in animals. Following these encouraging results human trials to evaluate the clinical application of electrical carotid sinus manipulation in the treatment of systemic hypertension have commenced, and results so far indicate that this represents an exciting potential tool in the clinician’s armament against chronic arterial hypertension. PMID:20037502

Carotid-cardiac baroreflex influence on forearm vascular resistance during low level LBNP

NASA Technical Reports Server (NTRS)

Ludwig, David

1990-01-01

Twelve healthy males were tested at low levels of lower body negative pressure (LBNP) with and without artificial stimulation of the carotid-cardiac baroreceptors. The carotid-cardiac baroreceptors were stimulated by applying a pressure of 10 mmHg to the carotid artery via a pressurized neck chamber. During the procedure, forearm blood flow (FBF) and forearm vascular resistance (FVR) were measured using a Whitney mercury silastic strain gauge technique. FBF decreased while FVR increased with increased intensity of LBNP. Both FBF and FVR were unaffected by carotid-cardiac baroreceptor stimulation.

Dynamic analysis of renal nerve activity responses to baroreceptor denervation in hypertensive rats.

PubMed

DiBona, G F; Jones, S Y

2001-04-01

Sinoaortic and cardiac baroreflexes exert important control over renal sympathetic nerve activity. Alterations in these reflex mechanisms contribute to renal sympathoexcitation in hypertension. Nonlinear dynamic analysis was used to examine the chaotic behavior of renal sympathetic nerve activity in normotensive Sprague-Dawley and Wistar-Kyoto rats and spontaneously hypertensive rats before and after complete baroreceptor denervation (sinoaortic and cardiac baroreceptor denervation). The peak interval sequence of synchronized renal sympathetic nerve discharge was extracted and used for analysis. In all rat strains, this yielded systems whose correlation dimensions converged to similar low values over the embedding dimension range of 10 to 15 and whose greatest Lyapunov exponents were positive. In Sprague-Dawley and Wistar-Kyoto rats, compete baroreceptor denervation was associated with decreases in the correlation dimensions (Sprague-DAWLEY: 2.42+/-0.04 to 2.16+/-0.04; Wistar-KYOTO: 2.44+/-0.04 to 2.34+/-0.04) and in the greatest Lyapunov exponents (Sprague-DAWLEY: 0.199+/-0.004 to 0.130+/-0.015; Wistar-KYOTO: 0.196+/-0.002 to 0.136+/-0.010). Spontaneously hypertensive rats had a similar correlation dimension, which was unaffected by complete baroreceptor denervation (2.42+/-0.02 versus 2.42+/-0.03), and a lower value for the greatest Lyapunov exponent, which decreased to a lesser extent after complete baroreceptor denervation (0.183+/-0.006 versus 0.158+/-0.006). These results indicate that removal of sinoaortic and cardiac baroreceptor regulation of renal sympathetic nerve activity is associated with a greater decrease in the chaotic behavior of renal sympathetic nerve activity in normotensive compared with hypertensive rats. This suggests that the central neural mechanisms that regulate renal sympathetic nerve activity in response to alterations in cardiovascular reflex inputs are different in spontaneously hypertensive rats from those in Sprague-Dawley and Wistar-Kyoto rats.

Short-duration spaceflight impairs human carotid baroreceptor-cardiac reflex responses

NASA Astrophysics Data System (ADS)

Fritsch, Janice M.; Charles, John B.; Bennett, Barbara S.; Jones, Michele M.; Eckberg, Dwain L.

1992-08-01

The effect of a spaceflight on the vagally mediated baroreceptor-cardiac reflex responses of humans were investigated by measuring the responses (provoked by neck pressure changes) in supine position and the heart rate and blood pressure in the supine and standing positions in 16 astronauts before and after 4- to 5-day long Space Shuttle missions. The results showed that exposures to spaceflight resulted in reduced baseline levels of the vagal-cardiac outflow and the vagally mediated responses to changes of the arterial baroreceptor input and that these changes contribute to postflight reductions of astronauts' ability to maintain standing arterial pressures.

A model-based approach for the evaluation of vagal and sympathetic activities in a newborn lamb.

PubMed

Le Rolle, Virginie; Ojeda, David; Beuchée, Alain; Praud, Jean-Paul; Pladys, Patrick; Hernández, Alfredo I

2013-01-01

This paper proposes a baroreflex model and a recursive identification method to estimate the time-varying vagal and sympathetic contributions to heart rate variability during autonomic maneuvers. The baroreflex model includes baroreceptors, cardiovascular control center, parasympathetic and sympathetic pathways. The gains of the global afferent sympathetic and vagal pathways are identified recursively. The method has been validated on data from newborn lambs, which have been acquired during the application of an autonomic maneuver, without medication and under beta-blockers. Results show a close match between experimental and simulated signals under both conditions. The vagal and sympathetic contributions have been simulated and, as expected, it is possible to observe different baroreflex responses under beta-blockers compared to baseline conditions.

Role of Autonomic Reflex Arcs in Cardiovascular Responses to Air Pollution Exposure

PubMed Central

Hazari, Mehdi S.; Farraj, Aimen K.

2016-01-01

The body responds to environmental stressors by triggering autonomic reflexes in the pulmonary receptors, baroreceptors, and chemoreceptors to maintain homeostasis. Numerous studies have shown that exposure to various gases and airborne particles can alter the functional outcome of these reflexes, particularly with respect to the cardiovascular system. Modulation of autonomic neural input to the heart and vasculature following direct activation of sensory nerves in the respiratory system, elicitation of oxidative stress and inflammation, or through other mechanisms is one of the primary ways that exposure to air pollution affects normal cardiovascular function. Any homeostatic process that utilizes the autonomic nervous system to regulate organ function might be affected. Thus, air pollution and other inhaled environmental irritants have the potential to alter both local airway function and baro-and chemoreflex responses, which modulate autonomic control of blood pressure and detect concentrations of key gases in the body. While each of these reflex pathways causes distinct responses, the systems are heavily integrated and communicate through overlapping regions of the brainstem to cause global effects. This short review summarizes the function of major pulmonary sensory receptors, baroreceptors, and carotid body chemoreceptors and discusses the impacts of air pollution exposure on these systems. PMID:25123706

Signal transduction of aortic and carotid sinus baroreceptors is not modified by central command during spontaneous motor activity in decerebrate cats.

PubMed

Matsukawa, Kanji; Ishii, Kei; Kadowaki, Akito; Ishida, Tomoko; Idesako, Mitsuhiro; Liang, Nan

2014-05-15

Our laboratory has suggested that central command provides selective inhibition of the cardiomotor component of aortic baroreflex at the start of exercise, preserving carotid sinus baroreflex. It is postulated that central command may modify the signal transduction of aortic baroreceptors, so as to decrease aortic baroreceptor input to the cardiovascular centers, and, thereby, can cause the selective inhibition of aortic baroreflex. To test the hypothesis, we directly analyzed the responses in multifiber aortic nerve activity (AoNA) and carotid sinus nerve activity (CsNA) during spontaneous motor activity in decerebrate, paralyzed cats. The increases of 62-104% in mean AoNA and CsNA were found during spontaneous motor activity, in proportion to a rise of 35 ± 3 mmHg (means ± SE) in mean arterial blood pressure (MAP), and had an attenuating tendency by restraining heart rate (HR) at the lower intrinsic frequency of 154 ± 6 beats/min. Brief occlusion of the abdominal aorta was conducted before and during spontaneous motor activity to produce a mechanically evoked increase in MAP and, thereby, to examine the stimulus-response relationship of arterial baroreceptors. Although the sensitivity of the MAP-HR baroreflex curve was markedly blunted during spontaneous motor activity, the stimulus-response relationships of AoNA and CsNA were not influenced by spontaneous motor activity, irrespective of the absence or presence of the HR restraint. Thus, it is concluded that aortic and carotid sinus baroreceptors can code beat-by-beat blood pressure during spontaneous motor activity in decerebrate cats and that central command is unlikely to modulate the signal transduction of arterial baroreceptors. Copyright © 2014 the American Physiological Society.

Effect of angiotension II on voltage-gated sodium currents in aortic baroreceptor neurons and arterial baroreflex sensitivity in heart failure rats

PubMed Central

Zhang, Dongze; Liu, Jinxu; Zheng, Hong; Tu, Huiyin; Muelleman, Robert L.; Li, Yu-Long

2016-01-01

Impairment of arterial baroreflex sensitivity is associated with mortality in patients with chronic heart failure (CHF). Elevation of plasma angiotension II (Ang II) contributes to arterial baroreflex dysfunction in CHF. A reduced number of voltage-gated sodium (Nav) channels in aortic baroreceptor neurons are involved in CHF-blunted arterial baroreflex. In this study, we investigated acute effect of Ang II on Nav currents in the aortic baroreceptor neuron and on arterial baroreflex in sham and coronary artery ligation-induced CHF rats. Using Ang II 125I radioimmunoassay, real-time RT-PCR and western blot, we found that Ang II levels, and mRNA and protein expression of angiotension II type 1 receptor (AT1R) in nodose ganglia (NG) from CHF rats were higher than that from sham rats. Local microinjection of Ang II (0.2 nmol) into the NG decreased the arterial baroreflex sensitivity in sham rats, whereas losartan (1 nmol, an AT1R antagonist) improved the arterial baroreflex sensitivity in CHF rats. Data from patch-clamp recording showed that Ang II (100 nM) acutely inhibited Nav currents in the aortic baroreceptor neurons from sham and CHF rats. In particular, inhibitory effect of Ang II on Nav currents in the aortic baroreceptor neurons was larger in CHF rats than that in sham rats. Losartan (1 μM) totally abolished the inhibitory effect of Ang II on Nav currents in sham and CHF aortic baroreceptor neurons. These results suggest that elevation of endogenous Ang II in the NG contributes to impairment of the arterial baroreflex function in CHF rats through inhibiting Nav channels. PMID:25827427

Nocturnal snoring decreases daytime baroreceptor sensitivity.

PubMed

Schöbel, Christoph; Fietze, Ingo; Glos, Martin; Schary, Inett; Blau, Alexander; Baumann, Gert; Penzel, Thomas

2014-07-01

In patients with obstructive sleep apnea heart rate variability and baroreceptor sensitivity during night and daytime are impaired. Snoring without obstructive sleep apnea may already influence heart rate variability and baroreceptor sensitivity during daytime. Cardiovascular daytime testing was performed in 11 snorers and age, BMI, and gender matched controls. Sleep apnea and snoring were quantified by sleep recordings. Paced breathing was performed during daytime with ECG, non-invasive blood pressure, and respiration recorded. Heart rate variability and blood pressure variability were analyzed in the time and frequency domain. Baroreceptor sensitivity (alpha gain) was calculated. In snorers a significant increase in high frequency systolic blood pressure variability (SBPV-HF) compared to control group (0.37 mm Hg(2) vs. 0.11 mm Hg(2) for 12 breaths and 0.35 mm Hg(2) vs. 0.10 mm Hg(2) for 15 breaths) was demonstrated. Furthermore a lower baroreceptor sensitivity was found in snorers compared to controls (9.2 ms/mm Hg vs. 16.2 ms/mm Hg for 12 breaths and 8.5 ms/mm Hg vs. 17.4 ms/mm Hg for 15 breaths per minute) using the paced breathing protocol. Mean heart rate was elevated in snorers as well. Snorers may have a reduced parasympathetic tone during daytime rather than an increased sympathetic tone. Copyright © 2014 Elsevier Ltd. All rights reserved.

Sensing of blood pressure increase by transient receptor potential vanilloid 1 receptors on baroreceptors.

PubMed

Sun, Hao; Li, De-Pei; Chen, Shao-Rui; Hittelman, Walter N; Pan, Hui-Lin

2009-12-01

The arterial baroreceptor is critically involved in the autonomic regulation of homoeostasis. The transient receptor potential vanilloid 1 (TRPV1) receptor is expressed on both somatic and visceral sensory neurons. Here, we examined the TRPV1 innervation of baroreceptive pathways and its functional significance in the baroreflex. Resiniferatoxin (RTX), an ultrapotent analog of capsaicin, was used to ablate TRPV1-expressing afferent neurons and fibers in adult rats. Immunofluorescence labeling revealed that TRPV1 immunoreactivity was present on nerve fibers and terminals in the adventitia of the ascending aorta and aortic arch, the nodose ganglion neurons, and afferent fibers in the solitary tract of the brainstem. RTX treatment eliminated TRPV1 immunoreactivities in the aorta, nodose ganglion, and solitary tract. Renal sympathetic nerve activity, blood pressure, and heart rate were recorded in anesthetized rats. The baroreflex was triggered by lowering and raising blood pressure through intravenous infusion of sodium nitroprusside and phenylephrine, respectively. Inhibition of sympathetic nerve activity and heart rate by the phenylephrine-induced increase in blood pressure was largely impaired in RTX-treated rats. The maximum gain of the baroreflex function was significantly lower in RTX-treated than vehicle-treated rats. Furthermore, blocking of TRPV1 receptors significantly blunted the baroreflex and decreased the maximum gain of baroreflex function in the high blood pressure range. Our findings provide important new information that TRPV1 is expressed along the entire baroreceptive afferent pathway. TRPV1 receptors expressed on baroreceptive nerve endings can function as mechanoreceptors to detect the increase in blood pressure and maintain the homoeostasis.

Sensing of Blood Pressure Increase by Transient Receptor Potential Vanilloid 1 Receptors on Baroreceptors

PubMed Central

Sun, Hao; Li, De-Pei; Chen, Shao-Rui; Hittelman, Walter N.

2009-01-01

The arterial baroreceptor is critically involved in the autonomic regulation of homoeostasis. The transient receptor potential vanilloid 1 (TRPV1) receptor is expressed on both somatic and visceral sensory neurons. Here, we examined the TRPV1 innervation of baroreceptive pathways and its functional significance in the baroreflex. Resiniferatoxin (RTX), an ultrapotent analog of capsaicin, was used to ablate TRPV1-expressing afferent neurons and fibers in adult rats. Immunofluorescence labeling revealed that TRPV1 immunoreactivity was present on nerve fibers and terminals in the adventitia of the ascending aorta and aortic arch, the nodose ganglion neurons, and afferent fibers in the solitary tract of the brainstem. RTX treatment eliminated TRPV1 immunoreactivities in the aorta, nodose ganglion, and solitary tract. Renal sympathetic nerve activity, blood pressure, and heart rate were recorded in anesthetized rats. The baroreflex was triggered by lowering and raising blood pressure through intravenous infusion of sodium nitroprusside and phenylephrine, respectively. Inhibition of sympathetic nerve activity and heart rate by the phenylephrine-induced increase in blood pressure was largely impaired in RTX-treated rats. The maximum gain of the baroreflex function was significantly lower in RTX-treated than vehicle-treated rats. Furthermore, blocking of TRPV1 receptors significantly blunted the baroreflex and decreased the maximum gain of baroreflex function in the high blood pressure range. Our findings provide important new information that TRPV1 is expressed along the entire baroreceptive afferent pathway. TRPV1 receptors expressed on baroreceptive nerve endings can function as mechanoreceptors to detect the increase in blood pressure and maintain the homoeostasis. PMID:19726694

Cardiopulmonary and arterial baroreceptor unloading during passive hyperthermia does not contribute to hyperthermia-induced hyperventilation.

PubMed

Lucas, Rebekah A I; Pearson, James; Schlader, Zachary J; Crandall, Craig G

2015-11-01

What is the central question of this study? Does baroreceptor unloading during passive hyperthermia contribute to increases in ventilation and decreases in end-tidal carbon dioxide during that exposure? What is the main finding and its importance? Hyperthermic hyperventilation is not mitigated by expanding central blood volume and reloading the cardiopulmonary baroreceptors via rapid saline infusion or by reloading the arterial baroreceptors via phenylephrine administration. The absence of a reduction in ventilation upon reloading the baroreceptors to pre-hyperthermic levels indicates that cardiopulmonary and arterial baroreceptor unloading with hyperthermia is unlikely to contribute to hyperthermic hyperventilation in humans. This study tested the hypothesis that baroreceptor unloading during passive hyperthermia contributes to increases in ventilation and decreases in end-tidal partial pressure of carbon dioxide (P ET ,CO2) during that exposure. Two protocols were performed, in which healthy subjects underwent passive hyperthermia (increasing intestinal temperature by ∼1.8°C) to cause a sustained increase in ventilation and reduction in P ET ,CO2. Upon attaining hyperthermic hyperventilation, in protocol 1 (n = 10; three females) a bolus (19 ± 2 ml kg(-1) ) of warm (∼38°C) isotonic saline was rapidly (5-10 min) infused intravenously to restore reductions in central venous pressure, whereas in protocol 2 (n = 11; five females) phenylephrine was infused intravenously (60-120 μg min(-1) ) to return mean arterial pressure to normothermic levels. In protocol 1, hyperthermia increased ventilation (by 2.2 ± 1.7 l min(-1) , P < 0.01), while reducing P ET ,CO2 (by 4 ± 3 mmHg, P = 0.04) and central venous pressure (by 5 ± 1 mmHg, P <0.01). Saline infusion increased central venous pressure by 5 ± 1 mmHg (P < 0.01), restoring it to normothermic values, but did not change ventilation or P ET ,CO2 (P > 0.05). In protocol 2, hyperthermia increased ventilation (by 5.0 ± 2.7 l min(-1) , P <0.01) and reduced P ET ,CO2 (by 5 ± 2 mmHg, P < 0.01) and mean arterial pressure (by 9 ± 7 mmHg, P <0.01). Phenylephrine infusion increased mean arterial pressure by 12 ± 3 mmHg (P < 0.01), restoring it to normothermic values, but did not change ventilation or P ET ,CO2 (P > 0.05). The absence of a reduction in ventilation upon reloading the cardiopulmonary and arterial baroreceptors to pre-hyperthermic levels indicates that baroreceptor unloading with hyperthermia is unlikely to contribute to hyperthermic hyperventilation in humans. © 2015 The Authors. Experimental Physiology © 2015 The Physiological Society.

Device for rapid quantification of human carotid baroreceptor-cardiac reflex responses

NASA Technical Reports Server (NTRS)

Sprenkle, J. M.; Eckberg, D. L.; Goble, R. L.; Schelhorn, J. J.; Halliday, H. C.

1986-01-01

A new device has been designed, constructed, and evaluated to characterize the human carotid baroreceptor-cardiac reflex response relation rapidly. This system was designed for study of reflex responses of astronauts before, during, and after space travel. The system comprises a new tightly sealing silicon rubber neck chamber, a stepping motor-driven electrodeposited nickel bellows pressure system, capable of delivering sequential R-wave-triggered neck chamber pressure changes between +40 and -65 mmHg, and a microprocessor-based electronics system for control of pressure steps and analysis and display of responses. This new system provokes classic sigmoid baroreceptor-cardiac reflex responses with threshold, linear, and saturation ranges in most human volunteers during one held expiration.

Reflex limb dilatation following norepinephrine and angiotensin II in conscious dogs

NASA Technical Reports Server (NTRS)

Vatner, S. F.; Mcritchie, R. J.

1976-01-01

The extent to which norepinephrine (NE) and angiotensin II (AN) constrict the mesenteric, renal, and iliac beds in conscious dogs is evaluated with a view to elicit opposing reflex actions tempering the vasoconstriction in the limb of the animals tested. The afferent and efferent mechanisms mediating this reflex are analyzed. It is shown that intravenous NE and AN cause striking reflex iliac dilatation in the limb of the conscious dog. The afferent arc of this reflex involves both arterial baroreceptor and vagal path-ways, whereas the efferent mechanism involves an interaction of alpha-adrenergic and histaminergic receptors.

Increase in sensitivity of the baroreceptor reflex following microinjection of carbachol into the posterior hypothalamic nucleus of awake rats.

PubMed

Newey, C R; Martin, J R

2016-01-01

In a rat model, the baroreceptor reflex can be assessed by graded infusions of either phenylephrine or sodium nitroprusside with continuous hemodynamic monitoring. Microinjection of the cholinergic agonist carbachol (CCh) into the posterior hypothalamic nucleus (PHN) evokes an increase in mean arterial pressure and a change in heart rate. Lower doses of CCh evoke only tachycardia, whereas middle and higher doses evoke a biphasic change in heart rate of tachycardia followed by bradycardia. The bradycardia following the microinjection of CCh into the PHN can be attenuated by the previous administration of the vasopressin V1 receptor antagonist [d(CH2 )5 Tyr(Me)] arginine vasopressin (AVPX). Circulating arginine vasopressin (AVP) has been shown to increase the sensitivity of the baroreceptor reflex by stimulating vasopressin V1 receptors in the area postrema. The attenuation by AVPX of the bradycardia that results following the high doses of CCh suggests that AVP is released into the circulation following stimulation of cholinergic systems within the PHN. Thus, microinjection of a high dose of CCh (11 nmol) into the PHN alters the sensitivity of the baroreceptor reflex by increasing peripheral levels of AVP. © 2016 John Wiley & Sons Ltd.

Reflex effects on components of synchronized renal sympathetic nerve activity.

PubMed

DiBona, G F; Jones, S Y

1998-09-01

The effects of peripheral thermal receptor stimulation (tail in hot water, n = 8, anesthetized) and cardiac baroreceptor stimulation (volume loading, n = 8, conscious) on components of synchronized renal sympathetic nerve activity (RSNA) were examined in rats. The peak height and peak frequency of synchronized RSNA were determined. The renal sympathoexcitatory response to peripheral thermal receptor stimulation was associated with an increase in the peak height. The renal sympathoinhibitory response to cardiac baroreceptor stimulation was associated with a decrease in the peak height. Although heart rate was significantly increased with peripheral thermal receptor stimulation and significantly decreased with cardiac baroreceptor stimulation, peak frequency was unchanged. As peak height reflects the number of active fibers, reflex increases and decreases in synchronized RSNA are mediated by parallel increases and decreases in the number of active renal nerve fibers rather than changes in the centrally based rhythm or peak frequency. The increase in the number of active renal nerve fibers produced by peripheral thermal receptor stimulation reflects the engagement of a unique group of silent renal sympathetic nerve fibers with a characteristic response pattern to stimulation of arterial baroreceptors, peripheral and central chemoreceptors, and peripheral thermal receptors.

Effects of chronic baroreceptor stimulation on the autonomic cardiovascular regulation in patients with drug-resistant arterial hypertension.

PubMed

Wustmann, Kerstin; Kucera, Jan P; Scheffers, Ingrid; Mohaupt, Markus; Kroon, Abraham A; de Leeuw, Peter W; Schmidli, Jürg; Allemann, Yves; Delacrétaz, Etienne

2009-09-01

In patients with drug-resistant hypertension, chronic electric stimulation of the carotid baroreflex is an investigational therapy for blood pressure reduction. We hypothesized that changes in cardiac autonomic regulation can be demonstrated in response to chronic baroreceptor stimulation, and we analyzed the correlation with blood pressure changes. Twenty-one patients with drug-resistant hypertension were prospectively included in a substudy of the Device Based Therapy in Hypertension Trial. Heart rate variability and heart rate turbulence were analyzed using 24-hour ECG. Recordings were obtained 1 month after device implantation with the stimulator off and after 3 months of chronic electric stimulation (stimulator on). Chronic baroreceptor stimulation decreased office blood pressure from 185+/-31/109+/-24 mm Hg to 154+/-23/95+/-16 mm Hg (P<0.0001/P=0.002). Mean heart rate decreased from 81+/-11 to 76+/-10 beats per minute(-1) (P=0.001). Heart rate variability frequency-domain parameters assessed using fast Fourier transformation (FFT; ratio of low frequency:high frequency: 2.78 versus 2.24 for off versus on; P<0.001) were significantly changed during stimulation of the carotid baroreceptor, and heart rate turbulence onset was significantly decreased (turbulence onset: -0.002 versus -0.015 for off versus on; P=0.004). In conclusion, chronic baroreceptor stimulation causes sustained changes in heart rate variability and heart rate turbulence that are consistent with inhibition of sympathetic activity and increase of parasympathetic activity in patients with drug-resistant systemic hypertension; these changes correlate with blood pressure reduction. Whether the autonomic modulation has favorable cardiovascular effects beyond blood pressure control should be investigated in further studies.

Verapamil protective effect on natural and artificial magnetic field cardiovascular impact.

PubMed

Gmitrov, Juraj; Ohkubo, Chiyoji

2002-10-01

Previously we found an opposite effect of artificial static magnetic field (SMF) and natural geomagnetic field (GMF) on arterial baroreceptors. A 0.35 T SMF increased baroreflex sensitivity (BRS), whereas GMF disturbance decreased BRS. Here, we investigated interrelated impacts on arterial baroreceptors of 0.35 T SMF, generated by Nd(2)-Fe(14)-B alloy magnets, GMF, and verapamil, a Ca(2+) channel blocking agent. We measured BRS in rabbits before and after local SMF exposure of sinocarotid baroreceptors or after simultaneous SMF and verapamil application, in conjunction with geomagnetic disturbance during actual experimental run (determined by K-index) and geomagnetic disturbance over the preceding 24 h of each experiment (A(k)-index). BRS was estimated from peak responses of mean arterial pressure (MAP) and heart rate, expressed as percentages of the resting values preceding each pair of pressure (phenylephrine) and depressor drug (nitroprusside) injections. Prior to verapamil and/or SMF application we found a significant positive correlation of K-index with MAP (t = 2.39, P =.021, n = 44), but negative with BRS (t = -4.60, P =.0003, n = 44), and found a negative correlation of A(k)-index with BRS (t = -2.7, P = 0.01, n = 44). SMF induced an increase in BRS (0.79 +/- 0.1 vs. 1.15 +/- 0.1 bpm%/mmHg%, initial value vs. SMF exposure, P <.0002, n = 26). Verapamil infusion blocked the SMF and GMF effect on BRS, indicating Ca(2+) channels as a possible site of both fields' impact. SMF and GMF probably affect baroreceptor sensory transduction, modulating baroreceptor membranes' Ca(2+) channel permeability. Copyright 2002 Wiley-Liss, Inc.

Systemic arterial baroreceptors in ducks and the consequences of their denervation on some cardiovascular responses to diving

PubMed Central

Jones, D. R.

1973-01-01

1. In the duck systemic arterial baroreceptors which cause bradycardia in response to induced hypertension are located in the walls of the ascending aorta, innervated by the depressor nerves. 2. The location of the baroreceptors was confirmed both histologically and by recording activity from the depressor nerve. Stimulation of the central cut end of a depressor nerve caused transient bradycardia and a fall in blood pressure which was maintained throughout the period of stimulation. 3. Cardiovascular adjustments to submergence of 2 min duration were monitored in intact, sham-operated and denervated ducks. The sham-operated and denervated ducks were used in the experiments some 20-50 days post-operation. The denervations were checked at post-mortem. 4. In the first series of experiments on young ducks mean arterial pressure during a 2 min dive fell by 30% in intact, 17·5% in sham-operated, and 48% in denervated ducks. In all ducks heart rate was reduced by 84-85%. 5. In a second series of experiments on older ducks sciatic artery blood flow was also recorded and mean arterial blood pressure fell by 9·2% in intact and by 53% in denervated animals, although there were no significant differences in heart rate during the 2 min dives. In normal animals sciatic vascular resistance increased after 2 min submergence by 7·86 ± 1·7 times, whereas in denervated ducks it increased by only 2·32 ± 0·5 times. 6. The role of systemic arterial baroreceptors in generation of the cardiovascular responses to submergence in ducks is discussed in terms of the input supplied by the baroreceptors to the central nervous system. ImagesPlate 1 PMID:4764429

Substance P immunoreactive nerve terminals in the dorsolateral nucleus of the tractus solitarius: roles in the baroreceptor reflex.

PubMed

Massari, V J; Shirahata, M; Johnson, T A; Lauenstein, J M; Gatti, P J

1998-03-02

Physiological and light microscopic evidence suggest that substance P (SP) may be a neurotransmitter contained in first-order sensory baroreceptor afferents; however, ultrastructural support for this hypothesis is lacking. We have traced the central projections of the carotid sinus nerve (CSN) in the cat by utilizing the transganglionic transport of horseradish peroxidase (HRP). The dorsolateral subnucleus of the nucleus tractus solitarius (dlNTS) was processed for the histochemical visualization of transganglionically labeled CSN afferents and for the immunocytochemical visualization of SP by dual labeling light and electron microscopic methods. Either HRP or SP was readily identified in single-labeled unmyelinated axons, myelinated axons, and nerve terminals in the dlNTS. SP immunoreactivity was also identified in unmyelinated axons, myelinated axons, and nerve terminals in the dlNTS, which were simultaneously identified as CSN primary afferents. However, only 15% of CSN terminals in the dlNTS were immunoreactive for SP. Therefore, while the ultrastructural data support the hypothesis that SP immunoreactive first-order neurons are involved in the origination of the baroreceptor reflex, they suggest that only a modest part of the total sensory input conveyed from the carotid sinus baroreceptors to the dlNTS is mediated by SP immunoreactive CSN terminals. Five types of axo-axonic synapses were observed in the dlNTS. SP immunoreactive CSN afferents were very rarely involved in these synapses. Furthermore, SP terminals were never observed to form the presynaptic element in an axo-axonic synapse with a CSN afferent. Therefore, SP does not appear to be involved in the modulation of the baroreceptor reflex in the dlNTS. Copyright 1998 Elsevier Science B.V.

Influence of central venous pressure upon sinus node responses to arterial baroreflex stimulation in man

NASA Technical Reports Server (NTRS)

Mark, A. L.; Takeshita, A.; Eckberg, D. L.; Abboud, F. M.

1978-01-01

Measurements were made of sinus node responses to arterial baroreceptor stimulation with phenylephrine injection or neck suction, before and during changes of central venous pressure provoked by lower body negative pressure or leg and lower truck elevation. Variations of central venous pressure between 1.1 and 9.0 mm Hg did not influence arterial baroreflex mediated bradycardia. Baroreflex sinus node responses were augmented by intravenous propranolol, but the level of responses after propranolol was comparable during the control state, lower body negative pressure, and leg and trunk elevation. Sinus node responses to very brief baroreceptor stimuli applied during the transitions of central venous pressure also were comparable in the three states. The authors conclude that physiological variations of central venous pressure do not influence sinus node responses to arterial baroreceptor stimulation in man.

Effects of horizontal body casting on the baroreceptor reflex control of heart rate

NASA Technical Reports Server (NTRS)

Billman, G. E.; Dickey, D. T.; Sandler, H.; Stone, H. L.

1982-01-01

The purpose of this study was to investigate the effects of long-term horizontal body position on baroreceptor reflex control of heart rate. Six male rhesus monkeys (6.2-9.4 kg) were given bolus injections of 4.0 microgram/kg, phenylephrine during each of the following conditions: awake, anesthetized (10 mg/kg ketamine HCl), and after beta-blockade (1 mg/kg propranolol HCl) before, 7, 14, and 28 days after being placed in a horizontal body cast. R-R interval vs. systolic arterial pressure was plotted, and the slope was determined by least-squares-fit linear regression. Baroreceptor slope was significantly reduced by 7 days of horizontal body position and remained attenuated throughout the 28-day restraint period both before and after beta-receptor blockade. These data are consistent with the thesis that prolonged exposure to a zero-gravity environment impairs autonomic reflex regulation of the cardiovascular system.

Effects of Repeated Valsalva Maneuver Straining on Cardiac and Vasoconstrictive Baroreflex Responses

DTIC Science & Technology

2003-03-01

of blood pressure regulation that differ in men repeatedly exposed to high G acceleration. Am J Physiol Regul Integr Comp Physiol 2001; 280:R947–58. 10...Methods: We tested this hypothesis by measuring cardiac baroreflex responses to carotid baroreceptor stimulation (neck pressures ), and changes in heart rate...hypothesis is the observation that elevated pulse pressures in isolated carotid sinuses of dogs sen- sitized baroreceptor afferent firing (4,5). Elevated arte

Effect of baroreceptor denervation on the autonomic control of arterial pressure in conscious mice.

PubMed

Rodrigues, Fernanda Luciano; de Oliveira, Mauro; Salgado, Helio Cesar; Fazan, Rubens

2011-09-01

This study evaluated the role of arterial baroreceptors in arterial pressure (AP) and pulse interval (PI) regulation in conscious C57BL mice. Male animals, implanted with catheters in a femoral artery and a jugular vein, were submitted to sino-aortic (SAD), aortic (Ao-X) or carotid sinus denervation (Ca-X), 5 days prior to the experiments. After basal recording of AP, the lack of reflex bradycardia elicited by administration of phenylephrine was used to confirm the efficacy of SAD, and cardiac autonomic blockade with methylatropine and propranolol was performed. The AP and PI variability were calculated in the time and frequency domains (spectral analysis/fast Fourier transform) with the spectra quantified in low- (LF; 0.25-1 Hz) and high-frequency bands (HF; 1-5 Hz). Basal AP and AP variability were higher after SAD, Ao-X or Ca-X than in intact mice. Pulse interval was similar among the groups, whereas PI variability was lower after SAD. Atropine elicited a slight tachycardia in control mice but did not change PI after total or partial denervation. The bradycardia caused by propranolol was higher after SAD, Ao-X or Ca-X compared with intact mice. The increase in the variability of AP was accompanied by a marked increase in the LF and HF power of the AP spectra after baroreceptor denervation. The LF and HF power of the PI were reduced by SAD and by Ao-X or Ca-X. Therefore, both sino-aortic and partial baroreceptor denervation in mice elicits hypertension and a remarkable increase in AP variability and cardiac sympathetic tonus. Spectral analysis showed an important contribution of the baroreflex in the power of LF oscillations of the PI spectra. Both sets of baroreceptors seem to be equally important in the autonomic regulation of the cardiovascular system in mice.

Phase dependencies of the human baroreceptor reflex

NASA Technical Reports Server (NTRS)

Seidel, H.; Herzel, H.; Eckberg, D. L.

1997-01-01

We studied the influence of respiratory and cardiac phase on responses of the cardiac pacemaker to brief (0.35-s) increases of carotid baroreceptor afferent traffic provoked by neck suction in seven healthy young adult subjects. Cardiac responses to neck suction were measured indirectly from electrocardiographic changes of heart period. Our results show that it is possible to separate the influences of respiratory and cardiac phases at the onset of a neck suction impulse by a product of two factors: one depending only on the respiratory phase and one depending only on the cardiac phase. This result is consistent with the hypothesis that efferent vagal activity is a function of afferent baroreceptor activity, whereas respiratory neurons modulate that medullary throughput independent of the cardiac phase. Furthermore, we have shown that stimulus broadening and stimulus cropping influence the outcome of neck suction experiments in a way that makes it virtually impossible to obtain information on the phase dependency of the cardiac pacemaker's sensitivity to vagal stimulation without accurate knowledge of the functional shape of stimulus broadening.

Spaceflight alters autonomic regulation of arterial pressure in humans

NASA Technical Reports Server (NTRS)

Fritsch-Yelle, Janice M.; Charles, John B.; Jones, Michele M.; Beightol, Larry A.; Eckberg, Dwain L.

1994-01-01

Spaceflight is associated with decreased orthostatic tolerance after landing. Short-duration spaceflight (4 - 5 days) impairs one neutral mechanism: the carotid baroreceptor-cardiac reflex. To understand the effects of longer-duration spaceflight on baroreflex function, we measured R-R interval power spectra, antecubital vein plasma catecholamine levels, carotid baroreceptor-cardiac reflex responses, responses to Valsalva maneuvers, and orthostatic tolerance in 16 astronauts before and after shuttle missions lasting 8 - 14 days. We found the following changes between preflight and landing day: (1) orthostatic tolerance decreased; (2) R-R interval spectral power in the 0.05- to 0.15-Hz band increased; (3) plasma norepinephrine and epinephrine levels increased; (4) the slope, range, and operational point of the carotid baroreceptor cardiac reflex response decreased; and (5) blood pressure and heart rate responses to Valsalva maneuvers were altered. Autonomic changes persisted for several days after landing. These results provide further evidence of functionally relevent reductions in parasympathetic and increases in sympathetic influences on arterial pressure control after spaceflight.

Influence of neonatally administered capsaicin on baroreceptor and chemoreceptor reflexes in the adult rat.

PubMed Central

Bond, S. M.; Cervero, F.; McQueen, D. S.

1982-01-01

1 Baroreceptor and chemoreceptor reflex activity was studied in anaesthetized adult rats which had been treated neonatally with a single injection of capsaicin (50 mg/kg s.c.). 2 Pressor responses to bilateral carotid artery occlusion were significantly lower in capsaicin-treated rats compared with vehicle-treated controls. Pressor responses to intravenously injected noradrenaline were similar in the two groups of rats. 3 Resting respiratory minute volume and tidal volume were lower in anaesthetized capsaicin-treated animals than in vehicle-treated controls, but there was no significant difference in respiratory frequency. 4 The increases in respiration evoked by intravenous administration of the peripheral arterial chemoreceptor stimulant, sodium cyanide, or by breathing a hypoxic gas mixture, were significantly lower in capsaicin-treated rats compared with the controls. 5 It is concluded that baroreceptor and chemoreceptor reflex activity are significantly reduced in anaesthetized adult rats which had been treated neonatally with capsaicin, and that this is likely to result from the destruction of unmyelinated baro- and chemoreceptor afferent fibres. PMID:6182938

``Smart'' baroreception along the aortic arch, with reference to essential hypertension

NASA Astrophysics Data System (ADS)

Kember, G. C.; Zamir, M.; Armour, J. A.

2004-11-01

Beat-to-beat regulation of heart rate is dependent upon sensing of local stretching or local “disortion” by aortic baroreceptors. Distortions of the aortic wall are due mainly to left ventricular output and to reflected waves arising from the arterial tree. Distortions are generally believed to be useful in cardiac control since stretch receptors or aortic baroreceptors embedded in the adventitia of the aortic wall, transduce the distortions to cardiovascular neural reflex pathways responsible for beat-to-beat regulation of heart rate. Aortic neuroanatomy studies have also found a continuous strip of mechanosensory neurites spread along the aortic inner arch. Although their purpose is now unknown, such a combined sensing capacity would allow measurement of the space and time dependence of inner arch wall distortions due, among other things, to traveling waves associated with pulsatile flow in an elastic tube. We call this sensing capability-“smart baroreception.” In this paper we use an arterial tree model to show that the cumulative effects of wave reflections, from many sites far downstream, have a surprisingly pronounced effect on the pressure distribution in the root segment of the tree. By this mechanism global hemodynamics can be focused by wave reflections back to the aortic arch, where they can rapidly impact cardiac control via smart baroreception. Such sensing is likely important to maintain efficient heart function. However, alterations in the arterial tree due to aging and other natural processes can lead in such a system to altered cardiac control and essential hypertension.

Short-term Exposure to Microgravity and the Associated Risk of Sudden Cardiac Arrest: Implications for Commercial Spaceflight

NASA Astrophysics Data System (ADS)

Laing, Kevin J. C.; Russamono, Thais

2013-02-01

The likelihood of trained astronauts developing a life threatening cardiac event during spaceflight is relatively rare, whilst the incidence in untrained individuals is unknown. Space tourists who live a sedentary lifestyle have reduced cardiovascular function, but the associated danger of sudden cardiac arrest (SCA) during a suborbital spaceflight (SOSF) is unclear. Risk during SOSF was examined by reviewing several microgravity studies and methods of determining poor cardiovascular condition. Accurately assessing cardiovascular function and improving baroreceptor sensitivity through exercise is suggested to reduce the incidence of SCA during future SOSFs. Future studies will benefit from past participants sharing medical history; allowing creation of risk profiles and suitable guidelines.

Stress--the battle for hearts and minds: links between depression, stress and ischemic heart disease.

PubMed

Korszun, Ania; Frenneaux, Michael P

2006-09-01

Depression and ischemic heart disease (IHD) are strongly related common disorders. Depression itself is an independent cardiac risk factor and is associated with a two- to threefold increase in IHD mortality. Attention has now shifted to identifying the common underlying mechanisms that could make individuals susceptible to both disorders. Abnormalities that have been implicated in this relationship include abnormal platelet activation, decreased baroreceptor sensitivity and endothelial dysfunction. Depression and IHD both have a high association with environmental stress, and depression is characterized by abnormalities of the stress-hormone axis. This review provides a brief overview of some recent developments in our understanding of the pathophysiological links between stress, depression and IHD.

Mechanisms of tubular sodium chloride transport.

PubMed

Venkatesh, S; Schrier, R W; Andreoli, T E

1998-11-01

Extracellular fluid volume is determined by sodium and its accompanying anions. There are control mechanisms which regulate sodium balance in the body. These include high and low pressure baroreceptors, intrarenal baroreceptors, renal autoregulation, tubuloglomerular feedback, aldosterone, and numerous other physical and hormonal factors. Sodium transport by the nephron involves active and passive processes which occur in several different nephron segments. Mechanisms of cotransport, Na(+)-H+ exchange, antiporters and ion-specific channels are all utilized by the nephron to maintain sodium balance. These regulatory factors and transport mechanisms for sodium in the kidney will he discussed in detail.

Rapid resetting of rabbit aortic baroreceptors and reflex heart rate responses by directional changes in blood pressure.

PubMed

Burke, S L; Dorward, P K; Korner, P I

1986-09-01

In both anaesthetized and conscious rabbits, perivascular balloon inflations slowly raised or lowered mean arterial pressure (M.A.P.), at 1-2 mmHg/s, from resting to various plateau pressures. Deflations then returned the M.A.P. to resting. 'Steady-state' curves relating M.A.P. to unitary aortic baroreceptor firing, integrated aortic nerve activity and heart rate were derived during the primary and return pressure changes and they formed typical hysteresis loops. In single units, return M.A.P.-frequency curves were shifted in the same direction as the primary pressure changes by an average 0.37 mmHg per mmHg change in M.A.P. Shifts were linearly related to the changes in M.A.P. between resting and plateau levels for all pressure rises and for falls less than 30 mmHg. They were established within 30 s and were quantitatively similar to the rapid resetting of baroreceptor function curves found 15 min-2 h after a change in resting M.A.P. (Dorward, Andresen, Burke, Oliver & Korner, 1982). Unit threshold pressures were shifted within 20 s to the same extent as the over-all curve shift to which they contributed. In the whole aortic nerve, return M.A.P.-integrated activity curves were shifted to same degree as unit function curves in both anaesthetized and conscious rabbits. Simultaneous shifts of return reflex M.A.P.-heart rate curves were also seen in conscious rabbits within 30 s. During M.A.P. falls, receptor and reflex hysteresis was similar, but during M.A.P. rises, reflex shifts were double baroreceptor shifts, suggesting the involvement of other pressure-sensitive receptors. We conclude that hysteresis shifts in baroreceptor function curves, which follow the reversal of slow ramp changes in blood pressure are a form of rapid resetting. They are accompanied by rapid resetting of reflex heart rate responses. We regard this as an important mechanism in blood pressure control which produces relatively high-gain reflex responses, during slow directional pressure changes, over a wider range of absolute pressure levels than would otherwise be possible.

Dynamic interactions between arterial pressure and sympathetic nerve activity: role of arterial baroreceptors.

PubMed

Julien, Claude; Chapuis, Bruno; Cheng, Yong; Barrès, Christian

2003-10-01

The role of arterial baroreceptors in controlling arterial pressure (AP) variability through changes in sympathetic nerve activity was examined in conscious rats. AP and renal sympathetic nerve activity (RSNA) were measured continuously during 1-h periods in freely behaving rats that had been subjected to sinoaortic baroreceptor denervation (SAD) or a sham operation 2 wk before study (n = 10 in each group). Fast Fourier transform analysis revealed that chronic SAD did not alter high-frequency (0.75-5 Hz) respiratory-related oscillations of mean AP (MAP) and RSNA, decreased by approximately 50% spectral power of both variables in the midfrequency band (MF, 0.27-0.74 Hz) containing the so-called Mayer waves, and induced an eightfold increase in MAP power without altering RSNA power in the low-frequency band (0.005-0.27 Hz). In both groups of rats, coherence between RSNA and MAP was maximal in the MF band and was usually weak at lower frequencies. In SAD rats, the transfer function from RSNA to MAP showed the characteristics of a second-order low-pass filter containing a fixed time delay ( approximately 0.5 s). These results indicate that arterial baroreceptors are not involved in production of respiratory-related oscillations of RSNA but play a major role in the genesis of synchronous oscillations of MAP and RSNA at the frequency of Mayer waves. The weak coupling between slow fluctuations of RSNA and MAP in sham-operated and SAD rats points to the interference of noise sources unrelated to RSNA affecting MAP and of noise sources unrelated to MAP affecting RSNA.

Effects of chronic lesions of the anteroventral third ventricle region on baroreceptor reflex function in conscious rats

NASA Technical Reports Server (NTRS)

Lewis, S. J.; Whalen, E. J.; Beltz, T. G.; Johnson, A. K.

1999-01-01

This study determined baroreceptor reflex (BR) function in conscious rats which had received sham or electrolytic lesions of the anteroventral third ventricle (AV3V) 54-56 days previously. Resting mean arterial pressure (MAP) and heart rate (HR) values of the AV3V-lesion rats were similar to those of sham-lesion rats (P>0.05 for both comparisons). The sensitivity of the BR-mediated tachycardia in AV3V-lesion was greater than in sham-lesion rats (-9. 92+/-1.00 vs. -4.54+/-0.45 bpm/mmHg, P<0.05). The sensitivity of the BR-mediated bradycardia in AV3V-lesion rats was also greater than in rats with sham lesions (-3.56+/-0.38 vs. -2.06+/-0.42 bpm/mmHg, P<0. 05). The AV3V lesions did not affect other BR parameters. These findings demonstrate that chronic lesions of the AV3V region increase the sensitivity of the baroreceptor HR reflex in conscious rats. Copyright 1999 Published by Elsevier Science B.V.

Carotid baroreflex response following 30 days exposure to simulated microgravity

NASA Technical Reports Server (NTRS)

Convertino, V. A.; Doerr, D. F.; Eckberg, D. L.; Fritsch, J. M.; Vernikos-Danellis, J.

1989-01-01

The mechanism of the carotid-baroreflex response to weightlessness was investigated in human subjects exposed to simulated microgravity (30 days of 6-day head-down bed rest followed by 5 days of recovery). Baroreceptor-cardiac reflex responses were elicited by a complex sequence of pressure changes delivered to a neck chamber device. The shape of the sigmoid baroreceptor-cardiac response curve was examined for alterations and the occurrence of resetting, as well as for a possible association of the impaired baroreflex function with hypotension during the postexposure orthostatic stress. It was found that the exposure to head-down bed rest caused a significant shift on the R-R interval axis, which paralleled reductions and elevations in baseline HR such that the baseline R-R (operational point) remained in the same position on the response curve. This shift in the location of the reflex relation indicates a significant resetting of the carotid baroreceptors, which may represent an appropriate adaptation which contributes to the maintenance of a constant resting arterial blood pressure before, during, and after bed rest, observed in these study.

Mechanism of smart baroreception in the aortic arch

NASA Astrophysics Data System (ADS)

Kember, G. C.; Armour, J. A.; Zamir, M.

2006-09-01

A mechanism is proposed by which the patch of baroreceptors along the inner curvature of the arch of the aorta can sense hemodynamic events occurring downstream from the aortic arch, in the periphery of the arterial tree. Based on a solution of equations governing the elastic movements of the aortic wall, it is shown that the pressure distribution along the patch of baroreceptors has the same functional form as the distribution of strain along the patch. The significance of these findings are discussed, particularly as they relate to the possibility of a neuromechanical basis of essential hypertension.

Cardiovascular function in space flight

NASA Technical Reports Server (NTRS)

Nicogossian, A. E.; Charles, J. B.; Bungo, M. W.; Leach-Huntoon, C. S.

1990-01-01

Postflight orthostatic intolerance and cardiac hemodynamics associated with manned space flight have been investigated on seven STS missions. Orthostatic heart rates appear to be influenced by the mission duration. The rates increase during the first 7-10 days of flight and recover partially after that. Fluid loading is used as a countermeasure to the postflight orthostatic intolerance. The carotid baroreceptor function shows only slight responsiveness to orthostatic stimulation. Plots of the baroreceptor function are presented. It is concluded that an early adaptation to the space flight conditions involves a fluid shift and that the subsequent alterations in the neutral controlling mechanisms contribute to the orthoststic intolerance.

[Studies on the role of high pressure baroreceptors in vasopressin (ADH) secretion. Effect of occlusion of common carotid and vertebral arteries on blood ADH level (author's transl)].

PubMed

Matsuzaki, M

1977-08-20

The role of baroreceptors in common carotid and vertebral arteries and arteries in the thoracic cavity in vasopressin secretion was investigated in this study. Effects of bilateral occlusion of common carotid and vertebral arteries on blood ADH level as well as mean arterial pressure were studied in common carotid arterial plexus-denervated dogs, cervically vagotomized dogs and intact dogs. Blood ADH titers were determined by bioassay technic before and 5 minutes after the occlusion of the arteries and were compared with the changes of mean arterial pressure (MAP). The following results were obtained. (1) Blood ADH titers and MAP were elevated by the occlusion of the common carotid arteries in both intact and vagotomized dogs, while they were not significantly affected in denervated dogs. Elevation of blood ADH titers was more pronounced in vagotomized dogs than in intact dogs. (2) Blood ADH titers and MAP were elevated by the occlusion of vertebral arteries in all groups of dogs. However, the elevation of blood ADH titers in denervated dogs was more pronounced than in intact dogs, but less than in vagotomized dogs. (3) The effects of the occlusion of common carotid arteries on blood ADH titers and MPA were more pronounced than those of the occlusion of vertebral arteries. These results may suggest that: a. baroreceptors involved in vasopressin secretion are present in vertebral arteries as well, and that b. the intrathoracic baroreceptors are dominant in controlling vasopressin secretion, while those in common carotid arteries are secondly and those in vertebral arteries thirdly dominant.

Evidence against high pressure, arterial baroreceptors in the abdominal viscera of cats.

PubMed

Martin, S E; Longhurst, J C

1986-12-01

The abdominal viscera of cats have been postulated to contain a site of cardiovascular regulation. In particular, a baroreceptive function has been ascribed to splanchnic afferent nerves. We wished to determine whether afferents with a cardiac-rhythmic discharge functioned as arterial baroreceptors. Nineteen afferents with a cardiac rhythmic discharge were studied. All afferents were A fibers, whose endings were located in either the pancreas, mesentery, or porta hepatis region. We examined their characteristics of discharge with regard to changes in mean pressure, pulse pressure, and dP/dt of the arterial pulse. Hemodynamic alterations were achieved by intravenous administration of isoproterenol, norepinephrine, or phenylephrine and by occlusion of the descending thoracic aorta. After isoproterenol, increases in nerve activity occurred when pulse pressure and dP/dt were increased but while mean pressure was decreasing, indicating that mean pressure was not the stimulus for discharge of these afferents. Additionally, under similar hemodynamic conditions, afferents did not demonstrate reproducible patterns of activity. The afferents generally discharged with one impulse per cardiac cycle, rarely with two to three impulses per cycle. None demonstrated a bursting pattern even when arterial blood pressure was quite elevated. The spontaneous pattern of discharge changed frequently, often after the viscera were repositioned, and sometimes remained even after complete occlusion of the aorta. The data indicate that these visceral afferents do not respond as high pressure, arterial baroreceptors. All afferents adapted extremely rapidly and exhibited a low gain (0.02 +/- 0.00 impulses X s-1 X mmHg-1), indicating that these fibers would be ineffective in signaling physiologically significant changes in hemodynamic variables. The data from this study do not support the existence of baroreceptors in the abdominal viscera of cats.

Acute baroreflex resetting: differential control of pressure and nerve activity.

PubMed

Drummond, H A; Seagard, J L

1996-03-01

This study evaluated acute resetting of carotid baroreflex control of arterial blood pressure and renal or thoracic sympathetic nerve activity in thiopental-anesthetized mongrel dogs with the use of a vascularly isolated carotid sinus preparation, the experimental model used previously to characterize acute resetting in carotid baroreceptor afferent fibers. Carotid baroreceptors were conditioned with a pulsatile pressure for 20 minutes at three pressure ranges: low (50 to 75 mm Hg), mid (100 to 125), or high (150 to 175). Blood pressure and nerve activity were recorded in response to slow ramp increases in sinus pressure; nonlinear regression and best-fit analyses were used for determination of curve fit parameters of the blood pressure and nerve activity versus sinus pressure response curves. Carotid sinus pressure thresholds for blood pressure and renal nerve activity responses at all conditioning pressures were significantly different; however, only the pressure threshold for thoracic nerve activity at the low conditioning pressure was significantly different from the responses at other conditioning pressures. Average renal activity resetting (0.506 +/- 0.072) was significantly greater than blood pressure resetting (0.335 +/- 0.046) in the same dogs, and thoracic activity (0.200 +/- 0.057) was not different from blood pressure resetting (0.194 +/- 0.031) in the same dogs. In a previous investigation, our laboratory had demonstrated that type 1 carotid baroreceptors acutely reset at a value of about 0.15. These results indicate that (1) renal and thoracic nerve activities and blood pressure acutely reset to a greater degree than type 1 carotid baroreceptors and that (2) renal activity acutely resets to a greater degree than blood pressure and thoracic nerve activity.

Impact of cardiac hypertrophy on arterial and cardiopulmonary baroreflex control of renal sympathetic nerve activity in anaesthetized rats.

PubMed

Flanagan, Evelyn T; Buckley, Maria M; Aherne, Claire M; Lainis, Fredolin; Sattar, Munavvar; Johns, Edward J

2008-09-01

This study aimed to quantify the effect of cardiac hypertrophy induced with isoprenaline and caffeine on reflex regulation of renal sympathetic nerve activity by the arterial and cardiopulmonary baroreceptors. Male Wistar rats, untreated or given water containing caffeine and subcutaneous (s.c.) isoprenaline every 72 h for 2 weeks or thyroxine s.c. for 7 days, were anaesthetized and prepared for measurement of renal sympathetic nerve activity or cardiac indices. Both isoprenaline-caffeine and thyroxine treatment blunted weight gain but increased heart weight and heart weight to body weight ratio by 40 and 14% (both P<0.01), respectively. In the isoprenaline-caffeine group, the maximal rate of change of left ventricular pressure and the contractility index were higher by 17 and 14% (both P<0.01), respectively, compared with untreated rats. In the isoprenaline-caffeine-treated rats, baroreflex gain curve sensitivity was depressed by approximately 30% (P<0/05), while the mid-point blood pressure was lower, by 15% (P<0/05), and the range of the curve was 60% (P<0.05) greater than in the untreated rats. An acute intravenous infusion of a saline load decreased renal sympathetic nerve activity by 42% (P<0.05) in the untreated rats but had no effect in the isoprenaline-caffeine- or the thyroxine-treated groups. The isoprenaline-caffeine treatment induced cardiac hypertrophy with raised cardiac performance and an associated depression in the reflex regulation of renal sympathetic nerve activity by both high- and low-pressure baroreceptors. The thyroxine-induced cardiac hypertrophy also blunted the low-pressure baroreceptor-mediated renal sympatho-inhibition. These findings demonstrate that in cardiac hypertrophy without impaired cardiac function, there is a blunted baroreceptor control of renal sympathetic outflow.

Cardiovascular function in space flight

NASA Astrophysics Data System (ADS)

Nicgossian, A. E.; Charles, J. B.; Bungo, M. W.; Leach-Huntoon, C. S.

Changes in orthostatic heart rate have been noted universally in Soviet and U.S. crewmembers post space flight. The magnitude of these changes appears to be influenced by mission duration, with increasing orthostatic intolerance for the first 7-10 days of flight and then a partial recovery in the orthostatic heart rate response. Fluid loading has been used as a countermeasure to this postflight orthostatic intolerance. Previous reports have documented the effectiveness of this technique, but it has also been noted that the effectiveness of volume expansion diminishes as flight duration exceeds one week. The response of carotid baroreceptor function was investigated utilizing a commercially available neck collar which could apply positive and negative pressure to effect receptor stimulation. Bedrest studies had validated the usefulness and validity of the device. In these studies it was shown that carotid baroreceptor function curves demonstrated less responsiveness to orthostatic stimulation than control individuals. Twelve Space Shuttle crewmembers were examined pre- and postflight from flights lasting from 4-5 days. Plots of baroreceptor function were constructed and plotted as change in R-R interval vs. carotid distending pressure (an orthostatic stimulus). Typical sigmoidal curves were obtained. Postflight the resting heart rate was higher (smaller R-R interval) and the range of R-R value and the slope of the carotid sigmoidal response were both depressed. These changes were not significant immediately postflight (L+O), but did become significant by the second day postflight (L+2), and remained suppressed for several days thereafter. It is hypothesized that the early adaptation to space flight involves a central fluid shift during the initial days of flight, but subsequent alterations in neural controlling mechanisms (such as carotid baroreceptor function) contribute to orthostatic intolerance.

Cardiovascular function in space flight

NASA Technical Reports Server (NTRS)

Nicogossian, A. E.; Charles, J. B.; Bungo, M. W.; Leach-Huntoon, C. S.; Nicgossian, A. E.

1991-01-01

Changes in orthostatic heart rate have been noted universally in Soviet and U.S. crewmembers post space flight. The magnitude of these changes appears to be influenced by mission duration, with increasing orthostatic intolerance for the first 7-10 days of flight and then a partial recovery in the orthostatic heart rate response. Fluid loading has been used as a countermeasure to this postflight orthostatic intolerance. Previous reports have documented the effectiveness of this technique, but it has also been noted that the effectiveness of volume expansion diminishes as flight duration exceeds one week. The response of carotid baroreceptor function was investigated utilizing a commercially available neck collar which could apply positive and negative pressure to effect receptor stimulation. Bedrest studies had validated the usefulness and validity of the device. In these studies it was shown that carotid baroreceptor function curves demonstrated less responsiveness to orthostatic stimulation than control individuals. Twelve Space Shuttle crewmembers were examined pre- and postflight from flights lasting from 4-5 days. Plots of baroreceptor function were constructed and plotted as change in R-R interval vs. carotid distending pressure (an orthostatic stimulus). Typical sigmoidal curves were obtained. Postflight the resting heart rate was higher (smaller R-R interval) and the range of R-R value and the slope of the carotid sigmoidal response were both depressed. These changes were not significant immediately postflight (L + O), but did become significant by the second day postflight (L + 2), and remained suppressed for several days thereafter. It is hypothesized that the early adaptation to space flight involves a central fluid shift during the initial days of flight, but subsequent alterations in neural controlling mechanisms (such as carotid baroreceptor function) contribute to orthostatic intolerance.

Estimation of arterial baroreflex sensitivity in relation to carotid artery stiffness.

PubMed

Lipponen, Jukka A; Tarvainen, Mika P; Laitinen, Tomi; Karjalainen, Pasi A; Vanninen, Joonas; Koponen, Timo; Lyyra-Laitinen, Tiina

2012-01-01

Arterial baroreflex has a significant role in regulating blood pressure. It is known that increased stiffness of the carotid sinus affects mecanotransduction of baroreceptors and therefore limits baroreceptors capability to detect changes in blood pressure. By using high resolution ultrasound video signal and continuous measurement of electrocardiogram (ECG) and blood pressure, it is possible to define elastic properties of artery simultaneously with baroreflex sensitivity parameters. In this paper dataset which consist 38 subjects, 11 diabetics and 27 healthy controls was analyzed. Use of diabetic and healthy test subjects gives wide scale of arteries with different elasticity properties, which provide opportunity to validate baroreflex and artery stiffness estimation methods.

Altered baroreflex control of forearm vascular resistance during simulated microgravity

NASA Technical Reports Server (NTRS)

Convertino, V. A.; Doerr, D. F.; Vernikos, J.

1994-01-01

Reflex peripheral vasoconstriction induced by activation of cardiopulmonary baroreceptors in response to reduced central venous pressure (CVP) is a basic mechanism for elevating systemic vascular resistance and defending arterial blood pressure during orthostatically-induced reductions in cardiac filling and output. The sensitivity of the cardiopulmonary baroreflex response [defined as the slope of the relationship between changes in forearm vascular resistance (FVR) and CVP] and the resultant vasoconstriction are closely and inversely associated with the amount of circulating blood volume. Thus, a high-gain FVR response will be elicited by a hypovolemic state. Exposure to microgravity during spaceflight results in reduced plasma volume. It is therefore reasonable to expect that the FVR response to cardiopulmonary baroreceptor unloading would be accentuated following adaptation to microgravity. Such data could provide better insight about the physiological mechanisms underlying alterations in blood pressure control following spaceflight. We therefore exposed eleven men to 6 degrees head-down bedrest for 7 days and measured specific hemodynamic responses to low levels of the lower body negative pressure to determine if there are alterations in cardiopulmonary baroreceptor stimulus-FVR reflex response relationship during prolonged exposure to an analog of microgravity.

Overexpression of oxytocin receptors in the hypothalamic PVN increases baroreceptor reflex sensitivity and buffers BP variability in conscious rats

PubMed Central

Lozić, Maja; Greenwood, Michael; Šarenac, Olivera; Martin, Andrew; Hindmarch, Charles; Tasić, Tatjana; Paton, Julian; Murphy, David; Japundžić-Žigon, Nina

2014-01-01

Background and Purpose The paraventricular nucleus (PVN) of the hypothalamus is an important integrative site for neuroendocrine control of the circulation. We investigated the role of oxytocin receptors (OT receptors) in PVN in cardiovascular homeostasis. Experimental Approach Experiments were performed in conscious male Wistar rats equipped with a radiotelemetric device. The PVN was unilaterally co-transfected with an adenoviral vector (Ad), engineered to overexpress OT receptors, and an enhanced green fluorescent protein (eGFP) tag. Control groups: PVN was transfected with an Ad expressing eGFP alone or untransfected, sham rats (Wt). Recordings were obtained without and with selective blockade of OT receptors (OTX), during both baseline and stressful conditions. Baroreceptor reflex sensitivity (BRS) and cardiovascular short-term variability were evaluated using the sequence method and spectral methodology respectively. Key Results Under baseline conditions, rats overexpressing OT receptors (OTR) exhibited enhanced BRS and reduced BP variability compared to control groups. Exposure to stress increased BP, BP variability and HR in all rats. In control groups, but not in OTR rats, BRS decreased during stress. Pretreatment of OTR rats with OTX reduced BRS and enhanced BP and HR variability under baseline and stressful conditions. Pretreatment of Wt rats with OTX, reduced BRS and increased BP variability under baseline and stressful conditions, but only increased HR variability during stress. Conclusions and Implications OT receptors in PVN are involved in tonic neural control of BRS and cardiovascular short-term variability. The failure of this mechanism could critically contribute to the loss of autonomic control in cardiovascular disease. PMID:24834854

Treatment of Post-SCI Hypotension

ClinicalTrials.gov

2018-02-15

Spinal Cord Injury; Autonomic Dysreflexia; Orthostatic Hypotension; Baroreceptor Integrity; Sympathetic Integrity; Vagal Integrity; Hypotension; Cerebral Blood Flow; Blood Pressure; Venous Occlusion Plethysmography

Effects of chronic treatment with cyclooxygenase inhibitor, indomethacin on oral contraceptive-induced high blood pressure in female rats.

PubMed

Olatunji, L A; Soladoye, A O

2010-03-01

The present study sought to investigate the effects of prostaglandins synthesis inhibition with indomethacin on blood pressure, heart rate, cardiac weight, plasma electrolytes and cardiovascular responses to arterial baroreceptor stimulation in Oral contraceptive (OC) treated female Sprague-Dawley rats. Oral administration of synthetic oestrogen, ethinyl oestradiol in combination with progestogen, norgestrel for ten weeks significantly increased blood pressure and cardiac weight compared with those of the control rats. Concomitant treatment with indomethacin significantly abrogated increase in blood pressure but did not affect the increase in cardiac weight induced by OC. Heart rate, plasma sodium and potassium concentrations were not affected by OC and/or indomethacin treatment. OC treatment did not alter sympathetic-mediated pressor and tachycardiac responses caused by bilateral carotid baroreceptors unloading. However, these responses were significantly attenuated by indomethacin treatment. These results demonstrated that rat model of OC-induced high blood pressure developed cardiac hypertrophy that is not associated with altered sympathetic-mediated cardiovascular responses to arterial baroreceptor stimulation. The finding that indomethacin prevented OC-induced high blood pressure, but not associated cardiac hypertrophy implies that synthesis of prostaglandins may be an important determinant of OC-induced hypertension, while associated cardiac hypertrophy may not be pressure overload-dependent.

Phasic negative intrathoracic pressures enhance the vascular responses to stimulation of pulmonary arterial baroreceptors in closed-chest anaesthetized dogs

PubMed Central

Moore, Jonathan P; Hainsworth, Roger; Drinkhill, Mark J

2004-01-01

We investigated whether the reflex responses to stimulation of pulmonary arterial baroreceptors were altered by intrathoracic pressure changes similar to those encountered during normal breathing. Dogs were anaesthetized with α-chloralose, a cardiopulmonary bypass was established, and the pulmonary trunk and its main branches as far as the first lobar arteries were vascularly isolated and perfused with venous blood. The chest was closed following connection to the perfusion circuit and pressures distending the aortic arch, carotid sinus and coronary artery baroreceptors were controlled. Changes in the descending aortic (systemic) perfusion pressure (SPP; flow constant) were used to assess changes in systemic vascular resistance. Values of SPP were plotted against mean pulmonary arterial pressure (PAP) and sigmoid functions applied. From these curves we derived the threshold pressures (corresponding to 5% of the overall response of SPP), the maximum slopes (equivalent to peak gain) and the corresponding PAP (equivalent to ‘set point’). Stimulus–response curves were compared between data obtained with intrathoracic pressure at atmospheric and with a phasic intrathoracic pressure ranging from atmospheric to around −10 mmHg (18 cycles min−1). Results were obtained from seven dogs and are given as means ±s.e.m. Compared to the values obtained when intrathoracic pressure was at atmospheric, the phasic intrathoracic pressure decreased the pulmonary arterial threshold pressure in five dogs; average change from 28.4 ± 5.9 to 19.3 ± 5.9 mmHg (P > 0.05). The inflexion pressure was significantly reduced from 37.8 ± 4.8 to 27.4 ± 4.0 mmHg (P < 0.03), but the slopes of the curves were not consistently changed. These results have shown that a phasic intrathoracic pressure, which simulates respiratory oscillations, displaces the stimulus–response curve of the pulmonary arterial baroreceptors to lower pressures so that it lies within a physiological range of pressures. PMID:14724182

Thoracoscopic sympathectomy increases efferent cardiac vagal activity and baroreceptor sensitivity.

PubMed

Bygstad, Elisabeth; Terkelsen, Astrid J; Pilegaard, Hans K; Hansen, John; Mølgaard, Henning; Hjortdal, Vibeke E

2013-09-01

Thoracoscopic sympathectomy at levels T2 or T2-T3 is a treatment for focal hyperhidrosis and facial blushing. These levels of the sympathetic trunk innervate the heart, and consequently, the procedure is reported to change the heart rate variability due to changes in efferent cardiac autonomic activity. Our objective was to investigate the effects of thoracoscopic sympathectomy on global autonomic control, including baroreceptor sensitivity. Eight patients (6 F, median age 28 years [range 20-58 years]) were exposed to the tilt-table test and cardiopulmonary exercise test before, and 3 months after, thoracoscopic sympathectomy. Eight healthy age-, gender- and BMI-matched controls were used as controls and underwent the same tests once. During tilt-table testing electrocardiogram, blood pressure, impedance cardiography and respiration were measured continuously, and efferent cardiac autonomic balance was estimated. The heart rate measured during orthostatic stress test was lowered after thoracoscopic sympathectomy (between-group; P = 0.01) due to a change in autonomic tone, with increased vagal (high-frequency power n.u.; P = 0.001), and reduced sympathetic efferent cardiac activity (low-frequency power n.u.; P < 0.001). Baroreceptor sensitivity measured during rest was increased (26 ± 13 vs 44 ± 19 ms/mmHg; P = 0.01), and diastolic blood pressure reduced after surgery (P = 0.01). The increases in systolic blood pressure and the sympathetic marker CCV-LF in response to orthostatic stress were higher before sympathectomy, with almost no increases post-surgically (condition × group interaction; P = 0.01 and P = 0.001, respectively). We found no change in post-procedure exercise capacity, although patients had a lower peak VO2 and maximal cardiac index than controls. Thoracoscopic sympathectomy changes the autonomic tone towards increased vagal activity; this is potentially cardioprotective. To our knowledge, this is the first study to show increased baroreceptor sensitivity after thoracoscopic sympathectomy.

Cardiopulmonary and arterial baroreceptor unloading during passive hyperthermia does not contribute to hyperthermia-induced hyperventilation

PubMed Central

Lucas, Rebekah A. I.; Pearson, James; Schlader, Zachary J.; Crandall, Craig G.

2016-01-01

This study tested the hypothesis that baroreceptor unloading during passive hyperthermia contributes to increases in ventilation and decreases in end-tidal partial pressure of carbon dioxide (PET,CO2) during that exposure. Two protocols were performed, in which healthy subjects underwent passive hyperthermia (increasing intestinal temperature by ~1.8°C) to cause a sustained increase in ventilation and reduction in PET,CO2. Upon attaining hyperthermic hyperventilation, in protocol 1 (n = 10; three females) a bolus (19 ± 2 ml kg−1) of warm (~38°C) isotonic saline was rapidly (5–10 min) infused intravenously to restore reductions in central venous pressure, whereas in protocol 2 (n = 11; five females) phenylephrine was infused intravenously (60–120 μg min−1) to return mean arterial pressure to normothermic levels. In protocol 1, hyperthermia increased ventilation (by 2.2 ± 1.7 l min−1, P < 0.01), while reducing PET,CO2 (by 4 ± 3 mmHg, P = 0.04) and central venous pressure (by 5 ± 1 mmHg, P <0.01). Saline infusion increased central venous pressure by 5 ± 1 mmHg (P < 0.01), restoring it to normothermic values, but did not change ventilation or PET,CO2 (P > 0.05). In protocol 2, hyperthermia increased ventilation (by 5.0 ± 2.7l min−1, P <0.01) and reduced PET ,CO2 (by 5 ± 2 mmHg, P < 0.01) and mean arterial pressure (by 9 ± 7 mmHg, P <0.01). Phenylephrine infusion increased mean arterial pressure by 12 ± 3 mmHg (P < 0.01), restoring it to normothermic values, but did not change ventilation or PET,CO2 (P > 0.05). The absence of a reduction in ventilation upon reloading the cardiopulmonary and arterial baroreceptors to pre-hyperthermic levels indicates that baroreceptor unloading with hyperthermia is unlikely to contribute to hyperthermic hyperventilation in humans. PMID:26299270

Vasopressin responses to unloading arterial baroreceptors during cardiac nerve blockade in conscious dogs

NASA Technical Reports Server (NTRS)

O'Donnell, C. P.; Keil, L. C.; Thrasher, T. N.

1992-01-01

We examined the relative contributions of afferent input from the heart and from arterial baroreceptors in the stimulation of arginine vasopressin (AVP) secretion in response to hypotension caused by thoracic inferior vena caval constriction (TIVCC). Afferent input from cardiac receptors was reversibly blocked by infusing 2% procaine into the pericardial space to anesthetize the cardiac nerves. Acute cardiac nerve blockade (CNB) alone caused a rise in mean arterial pressure (MAP) of 24 +/- 3 mmHg but no change in plasma AVP. If the rise in MAP was prevented by TIVCC, plasma AVP increased by 39 +/- 15 pg/ml, and if MAP was allowed to increase and then was forced back to control by TIVCC, plasma AVP increased by 34 +/- 15 pg/ml. Thus the rise in MAP during CNB stimulated arterial baroreceptors, which in turn compensated for the loss of inhibitory input from cardiac receptors on AVP secretion. These results indicate that the maximum secretory response resulting from complete unloading of cardiac receptors at a normal MAP results in a mean increase in plasma AVP of 39 pg/ml in this group of dogs. When MAP was reduced 25% below control levels (from 95 +/- 5 to 69 +/- 3 mmHg) by TIVCC during pericardial saline infusion, plasma AVP increased by 79 +/- 42 pg/ml. However, the same degree of hypotension during CNB (MAP was reduced from 120 +/- 5 to 71 +/- 3 mmHg) led to a greater (P less than 0.05) increase in plasma AVP of 130 +/- 33 pg/ml. Because completely unloading cardiac receptors can account for an increase of only 39 pg/ml on average in this group of dogs, the remainder of the increase in plasma AVP must be due to other sources of stimulation. We suggest that the principal stimulus to AVP secretion after acute CNB in these studies arises from unloading the arterial baroreceptors.

Medial prefrontal cortex TRPV1 channels modulate the baroreflex cardiac activity in rats

PubMed Central

Lagatta, D C; Ferreira‐Junior, N C

2015-01-01

Background and Purpose The ventral portion of the medial prefrontal cortex (vMPFC) comprises the infralimbic (IL), prelimbic (PL) and dorsopenducular (DP) cortices. The IL and PL regions facilitate the baroreceptor reflex arc. This facilitatory effect on the baroreflex is thought to be mediated by vMPFC glutamatergic transmission, through NMDA receptors. The glutamatergic transmission can be modulated by other neurotransmitters, such as the endocannabinoids, which are agonists of the TRPV1 receptor. TRPV1 channels facilitate glutamatergic transmission in the brain. Thus, we hypothesized that TRPV1 receptors in the vMPFC enhance the cardiac baroreflex response. Experimental Approach Stainless steel guide cannulae were bilaterally implanted into the vMPFC of male Wistar rats. Afterwards, a catheter was inserted into the femoral artery, for recording MAP and HR, and into the femoral vein for assessing baroreflex activation. Key Results Microinjections of the TRPV1 receptor antagonists capsazepine and 6‐iodo‐nordihydrocapsaicin (6‐IODO) into the vMPFC reduced the cardiac baroreflex activity in unanaesthetized rats. Capsaicin microinjected into the vMPFC increased the cardiac baroreflex activity in unanaesthetized rats. When an ineffective dose of the TRPV1 receptor antagonist 6‐IODO was used, the capsaicin‐induced increase in the cardiac baroreflex response was abolished. The higher doses of capsaicin administered into the vMPFC after the ineffective dose of 6‐IODO displaced the dose–response curve of the baroreflex parameters to the right, with no alteration in the maximum effect of capsaicin. Conclusions and Implications The results of the present study show that stimulation of the TRPV1 receptors in the vMPFC increases the cardiac baroreceptor reflex response. PMID:26360139

Extended duration orbiter medical project variability of blood pressure and heart rate (STS-50/USML-1)

NASA Technical Reports Server (NTRS)

Fritsch-Yelle, Janice M.; Charles, John B.; Boettcher, Sheila W.

1994-01-01

Decreases in arterial baroreflex function after space flight may be related to changes in blood pressure and heart rate patterns during flight. Ambulatory blood pressure and heart rate were measured for 24 hours, in fourteen astronauts on two occasions before flight, two to three occasions in flight, and 2 days after landing on Shuttle missions lasting 4 to 14 days. Blood pressure and heart rate were recorded every 20minutes during awake periods and every 30 minutes during sleep. In pre- and postflight studies, the 24-hour ambulatory measurements were followed by studies of carotid baroreceptor-cardiac reflex responses. Carotid baroreceptors were stimulated using a sequence of neck pressure and suction from +40 to -65 mmHg.

ROLE OF SYMPATHETIC NERVOUS SYSTEM IN OBESITY RELATED HYPERTENSION

PubMed Central

da Silva, Alexandre; doCarmo, Jussara; Dubinion, John; Hall, John E.

2010-01-01

Obesity is recognized as a major, worldwide, health problem. Excess weight is a major cause of increased blood pressure in most patients with essential hypertension, and greatly increases the risk for diabetes, cardiovascular diseases, and end stage renal disease. Although the mechanisms by which obesity raises blood pressure are not completely understood, increased renal sodium reabsorption, impaired pressure natriuresis, and volume expansion appear to play important roles. Several potential mechanisms have been suggested to contribute to altered kidney function and hypertension in obesity, including activation of the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS), and physical compression of the kidneys, especially when visceral obesity is present. Activation of the SNS in obesity may be due, in part, to hyperleptinemia and other factors secreted by adipocytes and the gastrointestinal tract, activation of the central nervous melanocortin pathway, and baroreceptor dysfunction. PMID:19442330

Baroreflex dysfunction induced by microgravity: potential relevance to postflight orthostatic intolerance

NASA Technical Reports Server (NTRS)

Ertl, A. C.; Diedrich, A.; Biaggioni, I.; Robertson, D. (Principal Investigator)

2000-01-01

Microgravity imposes adaptive changes in the human body. This review focuses on the changes in baroreflex function produced by actual spaceflight, or by experimental models that simulate microgravity, e.g., bed rest. We will analyze separately studies involving baroreflexes arising from carotid sinus and aortic arch afferents ("high-pressure baroreceptors"), and cardiopulmonary afferents ("low-pressure receptors"). Studies from unrelated laboratories using different techniques have concluded that actual or simulated exposure to microgravity reduces baroreflex function arising from carotid sinus afferents ("carotic-cardiac baroreflex"). The techniques used to study the carotid-cardiac baroreflex, using neck suction and compression to simulate changes in blood pressure, have been extensively validated. In contrast, it is more difficult to selectively study aortic arch or cardiopulmonary baroreceptors. Nonetheless, studies that have examined these baroreceptors suggest that microgravity produces the opposite effect, ie, an increase in the gain of aortic arch and cardiopulmonary baroreflexes. Furthermore, most studies have focus on instantaneous changes in heart rate, which almost exclusively examines the vagal limb of the baroreflex. In comparison, there is limited information about the effect of microgravity on sympathetic function. A substantial proportion of subjects exposed to microgravity develop transient orthostatic intolerance. It has been proposed that alterations in baroreflex function play a role in the orthostatic intolerance induced by microgravity. The evidence in favor and against this hypothesis is reviewed.

Simultaneous encoding of carotid sinus pressure and dP/dt by NTS target neurons of myelinated baroreceptors.

PubMed

Rogers, R F; Rose, W C; Schwaber, J S

1996-10-01

1. We seek to understand the baroreceptor signal processing that occurs centrally, beginning with the transformation of the signal at the first stage of processing. Because quantitative descriptions of the encoding of mean arterial pressure and its derivative with respect to time by baroreceptive second-order neurons have been unavailable, we characterized the responses of nucleus tractus solitarius (NTS) neurons that receive direct myelinated baroreceptor inputs to combinations of these two stimulus variables. 2. In anesthetized, paralyzed, artificially ventilated rabbits, the carotid sinus was vascularly isolated and the carotid sinus nerve was dissected free from surrounding tissue. Single-unit extracellular recordings were made from NTS neurons that received direct (with the use of physiological criteria) synaptic inputs from carotid sinus baroreceptors with myelinated axons. The vast majority of these neurons did not receive ipsilateral aortic nerve convergent inputs. With the use of a computer-controlled linear motor, a piecewise linear pressure waveform containing 32 combinations of pressure and its rate of change with respect to time (dP/dt) was delivered to the ipsilateral carotid sinus. 3. The average NTS firing frequency during the different stimulus combinations of pressure and dP/dt was a nonlinear and interdependent function of both variables. Most notable was the "extinctive" encoding of carotid sinus pressure by these neurons. This was characterized by an increase in firing frequency going from low to medium mean pressures (analyzed at certain positive dP/dt values) followed by a decrease in activity during high-pressure stimuli. All second-order neurons analyzed had their maximal firing rates when dP/dt was positive. 4. All neurons had their maximal firing frequency locations ("receptive field centers") at just 3 of 32 possible pressure-dP/dt coordinates. The responses of a small population of neurons were used to generate a composite description of the encoding of pressure and dP/dt. When combined as a composite of individually normalized values, the encoding of carotid sinus pressure and dP/dt may be approximated with the use of two-dimensional Gaussian functions. 5. We conclude that the population of NTS neurons recorded most faithfully encodes the rate and direction of (mean) pressure change, as opposed to providing the CNS with an unambiguous encoding of absolute pressure. Instead, the activity of these neurons, individually or as a population, serves as an estimate for the first derivative of the myelinated baroreceptor signal's encoding of mean pressure. We therefore speculate that the output of these individual neurons is useful in dynamic, rather than static, arterial pressure control.

Reflexes from pulmonary arterial baroreceptors in dogs: interaction with carotid sinus baroreceptors

PubMed Central

Moore, Jonathan P; Hainsworth, Roger; Drinkhill, Mark J

2011-01-01

Abstract In contrast to the reflex vasodilatation occurring in response to stimulation of baroreceptors in the aortic arch, carotid sinuses and coronary arteries, stimulation of receptors in the wall of pulmonary arteries results in reflex systemic vasoconstriction. It is rare for interventions to activate only one reflexogenic region, therefore we investigated how these two types of reflexes interact. In anaesthetized dogs connected to cardiopulmonary bypass, reflexogenic areas of the carotid sinuses, aortic arch and coronary arteries and the pulmonary artery were subjected to independently controlled pressures. Systemic perfusion pressure (SPP) measured in the descending aorta (constant flow) provided an index of systemic vascular resistance. In other experiments, sympathetic efferent neural activity was recorded in fibres dissected from the renal nerve (RSNA). Physiological increases in pulmonary arterial pressure (PAP) induced significant increases in SPP (+39.1 ± 10.4 mmHg) and RSNA (+17.6 ± 2.2 impulses s−1) whereas increases in carotid sinus pressure (CSP) induced significant decreases in SPP (−42.6 ± 10.8 mmHg) and RSNA (−42.8 ± 18.2 impulses s−1) (P < 0.05 for each comparison; paired t test). To examine possible interactions, PAP was changed at different levels of CSP in both studies. With CSP controlled at 124 ± 2 mmHg, the threshold, ‘set point’ and saturation pressures of the PAP–SPP relationship were higher than those with CSP at 60 ± 1 mmHg; this rightward shift was associated with a significant decrease in the reflex gain. Similarly, increasing CSP produced a rightward shift of the PAP–RSNA relationship, although the effect on reflex gain was inconsistent. Furthermore, the responses to changes in CSP were influenced by setting PAP at different levels; increasing the level of PAP from 5 ± 1 to 33 ± 3 mmHg significantly increased the set point and threshold pressures of the CSP–SPP relationship; the reflex gain was not affected. These results indicate the existence of interaction between pulmonary arterial and carotid sinus baroreceptor reflexes; physiological and pathological states that alter the stimulus to one may alter the reflex responses from the other. PMID:21690195

Measuring high pressure baroreceptor sensitivity in the rat.

PubMed

Shiry, L J; Hamlin, R L

2011-01-01

The high pressure baroreceptor reflex rapidly buffers changes in systemic arterial pressure in response to postural changes, altered gravitational conditions, diseases, and pharmacological agents. Drug-induced exaggeration of changes in heart rate and in systemic arterial pressure is a leading cause of adverse events and of patients terminating use of drugs, particularly in the aging population. This paper presents a facile method for monitoring the high pressure baroreceptor reflex in rats, and presents an alternative to quantifying the magnitude of this reflex using 2 dependent variables, heart rate and systemic arterial pressure, rather than merely change in heart rate. Twenty-four rats were allocated to 3 groups: group I anesthetized with 100mg/kg thiopental, group II anesthetized with 2% isoflurane given by inhalation, group III anesthetized with thiopental but pretreated for 2weeks with 2μg/kg aldosterone given SQ bid. After induction to anesthesia, hair was clipped from the ventral aspect of the neck, and petrolatum was applied to the skin to permit an air-tight seal with a glass funnel attached to a source of variable and controllable negative pressure. Systemic arterial pressure, ECG, heart rate, and a force of suction applied to the neck were all recorded continuously. After baseline recordings, a force of -20mmHg was applied for 20s over the carotid artery. In rats receiving thiopental, the average changes in heart rate and systemic arterial pressure following the application of -20mmHg neck suction were 30±11bpm and 45±14mmHg, respectively. The ratios of change in heart and change in systemic arterial pressure to application of negative force over the carotid sinus are 1.5±0.6bpm/mmHg and 0.7±04mmHg/mmHg, respectively. Mean values for heart rate and for mean systemic arterial pressure during baseline and after application of neck suction for 20s showed little to no decrease (i.e., blunting) in rats anesthetized with isoflurane or pretreated with aldosterone. Thus this methodology was able to detect, in rats, blunting of baroreceptor function for at least 2 perturbations of this important homeostatic control system. Copyright © 2011. Published by Elsevier Inc.

Neurons in the posterior insular cortex are responsive to gustatory stimulation of the pharyngolarynx, baroreceptor and chemoreceptor stimulation, and tail pinch in rats.

PubMed

Hanamori, T; Kunitake, T; Kato, K; Kannan, H

1998-02-23

Extracellular unit responses to gustatory stimulation of the pharyngolaryngeal region, baroreceptor and chemoreceptor stimulation, and tail pinch were recorded from the insular cortex of anesthetized and paralyzed rats. Of the 32 neurons identified, 28 responded to at least one of the nine stimuli used in the present study. Of the 32 neurons, 11 showed an excitatory response to tail pinch, 13 showed an inhibitory response, and the remaining eight had no response. Of the 32 neurons, eight responded to baroreceptor stimulation by an intravenous (i.v.) injection of methoxamine hydrochloride (Mex), four were excitatory and four were inhibitory. Thirteen neurons were excited and six neurons were inhibited by an arterial chemoreceptor stimulation by an i.v. injection of sodium cyanide (NaCN). Twenty-two neurons were responsive to at least one of the gustatory stimuli (deionized water, 1.0 M NaCl, 30 mM HCl, 30 mM quinine HCl, and 1.0 M sucrose); five to 11 excitatory neurons and three to seven inhibitory neurons for each stimulus. A large number of the neurons (25/32) received converging inputs from more than one stimulus among the nine stimuli used in the present study. Most neurons (23/32) received converging inputs from different modalities (gustatory, visceral, and tail pinch). The neurons responded were located in the insular cortex between 2.0 mm anterior and 0.2 mm posterior to the anterior edge of the joining of the anterior commissure (AC); the mean location was 1.2 mm (n=28) anterior to the AC. This indicates that most of the neurons identified in the present study seem to be located in the region posterior to the taste area and anterior to the visceral area in the insular cortex. These results indicate that the insular cortex neurons distributing between the taste area and the visceral area receive convergent inputs from gustatory, baroreceptor, chemoreceptor, and nociceptive organs. Copyright 1998 Elsevier Science B.V.

The carotid baroreflex modifies the pressor threshold of the muscle metaboreflex in humans.

PubMed

Ichinose, Masashi; Ichinose-Kuwahara, Tomoko; Watanabe, Kazuhito; Kondo, Narihiko; Nishiyasu, Takeshi

2017-09-01

The purpose of the present study was to test our hypothesis that unloading the carotid baroreceptors alters the threshold and gain of the muscle metaboreflex in humans. Ten healthy subjects performed a static handgrip exercise at 50% of maximum voluntary contraction. Contraction was sustained for 15, 30, 45, and 60 s and was followed by 3 min of forearm circulatory arrest, during which forearm muscular pH is known to decrease linearly with increasing contraction time. The carotid baroreceptors were unloaded by applying 0.1-Hz sinusoidal neck pressure (oscillating from +15 to +50 mmHg) during ischemia. We estimated the threshold and gain of the muscle metaboreflex by analyzing the relationship between the cardiovascular responses during ischemia and the amount of work done during the exercise. In the condition with unloading of the carotid baroreceptors, the muscle metaboreflex thresholds for mean arterial blood pressure (MAP) and total vascular resistance (TVR) corresponded to significantly lower work levels than the control condition (threshold for MAP: 795 ± 102 vs. 662 ± 208 mmHg and threshold for TVR: 818 ± 213 vs. 572 ± 292 kg·s, P < 0.05), but the gains did not differ between the two conditions (gain for MAP: 4.9 ± 1.7 vs. 4.4 ± 1.6 mmHg·kg·s -1 ·100 and gain for TVR: 1.3 ± 0.8 vs. 1.3 ± 0.7 mmHg·l -1 ·min -1 ·kg·s -1 ·100). We conclude that the carotid baroreflex modifies the muscle metaboreflex threshold in humans. Our results suggest the carotid baroreflex brakes the muscle metaboreflex, thereby inhibiting muscle metaboreflex-mediated pressor and vasoconstriction responses. NEW & NOTEWORTHY We found that unloading the carotid baroreceptors shifts the pressor threshold of the muscle metaboreflex toward lower metabolic stimulation levels in humans. This finding indicates that, in the normal loading state, the carotid baroreflex inhibits the muscle metaboreflex pressor response by shifting the reflex threshold to higher metabolic stimulation levels. Copyright © 2017 the American Physiological Society.

Carotid interventions and blood pressure.

PubMed

Hirschl, Mirko; Kundi, Michael

2014-12-01

Arterial baroreceptors are pressure sensors found in the carotid sinus near the bifurcation of the carotid artery and in the aortic arch. Carotid interventions, whether endovascular or surgical, affect this complicated control system and the post-interventional blood pressure behavior. Comparisons between the intervention techniques, however, are challenging due to the varying measurement methods, duration of observation, and patient populations. The question as to which interventional method is preferable, if undisturbed regulation of blood pressure is concerned, still remains unanswered. The fact that blood pressure events (i.e., hemodynamic instability, hypertension, unstable blood pressure) frequently occur both immediately after intervention and in the long term, mandates a particularly careful cardiopulmonary and blood pressure monitoring. Direct and indirect measurements of baroreceptor sensitivity can be helpful in identifying high-risk patients, although the association to hard clinical endpoints is rarely documented for methodological reasons.

Influence of cigarette smoking on human autonomic function

NASA Technical Reports Server (NTRS)

Niedermaier, O. N.; Smith, M. L.; Beightol, L. A.; Zukowska-Grojec, Z.; Goldstein, D. S.; Eckberg, D. L.

1993-01-01

BACKGROUND. Although cigarette smoking is known to lead to widespread augmentation of sympathetic nervous system activity, little is known about the effects of smoking on directly measured human sympathetic activity and its reflex control. METHODS AND RESULTS. We studied the acute effects of smoking two research-grade cigarettes on muscle sympathetic nerve activity and on arterial baroreflex-mediated changes of sympathetic and vagal neural cardiovascular outflows in eight healthy habitual smokers. Measurements were made during frequency-controlled breathing, graded Valsalva maneuvers, and carotid baroreceptor stimulation with ramped sequences of neck pressure and suction. Smoking provoked the following changes: Arterial pressure increased significantly, and RR intervals, RR interval spectral power at the respiratory frequency, and muscle sympathetic nerve activity decreased. Plasma nicotine levels increased significantly, but plasma epinephrine, norepinephrine, and neuropeptide Y levels did not change. Peak sympathetic nerve activity during and systolic pressure overshoots after Valsalva straining increased significantly in proportion to increases of plasma nicotine levels. The average carotid baroreceptor-cardiac reflex relation shifted rightward and downward on arterial pressure and RR interval axes; average gain, operational point, and response range did not change. CONCLUSIONS. In habitual smokers, smoking acutely reduces baseline levels of vagal-cardiac nerve activity and completely resets vagally mediated arterial baroreceptor-cardiac reflex responses. Smoking also reduces muscle sympathetic nerve activity but augments increases of sympathetic activity triggered by brief arterial pressure reductions. This pattern of autonomic changes is likely to influence smokers' responses to acute arterial pressure reductions importantly.

Hormone phase influences sympathetic responses to high levels of lower body negative pressure in young healthy women.

PubMed

Usselman, Charlotte W; Nielson, Chantelle A; Luchyshyn, Torri A; Gimon, Tamara I; Coverdale, Nicole S; Van Uum, Stan H M; Shoemaker, J Kevin

2016-11-01

We tested the hypothesis that sympathetic responses to baroreceptor unloading may be affected by circulating sex hormones. During lower body negative pressure at -30, -60, and -80 mmHg, muscle sympathetic nerve activity (MSNA), heart rate, and blood pressure were recorded in women who were taking (n = 8) or not taking (n = 9) hormonal contraceptives. All women were tested twice, once during the low-hormone phase (i.e., the early follicular phase of the menstrual cycle and the placebo phase of hormonal contraceptive use), and again during the high-hormone phase (i.e., the midluteal phase of the menstrual cycle and active phase of contraceptive use). During baroreceptor unloading, the reductions in stroke volume and resultant increases in MSNA and total peripheral resistance were greater in high-hormone than low-hormone phases in both groups. When normalized to the fall in stroke volume, increases in MSNA were no longer different between hormone phases. While stroke volume and sympathetic responses were similar between women taking and not taking hormonal contraceptives, mean arterial pressure was maintained during baroreceptor unloading in women not taking hormonal contraceptives but not in women using hormonal contraceptives. These data suggest that differences in sympathetic activation between hormone phases, as elicited by lower body negative pressure, are the result of hormonally mediated changes in the hemodynamic consequences of negative pressure, rather than centrally driven alterations to sympathetic regulation. Copyright © 2016 the American Physiological Society.

Central estrogenic pathways protect against the depressant action of acute nicotine on reflex tachycardia in female rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

El-Mas, Mahmoud M., E-mail: mahelm@hotmail.com; Fouda, Mohamed A.; El-gowilly, Sahar M.

We have previously shown that acute exposure of male rats to nicotine preferentially attenuates baroreceptor-mediated control of reflex tachycardia in contrast to no effect on reflex bradycardia. Here, we investigated whether female rats are as sensitive as their male counterparts to the baroreflex depressant effect of nicotine and whether this interaction is modulated by estrogen. Baroreflex curves relating reflex chronotropic responses evoked by i.v. doses (1–16 μg/kg) of phenylephrine (PE) or sodium nitroprusside (SNP), were constructed in conscious freely moving proestrus, ovariectomized (OVX), and estrogen (50 μg/kg/day s.c., 5 days)-replaced OVX (OVXE{sub 2}) rats. Slopes of the curves were takenmore » as a measure of baroreflex sensitivity (BRS{sub PE} and BRS{sub SNP}). Nicotine (100 μg/kg i.v.) reduced BRS{sub SNP} in OVX rats but not in proestrus or OVXE{sub 2} rats. The attenuation of reflex tachycardia by nicotine was also evident in diestrus rats, which exhibited plasma estrogen levels similar to those of OVX rats. BRS{sub PE} was not affected by nicotine in all rat preparations. Experiments were then extended to determine whether central estrogenic receptors modulate the nicotine–BRS{sub SNP} interaction. Intracisteral (i.c.) treatment of OVX rats with estrogen sulfate (0.2 μg/rat) abolished the BRS{sub SNP} attenuating effect of i.v. nicotine. This protective effect of estrogen disappeared when OVX rats were pretreated with i.c. ICI 182,780 (50 μg/rat, selective estrogen receptor antagonist). Together, these findings suggest that central neural pools of estrogen receptors underlie the protection offered by E{sub 2} against nicotine-induced baroreceptor dysfunction in female rats. -- Highlights: ► Estrogen protects against the depressant effect of nicotine on reflex tachycardia. ► The baroreflex response and estrogen status affect the nicotine–BRS interaction. ► The protection offered by estrogen is mediated via central estrogen receptors.« less

Intrapericardial denervation - Radial artery blood flow and heart rate responses to LBNP

NASA Technical Reports Server (NTRS)

Mckeever, Kenneth H.; Skidmore, Michael G.; Keil, Lanny C.; Sandler, Harold

1990-01-01

The effects of intrapericardial denervation on the radial artery blood flow velocity (RABFV) and heart rate (HR) responses to LBNP in rhesus monkeys were investigated by measuring the RABFV transcutaneously by a continuous-wave Doppler ultrasonic flowmeter in order to derive an index of forearm blood flow response to low (0 to -20 mm Hg) and high (0 to -60 mm Hg) ramp exposures during supine LBNP. Four of the eight subjects were subjected to efferent and afferent cardiac denervation. It was found that, during low levels of LBNP, monkeys with cardiac denervation exhibited no cardiopulmonary baroreceptor-mediated change in the RABFV or HR, unlike the intact animals, which showed steady decreases in RABFV during both high- and low-pressure protocols. It is suggested that forearm blood flow and HR responses to low-level LBNP, along with pharmacological challenge, are viable physiological tests for verifying the completeness of atrial and cardiopulmonary baroreceptor denervation.

System identification of dynamic closed-loop control of total peripheral resistance by arterial and cardiopulmonary baroreceptors

NASA Astrophysics Data System (ADS)

Nikolai Aljuri, A.; Bursac, Nenad; Marini, Robert; Cohen, Richard J.

2001-08-01

Prolonged exposure to microgravity in space flight missions (days) impairs the mechanisms responsible for defense of arterial blood pressure (ABP) and cardiac output (CO) against orthostatic stress in the post-flight period. The mechanisms responsible for the observed orthostatic intolerance are not yet completely understood. Additionally, effective counter measures to attenuate this pathophysiological response are not available. The aim of this study was to investigate the ability of our proposed system identification method to predict closed-loop dynamic changes in TPR induced by changes in mean arterial pressure (MAP) and right atrial pressure (RAP). For this purpose we designed and employed a novel experimental animal model for the examination of arterial and cardiopulmonary baroreceptors in the dynamic closed-loop control of total peripheral resistance (TPR), and applied system identification to the analysis of beat-to-beat fluctuations in the measured signals.

Responses of neurons in the caudal medullary lateral tegmental field to visceral inputs and vestibular stimulation in vertical planes

PubMed Central

Moy, Jennifer D.; Miller, Daniel J.; Catanzaro, Michael F.; Boyle, Bret M.; Ogburn, Sarah W.; Cotter, Lucy A.; McCall, Andrew A.

2012-01-01

The dorsolateral reticular formation of the caudal medulla, or the lateral tegmental field (LTF), has been classified as the brain's “vomiting center”, as well as an important region in regulating sympathetic outflow. We examined the responses of LTF neurons in cats to rotations of the body that activate vestibular receptors, as well as to stimulation of baroreceptors (through mechanical stretch of the carotid sinus) and gastrointestinal receptors (through the intragastric administration of the emetic compound copper sulfate). Approximately half of the LTF neurons exhibited graviceptive responses to vestibular stimulation, similar to primary afferents innervating otolith organs. The other half of the neurons had complex responses, including spatiotemporal convergence behavior, suggesting that they received convergent inputs from a variety of vestibular receptors. Neurons that received gastrointestinal and baroreceptor inputs had similar complex responses to vestibular stimulation; such responses are expected for neurons that contribute to the generation of motion sickness. LTF units with convergent baroreceptor and vestibular inputs may participate in producing the cardiovascular system components of motion sickness, such as the changes in skin blood flow that result in pallor. The administration of copper sulfate often modulated the gain of responses of LTF neurons to vestibular stimulation, particularly for units whose spontaneous firing rate was altered by infusion of drug (median of 459%). The present results raise the prospect that emetic signals from the gastrointestinal tract modify the processing of vestibular inputs by LTF neurons, thereby affecting the probability that vomiting will occur as a consequence of motion sickness. PMID:22955058

Asymmetries in reciprocal baroreflex mechanisms and chronic pain severity: Focusing on irritable bowel syndrome.

PubMed

Davydov, D M; Naliboff, B; Shahabi, L; Shapiro, D

2018-02-01

Objective measures of pain severity remain ill defined, although its accurate measurement is critical. Reciprocal baroreflex mechanisms of blood pressure (BP) control were found to impact differently on pain regulation, and thus their asymmetry was hypothesized to also connect to chronic pain duration and severity. Seventy-eight female patients with irritable bowel syndrome (IBS) and 27 healthy women were assessed for IBS severity and chronicity, negative affect, and various measures of resting autonomic function including BP, heart rate and its variability (HRV), baroreceptor-sensitivity to activations and inhibitions, gains of brady- and tachy-cardiac baro-responses, gains of BP falls/rises, and BP start points for these spontaneous baroreflexes. IBS directly and indirectly (through increased negative affect) was associated with asymmetry between baroreceptor activations/inhibitions compared to symmetrical baroreflex reciprocity in the healthy women. In the IBS group, independently of specific IBS symptoms, pain chronicity was associated with (i) decreased BP falls coupled with either (a) decreased tachycardia associated with lower disease severity (earlier "pain resilience" mechanism), or (b) decreased bradycardia associated with higher disease severity (later "pain decompensation" mechanism), or (ii) increased BP start point for baroreceptor activations coupled with either (a) BP increase (delayed "pain adaptation" mechanism) or (b) affect-related HRV decrease (delayed "pain aggravation" mechanism). We anticipate the findings to be a starting point for validating these autonomic metrics of pain suffering and pain coping mechanisms in other chronic pain syndromes to suggest them as biomarkers of its severity and duration for profiling and correct management of chronic pain patients. © 2017 John Wiley & Sons Ltd.

Role of Nitric Oxide in the Regulation of Renin and Vasopressin Secretion

NASA Technical Reports Server (NTRS)

Reid, Ian A.

1994-01-01

Research during recent years has established nitric oxide as a unique signaling molecule that plays important roles in the regulation of the cardiovascular, nervous, immune, and other systems. Nitric oxide has also been implicated in the control of the secretion of hormones by the pancreas, hypothalamus, and anterior pituitary gland, and evidence is accumulating that it contributes to the regulation of the secretion of renin and vasopressin, hormones that play key roles in the control of sodium and water balance. Several lines of evidence have implicated nitric oxide in the control of renin secretion. The enzyme nitric oxide synthase is present in vascular and tubular elements of the kidney, particularly in cells of the macula densa, a structure that plays an important role in the control of renin secretion. Guanylyl cyclase, a major target for nitric oxide, is also present in the kidney. Drugs that inhibit nitric oxide synthesis generally suppress renin release in vivo and in vitro, suggesting a stimulatory role for the L-arginine/nitric oxide pathway in the control of renin secretion. Under some conditions, however, blockade of nitric oxide synthesis increases renin secretion. Recent studies indicate that nitric oxide not only contributes to the regulation of basal renin secretion, but also participates in the renin secretory responses to activation of the renal baroreceptor, macula densa, and beta adrenoceptor mechanisms that regulate renin secretion. Histochemical and immunocytochemical studies have revealed the presence of nitric oxide synthase in the supraoptic and paraventricular nuclei of the hypothalamus and in the posterior pituitary gland. Colocalization of nitric oxide synthase and vasopressin has been demonstrated in some hypothalamic neurons. Nitric oxide synthase activity in the hypothalamus and pituitary is increased by maneuvers known to stimulate vasopressin secretion, including salt loading and dehydration, Administration of L-arginine and nitric oxide donors in vitro and in vivo has variable effects on vasopressin secretion, but the most common one is inhibition. Blockade of nitric oxide synthesis has been reported to increase vasopressin secretion, but again variable results have been obtained. An attractive working hypothesis is that nitric oxide serves a neuromodulatory role as an inhibitor of vasopressin secretion.

Role of Autonomic Reflex Arcs in Cardiovascular Responses to Air Pollution Exposure

EPA Science Inventory

The body responds to environmental stressors by triggering autonomic reflexes in the pulmonary receptors, baroreceptors, and chemoreceptors to maintain homeostasis. Numerous studies have shown that exposure to various gases and airborne particles can alter the functional outcome ...

Effects of repeated Valsalva maneuver straining on cardiac and vasoconstrictive baroreflex responses

NASA Technical Reports Server (NTRS)

Convertino, Victor A.; Ratliff, Duane A.; Doerr, Donald F.; Ludwig, David A.; Muniz, Gary W.; Benedetti, Erik; Chavarria, Jose; Koreen, Susan; Nguyen, Claude; Wang, Jeff

2003-01-01

INTRODUCTION: We hypothesized that repeated respiratory straining maneuvers (repeated SM) designed to elevate arterial BPs (arterial baroreceptor loading) would acutely increase baroreflex responses. METHODS: We tested this hypothesis by measuring cardiac baroreflex responses to carotid baroreceptor stimulation (neck pressures), and changes in heart rate and diastolic BP after reductions in BP induced by a 15-s Valsalva maneuver in 10 female and 10 male subjects at 1, 3, 6, and 24 h after performing repeated SM. Baroreflex responses were also measured in each subject at 1, 3, 6, and 24 h at the same time on a separate day without repeated SM (control) in a randomized, counter-balanced cross-over experimental design. RESULTS: There was no statistical difference in carotid-cardiac and peripheral vascular baroreflex responses measured across time following repeated SM compared with the control condition. Integrated cardiac baroreflex response (deltaHR/ deltaSBP) measured during performance of a Valsalva maneuver was increased by approximately 50% to 1.1 +/- 0.2 bpm x mm Hg(-1) at 1 h and 1.0 +/- 0.1 bpm x mm Hg(-1) at 3 h following repeated SM compared with the control condition (0.7 +/- 0.1 bpm x mm Hg(-1) at both 1 and 3 h, respectively). However, integrated cardiac baroreflex response after repeated SM returned to control levels at 6 and 24 h after training. These responses did not differ between men and women. CONCLUSIONS: Our results are consistent with the notion that arterial baroreceptor loading induced by repeated SM increased aortic, but not carotid, cardiac baroreflex responses for as long as 3 h after repeated SM. We conclude that repeated SM increases cardiac baroreflex responsiveness which may provide patients, astronauts, and high-performance aircraft pilots with protection from development of orthostatic hypotension.

Favorable effects of carotid endarterectomy on baroreflex sensitivity and cardiovascular neural modulation: a 4-month follow-up.

PubMed

Dalla Vecchia, Laura; Barbic, Franca; Galli, Andrea; Pisacreta, Massimo; Gornati, Rosella; Porretta, Tiziano; Porta, Alberto; Furlan, Raffaello

2013-06-15

Carotid surgery variably modifies carotid afferent innervation, thus affecting arterial baroreceptor sensitivity. Low arterial baroreflex sensitivity is a well-known independent risk factor for cardiovascular diseases. The aim of this study was to assess the 4-mo effects of carotid endarterectomy (CEA) on arterial baroreceptor sensitivity and cardiovascular autonomic profile in patients with unilateral carotid stenosis. We enrolled 20 patients (72 ± 8 yr) with unilateral >70% carotid stenosis. ECG, beat-by-beat blood pressure, and respiration were continuously recorded before and 126 ± 9 days after CEA, at rest and during a 75° head-up tilt. Both pharmacological (modified Oxford technique, BRS) and spontaneous (index α, spectral analysis) arterial baroreflex sensitivity were assessed. Cardiovascular autonomic profile was evaluated by plasma catecholamines and spectral indexes of cardiac sympathovagal modulation [low-frequency R-R interval (LFRR), low frequency-to high frequency ratio (LF/HF), high-frequency R-R interval (HFRR)] and sympathetic vasomotor control [low-frequency systolic arterial pressure (LFSAP)] obtained from heart rate and SAP variability. After CEA, both the index α and BRS were higher (P < 0.02) at rest. SAP variance decreased both at rest and during tilt (P < 0.02). Before surgery, tilt did not modify the autonomic profile compared with baseline. After CEA, tilt increased LF/HF and LFSAP and reduced HFRR compared with rest (P < 0.02). Four months after CEA was performed, arterial baroreflex sensitivity was enhanced. Accordingly, the patients' autonomic profile had shifted toward reduced cardiac and vascular sympathetic activation and enhanced cardiac vagal activity. The capability to increase cardiovascular sympathetic activation in response to orthostasis was restored. Baroreceptor sensitivity improvement might play an additional role in the more favorable outcome observed in patients after carotid surgery.

Expression of the P/Q (Cav2.1) calcium channel in nodose sensory neurons and arterial baroreceptors.

PubMed

Tatalovic, Milos; Glazebrook, Patricia A; Kunze, Diana L

2012-06-27

The predominant calcium current in nodose sensory neurons, including the subpopulation of baroreceptor neurons, is the N-type channel, Cav2.2. It is also the primary calcium channel responsible for transmitter release at their presynaptic terminals in the nucleus of the solitary tract in the brainstem. The P/Q channel, Cav2.1, the other major calcium channel responsible for transmitter release at mammalian synapses, represents only 15-20% of total calcium current in the general population of sensory neurons and makes a minor contribution to transmitter release at the presynaptic terminal. In the present study we identified a subpopulation of the largest nodose neurons (capacitance>50pF) in which, surprisingly, Cav2.1 represents over 50% of the total calcium current, differing from the remainder of the population. Consistent with these electrophysiological data, anti-Cav2.1 antibody labeling was more membrane delimited in a subgroup of the large neurons in slices of nodose ganglia. Data reported in other synapses in the central nervous system assign different roles in synaptic information transfer to the P/Q-type versus N-type calcium channels. The study raises the possibility that the P/Q channel which has been associated with high fidelity transmission at other central synapses serves a similar function in this group of large myelinated sensory afferents, including arterial baroreceptors where a high frequency regular discharge pattern signals the pressure pulse. This contrasts to the irregular lower frequency discharge of the unmyelinated fibers that make up the majority of the sensory population and that utilize the N-type channel in synaptic transmission. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Reduced carotid baroreceptor distensibility-induced baroreflex resetting contributes to impairment of sodium regulation in rats fed a high-fat diet.

PubMed

Abe, Chikara; Nagai, Yuko; Yamaguchi, Aoi; Aoki, Hitomi; Shimizu, Shuji; Akiyama, Tsuyoshi; Kawada, Toru; Sugimachi, Masaru; Morita, Hironobu

2015-04-15

Decreased carotid arterial compliance has been reported in obese subjects and animals. Carotid baroreceptors are located at the bifurcation of the common carotid artery, and respond to distension of the arterial wall, suggesting that higher pressure is required to obtain the same distension in obese subjects and animals. A hyperosmotic NaCl solution induces circulatory volume expansion and arterial pressure (AP) increase, which reflexively augment renal excretion. Thus, we hypothesized that sodium regulation via the baroreflex might be impaired in response to chronic hyperosmotic NaCl infusion in rats fed a high-fat diet. To examine this hypothesis, we used rats fed a high-fat (Fat) or normal (NFD) diet, and measured mean AP, water and sodium balance, and renal function in response to chronic infusion of hyperosmotic NaCl solution via a venous catheter. Furthermore, we examined arterial baroreflex characteristics with static open-loop analysis and distensibility of the common carotid artery. Significant positive water and sodium balance was observed on the 1st day of 9% NaCl infusion; however, this disappeared by the 2nd day in Fat rats. Mean AP was significantly higher during 9% NaCl infusion in Fat rats compared with NFD rats. In the open-loop analysis of carotid sinus baroreflex, a rightward shift of the neural arc was observed in Fat rats compared with NFD rats. Furthermore, distensibility of the common carotid artery was significantly reduced in Fat rats. These results indicate that a reduced baroreceptor distensibility-induced rightward shift of the neural arc might contribute to impairment of sodium regulation in Fat rats. Copyright © 2015 the American Physiological Society.

Pulmonary arterial distension and vagal afferent nerve activity in anaesthetized dogs.

PubMed

Moore, Jonathan P; Hainsworth, Roger; Drinkhill, Mark J

2004-03-16

Distension of the main pulmonary artery and its bifurcation are known to result in a reflex vasoconstriction and increased respiratory drive; however, these responses are observed at abnormally high distending pressures. In this study we recorded afferent activity from pulmonary arterial baroreceptors to investigate their stimulus-response characteristics and to determine whether they are influenced by physiological changes in intrathoracic pressure. In chloralose-anaesthetized dogs, a cardiopulmonary bypass was established, the pulmonary trunk and its main branches were vascularly isolated and perfused with venous blood at pulsatile pressures designed to simulate the normal pulmonary arterial pressure waveform. Afferent slips of a cervical vagus were dissected and nerve fibres identified that displayed discharge patterns with characteristics expected from pulmonary arterial baroreceptors. Recordings were obtained with (a) chest open (b) chest closed and resealed, and (c) with phasic negative intrathoracic pressures in the resealed chest. Pressure-discharge characteristics obtained in the open-chest animals indicated that the threshold pulmonary pressure (corresponding to 5% of the overall response) was 17.1 +/- 2.9 and the inflexion point of the curve was 29.2 +/- 3.3 mmHg (mean +/-S.E.M). In closed-chest animals the threshold and inflexion pressures were reduced to 12.0 +/- 1.7 and 20.7 +/- 1.8 mmHg. Application of phasic negative intrathoracic pressures further reduced the threshold and inflexion pressures to 9.5 +/- 1.2 mmHg (P < 0.05 vs. open) and 14.7 +/- 0.8 mmHg (P < 0.003 vs. open and P < 0.02 vs. atmospheric). These results indicate that under physiological conditions, with closed-chest and phasic negative intrathoracic pressure changes similar to those associated with normal breathing, activity from pulmonary baroreceptors is obtained at physiological pulmonary arterial pressures in intact animals.

Effects of weightlessness on human baroreflex function

NASA Technical Reports Server (NTRS)

Fritsch, Janice M.; Eckberg, Dwain L.

1992-01-01

Impaired cardiovascular function, characterized by orthostatic intolerance and reduced exercise capacity, is a result of space travel. We hypothesized that postflight baroreflex dysfunction may contribute. We studied the vagally mediated carotid baroreceptor-cardiac reflex response of 6 astronauts before, during, and after the ten day SLS-l mission. A series of R-waves triggered pressure and suction steps (from 40 to minus 65 mmHg) were delivered to a neck chamber during held expirtation. Resulting R-R interval changes were plotted against carotid distending pressure (systolic - neck pressure), and curve parameters calculated. After an initial rise, the operational point declined consistently during the flight and reached a nadir on landing day, but had recovered to preflight levels by L + 4. Slope and range of the response declined throughout the flight, were slightly recovered by the time measurements were made on landing day, but still were reduced on L + 4. These data indicate that space flight results in a significant impairment of the carotid baroreceptor cardiac reflex response.

High salt intake increases blood pressure via BDNF-mediated downregulation of KCC2 and impaired baroreflex inhibition of vasopressin neurons.

PubMed

Choe, Katrina Y; Han, Su Y; Gaub, Perrine; Shell, Brent; Voisin, Daniel L; Knapp, Blayne A; Barker, Philip A; Brown, Colin H; Cunningham, J Thomas; Bourque, Charles W

2015-02-04

The mechanisms by which dietary salt promotes hypertension are unknown. Previous work established that plasma [Na(+)] and osmolality rise in proportion with salt intake and thus promote release of vasopressin (VP) from the neurohypophysis. Although high levels of circulating VP can increase blood pressure, this effect is normally prevented by a potent GABAergic inhibition of VP neurons by aortic baroreceptors. Here we show that chronic high salt intake impairs baroreceptor inhibition of rat VP neurons through a brain-derived neurotrophic factor (BDNF)-dependent activation of TrkB receptors and downregulation of KCC2 expression, which prevents inhibitory GABAergic signaling. We show that high salt intake increases the spontaneous firing rate of VP neurons in vivo and that circulating VP contributes significantly to the elevation of arterial pressure under these conditions. These results provide the first demonstration that dietary salt can affect blood pressure through neurotrophin-induced plasticity in a central homeostatic circuit. Copyright © 2015 Elsevier Inc. All rights reserved.

System identification of dynamic closed-loop control of total peripheral resistance by arterial and cardiopulmonary baroreceptors

NASA Technical Reports Server (NTRS)

Aljuri, A. N.; Bursac, N.; Marini, R.; Cohen, R. J.

2001-01-01

Prolonged exposure to microgravity in space flight missions (days) impairs the mechanisms responsible for defense of arterial blood pressure (ABP) and cardiac output (CO) against orthostatic stress in the post-flight period. The mechanisms responsible for the observed orthostatic intolerance are not yet completely understood. Additionally, effective counter measures to attenuate this pathophysiological response are not available. The aim of this study was to investigate the ability of our proposed system identification method to predict closed-loop dynamic changes in TPR induced by changes in mean arterial pressure (MAP) and right atrial pressure (RAP). For this purpose we designed and employed a novel experimental animal model for the examination of arterial and cardiopulmonary baroreceptors in the dynamic closed-loop control of total peripheral resistance (TPR), and applied system identification to the analysis of beat-to-beat fluctuations in the measured signals. Grant numbers: NAG5-4989. c 2001. Elsevier Science Ltd. All rights reserved.

Cardiovascular autonomic modulation and activity of carotid baroreceptors at altitude.

PubMed

Bernardi, L; Passino, C; Spadacini, G; Calciati, A; Robergs, R; Greene, R; Martignoni, E; Anand, I; Appenzeller, O

1998-11-01

1. To assess the effects of acute exposure to high altitude on baroreceptor function in man we evaluated the effects of baroreceptor activation on R-R interval and blood pressure control at high altitude. We measured the low-frequency (LF) and high-frequency (HF) components in R-R, non-invasive blood pressure and skin blood flow, and the effect of baroreceptor modulation by 0. 1-Hz sinusoidal neck suction. Ten healthy sea-level natives and three high-altitude native, long-term sea-level residents were evaluated at sea level, upon arrival at 4970 m and 1 week later.2. Compared with sea level, acute high altitude decreased R-R and increased blood pressure in all subjects [sea-level natives: R-R from 1002+/-45 to 775+/-57 ms, systolic blood pressure from 130+/-3 to 150+/-8 mmHg; high-altitude natives: R-R from 809+/-116 to 749+/-47 ms, systolic blood pressure from 110+/-12 to 125+/-11 mmHg (P<0.05 for all)]. One week later systolic blood pressure was similar to values at sea level in all subjects, whereas R-R remained elevated in sea-level natives. The low-frequency power in R-R and systolic blood pressure increased in sea-level natives [R-R-LF from 47+/-8 to 65+/-10% (P<0.05), systolic blood pressure-LF from 1.7+/-0. 3 to 2.6+/-0.4 ln-mmHg2 (P<0.05)], but not in high-altitude natives (R-R-LF from 32+/-13 to 38+/-19%, systolic blood pressure-LF from 1. 9+/-0.5 to 1.7+/-0.8 ln-mmHg2). The R-R-HF decreased in sea-level natives but not in high-altitude natives, and no changes occurred in systolic blood pressure-HF. These changes remained evident 1 week later. Skin blood flow variability and its spectral components decreased markedly at high altitude in sea-level natives but showed no changes in high-altitude natives. Neck suction significantly increased the R-R- and systolic blood pressure-LF in all subjects at both sea level and high altitude.3. High altitude induces sympathetic activation in sea-level natives which is partially counteracted by active baroreflex. Despite long-term acclimatization at sea level, high-altitude natives also maintain active baroreflex at high altitude but with lower sympathetic activation, indicating a persisting high-altitude adaptation which may be genetic or due to baroreflex activity not completely lost by at least 1 year's sea-level residence.

Construction of a Lower Body Negative Pressure Chamber

ERIC Educational Resources Information Center

Esch, Ben T. A; Scott, Jessica M.; Warburton, Darren E. R.

2007-01-01

Lower body negative pressure (LBNP) is an established and important technique used to physiologically stress the human body, particularly the cardiovascular system. LBNP is most often used to simulate gravitational stress, but it has also been used to simulate hemorrhage, alter preload, and manipulate baroreceptors. During experimentation, the…

Learning from a Computer Tutor with Natural Language Capabilities

ERIC Educational Resources Information Center

Michael, Joel; Rovick, Allen; Glass, Michael; Zhou, Yujian; Evens, Martha

2003-01-01

CIRCSIM-Tutor is a computer tutor designed to carry out a natural language dialogue with a medical student. Its domain is the baroreceptor reflex, the part of the cardiovascular system that is responsible for maintaining a constant blood pressure. CIRCSIM-Tutor's interaction with students is modeled after the tutoring behavior of two experienced…

Studies on the Release of Renin by Direct and Reflex Activation of Renal Sympathetic Nerves.

ERIC Educational Resources Information Center

Donald, David E.

1979-01-01

Presents data on release of renin during direct and indirect stimulation of renal nerves. Conclusions show that renin release is influenced by change in activity of carotid and cardiopulmonary baroreceptor systems, and excitation of discrete areas of brain and hypothalamus by changes in renal sympathetic nerve. (Author/SA)

Rostral dorsolateral pontine neurons with sympathetic nerve-related activity.

PubMed

Barman, S M; Gebber, G L; Kitchens, H

1999-02-01

Spike-triggered averaging, arterial pulse-triggered analysis, and coherence analysis were used to classify rostral dorsolateral pontine (RDLP) neurons into groups whose naturally occurring discharges were correlated to only the 10-Hz rhythm (n = 29), to only the cardiac-related rhythm (n = 15), and to both rhythms (n = 15) in inferior cardiac sympathetic nerve discharge (SND) of urethan-anesthetized cats. Most of the neurons with activity correlated to only the cardiac-related rhythm were located medial to the other two groups of neurons. The firing rates of most RDLP neurons with activity correlated to only the 10-Hz rhythm (9 of 12) or both rhythms (7 of 8) were decreased during baroreceptor reflex-induced inhibition of SND produced by aortic obstruction; thus, they are presumed to be sympathoexcitatory. The firing rates of four of seven RDLP neurons with activity correlated to only the cardiac-related rhythm increased during baroreceptor reflex activation; thus, they may be sympathoinhibitory. We conclude that the RDLP contains a functionally heterogeneous population of neurons with sympathetic nerve-related activity. These neurons could not be antidromically activated by stimulation of the thoracic spinal cord.

[The cardiovagal, cardiosympathetic and vasosympathetic arterial baroreflexes and the neural control of short-term blood pressure].

PubMed

Robles-Cabrera, Adriana; Michel-Chávez, Anaclara; Callejas-Rojas, Rodolfo C; Malamud-Kessler, Caroline; Delgado, Guillermo; Estañol-Vidal, Bruno

2014-12-01

The factors that control the blood pressure are punctually regulated to keep it in reference values. These are maintained through autoregulatory mechanisms, humoral, nervous and endothelial-related. The humoral mechanisms are complex and modify the long-term blood pressure, in the other hand, the neurogenic mechanisms, are reflexive and can be observed in beat-to-beat changes of blood pressure. The nervous cardiovascular reflexes are mediated by high-pressure and low-pressure baroreceptors, as cardiovagal, cardiosympathetic and vasosympathetic. The arterial baroreceptor are stimulated when the blood volume-ejected by the ventricle distend the arterial walls. The neural discharge travels to the autonomic centers in the brain stem and the result is the modification of the heart rate and the vascular smooth muscle tone. This sudden modification is the responsible of the beat-to-beat (short-term) blood pressure variability. A review was made on the history of the physiology and experiments of the cardiovagal, cardiosympathetic and vasosympathetic baroreflexes and its influence in the short-term blood pressure variability.

Recurrent syncope, orthostatic hypotension and volatile hypertension: think outside the box.

PubMed

Aung, Thein; Fan, Wuqiang; Krishnamurthy, Mahesh

2013-01-01

The baroreceptors in the neck and aortic arch are important regulators of sudden blood pressure changes. They are innervated by CN IX and X and synapse in the brainstem. Baroreceptor failure is an under-recognized cause of recurrent syncope, orthostatic hypotension, and volatile hypertension, which is refractory to and may in fact worsen with conventional treatments. Baroreflex failure can be the result of neck and chest radiation, head and neck surgery, and cerebrovascular accidents involving the brainstem nuclei. The management of baroreflex failure is a challenge since patient education, lifestyle changes, and family support are extremely important in managing blood pressure. Leg exercises and Thrombo-Embolic Deterrent Stockings (TED) stockings are important in treating orthostatic hypotension. Clonidine is the antihypertensive of choice for supine hypertension. Low-dose benzodiazepines are helpful in suppressing sympathetic surges. We have encountered two patients with baroreflex failure after chemotherapy and radiation to the neck or upper chest. Temporal relationship between symptoms onset and the history of head, neck, and upper chest radiation or trauma is important in reaching a diagnosis.

Effects of aerobic or resistance exercise training on cardiovascular autonomic function of subjects with type 2 diabetes: A pilot study.

PubMed

Bellavere, F; Cacciatori, V; Bacchi, E; Gemma, M L; Raimondo, D; Negri, C; Thomaseth, K; Muggeo, M; Bonora, E; Moghetti, P

2018-03-01

Both aerobic (AER) and resistance (RES) training improve metabolic control in patients with type 2 diabetes (T2DM). However, information on the effects of these training modalities on cardiovascular autonomic control is limited. Our aim was to compare the effects of AER and RES training on cardiovascular autonomic function in these subjects. Cardiovascular autonomic control was assessed by Power Spectral Analysis (PSA) of Heart Rate Variability (HRV) and baroreceptors function indexes in 30 subjects with T2DM, randomly assigned to aerobic or resistance training for 4 months. In particular, PSA of HRV measured the Low Frequency (LF) and High Frequency (HF) bands of RR variations, expression of prevalent sympathetic and parasympathetic drive, respectively. Furthermore, we measured the correlation occurring between systolic blood pressure and heart rate during a standardized Valsalva maneuver using two indexes, b2 and b4, considered an expression of baroreceptor sensitivity and peripheral vasoactive adaptations during predominant sympathetic and parasympathetic drive, respectively. After training, the LF/HF ratio, which summarizes the sympatho-vagal balance in HRV control, was similarly decreased in the AER and RES groups. After AER, b2 and b4 significantly improved. After RES, changes of b2 were of borderline significance, whereas changes of b4 did not reach statistical significance. However, comparison of changes in baroreceptor sensitivity indexes between groups did not show statistically significant differences. Both aerobic and resistance training improve several indices of the autonomic control of the cardiovascular system in patients with T2DM. Although these improvements seem to occur to a similar extent in both training modalities, some differences cannot be ruled out. NCT01182948, clinicaltrials.gov. Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Active recovery attenuates the fall in sweat rate but not cutaneous vascular conductance after supine exercise.

PubMed

Wilson, Thad E; Carter, Robert; Cutler, Michael J; Cui, Jian; Smith, Michael L; Crandall, Craig G

2004-02-01

The purpose of this study was to identify whether baroreceptor unloading was responsible for less efficient heat loss responses (i.e., skin blood flow and sweat rate) previously reported during inactive compared with active recovery after upright cycle exercise (Carter R III, Wilson TE, Watenpaugh DE, Smith ML, and Crandall CG. J Appl Physiol 93: 1918-1929, 2002). Eight healthy adults performed two 15-min bouts of supine cycle exercise followed by inactive or active (no-load pedaling) supine recovery. Core temperature (T(core)), mean skin temperature (T(sk)), heart rate, mean arterial blood pressure (MAP), thoracic impedance, central venous pressure (n = 4), cutaneous vascular conductance (CVC; laser-Doppler flux/MAP expressed as percentage of maximal vasodilation), and sweat rate were measured throughout exercise and during 5 min of recovery. Exercise bouts were similar in power output, heart rate, T(core), and T(sk). Baroreceptor loading and thermal status were similar during trials because MAP (90 +/- 4, 88 +/- 4 mmHg), thoracic impedance (29 +/- 1, 28 +/- 2 Omega), central venous pressure (5 +/- 1, 4 +/- 1 mmHg), T(core) (37.5 +/- 0.1, 37.5 +/- 0.1 degrees C), and T(sk) (34.1 +/- 0.3, 34.2 +/- 0.2 degrees C) were not significantly different at 3 min of recovery between active and inactive recoveries, respectively; all P > 0.05. At 3 min of recovery, chest CVC was not significantly different between active (25 +/- 6% of maximum) and inactive (28 +/- 6% of maximum; P > 0.05) recovery. In contrast, at this time point, chest sweat rate was higher during active (0.45 +/- 0.16 mg.cm(-2).min(-1)) compared with inactive (0.34 +/- 0.19 mg.cm(-2).min(-1); P < 0.05) recovery. After exercise CVC and sweat rate are differentially controlled, with CVC being primarily influenced by baroreceptor loading status while sweat rate is influenced by other factors.

Arterial Baroreceptor Reflex Counteracts Long-Term Blood Pressure Increase in the Rat Model of Renovascular Hypertension

PubMed Central

Tsyrlin, Vitaly A.; Galagudza, Michael M.; Kuzmenko, Nataly V.; Pliss, Michael G.; Rubanova, Nataly S.; Shcherbin, Yury I.

2013-01-01

Introduction The present study tested the hypothesis that long-term effects of baroreceptor activation might contribute to the prevention of persistent arterial blood pressure (BP) increase in the rat model of renovascular hypertension (HTN). Methods Repetitive arterial baroreflex (BR) testing was performed in normo- and hypertensive rats. The relationship between initial arterial BR sensitivity and severity of subsequently induced two-kidney one-clip (2K1C) renovascular HTN was studied in Wistar rats. Additionally, the time course of changes in systolic BP (SBP) and cardiac beat-to-beat (RR) interval was studied for 8 weeks after the induction of 2K1C renovascular HTN in the rats with and without sinoaortic denervation (SAD). In a separate experimental series, cervical sympathetic nerve activity (cSNA) was assessed in controls, 2K1C rats, WKY rats, and SHR. Results The inverse correlation between arterial BR sensitivity and BP was observed in the hypertensive rats during repetitive arterial BR testing. The animals with greater initial arterial BR sensitivity developed lower BP values after renal artery clipping than those with lower initial arterial BR sensitivity. BP elevation during the first 8 weeks of renal artery clipping in 2K1C rats was associated with decreased sensitivity of arterial BR. Although SAD itself resulted only in greater BP variability but not in persistent BP rise, the subsequent renal artery clipping invariably resulted in the development of sustained HTN. The time to onset of HTN was found to be shorter in the rats with SAD than in those with intact baroreceptors. cSNA was significantly greater in the 2K1C rats than in controls. Conclusions Arterial BR appears to be an important mechanism of long-term regulation of BP, and is believed to be involved in the prevention of BP rise in the rat model of renovascular HTN. PMID:23762254

Baroreceptor unloading does not limit forearm sweat rate during severe passive heat stress.

PubMed

Schlader, Zachary J; Gagnon, Daniel; Lucas, Rebekah A I; Pearson, James; Crandall, Craig G

2015-02-15

This study tested the hypothesis that sweat rate during passive heat stress is limited by baroreceptor unloading associated with heat stress. Two protocols were performed in which healthy subjects underwent passive heat stress that elicited an increase in intestinal temperature of ∼1.8°C. Upon attaining this level of hyperthermia, in protocol 1 (n = 10, 3 females) a bolus (19 ml/kg) of warm (∼38°C) isotonic saline was rapidly (5-10 min) infused intravenously to elevate central venous pressure (CVP), while in protocol 2 (n = 11, 5 females) phenylephrine was infused intravenously (60-120 μg/min) to return mean arterial pressure (MAP) to normothermic levels. In protocol 1, heat stress reduced CVP from 3.9 ± 1.9 mmHg (normothermia) to -0.6 ± 1.4 mmHg (P < 0.001), while saline infusion returned CVP to normothermic levels (5.1 ± 1.7 mmHg; P > 0.999). Sweat rate was elevated by heat stress (1.21 ± 0.44 mg·cm(-2)·min(-1)) but remained unchanged during rapid saline infusion (1.26 ± 0.47 mg·cm(-2)·min(-1), P = 0.5), whereas cutaneous vascular conductance increased from 77 ± 10 to 101 ± 20% of local heating max (P = 0.029). In protocol 2, MAP was reduced with heat stress from 85 ± 7 mmHg to 76 ± 8 mmHg (P = 0.048). Although phenylephrine infusion returned MAP to normothermic levels (88 ± 7 mmHg; P > 0.999), sweat rate remained unchanged during phenylephrine infusion (1.39 ± 0.22 vs. 1.41 ± 0.24 mg·cm(-2)·min(-1); P > 0.999). These data indicate that both cardiopulmonary and arterial baroreceptor unloading do not limit increases in sweat rate during passive heat stress. Copyright © 2015 the American Physiological Society.

Discharges of aortic and carotid sinus baroreceptors during spontaneous motor activity and pharmacologically evoked pressor interventions.

PubMed

Matsukawa, Kanji; Ishii, Kei; Kadowaki, Akito; Ishida, Tomoko; Idesako, Mitsuhiro; Liang, Nan

2014-07-01

Our laboratory has demonstrated that the cardiomotor component of aortic baroreflex is temporarily inhibited at the onset of spontaneous motor activity in decerebrate cats, without altering carotid sinus baroreflex. A reason for this dissociation may be attributed to a difference in the responses between aortic nerve activity (AoNA) and carotid sinus nerve activity (CsNA) during spontaneous motor activity. The stimulus-response curves of AoNA and CsNA against mean arterial blood pressure (MAP) were compared between the pressor interventions evoked by spontaneous motor activity and by intravenous administration of phenylephrine or norepinephrine, in which the responses in heart rate (HR) were opposite (i.e., tachycardia vs. baroreflex bradycardia), despite the identical increase in MAP of 34-40 mmHg. In parallel to the pressor response, mean AoNA and CsNA increased similarly by 78-81 and by 88 % of the baseline control, respectively, irrespective of whether the pressor response was evoked by spontaneous motor activity or by a pharmacological intervention. The slope of the stimulus-response curve of the mean AoNA became greater (P < 0.05) during spontaneous motor activity as compared to the pharmacological intervention. On the other hand, the stimulus-response curve of the mean CsNA and its slope were equal (P > 0.05) between the two pressor interventions. Furthermore, the slopes of the stimulus-response curves of both diastolic AoNA and CsNA (defined as the minimal value within a beat) exhibited a greater increase during spontaneous motor activity. All differences in the slopes of the stimulus-response curves were abolished by restraining HR at the intrinsic cardiac frequency. In conclusion, mean mass activities of both aortic and carotid sinus baroreceptors are able to encode the beat-by-beat changes in MAP not only at rest but also during spontaneous motor activity and spontaneous motor activity-related reduction of aortic baroreceptor activity is denied accordingly.

Neurogenic regulation of renal tubular sodium reabsorption.

PubMed

DiBona, G F

1977-08-01

The evidence supporting a role for direct neurogenic control of renal tubular sodium reabsorption is reviewed. Electron microscopic and fluorescence histochemical studies have demonstrated adrenergic nerve terminals in direct contact with basement membranes of mammalian (rat, dog, and monkey) renal tubular epithelial cells. Low-level direct or baroreceptor reflex stimulation of renal sympathetic nerves produces an increase in renal tubular sodium reabsorption without alterations in glomerular filtration rate, renal blood flow, or intrarenal distribution of blood flow. Antinatriuresis was prevented by prior treatment of the kidney with guanethidine or phenoxybenzamine. Rat kidney micropuncture studies have localized a site of enhanced tubular sodium reabsorption to the proximal tubule. Possible indirect mediation of the antinatriuresis by other humoral agents known to be released from the kidney on renal nerve stimulation (angiotensin II, prostaglandin) was excluded by experiments with appropriate blocking agents. The possible effects of anesthesia and uncertainties about the completeness of surgical renal denervation and other tubular segmental sites of action are critically analyzed. The clinical implications of this mechanism in pathologic conditions of sodium and water retention are discussed and and a prospectus for future work is presented.

Visual- and Vestibular-Autonomic Influence on Short-Term Cardiovascular Regulatory Mechanisms

NASA Technical Reports Server (NTRS)

Mullen, Thomas J.; Ramsdell, Craig D.

1999-01-01

This synergy project was a one-year effort conducted cooperatively by members of the NSBRI Cardiovascular Alterations and Neurovestibular Adaptation Teams in collaboration with NASA Johnson Space Center (JSC) colleagues. The objective of this study was to evaluate visual autonomic interactions on short-term cardiovascular regulatory mechanisms. Based on established visual-vestibular and vestibular-autonomic shared neural pathways, we hypothesized that visually induced changes in orientation will trigger autonomic cardiovascular reflexes. A second objective was to compare baroreflex changes during postural changes as measured with the new Cardiovascular System Identification (CSI) technique with those measured using a neck barocuff. While the neck barocuff stimulates only the carotid baroreceptors, CSI provides a measure of overall baroreflex responsiveness. This study involved a repeated measures design with 16 healthy human subjects (8 M, 8 F) to examine cardiovascular regulatory responses during actual and virtual head-upright tilts. Baroreflex sensitivity was first evaluated with subjects in supine and upright positions during actual tilt-table testing using both neck barocuff and CSI methods. The responses to actual tilts during this first session were then compared to responses during visually induced tilt and/or rotation obtained during a second session.

Validation of spontaneous assessment of baroreceptor reflex sensitivity and its relation to heart rate variability in the ovine fetus pre- and near-term.

PubMed

Frasch, Martin G; Müller, Thomas; Szynkaruk, Mark; Schwab, Matthias

2009-09-01

Assessment of baroreceptor reflex sensitivity (BRS) in the ovine fetus provides insight into autonomic cardiovascular regulation. Currently, assessment of BRS relies on vasoactive drugs, but this approach is limited by feasibility issues and by the nonphysiologic nature of the stimulus. Thus we aimed to validate the method of spontaneous BRS assessment against the reference method of using vasoactive drugs in preterm (0.76 gestation, n = 16) and near-term (0.86 gestation, n = 16) chronically instrumented ovine fetuses. The BRS measures derived from the spontaneous and reference methods correlated at both gestational ages (R = 0.67 +/- 0.03). The sequence method of spontaneous BRS measures also correlated both to the root mean square of standard deviations (RMSSD), which is a measure of fetal heart rate variability reflecting vagal modulation (R = 0.69 +/- 0.03), and to fetal body weight (R = 0.65 +/- 0.03), which is a surrogate for growth trajectory of each fetus. The methodology presented may aid in developing new models to study BRS and cardiovascular control in ovine fetus in the last trimester of pregnancy.

Acute increases in arterial blood pressure produced by occlusion of the abdominal aorta induces antinociception: peripheral and central substrates.

PubMed

Thurston, C L; Randich, A

1990-06-11

Occlusion of the abdominal aorta proximal to the renal arteries results in an increase in arterial blood pressure, inhibition of forepaw and hindpaw withdrawal to a noxious mechanical stimulus, and inhibition of the tail-flick reflex to noxious heat. Occlusion of the abdominal aorta distal to the renal arteries does not elevate arterial blood pressure and produces no antinociceptive effects. Occlusion of the vena cava lowers arterial blood pressure and produces no antinociception. The inhibitory effects of occlusion of the abdominal aorta depend upon activation of high pressure baroreceptors since bilateral sinoaortic denervation, but not bilateral vagotomy, eliminates the inhibition with respect to all behavioral measures. The inhibitory effects with respect to the tail-flick reflex also depend upon activation of a descending inhibitory system since reversible cold block of the spinal cord at the level of the second thoracic vertebra eliminates the antinociception. This antinociception is also eliminated following intrathecal administration of the noradrenergic receptor antagonist phentolamine, but not by intrathecal administration of either methysergide or naloxone. These data support the view that activation of high pressure baroreceptors by increases in arterial blood pressure produces antinociception via activation of a spinopetal noradrenergic system.

Baroreflex modulation of muscle sympathetic nerve activity during cold pressor test in humans

NASA Technical Reports Server (NTRS)

Cui, Jian; Wilson, Thad E.; Crandall, Craig G.

2002-01-01

The purpose of this project was to test the hypothesis that baroreceptor modulation of muscle sympathetic nerve activity (MSNA) and heart rate is altered during the cold pressor test. Ten subjects were exposed to a cold pressor test by immersing a hand in ice water for 3 min while arterial blood pressure, heart rate, and MSNA were recorded. During the second and third minute of the cold pressor test, blood pressure was lowered and then raised by intravenous bolus infusions of sodium nitroprusside and phenylephrine HCl, respectively. The slope of the relationship between MSNA and diastolic blood pressure was more negative (P < 0.005) during the cold pressor test (-244.9 +/- 26.3 units x beat(-1) x mmHg(-1)) when compared with control conditions (-138.8 +/- 18.6 units x beat(-1) x mmHg(-1)), whereas no significant change in the slope of the relationship between heart rate and systolic blood pressure was observed. These data suggest that baroreceptors remain capable of modulating MSNA and heart rate during a cold pressor test; however, the sensitivity of baroreflex modulation of MSNA is elevated without altering the sensitivity of baroreflex control of heart rate.

Factor analytic reduction of the carotid-cardiac baroreflex parameters

NASA Technical Reports Server (NTRS)

Ludwig, David A.

1989-01-01

An accepted method for measuring the responsiveness of the carotid-cardiac baroreflex to arterial pressure changes is to artificially stimulate the baroreceptors in the neck. This is accomplished by using a pressurized neck cuff which constricts and distends the carotid artery and subsequently stimulates the baroreceptors. Nine physiological responses to this type of stimulation are quantified and used as indicators of the baroreflex. Thirty male humans between the ages 27 and 46 underwent the carotid-cardiac baroreflex test. The data for the nine response parameters were analyzed by principle component factor analysis. The results of this analysis indicated that 93 percent of the total variance across all nine parameters could be explained in four dimensions. Examination of the factor loadings following an orthogonal rotation of the principle components indicated four well defined dimensions. The first two dimensions reflected location points for R-R interval and carotid distending pressure respectively. The third dimension was composed of measures reflecting the gain of the reflex. The fourth dimension was the ratio of the resting R-R interval to R-R interval during simulated hypertension. The data suggests that the analysis of all nine baroreflex parameters is redundant.

Chewing-induced hypertension in afferent baroreflex failure: a sympathetic response?

PubMed

Fuente Mora, Cristina; Norcliffe-Kaufmann, Lucy; Palma, Jose-Alberto; Kaufmann, Horacio

2015-11-01

What is the central question of this study? Our goal was to understand the autonomic responses to eating in patients with congenital afferent baroreflex failure, by documenting changes in blood pressure and heart rate with chewing, swallowing and stomach distension. What is the main finding and its importance? Patients born with lesions in the afferent baroreceptor pathways have an exaggerated pressor response to food intake. This appears to be a sympathetically mediated response, triggered by chewing, that occurs independently of swallowing or distension of the stomach. The chewing-induced pressor response may be useful as a counter-manoeuvre to prevent orthostatic hypotension in these patients. Familial dysautonomia (FD) is a rare genetic disease with extremely labile blood pressure resulting from baroreflex deafferentation. Patients have marked surges in sympathetic activity, frequently surrounding meals. We conducted an observational study to document the autonomic responses to eating in patients with FD and to determine whether sympathetic activation was caused by chewing, swallowing or stomach distension. Blood pressure and R-R intervals were measured continuously while chewing gum (n = 15), eating (n = 20) and distending the stomach by percutaneous endoscopic gastrostomy tube feeding (n = 9). Responses were compared with those of normal control subjects (n = 10) and of patients with efferent autonomic failure (n = 10) who have chronically impaired sympathetic outflow. In patients with FD, eating was associated with a marked but transient pressor response (P < 0.0001) and additional signs of sympathetic activation, including tachycardia, diaphoresis and flushing of the skin. Chewing gum evoked a similar increase in blood pressure that was higher in patients with FD than in control subjects (P = 0.0001), but was absent in patients with autonomic failure. In patients with FD, distending the stomach by percutaneous endoscopic gastrostomy tube feeding failed to elicit a pressor response. The results provide indirect evidence that chewing triggers sympathetic activation. The increase in blood pressure is exaggerated in patients with FD as a result of blunted afferent baroreceptor signalling. The chewing pressor response may be useful as a counter-manoeuvre to raise blood pressure and prevent symptomatic orthostatic hypotension in patients with FD. © 2015 The Authors. Experimental Physiology © 2015 The Physiological Society.

The role of non-thermal factors in the control of skin blood flow during exercise.

PubMed Central

Nielsen, B.

1986-01-01

Arguments in favor of the importance of non-thermal factors in the control of skin circulation are presented. Such factors include exercise, posture, water and electrolyte balance, state of training, and acclimatization. The first three factors probably elicit their effects via high- and low-pressure baroreceptors, while the mechanisms involved for the remainder are unknown. PMID:3529655

Neurohumoral Mechanisms Associated with Orthostasis: Reaffirmation of the Significant Contribution of the Heart Rate Response

DTIC Science & Technology

2014-06-30

baroreceptor stimu- lation (i.e., lower arterial blood pressure ) suggests an association between a depressed baroreflex response and development of...orthostatic tolerance, blood pressure regulation, lower body negative pressure , parasympathetic activity, sympathetic activity, propranolol, atropine...body negative pressure (LBNP) so that comparisons of physiology in individuals with high and low tolerance to central hypovolemia could be studied at

Venous and autonomic function in formerly pre-eclamptic women and BMI-matched controls.

PubMed

Heidema, Wieteke M; van Drongelen, Joris; Spaanderman, Marc E A; Scholten, Ralph R

2018-03-25

Pre-pregnancy reduced plasma volume increases the risk on subsequent pre-eclamptic pregnancy. Reduced plasma volume is thought to reflect venous reserve capacity, especially when venous vasculature is constricted and sympathetic tone is elevated. As obesity might affect these variables and also relates to pre-eclampsia, increased body weight may underlie these observations. We hypothesized that the relationship between reduced venous reserve and preeclampsia is independent of body mass index (BMI). We compared the non-pregnant venous reserve capacity in 30 formerly pre-eclamptic women, equally divided in 3 BMI-classes (BMI 19.5-24.9, BMI 25-29.9, BMI ≥30) to 30 controls. Cases and controls were matched for BMI, age and parity. The venous reserve capacity was quantified by assessing plasma volume and venous compliance. The autonomic nervous system regulating the venous capacitance was evaluated with heart rate variability analysis in resting supine position and during positive head-up tilt (HUT). Formerly pre-eclamptic women had in supine position lower plasma volume than controls (1339 ± 79 vs 1547 ± 139 ml/m 2 (p<0.001)), lower venous compliance (0.04 ± 0.02 vs 0.07 ± 0.02 ml/dl/mmHg (p<0.001)), higher sympathetic tone (1.9 ± 0.1 vs 1.2 ± 0.7 mmHg 2 (p=0.002)) and lower baroreceptor sensitivity (8.7 ± 3.8 vs 19.0 ± 1.7 ms/mmHg (p<0.001)). During HUT, women with a history of preeclampsia have less modulatory capacity over venous compliance and baroreceptor sensitivity, while heart rate and sympathetic tone remain consistently higher. Women with a history of pre-eclampsia have, compared to BMI-matched controls, reduced venous reserve capacity. This is reflected by lower plasma volume and venous compliance, the autonomic balance is shifted towards sympathetic dominance and lower baroreceptor sensitivity. This suggests that not BMI, but underlying reduced venous reserve relates to pre-eclampsia. This article is protected by copyright. All rights reserved.

Phase transitions in the common brainstem and related systems investigated by nonstationary time series analysis.

PubMed

Lambertz, M; Vandenhouten, R; Grebe, R; Langhorst, P

2000-01-14

Neuronal activities of the reticular formation (RF) of the lower brainstem and the nucleus tractus solitarii (NTS, first relay station of baroreceptor afferents) were recorded together in the anesthized dog with related parameters of EEG, respiration and cardiovascular system. The RF neurons are part of the common brainstem system (CBS) which participates in regulation and coordination of cardiovascular, respiratory, somatomotor systems, and vigilance. Multiple time series of these physiological subsystems yield useful information about internal dynamic coordination of the organism. Essential problems are nonlinearity and instationarity of the signals, due to the dynamic complexity of the systems. Several time-resolving methods are presented to describe nonlinear dynamic couplings in the time course, particularly during phase transitions. The methods are applied to the recorded signals representing the complex couplings of the physiological subsystems. Phase transitions in these systems are detected by recurrence plots of the instationary signals. The pointwise transinformation and the pointwise conditional coupling divergence are measures of the mutual interaction of the subsystems in the state space. If the signals show marked rhythms, instantaneous frequencies and their shiftings are demonstrated by time frequency distributions, and instantaneous phase differences show couplings of oscillating subsystems. Transient signal components are reconstructed by wavelet packet time selective transient reconstruction. These methods are useful means for analyzing coupling characteristics of the complex physiological system, and detailed analyses of internal dynamic coordination of subsystems become possible. During phase transitions of the functional organization (a) the rhythms of the central neuronal activities and the peripheral systems are altered, (b) changes in the coupling between CBS neurons and cardiovascular signals, respiration and the EEG, and (c) between NTS neurons (influenced by baroreceptor afferents) and CBS neurons occur, and (d) the processing of baroreceptor input at the NTS neurons changes. The results of this complex analysis, which could not be done formerly in this manner, confirm and complete former investigations on the dynamic organization of the CBS with its changing relations to peripheral and other central nervous subsystems.

Increased Dietary Salt Changes Baroreceptor Sensitivity and Intrarenal Renin-Angiotensin System in Goldblatt Hypertension.

PubMed

Shimoura, Caroline G; Lincevicius, Gisele S; Nishi, Erika E; Girardi, Adriana C C; Simon, Karin A; Bergamaschi, Cassia T; Campos, Ruy R

2017-01-01

Renovascular hypertension (2-kidney 1-clip model (2K1C)) is characterized by renin-angiotensin system (RAS) activation. Increased Angiotensin II (AngII) leads to sympathoexcitation, oxidative stress, and alterations in sodium and water balance. The aim of this study was to evaluate whether a discrete increase in sodium chloride intake in 2K1C rats leads to changes in cardiovascular and autonomic function, oxidative stress, and renin angiotensin aldosterone system. After 4 weeks of induction of hypertension, rats were fed a normal sodium diet (0.4% NaCl) or a high-sodium diet (2% NaCl) for 2 consecutive weeks. Experiments were carried out for 6 weeks after clipping. Mean arterial pressure (MAP), renal sympathetic nerve activity (rSNA), arterial baroreflex control of rSNA, and heart rate (HR) were assessed. Thiobarbituric acid reactive substances and glutathione were measured as indicators of systemic oxidative stress. Angiostensin-converting enzyme (ACE), ACE2, and angiotensinogen were evaluated in clipped and unclipped kidneys as also urinary angiotensinogen and plasma renin activity. Angiotensinogen, plasma renin activity (PRA) and angiotensin-converting enzyme (ACE) and ACE2 in clipped and unclipped kidneys were evaluated. High-sodium diet did not change systemic oxidative stress, and basal values of MAP, HR, or rSNA; however, increased renal (-0.7±0.2 vs. -1.5±0.1 spikes/s/mm Hg) and cardiac (-0.9±0.14 vs. -1.5±0.14 bpm/mm Hg) baroreceptor reflex sensitivity in 2K1C rats. Although there was no alteration in PRA, a high-salt diet significantly decreased urinary angiotensinogen, ACE, and ACE2 expressions in the clipped and unclipped kidneys. Increased arterial baroreceptor control associated with a suppression of the intrarenal RAS in the 2K1C rats on high-salt diet provide a salt-resistant effect on hypertension and sympathoexcitation in renovascular hypertensive rats. © American Journal of Hypertension, Ltd 2016. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Heart rate and cardiovascular variability at high altitude.

PubMed

Bernardi, Luciano

2007-01-01

Primary effect of hypobaric hypoxia on the circulation is a direct vasodilatory effect on the peripheral circulation, which is normally prevented by a sympathetic-induced vasoconstriction. Most of the clinical methods for testing the baroreflex sensitivity only evaluate the cardiac-vagal branch of the baroreflex, but at altitude it is also of importance to test the vascular effects of the baroreflex. This is possible by directly measuring sympathetic efferent activity (by microneurography) or by directly stimulating the carotid baroreceptors (by the neck suction). By cyclical stimulation of the carotid baroreceptors, neck suction-synchronous reflex oscillations could be observed in a large number of signals, including RR interval, blood pressure, microcirculation, muscle sympathetic nerve activity. An increase in fluctuations at the same frequency of the stimulus was considered an evidence of the ability of the carotid baroreceptors to modulate a given physiological signal. The sinusoidal neck suction was set at 0.10 Hz (low-frequency stimulation), or to a frequency close to- but distinct from- the respiratory signal (0.20 Hz, high frequency stimulation, whereas respiration was fixed to 0.25 Hz). The method is noninvasive, without side effects connected to use of drugs, and evaluates both the response to the heart and to the blood pressure of the baroreflex. The altitude-induced sympathetic activation was evidenced in sea level natives by a decrease in RR interval, an increase in blood pressure and in the 0.1Hz components of cardiac and vascular signals. The arterial baroflex was active on RR interval and also in blood pressure, even during acute exposure to high altitude, thus indicating that it was counteracting and modulating the increase in sympathetic tone. Signs of exaggerated sympathetic activation were evident in subjects with severe acute mountain sickness, while successful therapy was associated with a restoration of autonomic modulation. Conversely, sympathetic activation was reduced( and baroflex enhanced) in himalayan high altitude natives. In conclusion, a comprehensive understanding of the mechanism taking place during the adaptation to high altitude requires a multisignal approach, also integrated with equipment designed to provide specific provocative tests, such as those necessary to measure the cardiorespiratory interactions.

Does the Menstrual Cycle Influence the Sensitivity of Vagally Mediated Baroreflexes?

DTIC Science & Technology

2002-06-01

the study. Baroreflex measurements We applied sequential neck pressure and suction to modulate carotid baroreceptors , and recorded the re- sulting...the day menses began was designated day 0). At the beginning of each data collection period, sphygmomanometric blood pressures were re- corded with...between arterial pressure and R-R interval, suggesting that high levels of sympathetic nervous activity or of plasma noradrenaline may override or inhibit

Inspiratory Resistance as a Potential Treatment for Orthostatic Intolerance and Hemorrhagic Shock

DTIC Science & Technology

2005-04-01

central blood volume by forcing the thoracic muscles to develop increased negative pressure , thus drawing venous blood from extrathoracic cavi- ties...cardiac baroreflex sensitivity associated with re- ductions of central blood volume during lower body negative pressure (LBNP) are reversed with...9:621–26. 8. Chapleau MW, Abboud FM. Contrasting effects of static and pulsatile pressure on carotid baroreceptor activity in dogs. Circ Res 1987; 61

Long-Term Monitoring of Physical Behavior Reveals Different Cardiac Responses to Physical Activity among Subjects with and without Chronic Neck Pain.

PubMed

Hallman, David M; Mathiassen, Svend Erik; Lyskov, Eugene

2015-01-01

We determined the extent to which heart rate variability (HRV) responses to daily physical activity differ between subjects with and without chronic neck pain. Twenty-nine subjects (13 women) with chronic neck pain and 27 age- and gender-matched healthy controls participated. Physical activity (accelerometry), HRV (heart rate monitor), and spatial location (Global Positioning System (GPS)) were recorded for 74 hours. GPS data were combined with a diary to identify periods of work and of leisure at home and elsewhere. Time- and frequency-domain HRV indices were calculated and stratified by period and activity type (lying/sitting, standing, or walking). ANCOVAs with multiple adjustments were used to disclose possible group differences in HRV. The pain group showed a reduced HRV response to physical activity compared with controls (p = .001), according to the sympathetic-baroreceptor HRV index (LF/HF, ratio between low- and high-frequency power), even after adjustment for leisure time physical activity, work stress, sleep quality, mental health, and aerobic capacity (p = .02). The parasympathetic response to physical activity did not differ between groups. Relying on long-term monitoring of physical behavior and heart rate variability, we found an aberrant sympathetic-baroreceptor response to daily physical activity among subjects with chronic neck pain.

The effect of (+)-lysergic acid diethylamide and other drugs on the carotid sinus reflex

PubMed Central

Ginzel, K. H.

1958-01-01

In cats, lysergic acid diethylamide (LSD) selectively blocked the reflex blood pressure rise following carotid chemoreceptor stimulation. It also reduced or abolished the chemoreceptor component of the pressor response to occlusion of the common carotid arteries. It did not inhibit the respiratory reflexes arising from the carotid chemoreceptors, unless spontaneous respiration was interfered with as a whole. The site of action was central, probably below the intercollicular level, regardless of whether the drug was administered by the intravenous route or into the lateral ventricle of the brain. LSD did not block the baroreceptor depressor reflex elicited by stimulation of one carotid sinus nerve. LSD frequently caused the systemic pressure to fall, even after vagotomy and atropine, and this effect might account for the occasional reduction of the baroreceptor component of the carotid occlusion response. On the other hand, no relationship was found between the action of LSD on vasomotor tone and its blocking effect on the chemoreceptor pressor reflex. Some derivatives of LSD produced effects similar to those described for LSD, whether or not they possessed a psychotropic action in man, and independently of their efficiency as antagonists to 5-hydroxytryptamine. Of a series of compounds chemically unrelated to LSD, chlorpromazine was found to block the chemoreceptor pressor rise after intracerebroventricular injection. PMID:13584725

The effect of (+)-lysergic acid diethylamide and other drugs on the carotid sinus reflex.

PubMed

GINZEL, K H

1958-09-01

In cats, lysergic acid diethylamide (LSD) selectively blocked the reflex blood pressure rise following carotid chemoreceptor stimulation. It also reduced or abolished the chemoreceptor component of the pressor response to occlusion of the common carotid arteries. It did not inhibit the respiratory reflexes arising from the carotid chemoreceptors, unless spontaneous respiration was interfered with as a whole. The site of action was central, probably below the intercollicular level, regardless of whether the drug was administered by the intravenous route or into the lateral ventricle of the brain.LSD did not block the baroreceptor depressor reflex elicited by stimulation of one carotid sinus nerve. LSD frequently caused the systemic pressure to fall, even after vagotomy and atropine, and this effect might account for the occasional reduction of the baroreceptor component of the carotid occlusion response. On the other hand, no relationship was found between the action of LSD on vasomotor tone and its blocking effect on the chemoreceptor pressor reflex.Some derivatives of LSD produced effects similar to those described for LSD, whether or not they possessed a psychotropic action in man, and independently of their efficiency as antagonists to 5-hydroxytryptamine. Of a series of compounds chemically unrelated to LSD, chlorpromazine was found to block the chemoreceptor pressor rise after intracerebroventricular injection.

Effect of hydration on plasma vasopressin, renin, and aldosterone responses to head-up tilt

NASA Technical Reports Server (NTRS)

Harrison, M. H.; Geelen, G.; Keil, L. C.; Wade, C. A.; Hill, L. C.

1986-01-01

If plasma vasopressin (PVP), plasma renin (PRA), and plasma aldosterone (PA) responses to change in posture are mediated only by alterations in intrathoracic baroreceptor activity hydration status should have minimal influence on these responses. To test this hypothesis, six male subjects underwent 45 min of 70 deg head-up tilt (HUT) following 26 h dehydration, and again, 105 min later, following rehydration. Compared with preceding supine hydrated control values, PVP, PRA, and PA increased (p less than 0.001) during dehydrated HUT, but only PVP and PRA increased during rehydrated HUT (p less than 0.001). The dissociation during rehydrated HUT of PRA and PA may have been related more to the reduction (p less than 0.001) in plasma potassium concentration than to the accompanying decrease (p less than 0.001) in plasma osmolality and sodium concentration. Although increases in PVP and PRA during HUT were attenuated (p less than 0.01) following rehydration, this attenuation was associated with the absence of symptoms of overt hypotension following rehydration. However, since rehydration did not abolish the increases in PVP and PRA induced by HUT, it is concluded that the present observations support the concept of intrathoracic baroreceptor involvement in the regulation of vasopressin secretion and renin release.

Cardiac-locked bursts of muscle sympathetic nerve activity are absent in familial dysautonomia

PubMed Central

Macefield, Vaughan G; Norcliffe-Kaufmann, Lucy; Axelrod, Felicia B; Kaufmann, Horacio

2013-01-01

Familial dysautonomia (Riley–Day syndrome) is an hereditary sensory and autonomic neuropathy (HSAN type III), expressed at birth, that is associated with reduced pain and temperature sensibilities and absent baroreflexes, causing orthostatic hypotension as well as labile blood pressure that increases markedly during emotional excitement. Given the apparent absence of functional baroreceptor afferents, we tested the hypothesis that the normal cardiac-locked bursts of muscle sympathetic nerve activity (MSNA) are absent in patients with familial dysautonomia. Tungsten microelectrodes were inserted percutaneously into muscle or cutaneous fascicles of the common peroneal nerve in 12 patients with familial dysautonomia. Spontaneous bursts of MSNA were absent in all patients, but in five patients we found evidence of tonically firing sympathetic neurones, with no cardiac rhythmicity, that increased their spontaneous discharge during emotional arousal but not during a manoeuvre that unloads the baroreceptors. Conversely, skin sympathetic nerve activity (SSNA), recorded in four patients, appeared normal. We conclude that the loss of phasic bursts of MSNA and the loss of baroreflex modulation of muscle vasoconstrictor drive contributes to the poor control of blood pressure in familial dysautonomia, and that the increase in tonic firing of muscle vasoconstrictor neurones contributes to the increase in blood pressure during emotional excitement. PMID:23165765

Abnormalities in substance P neurokinin-1 receptor binding in key brainstem nuclei in sudden infant death syndrome related to prematurity and sex.

PubMed

Bright, Fiona M; Vink, Robert; Byard, Roger W; Duncan, Jhodie R; Krous, Henry F; Paterson, David S

2017-01-01

Sudden infant death syndrome (SIDS) involves failure of arousal to potentially life threatening events, including hypoxia, during sleep. While neuronal dysfunction and abnormalities in neurotransmitter systems within the medulla oblongata have been implicated, the specific pathways associated with autonomic and cardiorespiratory failure are unknown. The neuropeptide substance P (SP) and its tachykinin neurokinin-1 receptor (NK1R) have been shown to play an integral role in the modulation of homeostatic function in the medulla, including regulation of respiratory rhythm generation, integration of cardiovascular control, and modulation of the baroreceptor reflex and mediation of the chemoreceptor reflex in response to hypoxia. Abnormalities in SP neurotransmission may therefore result in autonomic dysfunction during sleep and contribute to SIDS deaths. [125I] Bolton Hunter SP autoradiography was used to map the distribution and density of the SP, NK1R to 13 specific nuclei intimately related to cardiorespiratory function and autonomic control in the human infant medulla of 55 SIDS and 21 control (non-SIDS) infants. Compared to controls, SIDS cases exhibited a differential, abnormal developmental profile of the SP/NK1R system in the medulla. Furthermore the study revealed significantly decreased NK1R binding within key medullary nuclei in SIDS cases, principally in the nucleus tractus solitarii (NTS) and all three subdivisions of the inferior portion of the olivo-cerebellar complex; the principal inferior olivary complex (PIO), medial accessory olive (MAO) and dorsal accessory olive (DAO). Altered NK1R binding was significantly influenced by prematurity and male sex, which may explain the increased risk of SIDS in premature and male infants. Abnormal NK1R binding in these medullary nuclei may contribute to the defective interaction of critical medullary mechanisms with cerebellar sites, resulting in an inability of a SIDS infant to illicit appropriate respiratory and motor responses to life threatening challenges during sleep. These observations support the concept that abnormalities in a multi-neurotransmitter network within key nuclei of the medullary homeostatic system may underlie the pathogenesis of a subset of SIDS cases.

Abnormalities in substance P neurokinin-1 receptor binding in key brainstem nuclei in sudden infant death syndrome related to prematurity and sex

PubMed Central

Vink, Robert; Byard, Roger W.; Duncan, Jhodie R.; Krous, Henry F.; Paterson, David S.

2017-01-01

Sudden infant death syndrome (SIDS) involves failure of arousal to potentially life threatening events, including hypoxia, during sleep. While neuronal dysfunction and abnormalities in neurotransmitter systems within the medulla oblongata have been implicated, the specific pathways associated with autonomic and cardiorespiratory failure are unknown. The neuropeptide substance P (SP) and its tachykinin neurokinin-1 receptor (NK1R) have been shown to play an integral role in the modulation of homeostatic function in the medulla, including regulation of respiratory rhythm generation, integration of cardiovascular control, and modulation of the baroreceptor reflex and mediation of the chemoreceptor reflex in response to hypoxia. Abnormalities in SP neurotransmission may therefore result in autonomic dysfunction during sleep and contribute to SIDS deaths. [125I] Bolton Hunter SP autoradiography was used to map the distribution and density of the SP, NK1R to 13 specific nuclei intimately related to cardiorespiratory function and autonomic control in the human infant medulla of 55 SIDS and 21 control (non-SIDS) infants. Compared to controls, SIDS cases exhibited a differential, abnormal developmental profile of the SP/NK1R system in the medulla. Furthermore the study revealed significantly decreased NK1R binding within key medullary nuclei in SIDS cases, principally in the nucleus tractus solitarii (NTS) and all three subdivisions of the inferior portion of the olivo-cerebellar complex; the principal inferior olivary complex (PIO), medial accessory olive (MAO) and dorsal accessory olive (DAO). Altered NK1R binding was significantly influenced by prematurity and male sex, which may explain the increased risk of SIDS in premature and male infants. Abnormal NK1R binding in these medullary nuclei may contribute to the defective interaction of critical medullary mechanisms with cerebellar sites, resulting in an inability of a SIDS infant to illicit appropriate respiratory and motor responses to life threatening challenges during sleep. These observations support the concept that abnormalities in a multi-neurotransmitter network within key nuclei of the medullary homeostatic system may underlie the pathogenesis of a subset of SIDS cases. PMID:28931039

Congestive renal failure: the pathophysiology and treatment of renal venous hypertension.

PubMed

Ross, Edward A

2012-12-01

Longstanding experimental evidence supports the role of renal venous hypertension in causing kidney dysfunction and "congestive renal failure." A focus has been heart failure, in which the cardiorenal syndrome may partly be due to high venous pressure, rather than traditional mechanisms involving low cardiac output. Analogous diseases are intra-abdominal hypertension and renal vein thrombosis. Proposed pathophysiologic mechanisms include reduced transglomerular pressure, elevated renal interstitial pressure, myogenic and neural reflexes, baroreceptor stimulation, activation of sympathetic nervous and renin angiotensin aldosterone systems, and enhanced proinflammatory pathways. Most clinical trials have addressed the underlying condition rather than venous hypertension per se. Interpreting the effects of therapeutic interventions on renal venous congestion are therefore problematic because of such confounders as changes in left ventricular function, cardiac output, and blood pressure. Nevertheless, there is preliminary evidence from small studies of intense medical therapy or extracorporeal ultrafiltration for heart failure that there can be changes to central venous pressure that correlate inversely with renal function, independently from the cardiac index. Larger more rigorous trials are needed to definitively establish under what circumstances conventional pharmacologic or ultrafiltration goals might best be directed toward central venous pressures rather than left ventricular or cardiac output parameters. Copyright © 2012 Elsevier Inc. All rights reserved.

The Baroreflex as a Long-Term Controller of Arterial Pressure

PubMed Central

Iliescu, Radu

2015-01-01

Because of resetting, a role for baroreflexes in long-term control of arterial pressure has been commonly dismissed in the past. However, in recent years, this perspective has changed. Novel approaches for determining chronic neurohormonal and cardiovascular responses to natural variations in baroreceptor activity and to electrical stimulation of the carotid baroreflex indicate incomplete resetting and sustained responses that lead to long-term alterations in sympathetic activity and arterial pressure. PMID:25729060

Baroreflex-mediated heart rate and vascular resistance responses 24 h after maximal exercise

NASA Technical Reports Server (NTRS)

Convertino, Victor A.

2003-01-01

INTRODUCTION: Plasma volume, heart rate (HR) variability, and stimulus-response relationships for baroreflex control of forearm vascular resistance (FVR) and HR were studied in eight healthy men after and without performing a bout of maximal exercise to test the hypotheses that acute expansion of plasma volume is associated with 1) reduction in baroreflex-mediated HR response, and 2) altered operational range for central venous pressure (CVP). METHODS: The relationship between stimulus (DeltaCVP) and vasoconstrictive reflex response (DeltaFVR) during unloading of cardiopulmonary baroreceptors was assessed with lower-body negative pressure (LBNP, 0, -5, -10, -15, -20 mm Hg). The relationship between stimulus (Deltamean arterial pressure (MAP)) and cardiac reflex response (DeltaHR) during loading of arterial baroreceptors was assessed with steady-state infusion of phenylephrine (PE) designed to increase MAP by 15 mm Hg alone and during application of LBNP (PE+LBNP) and neck pressure (PE+LBNP+NP). Measurements of vascular volume and autonomic baroreflex responses were conducted on two different test days, each separated by at least 1 wk. On one day, baroreflex response was tested 24 h after graded cycle exercise to volitional exhaustion. On another day, measurement of baroreflex response was repeated with no exercise (control). The order of exercise and control treatments was counterbalanced. RESULTS: Baseline CVP was elevated (P = 0.04) from a control value of 10.5 +/- 0.4 to 12.3 +/- 0.4 mm Hg 24 h after exercise. Average DeltaFVR/DeltaCVP during LBNP was not different (P = 0.942) between the exercise (-1.35 +/- 0.32 pru x mm Hg-1) and control (-1.32 +/- 0.36 pru x mm Hg-1) conditions. However, maximal exercise caused a shift along the reflex response relationship to a higher CVP and lower FVR. HR baroreflex response (DeltaHR/DeltaMAP) to PE+LBNP+NP was lower (P = 0.015) after maximal exercise (-0.43 +/- 0.15 beats x min-1 x mm Hg-1) compared with the control condition (-0.83 +/- 0.14 beats x min-1 x mm Hg-1). CONCLUSION: Expansion of vascular volume after acute exercise is associated with altered operational range for CVP and reduced HR response to arterial baroreceptor stimulation.

Baroreflex regulation of blood pressure during dynamic exercise

NASA Technical Reports Server (NTRS)

Raven, P. B.; Potts, J. T.; Shi, X.; Blomqvist, C. G. (Principal Investigator)

1997-01-01

From the work of Potts et al. Papelier et al. and Shi et al. it is readily apparent that the arterial (aortic and carotid) baroreflexes are reset to function at the prevailing ABP of exercise. The blood pressure of exercise is the result of the hemodynamic (cardiac output and TPR) responses, which appear to be regulated by two redundant neural control systems, "Central Command" and the "exercise pressor reflex". Central Command is a feed-forward neural control system that operates in parallel with the neural regulation of the locomotor system and appears to establish the hemodynamic response to exercise. Within the central nervous system it appears that the HLR may be the operational site for Central Command. Specific neural sites within the HLR have been demonstrated in animals to be active during exercise. With the advent of positron emission tomography (PET) and single-photon emission computed tomography (SPECT), the anatomical areas of the human brain related to Central Command are being mapped. It also appears that the Nucleus Tractus Solitarius and the ventrolateral medulla may serve as an integrating site as they receive neural information from the working muscles via the group III/IV muscle afferents as well as from higher brain centers. This anatomical site within the CNS is now the focus of many investigations in which arterial baroreflex function, Central Command and the "exercise pressor reflex" appear to demonstrate inhibitory or facilitatory interaction. The concept of whether Central Command is the prime mover in the resetting of the arterial baroreceptors to function at the exercising ABP or whether the resetting is an integration of the "exercise pressor reflex" information with that of Central Command is now under intense investigation. However, it would be justified to conclude, from the data of Bevegard and Shepherd, Dicarlo and Bishop, Potts et al., and Papelier et al. that the act of exercise results in the resetting of the arterial baroreflex. In addition, if, as we have proposed, the cardiopulmonary baroreceptors primarily monitors and reflexly regulates cardiac filling volume, it would seem from the data of Mack et al. and Potts et al. that the cardiopulmonary baroreceptor is also reset at the beginning of exercise. Therefore, investigations of the neural mechanisms of regulation involving Central Command and cardiopulmonary afferents, similar to those being undertaken for the arterial baroreflex, need to be established.

BIOCONAID System (Bionic Control of Acceleration Induced Dimming).

DTIC Science & Technology

1981-07-01

Howard, P. , "The Physiology of Positive Acceleration," Chapter 23 in A Textbook of Aviation Physiology, Edited by J. A. Gilles, Pergamon Press...of the Carotid Sinus Baroreceptor Process in a Dog ," IEEE Trans. Biomed. Engineering, BME , Vol. 22, No. 3, pp. 502-507, 1975. 16. Leverett, S. D...Electromyogram, ’ IEEE Transactions on Biomedical Engineering. Vol. BME -24, No. 5, pp. 417-424, 1977. 26. Stoll, Alice M., "Human Tolerance to Positive G as

Experimenting With Baroreceptor Reflexes

NASA Technical Reports Server (NTRS)

Eckberg, Dwain L.; Goble, Ross L.

1988-01-01

Carotid arteries stimulated by pressure or suction on neck. Baro-Cuff is silicone-rubber chamber that fits on front of subject's neck. Electronic system, stepping motor, bellows, and umbilical tube furnish controlled pressure to chamber. Pressure sensor provides feedback to microprocessor in electronic system. Developed to study blood-pressure-reflex responses of astronauts in outer space. Useful for terrestrial studies of patients with congestive heart failure, chronic diabetes mellitus, and other conditions in which blood-pressure-reflex controls behave abnormally.

The Effect of Aircrew Age on +Gz Tolerance as Measured in a Human-Use Centrifuge

DTIC Science & Technology

2000-08-01

acceleration stress (+Gz). This type of acceleration displaces blood in the head to foot direction. As the pressure in the vessels of the lower body... blood in the lower extremities translates into reduced cardiac output provoking the cardiovascular system, mainly by the activation of baroreceptor ...This pressure aids the cardiovascular system to maintain adequate blood flow to the CNS by forcing blood towards the head "counteracting" the effect of

Effects of acute hyperthermia on the carotid baroreflex control of heart rate in humans

NASA Astrophysics Data System (ADS)

Yamazaki, F.; Sagawa, S.; Torii, R.; Endo, Y.; Shiraki, K.

The purpose of this study was to examine the effect of hyperthermia on the carotid baroreceptor-cardiac reflexes in humans. Nine healthy males underwent acute hyperthermia (esophageal temperature 38.0° C) produced by hot water-perfused suits. Beat-to-beat heart rate (HR) responses were determined during positive and negative R-wave-triggered neck pressure steps from +40 to -65 mm Hg during normothermia and hyperthermia. The carotid baroreceptor-cardiac reflex sensitivity was evaluated from the maximum slope of the HR response to changes in carotid distending pressure. Buffering capacity of the HR response to carotid distending pressure was evaluated in % from a reference point calculated as (HR at 0 mm Hg neck pressure-minimum HR)/HR range ×100. An upward shift of the curve was evident in hyperthermia because HR increased from 57.7+/-2.4 beats/min in normothermia to 88.7+/-4.1 beats/min in hyperthermia (P<0.05) without changes in mean arterial pressure. The maximum slope of the curve in hyperthermia was similar to that in normothermia. The reference point was increased (P<0.05) during hyperthermia. These results suggest that the sensitivity of the carotid baroreflex of HR remains unchanged in hyperthermia. However, the capacity for tachycardia response to rapid onset of hypotension is reduced and the capacity for bradycardia response to sudden hypertension is increased during acute hyperthermia.

New insights into differential baroreflex control of heart rate in humans

NASA Technical Reports Server (NTRS)

Fadel, P. J.; Stromstad, M.; Wray, D. W.; Smith, S. A.; Raven, P. B.; Secher, N. H.

2003-01-01

Recent data indicate that bilateral carotid sinus denervation in patients results in a chronic impairment in the rapid reflex control of blood pressure during orthostasis. These findings are inconsistent with previous human experimental investigations indicating a minimal role for the carotid baroreceptor-cardiac reflex in blood pressure control. Therefore, we reexamined arterial baroreflex [carotid (CBR) and aortic baroreflex (ABR)] control of heart rate (HR) using newly developed methodologies. In 10 healthy men, 27 +/- 1 yr old, an abrupt decrease in mean arterial pressure (MAP) was induced nonpharmacologically by releasing a unilateral arterial thigh cuff (300 Torr) after 9 min of resting leg ischemia under two conditions: 1) ABR and CBR deactivation (control) and 2) ABR deactivation. Under control conditions, cuff release decreased MAP by 13 +/- 1 mmHg, whereas HR increased 11 +/- 2 beats/min. During ABR deactivation, neck suction was gradually applied to maintain carotid sinus transmural pressure during the initial 20 s after cuff release (suction). This attenuated the increase in HR (6 +/- 1 beats/min) and caused a greater decrease in MAP (18 +/- 2 mmHg, P < 0.05). Furthermore, estimated cardiac baroreflex responsiveness (DeltaHR/DeltaMAP) was significantly reduced during suction compared with control conditions. These findings suggest that the carotid baroreceptors contribute more importantly to the reflex control of HR than previously reported in healthy individuals.

Effect of continuous negative-pressure breathing on skin blood flow during exercise in a hot environment.

PubMed

Nagashima, K; Nose, H; Takamata, A; Morimoto, T

1998-06-01

To assess the impact of continuous negative-pressure breathing (CNPB) on the regulation of skin blood flow, we measured forearm blood flow (FBF) by venous-occlusion plethysmography and laser-Doppler flow (LDF) at the anterior chest during exercise in a hot environment (ambient temperature = 30 degreesC, relative humidity = approximately 30%). Seven male subjects exercised in the upright position at an intensity of 60% peak oxygen consumption rate for 40 min with and without CNPB after 20 min of exercise. The esophageal temperature (Tes) in both conditions increased to 38.1 degreesC by the end of exercise, without any significant differences between the two trials. Mean arterial pressure (MAP) increased by approximately 15 mmHg by 8 min of exercise, without any significant difference between the two trials before CNPB. However, CNPB reduced MAP by approximately 10 mmHg after 24 min of exercise (P < 0.05). The increase in FBF and LDF in the control condition leveled off after 18 min of exercise above a Tes of 37.7 degreesC, whereas in the CNPB trial the increase continued, with a rise in Tes despite the decrease in MAP. These results suggest that CNPB enhances vasodilation of skin above a Tes of approximately 38 degrees C by stretching intrathoracic baroreceptors such as cardiopulmonary baroreceptors.

Blood pressure regulation via the epithelial sodium channel: from gene to kidney and beyond.

PubMed

Büsst, Cara J

2013-08-01

The epithelial sodium channel (ENaC) has long been recognized as playing a vital role in blood pressure (BP) regulation due to its involvement in fluid balance. The genes encoding the three ENaC subunits are likewise important contributors to hypertension, both in rare monogenic diseases and in the general population. The unusually high numbers of genetic variants associated with complex traits, including BP, that are located in non-coding areas suggest an involvement of these variants in regulatory functions. This may involve differential regulation of expression in different tissues. Emerging evidence indicates that the ENaC plays an important role in BP determination not only via its actions in the kidney, but also in other tissues commonly involved in BP regulation. The ENaC in the central nervous system is proposed to regulate BP via sympathetic nervous system activity. Recent evidence suggests that the ENaC contributes to vascular function and the myogenic response. Additional roles potentially include initiation of the baroreceptor reflex via ENaC in the baroreceptors and driving high salt intake with a 'taste for salt' via ENaC in the tongue. The present review describes the involvement of the ENaC in the determination of BP at a genetic and physiological level, detailing recent evidence for its role in the kidney and in other pertinent tissues. © 2013 Wiley Publishing Asia Pty Ltd.

Temporal analysis of the spontaneous baroreceptor reflex during mild emotional stress in the rat.

PubMed

Bajić, Dragana; Loncar-Turukalo, Tatjana; Stojicić, Sonja; Sarenac, Olivera; Bojić, Tijana; Murphy, David; Paton, Julian F R; Japundzić-Zigon, Nina

2010-03-01

The effect of emotional stress on the spontaneous baroreceptor reflex (sBRR) in freely moving rats was investigated. Six male Wistar rats equipped with an intra-arterial polyethylene catheter were exposed to a 2-min air-jet stress. For time course analysis of the sBRR response to stress, the records of systolic blood pressure (SBP) and pulse interval (PI) were divided into five regions: baseline (BASELINE), acute exposure to air-jet stress (STRESS), immediate recovery (IMMED. RECOVERY), remaining recovery (RECOVERY), and delayed response (DELAYED RESPONSE). In addition to sBRR sensitivity and effectiveness, we introduce the sequence coverage area and its median for evaluation of the sBRR operating range and set point. During exposure to STRESS and IMMED. RECOVERY, sBRR sensitivity was preserved, its effectiveness was decreased, its operating range was enlarged, and the set point was shifted towards higher SBP and lower PI values. According to the joint symbolic dynamics analysis, the SBP and PI relationship became less predictable hence more prone to respond to stress. In RECOVERY the parameters regained baseline values and DELAYED RESPONSE occurred during which re-setting of sBRR was noted. It follows that emotional stress modulates sBRR differentially during the time course of stress and recovery, affecting both linearity and unpredictability of the BP and PI relationship.

Injections of angiotensin-converting enzyme2 inhibitor MLN4760 into nucleus tractus solitarii reduce baroreceptor reflex sensitivity for heart rate control in rats

PubMed Central

Diz, Debra I.; Garcia-Espinosa, Maria A.; Gegick, Stephen; Tommasi, Ellen N.; Ferrario, Carlos M.; Tallant, E. Ann; Chappell, Mark C.; Gallagher, Patricia E.

2009-01-01

Injections of the angiotensin(1–7) [Ang(1–7)] antagonist [d-Ala7]-Ang(1–7) into the nucleus of the solitary tract (NTS) of Sprague–Dawley rats reduce baroreceptor reflex sensitivity (BRS) for control of heart rate by ~40%, whereas injections of the angiotensin II (Ang II) type 1 receptor antagonist candesartan increase BRS by 40% when reflex bradycardia is assessed. The enzyme angiotensin-converting enzyme 2 (ACE2) is known to convert Ang II to Ang(1–7). We report that ACE2 activity, as well as ACE and neprilysin activities, are present in plasma membrane fractions of the dorsomedial medulla of Sprague–Dawley rats. Moreover, we show that BRS for reflex bradycardia is attenuated (1.16±0.29 ms mmHg−1 before versus 0.33±0.11 ms mmHg−1 after; P < 0.05; n = 8) 30–60 min following injection of the selective ACE2 inhibitor MLN4760 (12 pmol in 120 nl) into the NTS. These findings support the concept that within the NTS, local synthesis of Ang(1–7) from Ang II is required for normal sensitivity for the baroreflex control of heart rate in response to increases in arterial pressure. PMID:18356558

Relationship between cerebral blood flow and blood pressure in long-term heart transplant recipients.

PubMed

Smirl, Jonathan D; Haykowsky, Mark J; Nelson, Michael D; Tzeng, Yu-Chieh; Marsden, Katelyn R; Jones, Helen; Ainslie, Philip N

2014-12-01

Heart transplant recipients are at an increased risk for cerebral hemorrhage and ischemic stroke; yet, the exact mechanism for this derangement remains unclear. We hypothesized that alterations in cerebrovascular regulation is principally involved. To test this hypothesis, we studied cerebral pressure-flow dynamics in 8 clinically stable male heart transplant recipients (62±8 years of age and 9±7 years post transplant, mean±SD), 9 male age-matched controls (63±8 years), and 10 male donor controls (27±5 years). To increase blood pressure variability and improve assessment of the pressure-flow dynamics, subjects performed squat-stand maneuvers at 0.05 and 0.10 Hz. Beat-to-beat blood pressure, middle cerebral artery velocity, and end-tidal carbon dioxide were continuously measured during 5 minutes of seated rest and throughout the squat-stand maneuvers. Cardiac baroreceptor sensitivity gain and cerebral pressure-flow responses were assessed with linear transfer function analysis. Heart transplant recipients had reductions in R-R interval power and baroreceptor sensitivity low frequency gain (P<0.01) compared with both control groups; however, these changes were unrelated to transfer function metrics. Thus, in contrast to our hypothesis, the increased risk of cerebrovascular complication after heart transplantation does not seem to be related to alterations in cerebral pressure-flow dynamics. Future research is, therefore, warranted. © 2014 American Heart Association, Inc.

Disease implication of hyper-Hippo signalling.

PubMed

Wang, Shu-Ping; Wang, Lan-Hsin

2016-10-01

The Hippo signalling pathway regulates cellular proliferation, apoptosis and differentiation, thus exerting profound effects on cellular homeostasis. Inhibition of Hippo signalling has been frequently implicated in human cancers, indicating a well-known tumour suppressor function of the Hippo pathway. However, it is less certain whether and how hyperactivation of the Hippo pathway affects biological outcome in living cells. This review describes current knowledge of the regulatory mechanisms of the Hippo pathway, mainly focusing on hyperactivation of the Hippo signalling nexus. The disease implications of hyperactivated Hippo signalling have also been discussed, including arrhythmogenic cardiomyopathy, Sveinsson's chorioretinal atrophy, Alzheimer's disease, amyotrophic lateral sclerosis and diabetes. By highlighting the significance of disease-relevant Hippo signalling activation, this review can offer exciting prospects to address the onset and potential reversal of Hippo-related disorders. © 2016 The Authors.

Disease implication of hyper-Hippo signalling

PubMed Central

Wang, Shu-Ping

2016-01-01

The Hippo signalling pathway regulates cellular proliferation, apoptosis and differentiation, thus exerting profound effects on cellular homeostasis. Inhibition of Hippo signalling has been frequently implicated in human cancers, indicating a well-known tumour suppressor function of the Hippo pathway. However, it is less certain whether and how hyperactivation of the Hippo pathway affects biological outcome in living cells. This review describes current knowledge of the regulatory mechanisms of the Hippo pathway, mainly focusing on hyperactivation of the Hippo signalling nexus. The disease implications of hyperactivated Hippo signalling have also been discussed, including arrhythmogenic cardiomyopathy, Sveinsson's chorioretinal atrophy, Alzheimer's disease, amyotrophic lateral sclerosis and diabetes. By highlighting the significance of disease-relevant Hippo signalling activation, this review can offer exciting prospects to address the onset and potential reversal of Hippo-related disorders. PMID:27805903

Ubiquitin-Dependent Regulation of the Mammalian Hippo Pathway: Therapeutic Implications for Cancer.

PubMed

Nguyen, Thanh Hung; Kugler, Jan-Michael

2018-04-17

The Hippo pathway serves as a key barrier for oncogenic transformation. It acts by limiting the activity of the proto-oncogenes YAP and TAZ. Reduced Hippo signaling and elevated YAP/TAZ activities are frequently observed in various types of tumors. Emerging evidence suggests that the ubiquitin system plays an important role in regulating Hippo pathway activity. Deregulation of ubiquitin ligases and of deubiquitinating enzymes has been implicated in increased YAP/TAZ activity in cancer. In this article, we review recent insights into the ubiquitin-mediated regulation of the mammalian Hippo pathway, its deregulation in cancer, and possibilities for targeting the Hippo pathway through the ubiquitin system.

Cardiovascular research in space - Considerations for the design of the human research facility of the United States Space Station

NASA Technical Reports Server (NTRS)

Charles, J. B.; Bungo, M. W.

1986-01-01

The design of the Space Station's Human Research Facility for the collection of information on the long-time physiological adjustments of humans to space is described. The Space Life Sciences-1 mission will carry a rack-mounted echocardiograph for cardiac imaging, a mass spectrometer for cardiac output and respiratory function assessments at rest and during exercise, and a device to stimulate the carotid sinus baroreceptors and measure the resulting changes in heart rate.

The canonical Wnt signaling pathway in autism.

PubMed

Zhang, Yinghua; Yuan, Xiangshan; Wang, Zhongping; Li, Ruixi

2014-01-01

Mounting attention is being focused on the canonical Wnt signaling pathway which has been implicated in the pathogenesis of autism in some our and other recent studies. The canonical Wnt pathway is involved in cell proliferation, differentiation and migration, especially during nervous system development. Given its various functions, dysfunction of the canonical Wnt pathway may exert adverse effects on neurodevelopment and therefore leads to the pathogenesis of autism. Here, we review human and animal studies that implicate the canonical Wnt signal transduction pathway in the pathogenesis of autism. We also describe the crosstalk between the canonical Wnt pathway and the Notch signaling pathway in several types of autism spectrum disorders, including Asperger syndrome and Fragile X. Further research on the crosstalk between the canonical Wnt signaling pathway and other signaling cascades in autism may be an efficient avenue to understand the etiology of autism and ultimately lead to alternative medications for autism-like phenotypes.

Ubiquitin-Dependent Regulation of the Mammalian Hippo Pathway: Therapeutic Implications for Cancer

PubMed Central

Nguyen, Thanh Hung

2018-01-01

The Hippo pathway serves as a key barrier for oncogenic transformation. It acts by limiting the activity of the proto-oncogenes YAP and TAZ. Reduced Hippo signaling and elevated YAP/TAZ activities are frequently observed in various types of tumors. Emerging evidence suggests that the ubiquitin system plays an important role in regulating Hippo pathway activity. Deregulation of ubiquitin ligases and of deubiquitinating enzymes has been implicated in increased YAP/TAZ activity in cancer. In this article, we review recent insights into the ubiquitin-mediated regulation of the mammalian Hippo pathway, its deregulation in cancer, and possibilities for targeting the Hippo pathway through the ubiquitin system. PMID:29673168

Interactions between cilazapril and propranolol in man; plasma drug concentrations, hormone and enzyme responses, haemodynamics, agonist dose-effect curves and baroreceptor reflex.

PubMed Central

Belz, G G; Essig, J; Kleinbloesem, C H; Hoogkamer, J F; Wiegand, U W; Wellstein, A

1988-01-01

1. The pharmacokinetics, hormonal and haemodynamic responses at rest and during challenges with angiotensin I (blood pressure), isoprenaline (heart rate), and noradrenaline (blood pressure) were investigated in six healthy male volunteers following a 1 week treatment with placebo, propranolol (120 mg day-1), cilazapril (2, 5 mg day-1), and a combination of both in a double-blind cross-over design. 2. Both drugs reduced systolic and diastolic blood pressure by about 7 mm Hg as compared with placebo. After coadministration, this drop in blood pressure was doubled and lasted longer than after the administration of the individual components. 3. Following cilazapril, a pronounced increase in plasma renin activity (PRA) was found (factor approximately 10 at drug peak concentrations). Coadministration of both drugs resulted only in a moderate increase in the PRA (factor approximately 3). Significant changes in plasma catecholamines were not observed. 4. Propranolol shifted the isoprenaline dose-effect curve to the right, and cilazapril that of angiotensin I, irrespective of the presence of the other drug. Cilazapril tended to shift the noradrenaline dose-effect curve somewhat to the right. 5. The gain of the baroreceptor reflex (angiotensin-stimulation) was not influenced by cilazapril but was lowered by propranolol, irrespective of the presence of the ACE inhibitor. 6. Except for a statistically not significant decrease in the peak concentrations of each drug during the combined therapy, a pharmacokinetic interaction between the two drugs was not found. PMID:2974715

Afferent fibres from pulmonary arterial baroreceptors in the left cardiac sympathetic nerve of the cat

PubMed Central

Nishi, K.; Sakanashi, M.; Takenaka, F.

1974-01-01

1. Afferent discharges were recorded from the left cardiac sympathetic nerve or the third sympathetic ramus communicans of anaesthetized cats. Twenty-one single units with baroreceptor activity were obtained. 2. The receptors of each unit were localized to the extrapulmonary part of the pulmonary artery, determined by direct mechanical probing of the wall of the pulmonary artery after death of the animals. Conduction velocity of the fibres ranged from 2·5 to 15·7 m/sec. 3. Afferent discharges occurred irregularly under artificial ventilation. The impulse activity was increased when pulmonary arterial pressure was raised by an intravenous infusion of Locke solution, or by occlusion of lung roots, and decreased by bleeding the animal from the femoral artery. 4. Above a threshold pressure, discharges occurred synchronously with the systolic pressure pulse in the pulmonary artery. A progressive further rise in pressure did not produce an increase in the number of impulses per heart beat. Occlusion of lung roots initially elicited a burst of discharges but the number of impulses for each cardiac cycle gradually decreased. 5. The receptors responded to repetitive mechanical stimuli up to a frequency of 10/sec, but failed to respond to stimuli delivered at 20/sec. 6. The results provide further evidence for the presence of afferent fibres in the cardiac sympathetic nerve. These afferent fibres are likely to provide the spinal cord with specific information only on transient changes in pulmonary arterial pressure. PMID:4850456

Baroreflex failure in a patient with central nervous system lesions involving the nucleus tractus solitarii

NASA Technical Reports Server (NTRS)

Biaggioni, I.; Whetsell, W. O.; Jobe, J.; Nadeau, J. H.

1994-01-01

Animal studies have shown the importance of the nucleus tractus solitarii, a collection of neurons in the brain stem, in the acute regulation of blood pressure. Impulses arising from the carotid and aortic baroreceptors converge in this center, where the first synapse of the baroreflex is located. Stimulation of the nucleus tractus solitarii provides an inhibitory signal to other brain stem structures, particularly the rostral ventrolateral medulla, resulting in a reduction in sympathetic outflow and a decrease in blood pressure. Conversely, experimental lesions of the nucleus tractus solitarii lead to loss of baroreflex control of blood pressure, sympathetic activation, and severe hypertension in animals. In humans, baroreflex failure due to deafferentation of baroreceptors has been previously reported and is characterized by episodes of severe hypertension and tachycardia. We present a patient with an undetermined process of the central nervous system characterized pathologically by ubiquitous infarctions that were particularly prominent in the nucleus tractus solitarii bilaterally but spared the rostral ventrolateral medulla. Absence of a functioning baroreflex was evidenced by the lack of reflex tachycardia to the hypotensive effects of sodium nitroprusside, exaggerated pressor responses to handgrip and cold pressor test, and exaggerated depressor responses to meals and centrally acting alpha 2-agonists. This clinicopathological correlate suggests that the patient's baroreflex failure can be explained by the unique combination of the destruction of sympathetic inhibitory centers (ie, the nucleus tractus solitarii) and preservation of centers that exert a positive modulation on sympathetic tone (ie, the rostral ventrolateral medulla).

Baroreflex Activation Therapy in Congestive Heart Failure: Novel Findings and Future Insights.

PubMed

Grassi, Guido; Brambilla, GianMaria; Pizzalla, Daniela Prata; Seravalle, Gino

2016-08-01

Congestive heart failure is characterized by hemodynamic and non-hemodynamic abnormalities, the latter including an activation of the sympathetic influences to the heart and peripheral circulation coupled with an impairment of baroreceptor control of autonomic function. Evidence has been provided that both these alterations are hallmark features of the disease with a specific relevance for the disease progression as well as for the development of life-threatening cardiac arrhythmias. In addition, a number of studies have documented in heart failure the adverse prognostic role of the sympathetic and baroreflex alterations, which both are regarded as major independent determinants of cardiovascular morbidity and mortality. This represents the pathophysiological and clinical background for the use of carotid baroreceptor activation therapy in the treatment of congestive heart failure. Promising data collected in experimental animal models of heart failure have supported the recent performance of pilot small-scale clinical studies, aimed at providing initial information in this area. The results of these studies demonstrated the clinical safety and efficacy of the intervention which has been tested in large-scale clinical studies. The present paper will critically review the background and main results of the published studies designed at defining the clinical impact of baroreflex activation therapy in congestive heart failure patients. Emphasis will be given to the strengths and limitations of such studies, which represent the background for the ongoing clinical trials testing the long-term effects of the device in heart failure patients.

Limb venous compliance responses to lower body negative pressure in humans with high blood pressure.

PubMed

Goulopoulou, S; Deruisseau, K C; Carhart, R; Kanaley, J A

2012-05-01

This study tested the hypothesis that limb venous responses to baroreceptor unloading are altered in individuals with high blood pressure (HBP) compared with normotensive (NT) controls. Calf venous compliance was assessed in 20 subjects with prehypertension and stage-1 hypertension (mean arterial pressure, MAP: 104±1 mm Hg) and 13 NT controls (MAP: 86±2 mm Hg) at baseline and during lower body negative pressure (LBNP), using venous occlusion plethysmography. Baroreflex sensitivity (BRS) was measured using the sequence technique and total peripheral resistance (TPR) was estimated from finger plethysmography. Baseline venous compliance was not different between groups, but the HBP group had lower baseline lnBRS (2.22±0.14 vs 2.7±0.18 ms mm Hg(-1)) and greater baseline TPR (3828±138 vs 3250±111 dyn sec(-1) cm(-5) m(2), P<0.05). Calf venous compliance was reduced in response to LBNP only in the NT group (P<0.05). The HBP group had a greater increase in TPR (ΔTPR) compared with the NT group (+1649±335 vs +718±196 dyn sec(-1) cm(-5) m(2), P<0.05). In conclusion, the early stages of hypertension are characterized by an attenuated venoconstrictor response to baroreceptor unloading, which may compensate for an exaggerated vasoconstrictor response and protect against further increases in blood pressure.

Increased renal sympathetic nerve activity leads to hypertension and renal dysfunction in offspring from diabetic mothers.

PubMed

de Almeida Chaves Rodrigues, Aline Fernanda; de Lima, Ingrid Lauren Brites; Bergamaschi, Cássia Toledo; Campos, Ruy Ribeiro; Hirata, Aparecida Emiko; Schoorlemmer, Guus Hermanus Maria; Gomes, Guiomar Nascimento

2013-01-15

The exposure of the fetus to a hyperglycemic environment promotes the development of hypertension and renal dysfunction in the offspring at adult age. We evaluated the role of renal nerves in the hypertension and renal changes seen in offspring of diabetic rats. Diabetes was induced in female Wistar rats (streptozotocin, 60 mg/kg ip) before mating. Male offspring from control and diabetic dams were studied at an age of 3 mo. Systolic blood pressure measured by tail cuff was increased in offspring of diabetic dams (146 ± 1.6 mmHg, n = 19, compared with 117 ± 1.4 mmHg, n = 18, in controls). Renal function, baseline renal sympathetic nerve activity (rSNA), and arterial baroreceptor control of rSNA were analyzed in anesthetized animals. Glomerular filtration rate, fractional sodium excretion, and urine flow were significantly reduced in offspring of diabetic dams. Two weeks after renal denervation, blood pressure and renal function in offspring from diabetic dams were similar to control, suggesting that renal nerves contribute to sodium retention in offspring from diabetic dams. Moreover, basal rSNA was increased in offspring from diabetic dams, and baroreceptor control of rSNA was impaired, with blunted responses to infusion of nitroprusside and phenylephrine. Thus, data from this study indicate that in offspring from diabetic mothers, renal nerves have a clear role in the etiology of hypertension; however, other factors may also contribute to this condition.

Influence of ventilation and hypocapnia on sympathetic nerve responses to hypoxia in normal humans.

PubMed

Somers, V K; Mark, A L; Zavala, D C; Abboud, F M

1989-11-01

The sympathetic response to hypoxia depends on the interaction between chemoreceptor stimulation (CRS) and the associated hyperventilation. We studied this interaction by measuring sympathetic nerve activity (SNA) to muscle in 13 normal subjects, while breathing room air, 14% O2, 10% O2, and 10% O2 with added CO2 to maintain isocapnia. Minute ventilation (VE) and blood pressure (BP) increased significantly more during isocapnic hypoxia (IHO) than hypocapnic hypoxia (HHO). In contrast, SNA increased more during HHO [40 +/- 10% (SE)] than during IHO (25 +/- 19%, P less than 0.05). To determine the reason for the lesser increase in SNA with IHO, 11 subjects underwent voluntary apnea during HHO and IHO. Apnea potentiated the SNA responses to IHO more than to HHO. SNA responses to IHO were 17 +/- 7% during breathing and 173 +/- 47% during apnea whereas SNA responses to HHO were 35 +/- 8% during breathing and 126 +/- 28% during apnea. During ventilation, the sympathoexcitation of IHO (compared with HHO) is suppressed, possibly for two reasons: 1) because of the inhibitory influence of activation of pulmonary afferents as a result of a greater increase in VE, and 2) because of the inhibitory influence of baroreceptor activation due to a greater rise in BP. Thus in humans, the ventilatory response to chemoreceptor stimulation predominates and restrains the sympathetic response. The SNA response to chemoreceptor stimulation represents the net effect of the excitatory influence of the chemoreflex and the inhibitory influence of pulmonary afferents and baroreceptor afferents.

Sequential modulation of cardiac autonomic control induced by cardiopulmonary and arterial baroreflex mechanisms

NASA Technical Reports Server (NTRS)

Furlan, R.; Jacob, G.; Palazzolo, L.; Rimoldi, A.; Diedrich, A.; Harris, P. A.; Porta, A.; Malliani, A.; Mosqueda-Garcia, R.; Robertson, D.

2001-01-01

BACKGROUND: Nonhypotensive lower body negative pressure (LBNP) induces a reflex increase in forearm vascular resistance and muscle sympathetic neural discharge without affecting mean heart rate. We tested the hypothesis that a reflex change of the autonomic modulation of heartbeat might arise during low intensity LBNP without changes of mean heart rate. METHODS AND RESULTS: Ten healthy volunteers underwent plasma catecholamine evaluation and a continuous recording of ECG, finger blood pressure, respiratory activity, and central venous pressure (CVP) during increasing levels of LBNP up to -40 mm Hg. Spectrum and cross-spectrum analyses assessed the changes in the spontaneous variability of R-R interval, respiration, systolic arterial pressure (SAP), and CVP and in the gain (alpha(LF)) of arterial baroreflex control of heart rate. Baroreceptor sensitivity was also evaluated by the SAP/R-R spontaneous sequences technique. LBNP began decreasing significantly: CVP at -10, R-R interval at -20, SAP at -40, and the indexes alpha(LF) and baroreceptor sensitivity at -30 and -20 mm Hg, compared with baseline conditions. Plasma norepinephrine increased significantly at -20 mm Hg. The normalized low-frequency component of R-R variability (LF(R-R)) progressively increased and was significantly higher than in the control condition at -15 mm Hg. CONCLUSIONS: Nonhypotensive LBNP elicits a reflex increase of cardiac sympathetic modulation, as evaluated by LF(R-R), which precedes the changes in the hemodynamics and in the indexes of arterial baroreflex control.

Respiratory modulation of human autonomic function on Earth.

PubMed

Eckberg, Dwain L; Cooke, William H; Diedrich, André; Biaggioni, Italo; Buckey, Jay C; Pawelczyk, James A; Ertl, Andrew C; Cox, James F; Kuusela, Tom A; Tahvanainen, Kari U O; Mano, Tadaaki; Iwase, Satoshi; Baisch, Friedhelm J; Levine, Benjamin D; Adams-Huet, Beverley; Robertson, David; Blomqvist, C Gunnar

2016-10-01

We studied healthy supine astronauts on Earth with electrocardiogram, non-invasive arterial pressure, respiratory carbon dioxide concentrations, breathing depth and sympathetic nerve recordings. The null hypotheses were that heart beat interval fluctuations at usual breathing frequencies are baroreflex mediated, that they persist during apnoea, and that autonomic responses to apnoea result from changes of chemoreceptor, baroreceptor or lung stretch receptor inputs. R-R interval fluctuations at usual breathing frequencies are unlikely to be baroreflex mediated, and disappear during apnoea. The subjects' responses to apnoea could not be attributed to changes of central chemoreceptor activity (hypocapnia prevailed); altered arterial baroreceptor input (vagal baroreflex gain declined and muscle sympathetic nerve burst areas, frequencies and probabilities increased, even as arterial pressure climbed to new levels); or altered pulmonary stretch receptor activity (major breathing frequency and tidal volume changes did not alter vagal tone or sympathetic activity). Apnoea responses of healthy subjects may result from changes of central respiratory motoneurone activity. We studied eight healthy, supine astronauts on Earth, who followed a simple protocol: they breathed at fixed or random frequencies, hyperventilated and then stopped breathing, as a means to modulate and expose to view important, but obscure central neurophysiological mechanisms. Our recordings included the electrocardiogram, finger photoplethysmographic arterial pressure, tidal volume, respiratory carbon dioxide concentrations and peroneal nerve muscle sympathetic activity. Arterial pressure, vagal tone and muscle sympathetic outflow were comparable during spontaneous and controlled-frequency breathing. Compared with spontaneous, 0.1 and 0.05 Hz breathing, however, breathing at usual frequencies (∼0.25 Hz) lowered arterial baroreflex gain, and provoked smaller arterial pressure and R-R interval fluctuations, which were separated by intervals that were likely to be too short and variable to be attributed to baroreflex physiology. R-R interval fluctuations at usual breathing frequencies disappear during apnoea, and thus cannot provide evidence for the existence of a central respiratory oscillation. Apnoea sets in motion a continuous and ever changing reorganization of the relations among stimulatory and inhibitory inputs and autonomic outputs, which, in our study, could not be attributed to altered chemoreceptor, baroreceptor, or pulmonary stretch receptor activity. We suggest that responses of healthy subjects to apnoea are driven importantly, and possibly prepotently, by changes of central respiratory motoneurone activity. The companion article extends these observations and asks the question, Might terrestrial responses to our 20 min breathing protocol find expression as long-term neuroplasticity in serial measurements made over 20 days during and following space travel? Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Arterial blood pressure oscillation after active standing up in kidney transplant recipients.

PubMed

Gerhardt, U; Schäfer, M; Hohage, H

2000-04-12

Dynamic arterial blood pressure (FINAPRES) response to active standing up, normally consisting of initial rise, fall and recovery above the baseline (overshoot), was compared with the early steady-state arterial blood pressure level to measure sympathetic vasomotor function in healthy subjects [group 1: n=50, 10 female subjects, age 51+/-2.5 years; weight 78+/-2.3 kg; height 174+/-1.4 cm (mean+/-standard error of the mean)] and in kidney transplant recipients under basal (group 2a: n=50, age 51.7+/-1.7 years; weight 77+/-2.1 kg; height 174+/-1.5 cm) and under high (group 2b: same subjects as in group 2a) cyclosporine A whole blood levels. Furthermore, baroreflex sensitivity and the activity of the generating compounds of the sympathetic nervous systems (Mayer waves) were measured. Systolic and diastolic overshoot values did not differ statistically significant in the present study. In the control subjects, a systolic overshoot of 15.4+/-2.7 mmHg and a diastolic overshoot of 15.2+/-2 mmHg was detected. The systolic overshoot disappeared in 57% of group 2a (-7.1+/-2.7 mmHg; P<0.001) and in 50% of group 2b recipients (-8.0+/-2.7 mmHg; P<0.001). Systolic early steady-state level was not lower in kidney transplant recipients before cyclosporine (baseline+2 mmHg) intake, but after cyclosporine administration (baseline-3 mmHg; controls: baseline+3 mmHg; P<0.05). There was a strong association between the overshoot and steady-state levels (P for chi(2)<0.001, n=150). Overshoot of group 1 levels (r=0.428; P<0.01) and group 2 levels (r=0.714; P<0. 001) correlated to their respective steady-state blood pressure. Furthermore, recipients had reduced baroreceptor sensitivities estimated by sequence analysis as compared to controls (10+/-1 ms/mmHg vs. 7.5+/-1.4 ms/mmHg; P<0.05). Mayer waves amplitudes of the heart rate spectrum were elevated statistically significant in renal transplant recipients (44.4+/-0.2 vs. 43.8+/-2.2 A.U.). In conclusion, baroreceptor reflex-dependent overshoot of the arterial blood pressure after active standing up is diminished in kidney transplant recipients, whereas no association to the cyclosporine A whole blood level has been detected. The reduced overshoot may be due to the diminished baroreceptor sensitivity which could be shown in renal transplant recipients.

Respiratory modulation of human autonomic function on Earth

PubMed Central

Cooke, William H.; Diedrich, André; Biaggioni, Italo; Buckey, Jay C.; Pawelczyk, James A.; Ertl, Andrew C.; Cox, James F.; Kuusela, Tom A.; Tahvanainen, Kari U. O.; Mano, Tadaaki; Iwase, Satoshi; Baisch, Friedhelm J.; Levine, Benjamin D.; Adams‐Huet, Beverley; Robertson, David; Blomqvist, C. Gunnar

2016-01-01

Key points We studied healthy supine astronauts on Earth with electrocardiogram, non‐invasive arterial pressure, respiratory carbon dioxide concentrations, breathing depth and sympathetic nerve recordings.The null hypotheses were that heart beat interval fluctuations at usual breathing frequencies are baroreflex mediated, that they persist during apnoea, and that autonomic responses to apnoea result from changes of chemoreceptor, baroreceptor or lung stretch receptor inputs.R‐R interval fluctuations at usual breathing frequencies are unlikely to be baroreflex mediated, and disappear during apnoea.The subjects’ responses to apnoea could not be attributed to changes of central chemoreceptor activity (hypocapnia prevailed); altered arterial baroreceptor input (vagal baroreflex gain declined and muscle sympathetic nerve burst areas, frequencies and probabilities increased, even as arterial pressure climbed to new levels); or altered pulmonary stretch receptor activity (major breathing frequency and tidal volume changes did not alter vagal tone or sympathetic activity). Apnoea responses of healthy subjects may result from changes of central respiratory motoneurone activity. Abstract We studied eight healthy, supine astronauts on Earth, who followed a simple protocol: they breathed at fixed or random frequencies, hyperventilated and then stopped breathing, as a means to modulate and expose to view important, but obscure central neurophysiological mechanisms. Our recordings included the electrocardiogram, finger photoplethysmographic arterial pressure, tidal volume, respiratory carbon dioxide concentrations and peroneal nerve muscle sympathetic activity. Arterial pressure, vagal tone and muscle sympathetic outflow were comparable during spontaneous and controlled‐frequency breathing. Compared with spontaneous, 0.1 and 0.05 Hz breathing, however, breathing at usual frequencies (∼0.25 Hz) lowered arterial baroreflex gain, and provoked smaller arterial pressure and R‐R interval fluctuations, which were separated by intervals that were likely to be too short and variable to be attributed to baroreflex physiology. R‐R interval fluctuations at usual breathing frequencies disappear during apnoea, and thus cannot provide evidence for the existence of a central respiratory oscillation. Apnoea sets in motion a continuous and ever changing reorganization of the relations among stimulatory and inhibitory inputs and autonomic outputs, which, in our study, could not be attributed to altered chemoreceptor, baroreceptor, or pulmonary stretch receptor activity. We suggest that responses of healthy subjects to apnoea are driven importantly, and possibly prepotently, by changes of central respiratory motoneurone activity. The companion article extends these observations and asks the question, Might terrestrial responses to our 20 min breathing protocol find expression as long‐term neuroplasticity in serial measurements made over 20 days during and following space travel? PMID:27028958

Neuronal pathway finding: from neurons to initial neural networks.

PubMed

Roscigno, Cecelia I

2004-10-01

Neuronal pathway finding is crucial for structured cellular organization and development of neural circuits within the nervous system. Neuronal pathway finding within the visual system has been extensively studied and therefore is used as a model to review existing knowledge regarding concepts of this developmental process. General principles of neuron pathway finding throughout the nervous system exist. Comprehension of these concepts guides neuroscience nurses in gaining an understanding of the developmental course of action, the implications of different anomalies, as well as the theoretical basis and nursing implications of some provocative new therapies being proposed to treat neurodegenerative diseases and neurologic injuries. These therapies have limitations in light of current ethical, developmental, and delivery modes and what is known about the development of neuronal pathways.

Role of microRNA Pathway in Mental Retardation

PubMed Central

Qurashi, Abrar; Chang, Shuang; Jin, Peng

2007-01-01

Deficits in cognitive functions lead to mental retardation (MR). Understanding the genetic basis of inherited MR has provided insights into the pathogenesis of MR. Fragile X syndrome is one of the most common forms of inherited MR, caused by the loss of functional Fragile X Mental Retardation Protein (FMRP). MicroRNAs (miRNAs) are endogenous, single-stranded RNAs between 18 and 25 nucleotides in length, which have been implicated in diversified biological pathways. Recent studies have linked the miRNA pathway to fragile X syndrome. Here we review the role of the miRNA pathway in fragile X syndrome and discuss its implication in MR in general. PMID:17982588

Role of the cerebellum and the vestibular apparatus in regulation of orthostatic reflexes in the cat

NASA Technical Reports Server (NTRS)

Doba, N.; Reis, D. J.

1974-01-01

The contribution of the fastigial nucleus and the vestibular nerves (eighth cranial nerves) to the orthostatic reflexes in anesthetized, paralyzed cats was studied. Bilateral lesions of the rostral fastigial nucleus resulted in impairment of the reflex changes in blood pressure, femoral arterial flow, and resistance evoked by head-up tilting to 30 deg or 60 deg. The rostral fastigial nucleus, which might be triggered by the vestibular apparatus, appears to participate in concert with the baroreceptors in the initiation and possibly the maintenance of the orthostatic reflexes.

Impaired pulmonary artery contractile responses in a rat model of microgravity: role of nitric oxide

NASA Technical Reports Server (NTRS)

Nyhan, Daniel; Kim, Soonyul; Dunbar, Stacey; Li, Dechun; Shoukas, Artin; Berkowitz, Dan E.

2002-01-01

Vascular contractile hyporesponsiveness is an important mechanism underlying orthostatic intolerance after microgravity. Baroreceptor reflexes can modulate both pulmonary resistance and capacitance function and thus cardiac output. We hypothesized, therefore, that pulmonary vasoreactivity is impaired in the hindlimb-unweighted (HLU) rat model of microgravity. Pulmonary artery (PA) contractile responses to phenylephrine (PE) and U-46619 (U4) were significantly decreased in the PAs from HLU vs. control (C) animals. N(G)-nitro-L-arginine methyl ester (10(-5) M) enhanced the contractile responses in the PA rings from both C and HLU animals and completely abolished the differential responses to PE and U4 in HLU vs. C animals. Vasorelaxant responses to ACh were significantly enhanced in PA rings from HLU rats compared with C. Moreover, vasorelaxant responses to sodium nitroprusside were also significantly enhanced. Endothelial nitric oxide synthase (eNOS) and soluble guanlyl cyclase expression were significantly enhanced in PA and lung tissue from HLU rats. In marked contrast, the expression of inducible nitric oxide synthase was unchanged in lung tissue. These data support the hypothesis that vascular contractile responsiveness is attenuated in PAs from HLU rats and that this hyporesponsiveness is due at least in part to increased nitric oxide synthase activity resulting from enhanced eNOS expression. These findings may have important implications for blood volume distribution and attenuated stroke volume responses to orthostatic stress after microgravity exposure.

Wnt and lithium: a common destiny in the therapy of nervous system pathologies?

PubMed

Meffre, Delphine; Grenier, Julien; Bernard, Sophie; Courtin, Françoise; Dudev, Todor; Shackleford, Ghjuvan'Ghjacumu; Jafarian-Tehrani, Mehrnaz; Massaad, Charbel

2014-04-01

Wnt signaling is required for neurogenesis, the fate of neural progenitors, the formation of neuronal circuits during development, neuron positioning and polarization, axon and dendrite development and finally for synaptogenesis. This signaling pathway is also implicated in the generation and differentiation of glial cells. In this review, we describe the mechanisms of action of Wnt signaling pathways and their implication in the development and correct functioning of the nervous system. We also illustrate how a dysregulated Wnt pathway could lead to psychiatric, neurodegenerative and demyelinating pathologies. Lithium, used for the treatment of bipolar disease, inhibits GSK3β, a central enzyme of the Wnt/β-catenin pathway. Thus, lithium could, to some extent, mimic Wnt pathway. We highlight the possible dialogue between lithium therapy and modulation of Wnt pathway in the treatment of the diseases of the nervous system.

Effect of dynamic exercise on human carotid-cardiac baroreflex latency

NASA Technical Reports Server (NTRS)

Potts, J. T.; Raven, P. B.

1995-01-01

We compared the beat-to-beat responses of heart rate (HR) after brief activation of carotid baroreceptors in resting humans with the responses obtained during mild-to-moderate levels of dynamic exercise [25 and 50% of peak O2 uptake (VO2peak)] to investigate the effect of exercise on baroreflex latency. Carotid baroreceptors were activated by a pressure pulse (5 s) of neck suction (NS, -80 Torr) and neck pressure (NP, +40 Torr) during held expiration. At rest the peak change in HR to NS/NP occurred during the first several heartbeats (1st-3rd beat), whereas during mild and moderate exercise peak HR responses occurred near the end of the NS/NP pulse (6th-8th beat). In contrast, time (s) to the peak change in HR was not different between rest and exercise (P > 0.05). Reflex tachycadia to NP progressively decreased during exercise (17 +/- 3, 10 +/- 1, and 4 +/- 1% of control, rest vs. 25% VO2peak, vs. 50% VO2peak, respectively, P < 0.05), and a strong positive correlation was found between the magnitude of the reflex tachycardia and a measure of HR variability (cardiac vagal tone index, r = 0.74, P < 0.0001). Reflex bradycardia to NS gradually increased during exercise (13 +/- 2, 17 +/- 2, and 18 +/- 2% of control, rest vs. 25% VO2peak, vs. 50% VO2peak, respectively, P = 0.10) and was negatively correlated with cardiac vagal tone (r = 0.42, P < 0.06).(ABSTRACT TRUNCATED AT 250 WORDS).

Resting spontaneous baroreflex sensitivity and cardiac autonomic control in anabolic androgenic steroid users

PubMed Central

dos Santos, Marcelo R.; Sayegh, Ana L.C.; Armani, Rafael; Costa-Hong, Valéria; de Souza, Francis R.; Toschi-Dias, Edgar; Bortolotto, Luiz A.; Yonamine, Mauricio; Negrão, Carlos E.; Alves, Maria-Janieire N.N.

2018-01-01

OBJECTIVES: Misuse of anabolic androgenic steroids in athletes is a strategy used to enhance strength and skeletal muscle hypertrophy. However, its abuse leads to an imbalance in muscle sympathetic nerve activity, increased vascular resistance, and increased blood pressure. However, the mechanisms underlying these alterations are still unknown. Therefore, we tested whether anabolic androgenic steroids could impair resting baroreflex sensitivity and cardiac sympathovagal control. In addition, we evaluate pulse wave velocity to ascertain the arterial stiffness of large vessels. METHODS: Fourteen male anabolic androgenic steroid users and 12 nonusers were studied. Heart rate, blood pressure, and respiratory rate were recorded. Baroreflex sensitivity was estimated by the sequence method, and cardiac autonomic control by analysis of the R-R interval. Pulse wave velocity was measured using a noninvasive automatic device. RESULTS: Mean spontaneous baroreflex sensitivity, baroreflex sensitivity to activation of the baroreceptors, and baroreflex sensitivity to deactivation of the baroreceptors were significantly lower in users than in nonusers. In the spectral analysis of heart rate variability, high frequency activity was lower, while low frequency activity was higher in users than in nonusers. Moreover, the sympathovagal balance was higher in users. Users showed higher pulse wave velocity than nonusers showing arterial stiffness of large vessels. Single linear regression analysis showed significant correlations between mean blood pressure and baroreflex sensitivity and pulse wave velocity. CONCLUSIONS: Our results provide evidence for lower baroreflex sensitivity and sympathovagal imbalance in anabolic androgenic steroid users. Moreover, anabolic androgenic steroid users showed arterial stiffness. Together, these alterations might be the mechanisms triggering the increased blood pressure in this population. PMID:29791601

Determinants of muscle metaboreflex and involvement of baroreflex in boys and young men.

PubMed

Dipla, Konstantina; Papadopoulos, Stavros; Zafeiridis, Andreas; Kyparos, Antonios; Nikolaidis, Michalis G; Vrabas, Ioannis S

2013-04-01

This study aimed to assess the arterial pressure (AP) determinants during the muscle metaboreflex in boys and men and to investigate the contribution of baroreflex and sympathovagal function to the metaboreflex-induced responses. Fourteen pre-adolescent boys and 13 men performed a protocol involving: baseline, isometric handgrip exercise, circulatory occlusion, and recovery. The same protocol was repeated without occlusion. During baseline, boys had lower beat-to-beat AP, higher heart rate (HR), and lower low/high frequency HR variability. During exercise, a parasympathetic withdrawal was evident in both groups. In adults, HR was the key contributor to the pressure response, with no changes in stroke volume, whereas in boys, the lower HR increase was counterbalanced by an increase in stroke volume, resulting in similar relative increases in AP in both groups. In recovery, boys exhibited a faster rate of HR-decay, rapid vagal reactivation, and greater decrease in TPR than men. An overshoot in baroreceptor sensitivity was observed in men. The isolated metaboreflex resulted in a similar AP elevation in both age groups (by ~15 mmHg), and attenuated spontaneous baroreceptor sensitivity. However, during the metaboreflex, pre-adolescent males exhibited a lower increase in peripheral resistance and a greater bradycardic response than adults, and a fast restoration of vagal activity to non-occlusion levels. During metaboreflex, boys were capable of eliciting a pressure response similar to the one elicited by men; however, the interplay of the mechanisms underlying the rise in AP differed between the two groups with the vagal contribution being greater in the younger participants.

Resting spontaneous baroreflex sensitivity and cardiac autonomic control in anabolic androgenic steroid users.

PubMed

Santos, Marcelo R Dos; Sayegh, Ana L C; Armani, Rafael; Costa-Hong, Valéria; Souza, Francis R de; Toschi-Dias, Edgar; Bortolotto, Luiz A; Yonamine, Mauricio; Negrão, Carlos E; Alves, Maria-Janieire N N

2018-05-21

Misuse of anabolic androgenic steroids in athletes is a strategy used to enhance strength and skeletal muscle hypertrophy. However, its abuse leads to an imbalance in muscle sympathetic nerve activity, increased vascular resistance, and increased blood pressure. However, the mechanisms underlying these alterations are still unknown. Therefore, we tested whether anabolic androgenic steroids could impair resting baroreflex sensitivity and cardiac sympathovagal control. In addition, we evaluate pulse wave velocity to ascertain the arterial stiffness of large vessels. Fourteen male anabolic androgenic steroid users and 12 nonusers were studied. Heart rate, blood pressure, and respiratory rate were recorded. Baroreflex sensitivity was estimated by the sequence method, and cardiac autonomic control by analysis of the R-R interval. Pulse wave velocity was measured using a noninvasive automatic device. Mean spontaneous baroreflex sensitivity, baroreflex sensitivity to activation of the baroreceptors, and baroreflex sensitivity to deactivation of the baroreceptors were significantly lower in users than in nonusers. In the spectral analysis of heart rate variability, high frequency activity was lower, while low frequency activity was higher in users than in nonusers. Moreover, the sympathovagal balance was higher in users. Users showed higher pulse wave velocity than nonusers showing arterial stiffness of large vessels. Single linear regression analysis showed significant correlations between mean blood pressure and baroreflex sensitivity and pulse wave velocity. Our results provide evidence for lower baroreflex sensitivity and sympathovagal imbalance in anabolic androgenic steroid users. Moreover, anabolic androgenic steroid users showed arterial stiffness. Together, these alterations might be the mechanisms triggering the increased blood pressure in this population.

Hyperthermia modifies muscle metaboreceptor and baroreceptor modulation of heat loss in humans.

PubMed

Binder, Konrad; Lynn, Aaron G; Gagnon, Daniel; Kondo, Narihiko; Kenny, Glen P

2012-02-15

The relative influence of muscle metabo- and baroreflex activity on heat loss responses during post-isometric handgrip (IHG) exercise ischemia remains unknown, particularly under heat stress. Therefore, we examined the separate and integrated influences of metabo- and baroreceptor-mediated reflex activity on sweat rate and cutaneous vascular conductance (CVC) under increasing levels of hyperthermia. Twelve men performed 1 min of IHG exercise at 60% of maximal voluntary contraction followed by 2 min of ischemia with simultaneous application of lower body positive pressure (LBPP, +40 mmHg), lower body negative pressure (LBNP, -20 mmHg), or no pressure (control) under no heat stress. On separate days, trials were repeated under heat stress conditions of 0.6°C (moderate heat stress) and 1.4°C (high heat stress) increase in esophageal temperature. For all conditions, mean arterial pressure was greater with LBPP and lower with LBNP than control during ischemia (all P ≤ 0.05). No differences in sweat rate were observed between pressure conditions, regardless of the level of hyperthermia (P > 0.05). Under moderate heat stress, no differences in CVC were observed between pressure conditions. However, under high heat stress, LBNP significantly reduced CVC by 21 ± 4% (P ≤ 0.05) and LBPP significantly elevated CVC by 14 ± 5% (P ≤ 0.05) relative to control. These results show that sweating during post-IHG exercise ischemia is activated by metaboreflex stimulation, and not by baroreflexes. In contrast, our results suggest that baroreflexes can influence the metaboreflex modulation of CVC, but only at greater levels of hyperthermia.

Effect of vasopressin blockade on blood pressure during water deprivation in intact and baroreceptor-denervated conscious dogs.

PubMed

Gregory, L C; Quillen, E W; Keil, L C; Chang, D; Reid, I A

1988-04-01

Previous studies have provided evidence that vasopressin plays an important role in blood pressure regulation during water deprivation. However, these investigations have been complicated by reflex compensatory increases in cardiac output and renin secretion. The aim of the present study was to investigate the effect of blockade of the vasoconstrictor action of vasopressin in conscious water-deprived dogs in which the low- and/or high-pressure baroreceptors were denervated to minimize reflex responses. Vasopressin blockade in sham-operated dogs (n = 7) did not change arterial pressure. Heart rate rose from 78 +/- 9 to 119 +/- 13 beats/min (P less than 0.01), and plasma renin activity increased from 10.9 +/- 2.1 to 21.6 +/- 4.6 ng.ml-1.3 h-1 (P less than 0.01). In carotid sinus-denervated dogs (n = 6), vasopressin blockade again failed to decrease arterial pressure. Heart rate increased from 105 +/- 10 to 132 +/- 10 beats/min (P less than 0.01), and plasma renin activity rose from 6.8 +/- 1.7 to 15.5 +/- 2.4 ng.ml-1.3 h-1 (P less than 0.01). The antagonist also failed to change blood pressure in cardiac-denervated dogs (n = 5). Heart rate increased from 111 +/- 9 to 119 +/- 1 beats/min (P less than 0.01), but plasma renin activity did not increase significantly. In marked contrast, vasopressin blockade in sinoaortic/cardiac-denervated dogs (n = 7) promptly decreased arterial pressure from 115 +/- 8 to 94 +/- 7 mmHg (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanism of thirst attenuation during head-out water immersion in men

NASA Technical Reports Server (NTRS)

Wada, F.; Sagawa, S.; Miki, K.; Nagaya, K.; Nakamitsu, S.; Shiraki, K.; Greenleaf, J. E.

1995-01-01

The purpose was to determine whether extracellular volume or osmolality was the major contributing factor for reduction of thirst in air and head-out water immersion in hypohydrated subjects. Eight males (19-25 yr) were subjected to thermoneutral immersion and thermoneutral air under two hydration conditions without further drinking: euhydration in water (Eu-H2O) and euhydration in air, and hypohydration in water (Hypo-H2O) and hypohydration in air (3.7% wt loss after exercise in heat). The increased thirst sensation with Hypo-H2O decreased (P < 0.05) within 10 min of immersion and continued thereafter. Mean plasma osmolality (288 +/- 1 mosmol/kgH2O) and sodium (140 +/- 1 meq/l) remained elevated, and plasma volume increased by 4.2 +/- 1.0% (P < 0.05) throughout Hypo-H2O. A sustained increase (P < 0.05) in stroke volume accompanied the prompt and sustained decrease in plasma renin activity and sustained increase (P < 0.05) in plasma atrial natriuretic peptide during Eu-H2O and Hypo-H2O. Plasma vasopressin decreased from 5.3 +/- 0.7 to 2.9 +/- 0.5 pg/ml (P < 0.05) during Hypo-H2O but was unchanged in Eu-H2O. These findings suggest a sustained stimulation of the atrial baroreceptors and reduction of a dipsogenic stimulus without major alterations of extracellular osmolality in Hypo-H2O. Thus it appears that vascular volume-induced stimuli of cardiopulmonary baroreceptors play a more important role than extracellular osmolality in reducing thirst sensations during immersion in hypohydrated subjects.

Tonic suppression of spontaneous baroreceptor reflex by endogenous angiotensins via AT(2) subtype receptors at nucleus reticularis ventrolateralis in the rat.

PubMed

Lin, K; Chan, S H; Chan, J Y

2001-04-01

We evaluated the role of endogenous angiotensins at the rostral nucleus reticularis ventrolateralis (NRVL) in the modulation of spontaneous baroreceptor reflex (BRR) response and the subtype of angiotensin receptors involved using rats anesthetized and maintained with pentobarbital sodium. Bilateral microinjection of angiotensin II (ANG II) or its active metabolite angiotensin III (ANG III) (5, 10, or 20 pmol) into the NRVL significantly suppressed the spontaneous BRR response, as represented by the magnitude of transfer function between systemic arterial pressure and heart rate signals. The inhibitory effect of ANG III (20 pmol) was discernibly reversed by coadministration with its peptide antagonist, [Ile(7)]ANG III (1.6 nmol), or the nonpeptide AT(2) receptor antagonist, PD-123319 (1.6 nmol), but not by the nonpeptide AT(1) receptor antagonist, losartan (1.6 nmol). On the other hand, the peptide antagonist, [Sar(1), Ile(8)]ANG II (1.6 nmol) or both non-peptide antagonists appreciably reversed the suppressive action of ANG II (20 pmol). Whereas losartan produced minimal effect, blocking the endogenous activity of the angiotensins by microinjection into the bilateral NRVL of PD-123319, [Sar(1), Ile(8)]ANG II or [Ile(7)]ANG III elicited significant enhancement of the spontaneous BRR response. We conclude that under physiologic conditions both endogenous ANG II and ANG III may exert a tonic inhibitory modulation on the spontaneous BRR response by acting selectively on the AT(2) subtype receptors at the NRVL. Copyright 2001 Wiley-Liss, Inc.

Nicotine impairs reflex renal nerve and respiratory activity in deoxycorticosterone acetate-salt rats.

PubMed

Whitescarver, S A; Roberts, A M; Stremel, R W; Jimenez, A E; Passmore, J C

1991-02-01

Smoking exacerbates the increase in arterial pressure in hypertension. The effect of nicotine on the baroreceptor-mediated reflex responses of renal nerve activity (RNA), heart rate, and respiratory activity (minute diaphragmatic activity [MDA]) after bolus injections of phenylephrine was compared in deoxycorticosterone acetate (DOCA)-salt sensitive and normotensive rats. Osmotic minipumps that dispensed either nicotine (2.4 mg/kg/day) or saline were implanted in DOCA and normotensive rats for 18 days. Anesthetized DOCA-nicotine, DOCA-saline, control-nicotine, and control-saline rats had mean arterial pressures (MAP) of 117 +/- 3, 110 +/- 9, 90 +/- 3, and 89 +/- 5 mm Hg, respectively. Nicotine decreased the sensitivity (p less than 0.05) of baroreceptor reflex control of RNA (% delta RNA/delta MAP) in the DOCA-nicotine rats (-0.92 +/- 0.08) compared with the DOCA-saline (-1.44 +/- 0.16), control-nicotine (-1.45 +/- 0.08), or control-saline (-1.45 +/- 0.21) rats. The reflex decrease in respiratory activity (% delta MDA/delta MAP x 100) was impaired (p less than 0.01) in both control-nicotine (-24.5 +/- 3.3) and DOCA-nicotine (-18.2 +/- 4.6) rats compared with control-saline (-59.2 +/- 9.1) and DOCA-saline (-52.5 +/- 9.9) rats. The reflex decrease in heart rate (absolute delta HR/delta MAP) in both DOCA-nicotine (1.56 +/- 0.17) and control-nicotine (1.54 +/- 0.24) rats was augmented compared with DOCA-saline and control-saline rats (0.91 +/- 0.12 and 0.97 +/- 0.14).(ABSTRACT TRUNCATED AT 250 WORDS)

βENaC is a molecular component of a VSMC mechanotransducer that contributes to renal blood flow regulation, protection from renal injury, and hypertension.

PubMed

Drummond, Heather A

2012-01-01

Pressure-induced constriction (also known as the "myogenic response") is an important mechano-dependent response in certain blood vessels. The response is mediated by vascular smooth muscle cells (VSMCs) and characterized by a pressure-induced vasoconstriction in small arteries and arterioles in the cerebral, mesenteric, cardiac, and renal beds. The myogenic response has two important roles; it is a mechanism of blood flow autoregulation and provides protection against systemic blood pressure-induced damage to delicate microvessels. However, the molecular mechanism(s) underlying initiation of myogenic response is unclear. Degenerin proteins have a strong evolutionary link to mechanotransduction in the nematode. Our laboratory has addressed the hypothesis that these proteins may also act as mechanosensors in certain mammalian tissues such as VSMCs and arterial baroreceptor neurons. This article discusses the importance of a specific degenerin protein, β Epithelial Na(+) Channel (βENaC) in pressure-induced vasoconstriction in renal vessels and arterial baroreflex function as determined in a mouse model of reduced βENaC (βENaC m/m). We propose that loss of baroreflex sensitivity (due to loss of baroreceptor βENaC) increases blood pressure variability, increasing the likelihood and magnitude of upward swings in systemic pressure. Furthermore, loss of the myogenic constrictor response (due to loss of VSMC βENaC) will permit those pressure swings to be transmitted to the microvasculature in βENaC m/m mice, thus increasing the susceptibility to renal injury and hypertension.

Feedback from the heart: Emotional learning and memory is controlled by cardiac cycle, interoceptive accuracy and personality.

PubMed

Pfeifer, Gaby; Garfinkel, Sarah N; Gould van Praag, Cassandra D; Sahota, Kuljit; Betka, Sophie; Critchley, Hugo D

2017-05-01

Feedback processing is critical to trial-and-error learning. Here, we examined whether interoceptive signals concerning the state of cardiovascular arousal influence the processing of reinforcing feedback during the learning of 'emotional' face-name pairs, with subsequent effects on retrieval. Participants (N=29) engaged in a learning task of face-name pairs (fearful, neutral, happy faces). Correct and incorrect learning decisions were reinforced by auditory feedback, which was delivered either at cardiac systole (on the heartbeat, when baroreceptors signal the contraction of the heart to the brain), or at diastole (between heartbeats during baroreceptor quiescence). We discovered a cardiac influence on feedback processing that enhanced the learning of fearful faces in people with heightened interoceptive ability. Individuals with enhanced accuracy on a heartbeat counting task learned fearful face-name pairs better when feedback was given at systole than at diastole. This effect was not present for neutral and happy faces. At retrieval, we also observed related effects of personality: First, individuals scoring higher for extraversion showed poorer retrieval accuracy. These individuals additionally manifested lower resting heart rate and lower state anxiety, suggesting that attenuated levels of cardiovascular arousal in extraverts underlies poorer performance. Second, higher extraversion scores predicted higher emotional intensity ratings of fearful faces reinforced at systole. Third, individuals scoring higher for neuroticism showed higher retrieval confidence for fearful faces reinforced at diastole. Our results show that cardiac signals shape feedback processing to influence learning of fearful faces, an effect underpinned by personality differences linked to psychophysiological arousal. Copyright © 2017 Elsevier B.V. All rights reserved.

mTOR Pathways in Cancer and Autophagy.

PubMed

Paquette, Mathieu; El-Houjeiri, Leeanna; Pause, Arnim

2018-01-12

TOR (target of rapamycin), an evolutionarily-conserved serine/threonine kinase, acts as a central regulator of cell growth, proliferation and survival in response to nutritional status, growth factor, and stress signals. It plays a crucial role in coordinating the balance between cell growth and cell death, depending on cellular conditions and needs. As such, TOR has been identified as a key modulator of autophagy for more than a decade, and several deregulations of this pathway have been implicated in a variety of pathological disorders, including cancer. At the molecular level, autophagy regulates several survival or death signaling pathways that may decide the fate of cancer cells; however, the relationship between autophagy pathways and cancer are still nascent. In this review, we discuss the recent cellular signaling pathways regulated by TOR, their interconnections to autophagy, and the clinical implications of TOR inhibitors in cancer.

Vestibulo-Sympathetic Responses

PubMed Central

Yates, Bill J; Bolton, Philip S.; Macefield, Vaughan G.

2014-01-01

Evidence accumulated over 30 years, from experiments on animals and human subjects, has conclusively demonstrated that inputs from the vestibular otolith organs contribute to the control of blood pressure during movement and changes in posture. This review considers the effects of gravity on the body axis, and the consequences of postural changes on blood distribution in the body. It then separately considers findings collected in experiments on animals and human subjects demonstrating that the vestibular system regulates blood distribution in the body during movement. Vestibulosympathetic reflexes differ from responses triggered by unloading of cardiovascular receptors such as baroreceptors and cardiopulmonary receptors, as they can be elicited before a change in blood distribution occurs in the body. Dissimilarities in the expression of vestibulosympathetic reflexes in humans and animals are also described. In particular, there is evidence from experiments in animals, but not humans, that vestibulosympathetic reflexes are patterned, and differ between body regions. Results from neurophysiological and neuroanatomical studies in animals are discussed that identify the neurons that mediate vestibulosympathetic responses, which include cells in the caudal aspect of the vestibular nucleus complex, interneurons in the lateral medullary reticular formation, and bulbospinal neurons in the rostral ventrolateral medulla (RVLM). Recent findings showing that cognition can modify the gain of vestibulosympathetic responses are also presented, and neural pathways that could mediate adaptive plasticity in the responses are proposed, including connections of the posterior cerebellar vermis with the vestibular nuclei and brainstem nuclei that regulate blood pressure. PMID:24715571

[Hypertension, cardiovascular reactivity to stress and sensibility to pain].

PubMed

Conde-Guzón, P A; Bartolomé-Albistegui, M T; Quirós-Expósito, P; Grzib-Schlosky, G

To provide a review of empirical evidence of decreased pain perception in hypertensive persons or exaggerated cardiovascular reactivity to stress. To following article will briefly review the existing literature on the association between hypoalgesia and high blood pressure. In particular, evidence of hypoalgesia in normotensive individuals at increased risk for hypertension (exaggerated cardiovascular reactivity to stress) will be offered in support of the notion that high cardiovascular reactivity to stress and decreased pain perception may result from a common physiological dysfunction. Cardiovascular reactivity refers to changes in cardiovascular activity associated primarily with exposure to psychological stress. Different individuals show different amounts of reactivity under the same conditions. The greater cardiovascular reactivity to behavioral stressors may play some role in the development of sustained arterial hypertension. Central opioid hyposensitivity is hypothesized as a mechanism of both hypoalgesia and exaggerated autonomic and neuroendocrine responses to stress in individuals at risk for hypertension. The paraventricular nucleus of the hypothalamus (PVN) serves the crucial function of integrating cardiovascular and painful responses. The central opioid hyposensitivity model of hypoalgesia asserts that attenuation of inhibitory opioid input to the PVN may have important consequences for pain modulation. These consequences includes: 1) greater activation of baroreceptor reflex arcs, 2) enhanced release of endogenous opioids during stress, and 3) increased stimulation of descending pain modulation pathways. High elevated thresholds to painful thermal stressors might serve as a behavioral marker of risk for hypertension before the onset of high blood pressure levels.

Qualitative evaluation of a local coronary heart disease treatment pathway: practical implications and theoretical framework

PubMed Central

2012-01-01

Background Coronary heart disease (CHD) is a common medical problem in general practice. Due to its chronic character, shared care of the patient between general practitioner (GP) and cardiologist (C) is required. In order to improve the cooperation between both medical specialists for patients with CHD, a local treatment pathway was developed. The objective of this study was first to evaluate GPs’ opinions regarding the pathway and its practical implications, and secondly to suggest a theoretical framework of the findings by feeding the identified key factors influencing the pathway implementation into a multi-dimensional model. Methods The evaluation of the pathway was conducted in a qualitative design on a sample of 12 pathway developers (8 GPs and 4 cardiologists) and 4 pathway users (GPs). Face-to face interviews, which were aligned with previously conducted studies of the department and assumptions of the theory of planned behaviour (TPB), were performed following a semi-structured interview guideline. These were audio-taped, transcribed verbatim, coded, and analyzed according to the standards of qualitative content analysis. Results We identified 10 frequently mentioned key factors having an impact on the implementation success of the CHD treatment pathway. We thereby differentiated between pathway related (pathway content, effort, individual flexibility, ownership), behaviour related (previous behaviour, support), interaction related (patient, shared care/colleagues), and system related factors (context, health care system). The overall evaluation of the CHD pathway was positive, but did not automatically lead to a change of clinical behaviour as some GPs felt to have already acted as the pathway recommends. Conclusions By providing an account of our experience creating and implementing an intersectoral care pathway for CHD, this study contributes to our knowledge of factors that may influence physicians’ decisions regarding the use of a local treatment pathway. An improved adaptation of the pathway in daily practice might be best achieved by a combined implementation strategy addressing internal and external factors. A simple, direct adaptation regards the design of the pathway material (e.g. layout, PC version), or the embedding of the pathway in another programme, like a Disease Management Programme (DMP). In addition to these practical implications, we propose a theoretical framework to understand the key factors’ influence on the pathway implementation, with the identified factors along the microlevel (pathway related factors), the mesolevel (interaction related factors), and system- related factors along the macrolevel. PMID:22584032

Qualitative evaluation of a local coronary heart disease treatment pathway: practical implications and theoretical framework.

PubMed

Kramer, Lena; Schlößler, Kathrin; Träger, Susanne; Donner-Banzhoff, Norbert

2012-05-14

Coronary heart disease (CHD) is a common medical problem in general practice. Due to its chronic character, shared care of the patient between general practitioner (GP) and cardiologist (C) is required. In order to improve the cooperation between both medical specialists for patients with CHD, a local treatment pathway was developed. The objective of this study was first to evaluate GPs' opinions regarding the pathway and its practical implications, and secondly to suggest a theoretical framework of the findings by feeding the identified key factors influencing the pathway implementation into a multi-dimensional model. The evaluation of the pathway was conducted in a qualitative design on a sample of 12 pathway developers (8 GPs and 4 cardiologists) and 4 pathway users (GPs). Face-to face interviews, which were aligned with previously conducted studies of the department and assumptions of the theory of planned behaviour (TPB), were performed following a semi-structured interview guideline. These were audio-taped, transcribed verbatim, coded, and analyzed according to the standards of qualitative content analysis. We identified 10 frequently mentioned key factors having an impact on the implementation success of the CHD treatment pathway. We thereby differentiated between pathway related (pathway content, effort, individual flexibility, ownership), behaviour related (previous behaviour, support), interaction related (patient, shared care/colleagues), and system related factors (context, health care system). The overall evaluation of the CHD pathway was positive, but did not automatically lead to a change of clinical behaviour as some GPs felt to have already acted as the pathway recommends. By providing an account of our experience creating and implementing an intersectoral care pathway for CHD, this study contributes to our knowledge of factors that may influence physicians' decisions regarding the use of a local treatment pathway. An improved adaptation of the pathway in daily practice might be best achieved by a combined implementation strategy addressing internal and external factors. A simple, direct adaptation regards the design of the pathway material (e.g. layout, PC version), or the embedding of the pathway in another programme, like a Disease Management Programme (DMP). In addition to these practical implications, we propose a theoretical framework to understand the key factors' influence on the pathway implementation, with the identified factors along the microlevel (pathway related factors), the mesolevel (interaction related factors), and system- related factors along the macrolevel.

Novel and nonpharmacologic approaches to cardio-protection in hypertension.

PubMed

Donazzan, Luca; Mahfoud, Felix; Linz, Dominik; Ewen, Sebastian; Ukena, Christian; Böhm, Michael

2014-05-01

Hypertension has wide (30-45 %) prevalence in the general population and is related to important increases in overall cardiovascular morbidity and mortality. Despite lifestyle modifications and optimal medical therapy (three drugs, one being diuretic), about 5-20 % of hypertensives are affected by resistant hypertension. Chronic high blood pressure has adverse effects on the heart and other organs such as the kidneys and vasculature. Renal sympathetic denervation and baroreceptor stimulation are invasive approaches initially investigated to treat resistant hypertension. Their pleiotropic effects appear promising in cardiovascular remodeling, heart failure and arrhythmias and could potentially affect cardiovascular morbidity and mortality.

A quantitative method for studying human arterial baroreflexes

NASA Technical Reports Server (NTRS)

Eckberg, Dwain L.; Fritsch, Janice M.; Goble, Ross L.

1991-01-01

A new system is described that delivers precise, stereotyped pressure changes to the human neck and elicits neurally-mediated heart rate changes. The centerpiece of this system is a Silastic chamber that is strapped to the anterior neck. This chamber is connected to a stepping-motor-controlled bellows assembly. A strain-gauge transducer measures the intensity of pressure changes. The entire system is controlled by microprocessors, and both stimuli and responses are displayed on a digital oscilloscope. The end-product of this system is a reproducible baroreceptor stimulus-cardiac response relation that can be recorded rapidly and safely in astronauts in space.

Approaches for targeting self-renewal pathways in cancer stem cells: implications for hematological treatments.

PubMed

Horne, Gillian A; Copland, Mhairi

2017-05-01

Self-renewal is considered a defining property of stem cells. Self-renewal is essential in embryogenesis and normal tissue repair and homeostasis. However, in cancer, self-renewal pathways, e.g. WNT, NOTCH, Hedgehog and BMP, frequently become de-regulated in stem cells, or more mature progenitor cells acquire self-renewal properties, resulting in abnormal tissue growth and tumorigenesis. Areas covered: This review considers the conserved embryonic self-renewal pathways, including WNT, NOTCH, Hedgehog and BMP. The article describes recent advances in our understanding of these pathways in leukemia and, more specifically, leukemia stem cells (LSC), how these pathways cross-talk and interact with the LSC microenvironment, and discusses the clinical implications and potential therapeutic strategies, both in preclinical and in clinical trials for hematological malignancies. Expert opinion: The conserved embryonic self-renewal pathways are frequently de-regulated in cancer stem cells (CSC), including LSCs. There is significant cross-talk between self-renewal pathways, and their downstream targets, and the microenvironment. Effective targeting of these pathways is challenging due to cross-talk, and importantly, because these pathways are important for normal stem cells as well as CSC, adverse effects on normal tissues may mean a therapeutic window cannot be identified. Nonetheless, several agents targeting these pathways are currently in clinical trials in hematological malignancies.

Multiple cytoskeletal pathways and PI3K signaling mediate CDC-42-induced neuronal protrusion in C. elegans.

PubMed

Alan, Jamie K; Struckhoff, Eric C; Lundquist, Erik A

2013-01-01

Rho GTPases are key regulators of cellular protrusion and are involved in many developmental events including axon guidance during nervous system development. Rho GTPase pathways display functional redundancy in developmental events, including axon guidance. Therefore, their roles can often be masked when using simple loss-of-function genetic approaches. As a complement to loss-of-function genetics, we constructed a constitutively activated CDC-42(G12V) expressed in C. elegans neurons. CDC-42(G12V) drove the formation of ectopic lamellipodial and filopodial protrusions in the PDE neurons, which resembled protrusions normally found on migrating growth cones of axons. We then used a candidate gene approach to identify molecules that mediate CDC-42(G12V)-induced ectopic protrusions by determining if loss of function of the genes could suppress CDC-42(G12V). Using this approach, we identified 3 cytoskeletal pathways previously implicated in axon guidance, the Arp2/3 complex, UNC-115/abLIM, and UNC-43/Ena. We also identified the Nck-interacting kinase MIG-15/NIK and p21-activated kinases (PAKs), also implicated in axon guidance. Finally, PI3K signaling was required, specifically the Rictor/mTORC2 branch but not the mTORC1 branch that has been implicated in other aspects of PI3K signaling including stress and aging. Our results indicate that multiple pathways can mediate CDC-42-induced neuronal protrusions that might be relevant to growth cone protrusions during axon pathfinding. Each of these pathways involves Rac GTPases, which might serve to integrate the pathways and coordinate the multiple CDC-42 pathways. These pathways might be relevant to developmental events such as axon pathfinding as well as disease states such as metastatic melanoma.

Multiple cytoskeletal pathways and PI3K signaling mediate CDC-42-induced neuronal protrusion in C. elegans

PubMed Central

Alan, Jamie K; Struckhoff, Eric C; Lundquist, Erik A

2013-01-01

Rho GTPases are key regulators of cellular protrusion and are involved in many developmental events including axon guidance during nervous system development. Rho GTPase pathways display functional redundancy in developmental events, including axon guidance. Therefore, their roles can often be masked when using simple loss-of-function genetic approaches. As a complement to loss-of-function genetics, we constructed a constitutively activated CDC-42(G12V) expressed in C. elegans neurons. CDC-42(G12V) drove the formation of ectopic lamellipodial and filopodial protrusions in the PDE neurons, which resembled protrusions normally found on migrating growth cones of axons. We then used a candidate gene approach to identify molecules that mediate CDC-42(G12V)-induced ectopic protrusions by determining if loss of function of the genes could suppress CDC-42(G12V). Using this approach, we identified 3 cytoskeletal pathways previously implicated in axon guidance, the Arp2/3 complex, UNC-115/abLIM, and UNC-43/Ena. We also identified the Nck-interacting kinase MIG-15/NIK and p21-activated kinases (PAKs), also implicated in axon guidance. Finally, PI3K signaling was required, specifically the Rictor/mTORC2 branch but not the mTORC1 branch that has been implicated in other aspects of PI3K signaling including stress and aging. Our results indicate that multiple pathways can mediate CDC-42-induced neuronal protrusions that might be relevant to growth cone protrusions during axon pathfinding. Each of these pathways involves Rac GTPases, which might serve to integrate the pathways and coordinate the multiple CDC-42 pathways. These pathways might be relevant to developmental events such as axon pathfinding as well as disease states such as metastatic melanoma. PMID:24149939

Improving care coordination using organisational routines.

PubMed

Prætorius, Thim

2016-01-01

The purpose of this paper is to systematically apply theory of organisational routines to standardised care pathways. The explanatory power of routines is used to address open questions in the care pathway literature about their coordinating and organising role, the way they change and can be replicated, the way they are influenced by the organisation and the way they influence health care professionals. Theory of routines is systematically applied to care pathways in order to develop theoretically derived propositions. Care pathways mirror routines by being recurrent, collective and embedded and specific to an organisation. In particular, care pathways resemble standard operating procedures that can give rise to recurrent collective action patterns. In all, 11 propositions related to five categories are proposed by building on these insights: care pathways and coordination, change, replication, the organisation and health care professionals. Research limitations/implications - The paper is conceptual and uses care pathways as illustrative instances of hospital routines. The propositions provide a starting point for empirical research. The analysis highlights implications that health care professionals and managers have to consider in relation to coordination, change, replication, the way the organisation influences care pathways and the way care pathways influence health care professionals. Originality/value - Theory on organisational routines offers fundamental, yet unexplored, insights into hospital processes, including in particular care coordination.

Hypothalamic modulation of the arterial chemoreceptor reflex in the anaesthetized cat: role of the nucleus tractus solitarii.

PubMed Central

Silva-Carvalho, L; Dawid-Milner, M S; Goldsmith, G E; Spyer, K M

1995-01-01

1. There is evidence in the literature of a mutual facilitatory interaction between the arterial chemoreceptor reflex and the alerting stage of the defence reaction, particularly in relation to the patterning of cardiorespiratory activity. The present study has been designed to test the hypothesis that a portion of this interaction involves synaptic interactions within the nucleus tractus solitarii (NTS). 2. The study has involved an analysis of the effective interactions between the stimulation of the arterial chemoreceptors and the hypothalamic defence area (HDA) on the activity of NTS neurones recorded in anaesthetized, paralysed and artificially ventilated cats. 3. A group of eighteen NTS neurones was classified as chemosensitive, on the basis of displaying EPSPs on sinus nerve stimulation (SN) and their failure to show an excitatory response to baroreceptor stimulation. Thirteen of these neurones displayed pronounced excitatory responses to chemoreceptor stimulation. In sixteen of these neurones HDA stimulation elicited an EPSP; in four of these sixteen neurones this early EPSP was followed by an IPSP. In the remaining two (of 18) neurones HDA stimulation provoked no obvious synaptic response but facilitated the efficacy of both chemoreceptor inputs and SN stimulation. 4. Neurones shown to receive convergent inputs from the arterial chemoreceptors (and SN stimulation) and HDA, often displayed excitatory responses to stimulation of other peripheral inputs. Vagally evoked EPSPs were observed in nine neurones, SLN-evoked responses in seven neurones and aortic nerve-evoked EPSPs in three neurones. 5. The organization of these synaptic interactions is discussed and these data are used to explain the pattern of interaction between chemoreceptor, baroreceptor and HDA inputs within the NTS. Conclusions are drawn regarding the functional role of different classes of NTS neurone, based on the findings in this and the accompanying two papers. PMID:8544136

Acute Cutaneous Microvascular Flow Responses to Whole-Body Tilting in Humans

NASA Technical Reports Server (NTRS)

Breit, Gregory A.; Watenpaugh, Donald E.; Ballard, Richard E.; Hargens, Alan R.

1993-01-01

The transition from upright to head-down tilt (HDT) posture in humans increases blood pressure superior to the heart and decreases pressure inferior to the heart. Consequently, above heart level, myogenic arteriolar tone probably increases with HDT, in opposition to the withdrawal of baroreceptor-mediated sympathetic tone. We hypothesized that due to antagonism between central and local controls, the response of the facial cutaneous micro- circulation to acute postural change will be weaker than that in the leg, where these two mechanisms reinforce each other. Cutaneous microvascular flow was measured by laser Doppler flowmetry simultaneously at the shin and the neck of 7 male and 3 female subjects. Subjects underwent a stepwise tilt protocol from standing control to 54 deg head-up tilt (HUT), 30 deg, 12 deg, 0 deg, -6 deg (HDT), -12 deg, -6 deg, 0 deg, 12 deg, 30 deg, 54 deg, and standing, for 30-sec periods with 10-sec transitions between postures. Flows at the shin and the neck increased significantly (P < 0.05) from standing baseline to 12 deg HUT (252 +/- 55 and 126 +/- 9% (bar-X +/- SE) of baseline, respectively). From 12 deg to -12 deg tilt, flows continued to increase at the shin (509 +/- 71% of baseline) but decreased at the neck to baseline levels (100 +/- 15% of baseline). Cutaneous microvascular flow recovered at both sites during the return to standing posture with significant hysteresis. Flow increases from standing to near-supine posture are attributed at both sites to baroreceptor-mediated vasodilation. The great dissimilarity in flow response magnitudes at the two measurement sites may be indicative of central/local regulatory antagonism above heart level and reinforcement below heart level.

Acute Cutaneous Microvascular Flow Responses to Whole-Body Tilting in Humans

NASA Technical Reports Server (NTRS)

Breit, Gregory A.; Watenpaugh, Donald E.; Ballard, Richard E.; Hargens, Alan R.

1993-01-01

The transition from upright to head-down tilt (HDT) posture in humans increases blood pressure superior to the heart and decreases pressure inferior to the heart. Consequently, above heart level, myogenic arteriolar tone probably increases with HDT, in opposition to the withdrawal of baroreceptor-mediated sympathetic tone. We hypothesized that due to antagonism between central and local controls, the response of the facial cutaneous microcirculation to acute postural change will be weaker than that in the leg, where these two mechanisms reinforce each other. Cutaneous microvascular flow was measured by laser Doppler flowmetry simultaneously at the shin and the neck of 7 male and 3 female subjects. Subjects underwent a stepwise tilt protocol from standing control to 54 deg head-up tilt (HUT), 30 deg, 12 deg, O deg, -6 deg (HDT), -12 deg, -6 deg, O deg, 12 deg, 30 deg, 54 deg, and standing, for 30-sec periods with 10-sec transitions between postures. Flows at the shin and the neck increased significantly (P less than 0.05) from standing baseline to 12 deg HUT (252 +/- 55 and 126 +/- 9% (bar X +/- SE) of baseline, respectively). From 12 deg to -12 deg tilt, flows continued to increase at the shin (509 +/- 71% of baseline) but decreased at the neck to baseline levels (100 +/- 15% of baseline). Cutaneous microvascular flow recovered at both sites during the return to standing posture with significant hysteresis. Flow increases from standing to near-supine posture are attributed at both sites to baroreceptor-mediated vasodilation. The great dissimilarity in flow response magnitudes at the two measurement sites may be indicative of central/local regulatory antagonism above heart level and reinforcement below heart level.

Hydralazine administration activates sympathetic preganglionic neurons whose activity mobilizes glucose and increases cardiovascular function.

PubMed

Parker, Lindsay M; Damanhuri, Hanafi A; Fletcher, Sophie P S; Goodchild, Ann K

2015-04-16

Hypotensive drugs have been used to identify central neurons that mediate compensatory baroreceptor reflex responses. Such drugs also increase blood glucose. Our aim was to identify the neurochemical phenotypes of sympathetic preganglionic neurons (SPN) and adrenal chromaffin cells activated following hydralazine (HDZ; 10mg/kg) administration in rats, and utilize this and SPN target organ destination to ascribe their function as cardiovascular or glucose regulating. Blood glucose was measured and adrenal chromaffin cell activation was assessed using c-Fos immunoreactivity (-ir) and phosphorylation of tyrosine hydroxylase, respectively. The activation and neurochemical phenotype of SPN innervating the adrenal glands and celiac ganglia were determined using the retrograde tracer cholera toxin B subunit, in combination with in situ hybridization and immunohistochemistry. Blood glucose was elevated at multiple time points following HDZ administration but little evidence of chromaffin cell activation was seen suggesting non-adrenal mechanisms contribute to the sustained hyperglycemia. 16±0.1% of T4-T11 SPN contained c-Fos and of these: 24.3±1.4% projected to adrenal glands and 29±5.5% projected to celiac ganglia with the rest innervating other targets. 62.8±1.4% of SPN innervating adrenal glands were activated and 29.9±3.3% expressed PPE mRNA whereas 53.2±8.6% of SPN innervating celiac ganglia were activated and 31.2±8.8% expressed PPE mRNA. CART-ir SPN innervating each target were also activated and did not co-express PPE mRNA. Neurochemical coding reveals that HDZ administration activates both PPE+SPN, whose activity increase glucose mobilization causing hyperglycemia, as well as CART+SPN whose activity drive vasomotor responses mediated by baroreceptor unloading to raise vascular tone and heart rate. Copyright © 2015 Elsevier B.V. All rights reserved.

Beat-to-beat blood pressure analysis after premature ventricular contraction indicates sensitive baroreceptor dysfunction in Parkinson's disease.

PubMed

Haensch, Carl-Albrecht; Jörg, Johannes

2006-04-01

Extrasystoles occur in normal subjects but are significant more frequently (16.25% vs. 55%; chi(2) = 19.3; P < 0.001) seen in Parkinson's disease (PD) patients. The extrasystolic decreases in stroke volume and systolic pressure activate sympathetic vasomotor innervation and lead to a blood pressure increase for a few heartbeats. The purpose of this study was to prove whether the short time analysis of this blood pressure regulation allows the assessment of sympathetic neurocirculatory function. Records of noninvasive blood pressure monitoring were reviewed from 40 PD patients and 80 controls. A battery of cardiovascular autonomic tests, including Valsalva maneuver, tilt-table testing, echocardiography, and cardiac scintigraphy with [(123)I]meta-iodobenzylguanidine were performed. Fifty-five percent of the PD patients had at least one premature ventricular contraction (PVC) in 10 minutes lying supine at rest. After every PVC (13 PVCs) recorded from normal subjects, we found an increase in systolic blood pressure above base line with a maximum at the seventh heart beat. In all of the 22 PD patients, the systolic blood pressure was significantly decreased less than baseline in every PVC from the second to the ninth postextrasystolic beat (P < 0.001). In both groups, the extrasystolic fall in blood pressure was on average approximately 22%. The postextrasystolic potentiation did not differ (5.3% vs. 4.4%, not significant). If a PVC occurs, the analysis of short-time blood pressure regulation is a sensitive tool for baroreceptor reflex function. The advantage of this method results from the independence of patients cooperation and the high sensitivity to prove a sympathetic neurocirculatory failure within 10 heart beats. Copyright 2005 Movement Disorder Society.

Physiology and pathophysiology of heart rate and blood pressure variability in humans: is power spectral analysis largely an index of baroreflex gain?

PubMed

Sleight, P; La Rovere, M T; Mortara, A; Pinna, G; Maestri, R; Leuzzi, S; Bianchini, B; Tavazzi, L; Bernardi, L

1995-01-01

1. It is often assumed that the power in the low- (around 0.10 Hz) and high-frequency (around 0.25 Hz) bands obtained by power spectral analysis of cardiovascular variables reflects sympathetic and vagal tone [corrected] respectively. An alternative model attributes the low-frequency band to a resonance in the control system that is produced by the inefficiently slow time constant of the reflex response to beat-to-beat changes in blood pressure effected by the sympathetic (with or without the parasympathetic) arm(s) of the baroreflex (De Boer model). 2. We have applied the De Boer model of circulatory variability to patients with varying baroreflex sensitivity to patients with varying baroreflex sensitivity and one normal subject, and have shown that the main differences in spectral power (for both low and high frequency) between and within subjects are caused by changes in the arterial baroreflex gain, particularly for vagal control of heart rate (R-R interval) and left ventricular stroke output. We have computed the power spectrum at rest and during neck suction (to stimulate carotid baroreceptors). We stimulated the baroreceptors at two frequencies (0.1 and 0.2 Hz), which were both distinct from the controlled respiration rate (0.25 Hz), in both normal subjects and heart failure patients with either sensitive or poor baroreflex control. 3. The data broadly confirm the De Boer model. The low-frequency (0.1 Hz) peak in either R-R or blood pressure variability) was spontaneously generated only if the baroreflex control of the autonomic outflow was relatively intact.(ABSTRACT TRUNCATED AT 250 WORDS)

Interaction of semicircular canal stimulation with carotid baroreceptor reflex control of heart rate

NASA Technical Reports Server (NTRS)

Convertino, V. A.

1998-01-01

The carotid-cardiac baroreflex contributes to the prediction of orthostatic tolerance; experimental attenuation of the reflex response leads to orthostatic hypotension in humans and animals. Anecdotal observations indicate that rotational head movements about the vertical axis of the body can also induce orthostatic bradycardia and hypotension through increased parasympathetic activity. We therefore measured the chronotropic response to carotid baroreceptor stimulation in 12 men during varying conditions of vestibulo-oculomotor stimulation to test the hypothesis that stimulation of the semicircular canals associated with head movements in the yaw plane inhibits cardioacceleration through a vagally mediated baroreflex. Carotid-cardiac baroreflex response was assessed by plotting R-R intervals (ms) at each of 8 neck pressure steps with their respective carotid distending pressures (mmHg). Calculated baroreflex gain (maximal slope of the stimulus-response relationship) was measured under 4 experimental conditions: 1) sinusoidal whole-body yaw rotation of the subject in the dark without visual fixation (combined vestibular-oculomotor stimulation); 2) yaw oscillation of the subject while tracking a small head-fixed light moving with the subject (vestibular stimulation without eye movements); 3) subject stationary while fixating on a small light oscillating in yaw at the same frequency, peak acceleration, and velocity as the chair (eye movements without vestibular stimulation); and 4) subject stationary in the dark (no eye or head motion). Head motion alone and with eye movement reduced baseline baroreflex responsiveness to the same stimulus by 30%. Inhibition of cardioacceleration during rotational head movements may have significant impact on functional performance in aerospace environments, particularly in high-performance aircraft pilots during high angular acceleration in aerial combat maneuvers or in astronauts upon return from spaceflight who already have attenuated baroreflex functions.

Exaggerated cardiovascular effects of cocaine in conscious dogs with pacing-induced dilated cardiomyopathy.

PubMed

Mathier, Michael A; Shen, You-Tang; Shannon, Richard P

2002-12-01

The aim of this study was to explore the characteristics and mechanisms of the cardiovascular effects of cocaine in dilated cardiomyopathy. We studied the cardiovascular responses to acute intravenous cocaine (1 mg/kg) in 8 conscious, chronically instrumented dogs before and after the development of dilated cardiomyopathy induced by rapid ventricular pacing. To help elucidate the role of altered baroreflex function in mediating the cardiovascular effects of cocaine, we also studied responses in 3 conscious, chronically instrumented dogs that had undergone surgical sinoaortic baroreceptor denervation. Cocaine produced greater increases in heart rate (+57 +/- 8% from 112 +/- 5 beats/min versus +28 +/- 3% from 100 +/- 4 beats/min; P <.01), first derivative of left ventricular pressure (+30 +/- 5% from 1,714 +/- 147 mm Hg/sec versus +15 +/- 3% from 3,032 +/- 199 mm Hg/sec; P <.01), coronary vascular resistance (+28 +/- 5% from 2.3 +/- 0.3 mm Hg/mL/min versus +11 +/- 5% from 2.2 +/- 0.3 mm Hg/mL/min; P <.05) and plasma norepinephrine concentration (+130 +/- 31% from 462 +/- 102 pg/mL versus +86 +/- 32% from 286 +/- 77 pg/mL; P <.05) in dogs with dilated cardiomyopathy as compared to controls. In addition, responses were much more rapid in onset following the development of dilated cardiomyopathy. Chronotropic and inotropic responses to cocaine were similarly rapid and exaggerated in dogs after baroreceptor denervation. Cocaine produces rapid and exaggerated chronotropic, inotropic, and coronary vasoconstrictor responses in conscious dogs with pacing-induced dilated cardiomyopathy. Alterations in arterial baroreflex function may play a role in these observations, which in turn may underlie the clinically observed association between cocaine and heart failure.

Effects of acute exercise on attenuated vagal baroreflex function during bed rest

NASA Technical Reports Server (NTRS)

Convertino, Victor A.; Doerr, Donald F.; Guell, Antonio; Marini, J.-F.

1992-01-01

We measured carotid baroreceptor-cardiac reflex responses in six healthy men, 24 h before and 24 h after a bout of leg exercise during 6 deg head-down bed rest to determine if depressed vagal baroreflex function associated with exposure to microgravity environments could be reversed by a single exposure to acute intense exercise. Baroreflex responses were measured before bed rest and on day 7 of bed rest. An exercise bout consisting of dynamic and isometric actions of the quadriceps at graded speeds and resistances was performed on day 8 of bed rest and measurements of baroreflex response were repeated 24 h later. Vagally-mediated cardiac responses were provoked with ramped neck pressure-suction sequences comprising pressure elevations to +40 mm Hg, followed by serial, R-wave triggered 15 mm Hg reductions, to -65 mm Hg. Baroreceptor stimulus-cardiac response relationships were derived by plotting each R-R interval as a function of systolic pressure less the neck chamber pressure applied during the interval. Compared with pre-bed rest baseline measurements, 7 d of bed rest decreased the gain (maximum slope) of the baroreflex stimulus-response relationship by 16.8 +/- 3.4 percent (p less than 0.05). On day 9 of bed rest, 24 h after exercise, the maximum slope of the baroreflex stimulus-response relationship was increased (p less than 0.05) by 10.7 +/- 3.7 percent above pre-bed rest levels and 34.3 +/- 7.9 percent above bed rest day 7. Our data verify that vagally-mediated baroreflex function is depressed by exposure to simulated microgravity and demonstrate that this effect can be acutely reversed by exposure to a single bout of intense exercise.

Smoking before isometric exercise amplifies myocardial stress and dysregulates baroreceptor sensitivity and cerebral oxygenation.

PubMed

Anyfanti, Panagiota; Triantafyllidou, Eleftheria; Papadopoulos, Stavros; Triantafyllou, Areti; Nikolaidis, Michalis G; Kyparos, Antonios; Vrabas, Ioannis S; Douma, Stella; Zafeiridis, Andreas; Dipla, Konstantina

2017-06-01

This crossover study examined whether acute cardiovascular responses, baroreceptor sensitivity (BRS), and brain oxygenation during isometric exercise are altered after cigarette smoking. Twelve young, habitual smokers randomly performed a smoking and a control protocol, during which participants smoked one cigarette (0.9 mg nicotine) or a sham cigarette, before exercise. Testing involved baseline, a 5-minute smoking, a 10-minute post-smoking rest, 3-minute handgrip exercise (30% maximum voluntary contraction), and recovery. Beat-to-beat blood pressure, heart rate (HR), and cerebral oxygenation (near infrared spectroscopy) were continuously monitored. Double-product, stroke volume (SV), cardiac output, systemic vascular resistance and BRS were assessed. During post-smoking rest, systolic or diastolic blood pressure (140.8 ± 12.1/87.0 ± 6.9 vs. 125.9 ± 7.1/77.3 ± 5.5 mm Hg), HR, and double product were higher in the smoking versus the control protocol, whereas BRS was lower (P < .05). During handgrip exercise, smoking resulted in greater HR and double product (17,240 ± 3893 vs. 15,424 ± 3173 mm Hg·bpm) and lower BRS versus the control protocol (P < .05), without significant differences in stroke volume and systemic vascular resistance between protocols. During recovery, smoking elicited a delayed return of brain oxygenation indices, lower BRS, and higher double product. Smoking a cigarette shortly before the exercise session amplifies myocardial stress and dysregulates autonomic function and cerebral oxygenation during exercise and recovery, even in young habitual smokers, perceived as free from long-term cardiovascular effects of smoking. Copyright © 2017 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.

Mechanism of Thirst Attenuation During Head-Out Water Immersion in Men

NASA Technical Reports Server (NTRS)

Wada, F.; Sagawa, S.; Miki, K.; Nagaya, K.; Nakamitsu, S.; Shiraki, K.; Greenleaf, J. E.

1994-01-01

The purpose was to determine whether extracellular volume or osmolality was the major contributing factor for reduction of thirst in air and head-out water immersion in hypohydrated subjects. Eight males (19 - 25 yr) were subjected to thermoneutral immersion and thermoneutral air under two hydration conditions without further drinking: euhydration in water (Eu-H2O) and euhydration in air, and hypohydration in water (Hypo-H2O) and hypohydration in air (3.7% wt loss after exercise in heat). The increased thirst sensation with Hypo-H2O decreased (P less than 0.05) within 10 min of immersion and continued thereafter. Mean plasma osmolality (288 +/- 1 mosmol/kg H2O) and sodium (140 +/- 1 meq/1) remained elevated, and plasma volume increased by 4.2 +/- 1.0% (P less than 0.05) throughout Hypo-H2O. A sustained increase (P less than 0.05) in stroke volume accompanied the prompt and sustained decrease in plasma renin activity and sustained increase (P less than 0.05) in plasma atrial natriuretic peptide during Eu-H2O and Hypo-H2O. Plasma vasopressin decreased from 5.3 +/- 0.7 to 2.9 +/- 0.5 pg/ml (P less than 0.05) during Hypo-H2O but was unchanged in Eu-H2O. These findings suggest a sustained stimulation of the atrial baroreceptors and reduction of a dipsogenic stimulus without major alterations of extracellular osmolality in Hypo-H2O. Thus it appears that vascular volume induced stimuli of cardiopulmonary baroreceptors play a more important role than extracellular osmolality in reducing thirst sensations during immersion in hypohydrated subjects. Thus the purpose for this study was to determine the relative importance of volume and osmotic stimuli, and associated hormonal interaction, for attenuation of thirst during immersion.

Computational models for the study of heart-lung interactions in mammals.

PubMed

Ben-Tal, Alona

2012-01-01

The operation and regulation of the lungs and the heart are closely related. This is evident when examining the anatomy within the thorax cavity, in the brainstem and in the aortic and carotid arteries where chemoreceptors and baroreceptors, which provide feedback affecting the regulation of both organs, are concentrated. This is also evident in phenomena such as respiratory sinus arrhythmia where the heart rate increases during inspiration and decreases during expiration, in other types of synchronization between the heart and the lungs known as cardioventilatory coupling and in the association between heart failure and sleep apnea where breathing is interrupted periodically by periods of no-breathing. The full implication and physiological significance of the cardiorespiratory coupling under normal, pathological, or extreme physiological conditions are still unknown and are subject to ongoing investigation both experimentally and theoretically using mathematical models. This article reviews mathematical models that take heart-lung interactions into account. The main ideas behind low dimensional, phenomenological models for the study of the heart-lung synchronization and sleep apnea are described first. Higher dimensions, physiology-based models are described next. These models can vary widely in detail and scope and are characterized by the way the heart-lung interaction is taken into account: via gas exchange, via the central nervous system, via the mechanical interactions, and via time delays. The article emphasizes the need for the integration of the different sources of heart-lung coupling as well as the different mathematical approaches. Copyright © 2011 Wiley Periodicals, Inc.

Developmental Pathways to Conduct Disorder: Implications for Future Directions in Research, Assessment, and Treatment

ERIC Educational Resources Information Center

Frick, Paul J.

2012-01-01

Research has indicated that there are several common pathways through which children and adolescents develop conduct disorder, each with different risk factors and each with different underlying developmental mechanisms leading to the child's aggressive and antisocial behavior. The current article briefly summarizes research on these pathways,…

Regulation of the Wnt/β-Catenin Signaling Pathway by Human Papillomavirus E6 and E7 Oncoproteins

PubMed Central

Muñoz Bello, Jesus Omar; Olmedo Nieva, Leslie; Contreras Paredes, Adriana; Fuentes Gonzalez, Alma Mariana; Rocha Zavaleta, Leticia; Lizano, Marcela

2015-01-01

Cell signaling pathways are the mechanisms by which cells transduce external stimuli, which control the transcription of genes, to regulate diverse biological effects. In cancer, distinct signaling pathways, such as the Wnt/β-catenin pathway, have been implicated in the deregulation of critical molecular processes that affect cell proliferation and differentiation. For example, changes in β-catenin localization have been identified in Human Papillomavirus (HPV)-related cancers as the lesion progresses. Specifically, β-catenin relocates from the membrane/cytoplasm to the nucleus, suggesting that this transcription regulator participates in cervical carcinogenesis. The E6 and E7 oncoproteins are responsible for the transforming activity of HPV, and some studies have implicated these viral oncoproteins in the regulation of the Wnt/β-catenin pathway. Nevertheless, new interactions of HPV oncoproteins with cellular proteins are emerging, and the study of the biological effects of such interactions will help to understand HPV-related carcinogenesis. This review addresses the accumulated evidence of the involvement of the HPV E6 and E7 oncoproteins in the activation of the Wnt/β-catenin pathway. PMID:26295406

Using in vivo probabilistic tractography to reveal two segregated dorsal ‘language-cognitive’ pathways in the human brain☆

PubMed Central

Cloutman, Lauren L.; Binney, Richard J.; Morris, David M.; Parker, Geoffrey J.M.; Lambon Ralph, Matthew A.

2013-01-01

Primate studies have recently identified the dorsal stream as constituting multiple dissociable pathways associated with a range of specialized cognitive functions. To elucidate the nature and number of dorsal pathways in the human brain, the current study utilized in vivo probabilistic tractography to map the structural connectivity associated with subdivisions of the left supramarginal gyrus (SMG). The left SMG is a prominent region within the dorsal stream, which has recently been parcellated into five structurally-distinct regions which possess a dorsal–ventral (and rostral-caudal) organisation, postulated to reflect areas of functional specialisation. The connectivity patterns reveal a dissociation of the arcuate fasciculus into at least two segregated pathways connecting frontal-parietal-temporal regions. Specifically, the connectivity of the inferior SMG, implicated as an acoustic-motor speech interface, is carried by an inner/ventro-dorsal arc of fibres, whilst the pathways of the posterior superior SMG, implicated in object use and cognitive control, forms a parallel outer/dorso-dorsal crescent. PMID:23937853

The diverse functions of Src family kinases in macrophages

PubMed Central

Abram, Clare L.; Lowell, Clifford A.

2015-01-01

Macrophages are key components of the innate immune response. These cells possess a diverse repertoire of receptors that allow them to respond to a host of external stimuli including cytokines, chemokines, and pathogen-associated molecules. Signals resulting from these stimuli activate a number of macrophage functional responses such as adhesion, migration, phagocytosis, proliferation, survival, cytokine release and production of reactive oxygen and nitrogen species. The cytoplasmic tyrosine kinase Src and its family members (SFKs) have been implicated in many intracellular signaling pathways in macrophages, initiated by a diverse set of receptors ranging from integrins to Toll-like receptors. However, it has been difficult to implicate any given member of the family in any specific pathway. SFKs appear to have overlapping and complementary functions in many pathways. Perhaps the function of these enzymes is to modulate the overall intracellular signaling network in macrophages, rather than operating as exclusive signaling switches for defined pathways. In general, SFKs may function more like rheostats, influencing the amplitude of many pathways. PMID:18508521

Clinical implications of hedgehog signaling pathway inhibitors

PubMed Central

Liu, Hailan; Gu, Dongsheng; Xie, Jingwu

2011-01-01

Hedgehog was first described in Drosophila melanogaster by the Nobel laureates Eric Wieschaus and Christiane Nüsslein-Volhard. The hedgehog (Hh) pathway is a major regulator of cell differentiation, proliferation, tissue polarity, stem cell maintenance, and Carcinogenesis. The first link of Hh signaling to cancer was established through studies of a rare familial disease, Gorlin syndrome, in 1996. Follow-up studies revealed activation of this pathway in basal cell carcinoma, medulloblastoma and, leukemia as well as in gastrointestinal, lung, ovarian, breast, and prostate cancer. Targeted inhibition of Hh signaling is now believed to be effective in the treatment and prevention of human cancer. The discovery and synthesis of specific inhibitors for this pathway are even more exciting. In this review, we summarize major advances in the understanding of Hh signaling pathway activation in human cancer, mouse models for studying Hh-mediated Carcinogenesis, the roles of Hh signaling in tumor development and metastasis, antagonists for Hh signaling and their clinical implications. PMID:21192841

Ecohydrology of the different photosynthetic pathways and implication for sustainable agriculture

NASA Astrophysics Data System (ADS)

Porporato, A. M.; Bartlett, M. S., Jr.; Hartzell, S. R.

2016-12-01

We use a recently proposed model that can simulate the different photosynthetic pathways coupled to the soil-plant-atmosphere continuum (SPAC) to discuss their ecohydrological implications in relation to water use and plant water stress in both natural and agricultural ecosystems. Built around the classical C3 photosynthesis core model (light reactions and Calvin cycle), the model includes a simple CO2-pump parameterization for C4 plants and a circadian rhythm and carbon storage components for the CAM (Crassulacean Acid Metabolism) plants. Its architecture takes advantage of the interesting modularity in which photosynthesis evolved in geological times to provide a relatively simple but comprehensive framework to explore the advantages and tradeoffs in water energy and carbon fluxes of the three photosynthetic pathways under fluctuating environmental forcing. We calibrate the model with reference to a series of C3,C4 and CAM plants, and discuss the trade-offs in water use and plan productivity and the related impact on hydrologic fluxes and soil biogeochemistry. We also consider some important crop species to analyze the implications of choosing crops with different photosynthetic pathways to improve sustainability of agriculture and irrigation in semiarid systems.

21 CFR 866.5320 - Properdin factor B immuno-logical test system.

Code of Federal Regulations, 2012 CFR

2012-04-01

... involvement of the alternative to the classical pathway of activation of complement (a group of plasma... the skin). Other diseases in which the alternate pathway of complement activation has been implicated...

21 CFR 866.5320 - Properdin factor B immuno-logical test system.

Code of Federal Regulations, 2014 CFR

2014-04-01

... involvement of the alternative to the classical pathway of activation of complement (a group of plasma... the skin). Other diseases in which the alternate pathway of complement activation has been implicated...

21 CFR 866.5320 - Properdin factor B immuno-logical test system.

Code of Federal Regulations, 2013 CFR

2013-04-01

... involvement of the alternative to the classical pathway of activation of complement (a group of plasma... the skin). Other diseases in which the alternate pathway of complement activation has been implicated...

Blood pressure control in resistant hypertension: new therapeutic options.

PubMed

Grassi, Guido; Quarti-Trevano, Fosca; Brambilla, Gianmaria; Seravalle, Gino

2010-11-01

Resistant hypertension, namely the hypertensive state characterized by the inability of multiple antihypertensive drug interventions to lower blood pressure to goal levels, represents a condition frequently detected in clinical practice. Its main features are represented by its heterogeneous etiology as well as its very high cardiovascular risk. This latter peculiarity has implemented the research for new approaches to the treatment of the disease. This article will focus on two of them, namely carotid baroreceptor electric stimulation and the renal denervation procedure. Clinical studies and large-scale clinical trials are presently ongoing with the aim of defining the long-term efficacy and safety profile of the two interventions.

Molecular Genetics of the PI3K-AKT-mTOR Pathway in Genodermatoses: Diagnostic Implications and Treatment Opportunities.

PubMed

Vahidnezhad, Hassan; Youssefian, Leila; Uitto, Jouni

2016-01-01

A number of critical signaling pathways are required for homeostatic regulation of cell survival, differentiation, and proliferation during organogenesis. One of them is the PI3K-AKT-mTOR pathway consisting of a cascade of inhibitor/activator molecules. Recently, a number of heritable diseases with skin involvement, manifesting particularly with tissue overgrowth, have been shown to result from mutations in the genes in the PI3K-AKT-mTOR and interacting intracellular pathways. Many of these conditions represent an overlapping spectrum of phenotypic manifestations forming a basis for novel, unifying classifications. Identification of the mutant genes and specific mutations in these patients has implications for diagnostics and genetic counseling and provides a rational basis for the development of novel treatment modalities for this currently intractable group of disorders. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Neural control of circulation and exercise: a translational approach disclosing interactions between central command, arterial baroreflex, and muscle metaboreflex.

PubMed

Michelini, Lisete C; O'Leary, Donal S; Raven, Peter B; Nóbrega, Antonio C L

2015-08-01

The last 100 years witnessed a rapid and progressive development of the body of knowledge concerning the neural control of the cardiovascular system in health and disease. The understanding of the complexity and the relevance of the neuroregulatory system continues to evolve and as a result raises new questions. The purpose of this review is to articulate results from studies involving experimental models in animals as well as in humans concerning the interaction between the neural mechanisms mediating the hemodynamic responses during exercise. The review describes the arterial baroreflex, the pivotal mechanism controlling mean arterial blood pressure and its fluctuations along with the two main activation mechanisms to exercise: central command (parallel activation of central somatomotor and autonomic descending pathways) and the muscle metaboreflex, the metabolic component of exercise pressor reflex (feedback from ergoreceptors within contracting skeletal muscles). In addition, the role of the cardiopulmonary baroreceptors in modulating the resetting of arterial baroreflex is identified, and the mechanisms in the central nervous system involved with the resetting of baroreflex function during dynamic exercise are also described. Approaching a very relevant clinical condition, the review also presents the concept that the impaired arterial baroreflex function is an integral component of the metaboreflex-mediated exaggerated sympathetic tone in subjects with heart failure. This increased sympathetic activity has a major role in causing the depressed ventricular function observed during submaximal dynamic exercise in these patients. The potential contribution of a metaboreflex arising from respiratory muscles is also considered. Copyright © 2015 the American Physiological Society.

Regulation of Breathing and Autonomic Outflows by Chemoreceptors

PubMed Central

Guyenet, Patrice G.

2016-01-01

Lung ventilation fluctuates widely with behavior but arterial PCO2 remains stable. Under normal conditions, the chemoreflexes contribute to PaCO2 stability by producing small corrective cardiorespiratory adjustments mediated by lower brainstem circuits. Carotid body (CB) information reaches the respiratory pattern generator (RPG) via nucleus solitarius (NTS) glutamatergic neurons which also target rostral ventrolateral medulla (RVLM) presympathetic neurons thereby raising sympathetic nerve activity (SNA). Chemoreceptors also regulate presympathetic neurons and cardiovagal preganglionic neurons indirectly via inputs from the RPG. Secondary effects of chemoreceptors on the autonomic outflows result from changes in lung stretch afferent and baroreceptor activity. Central respiratory chemosensitivity is caused by direct effects of acid on neurons and indirect effects of CO2 via astrocytes. Central respiratory chemoreceptors are not definitively identified but the retrotrapezoid nucleus (RTN) is a particularly strong candidate. The absence of RTN likely causes severe central apneas in congenital central hypoventilation syndrome. Like other stressors, intense chemosensory stimuli produce arousal and activate circuits that are wake- or attention-promoting. Such pathways (e.g., locus coeruleus, raphe, and orexin system) modulate the chemoreflexes in a state-dependent manner and their activation by strong chemosensory stimuli intensifies these reflexes. In essential hypertension, obstructive sleep apnea and congestive heart failure, chronically elevated CB afferent activity contributes to raising SNA but breathing is unchanged or becomes periodic (severe CHF). Extreme CNS hypoxia produces a stereotyped cardiorespiratory response (gasping, increased SNA). The effects of these various pathologies on brainstem cardiorespiratory networks are discussed, special consideration being given to the interactions between central and peripheral chemoreflexes. PMID:25428853

Insulin in the Brain: There and Back Again

PubMed Central

Banks, William A.; Owen, Joshua B.; Erickson, Michelle A

2012-01-01

Insulin performs unique functions within the CNS. Produced nearly exclusively by the pancreas, insulin crosses the blood-brain barrier (BBB) using a saturable transporter, affecting feeding and cognition through CNS mechanisms largely independent of glucose utilization. Whereas peripheral insulin acts primarily as a metabolic regulatory hormone, CNS insulin has an array of effects on brain that may more closely resemble the actions of the ancestral insulin molecule. Brain endothelial cells (BEC), the cells that form the vascular BBB and contain the transporter that translocates insulin from blood to brain, is itself regulated by insulin. The insulin transporter is altered by physiological and pathological factors including hyperglycemia and the diabetic state. The latter can lead to BBB disruption. Pericytes, pluripotent cells in intimate contact with the BEC, protect the integrity of the BBB and its ability to transport insulin. Most of insulin’s known actions within the CNS are mediated through two canonical pathways, the phosphoinositide-3 kinase (PI3)/Akt and Ras/mitogen activated kinase (MAPK) cascades. Resistance to insulin action within the CNS, sometimes referred to as diabetes mellitus type III, is associated with peripheral insulin resistance, but it is possible that variable hormonal resistance syndromes exist so that resistance at one tissue bed may be independent of that at others. CNS insulin resistance is associated with Alzheimer’s disease, depression, and impaired baroreceptor gain in pregnancy. These aspects of CNS insulin action and the control of its entry by the BBB are likely only a small part of the story of insulin within the brain. PMID:22820012

Neural control of circulation and exercise: a translational approach disclosing interactions between central command, arterial baroreflex, and muscle metaboreflex

PubMed Central

Michelini, Lisete C.; O'Leary, Donal S.; Raven, Peter B.

2015-01-01

The last 100 years witnessed a rapid and progressive development of the body of knowledge concerning the neural control of the cardiovascular system in health and disease. The understanding of the complexity and the relevance of the neuroregulatory system continues to evolve and as a result raises new questions. The purpose of this review is to articulate results from studies involving experimental models in animals as well as in humans concerning the interaction between the neural mechanisms mediating the hemodynamic responses during exercise. The review describes the arterial baroreflex, the pivotal mechanism controlling mean arterial blood pressure and its fluctuations along with the two main activation mechanisms to exercise: central command (parallel activation of central somatomotor and autonomic descending pathways) and the muscle metaboreflex, the metabolic component of exercise pressor reflex (feedback from ergoreceptors within contracting skeletal muscles). In addition, the role of the cardiopulmonary baroreceptors in modulating the resetting of arterial baroreflex is identified, and the mechanisms in the central nervous system involved with the resetting of baroreflex function during dynamic exercise are also described. Approaching a very relevant clinical condition, the review also presents the concept that the impaired arterial baroreflex function is an integral component of the metaboreflex-mediated exaggerated sympathetic tone in subjects with heart failure. This increased sympathetic activity has a major role in causing the depressed ventricular function observed during submaximal dynamic exercise in these patients. The potential contribution of a metaboreflex arising from respiratory muscles is also considered. PMID:26024683

Molecular pathways and therapeutic targets in lung cancer

PubMed Central

Shtivelman, Emma; Hensing, Thomas; Simon, George R.; Dennis, Phillip A.; Otterson, Gregory A.; Bueno, Raphael; Salgia, Ravi

2014-01-01

Lung cancer is still the leading cause of cancer death worldwide. Both histologically and molecularly lung cancer is heterogeneous. This review summarizes the current knowledge of the pathways involved in the various types of lung cancer with an emphasis on the clinical implications of the increasing number of actionable molecular targets. It describes the major pathways and molecular alterations implicated in the development and progression of non-small cell lung cancer (adenocarcinoma and squamous cancer), and of small cell carcinoma, emphasizing the molecular alterations comprising the specific blueprints in each group. The approved and investigational targeted therapies as well as the immune therapies, and clinical trials exploring the variety of targeted approaches to treatment of lung cancer are the main focus of this review. PMID:24722523

Have Clinical Trials Properly Assessed c-Met Inhibitors?

PubMed

Hughes, Veronica S; Siemann, Dietmar W

2018-02-01

The c-Met/HGF pathway is implicated in cancer progression and dissemination. Many inhibitors have been developed to target this pathway. Unfortunately, most trials have failed to demonstrate efficacy. However, clinical trials have not adequately tested the concept of c-Met pathway inhibition due to the lack of appropriate patient selection criteria. Copyright © 2017 Elsevier Inc. All rights reserved.

In Silico Analysis of Putrefaction Pathways in Bacteria and Its Implication in Colorectal Cancer

PubMed Central

Kaur, Harrisham; Das, Chandrani; Mande, Sharmila S.

2017-01-01

Fermentation of undigested proteins in human gastrointestinal tract (gut) by the resident microbiota, a process called bacterial putrefaction, can sometimes disrupt the gut homeostasis. In this process, essential amino acids (e.g., histidine, tryptophan, etc.) that are required by the host may be utilized by the gut microbes. In addition, some of the products of putrefaction, like ammonia, putrescine, cresol, indole, phenol, etc., have been implicated in the disease pathogenesis of colorectal cancer (CRC). We have investigated bacterial putrefaction pathways that are known to be associated with such metabolites. Results of the comprehensive in silico analysis of the selected putrefaction pathways across bacterial genomes revealed presence of these pathways in limited bacterial groups. Majority of these bacteria are commonly found in human gut. These include Bacillus, Clostridium, Enterobacter, Escherichia, Fusobacterium, Salmonella, etc. Interestingly, while pathogens utilize almost all the analyzed pathways, commensals prefer putrescine and H2S production pathways for metabolizing the undigested proteins. Further, comparison of the putrefaction pathways in the gut microbiomes of healthy, carcinoma and adenoma datasets indicate higher abundances of putrefying bacteria in the carcinoma stage of CRC. The insights obtained from the present study indicate utilization of possible microbiome-based therapies to minimize the adverse effects of gut microbiome in enteric diseases. PMID:29163445

Biomarkers in the Detection of Prostate Cancer in African Americans

DTIC Science & Technology

2014-09-01

tissues by Taqman low density array: application to Hedgehog and Wnt pathway analysis in ovarian endome- trioid adenocarcinoma . J. Mol. Diagn. 8 : 76...2007) Hedgehog pathway expression in heterogeneous pancreatic adenocarcinoma: implications for the molecular analysis of clinically available

Integrating Mechanisms for Insulin Resistance: Common Threads and Missing Links

PubMed Central

Samuel, Varman T.; Shulman, Gerald I.

2012-01-01

Insulin resistance is a complex metabolic disorder that defies a single etiological pathway. Accumulation of ectopic lipid metabolites, activation of the unfolded protein response (UPR) pathway and innate immune pathways have all been implicated in the pathogenesis of insulin resistance. However, these pathways are also closely linked to changes in fatty acid uptake, lipogenesis, and energy expenditure that can impact ectopic lipid deposition. Ultimately, accumulation of specific lipid metabolites (diacylglycerols and/or ceramides) in liver and skeletal muscle, may be a common pathway leading to impaired insulin signaling and insulin resistance. PMID:22385956

Th17 Cells Pathways in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorders: Pathophysiological and Therapeutic Implications

PubMed Central

Passos, Giordani Rodrigues Dos; Sato, Douglas Kazutoshi; Becker, Jefferson; Fujihara, Kazuo

2016-01-01

Several animal and human studies have implicated CD4+ T helper 17 (Th17) cells and their downstream pathways in the pathogenesis of central nervous system (CNS) autoimmunity in multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD), challenging the traditional Th1-Th2 paradigm. Th17 cells can efficiently cross the blood-brain barrier using alternate ways from Th1 cells, promote its disruption, and induce the activation of other inflammatory cells in the CNS. A number of environmental factors modulate the activity of Th17 pathways, so changes in the diet, exposure to infections, and other environmental factors can potentially change the risk of development of autoimmunity. Currently, new drugs targeting specific points of the Th17 pathways are already being tested in clinical trials and provide basis for the development of biomarkers to monitor disease activity. Herein, we review the key findings supporting the relevance of the Th17 pathways in the pathogenesis of MS and NMOSD, as well as their potential role as therapeutic targets in the treatment of immune-mediated CNS disorders. PMID:26941483

Proteomic pathway analysis of the hippocampus in schizophrenia and bipolar affective disorder implicates 14-3-3 signaling, aryl hydrocarbon receptor signaling, and glucose metabolism: potential roles in GABAergic interneuron pathology.

PubMed

Schubert, Klaus Oliver; Föcking, Melanie; Cotter, David R

2015-09-01

Neuropathological changes of the hippocampus have been associated with psychotic disorders such as schizophrenia and bipolar disorder. Recent work has particularly implicated hippocampal GABAergic interneurons in the pathophysiology of these diseases. However, the molecular mechanisms underlying structural and cellular hippocampal pathology remain poorly understood. We used data from comprehensive difference-in-gel electrophoresis (2-D DIGE) investigations of postmortem human hippocampus of people with schizophrenia and bipolar disorder, covering the acidic (isoelectric point (pI) between pH4 and 7) and, separately, the basic (pI between pH6 and 11) sub-proteome, for Ingenuity Pathway Analysis (IPA) of implicated protein networks and pathways. Comparing disease and control cases, we identified 58 unique differentially expressed proteins in schizophrenia, and 70 differentially expressed proteins in bipolar disorder, using mass spectrometry. IPA implicated, most prominently, 14-3-3 and aryl hydrocarbon receptor signaling in schizophrenia, and gluconeogenesis/glycolysis in bipolar disorder. Both disorders were characterized by alterations of proteins involved in the oxidative stress response, mitochondrial function, and protein-endocytosis, -trafficking, -degradation, and -ubiquitination. These findings are interpreted with a focus on GABAergic interneuron pathology in the hippocampus. Copyright © 2015 Elsevier B.V. All rights reserved.

The Effect of Physical Resistance Training on Baroreflex Sensitivity of Hypertensive Rats.

PubMed

Gomes, Moisés Felipe Pereira; Borges, Mariana Eiras; Rossi, Vitor de Almeida; Moura, Elizabeth de Orleans C de; Medeiros, Alessandra

2017-01-01

Baroreceptors act as regulators of blood pressure (BP); however, its sensitivity is impaired in hypertensive patients. Among the recommendations for BP reduction, exercise training has become an important adjuvant therapy in this population. However, there are many doubts about the effects of resistance exercise training in this population. To evaluate the effect of resistance exercise training on BP and baroreceptor sensitivity in spontaneously hypertensive rats (SHR). Rats SHR (n = 16) and Wistar (n = 16) at 8 weeks of age, at the beginning of the experiment, were randomly divided into 4 groups: sedentary control (CS, n = 8); trained control (CT, n = 8); sedentary SHR (HS, n = 8) and trained SHR (HT, n = 8). Resistance exercise training was performed in a stairmaster-type equipment (1.1 × 0.18 m, 2 cm between the steps, 80° incline) with weights attached to their tails, (5 days/week, 8 weeks). Baroreceptor reflex control of heart rate (HR) was tested by loading/unloading of baroreceptors with phenylephrine and sodium nitroprusside. Resistance exercise training increased the soleus muscle mass in SHR when compared to HS (HS 0.027 ± 0.002 g/mm and HT 0.056 ± 0.003 g/mm). Resistance exercise training did not alter BP. On the other hand, in relation to baroreflex sensitivity, bradycardic response was improved in the TH group when compared to HS (HS -1.3 ± 0.1 bpm/mmHg and HT -2.6 ± 0.2 bpm/mmHg) although tachycardia response was not altered by resistance exercise (CS -3.3 ± 0.2 bpm/mmHg, CT -3.3 ± 0.1 bpm/mmHg, HS -1.47 ± 0.06 bpm/mmHg and HT -1.6 ± 0.1 bpm/mmHg). Resistance exercise training was able to promote improvements on baroreflex sensitivity of SHR rats, through the improvement of bradycardic response, despite not having reduced BP. Os barorreceptores atuam como reguladores da pressão arterial (PA); no entanto, sua sensibilidade encontra-se prejudicada em pacientes hipertensos. Dentre as recomendações para a redução da PA, o treinamento físico tem se tornado um importante adjunto na terapia dessa população. Porém, ainda há diversos questionamentos sobre os efeitos de treinamento físico resistido nessa população. Avaliar o efeito do treinamento físico resistido na PA e na sensibilidade de barorreceptores em ratos espontaneamente hipertensos (SHR). Ratos SHR (n = 16) e Wistar (n = 16) com 08 semanas de idade foram aleatoriamente divididos em 4 grupos: controle sedentário (CS, n = 8); controle treinado (CT, n = 8); SHR sedentário (HS, n = 8) e SHR treinado (HT, n = 8). O treinamento físico foi realizado em aparato com degraus (1,1 × 0,18 m, 2 cm entre os degraus, 80° inclinação) com peso fixado na cauda, (5 vezes por semana durante 8 semanas). O controle barorreflexo da frequência cardíaca (FC) foi testado com estímulos de fenilefrina e nitroprussiato de sódio. O treinamento resistido foi capaz de aumentar a massa muscular do sóleo em ratos SHR (HS 0,027 ± 0,002 g/mm e HT 0,056 ± 0,003 g/mm). Não houve alteração da PA com o treinamento. Por outro lado, houve melhora na resposta bradicárdica da sensibilidade barorreflexa no grupo HT (HS -1,3 ± 0,1 bpm/mmHg e HT -2,6 ± 0,2 bpm/mmHg), no entanto, a resposta taquicárdica não foi alterada pelo exercício resistido (CS -3,3 ± 0,2 bpm/mmHg, CT -3,3 ± 0,1 bpm/mmHg, HS -1,47 ± 0,06 e HT -1,6 ± 0,1). O exercício físico resistido foi capaz de otimizar a sensibilidade barorreflexa dos ratos SHR por meio da melhora à resposta bradicárdica, apesar de não alterar a PA.

Exploring Genetic Attributions Underlying Radiotherapy-Induced Fatigue in Prostate Cancer Patients.

PubMed

Hashemi, Sepehr; Fernandez Martinez, Juan Luis; Saligan, Leorey; Sonis, Stephen

2017-09-01

Despite numerous proposed mechanisms, no definitive pathophysiology underlying radiotherapy-induced fatigue (RIF) has been established. However, the dysregulation of a set of 35 genes was recently validated to predict development of fatigue in prostate cancer patients receiving radiotherapy. To hypothesize novel pathways, and provide genetic targets for currently proposed pathways implicated in RIF development through analysis of the previously validated gene set. The gene set was analyzed for all phenotypic attributions implicated in the phenotype of fatigue. Initially, a "directed" approach was used by querying specific fatigue-related sub-phenotypes against all known phenotypic attributions of the gene set. Then, an "undirected" approach, reviewing the entirety of the literature referencing the 35 genes, was used to increase analysis sensitivity. The dysregulated genes attribute to neural, immunological, mitochondrial, muscular, and metabolic pathways. In addition, certain genes suggest phenotypes not previously emphasized in the context of RIF, such as ionizing radiation sensitivity, DNA damage, and altered DNA repair frequency. Several genes also associated with prostate cancer depression, possibly emphasizing variable radiosensitivity by RIF-prone patients, which may have palliative care implications. Despite the relevant findings, many of the 35 RIF-predictive genes are poorly characterized, warranting their investigation. The implications of herein presented RIF pathways are purely theoretical until specific end-point driven experiments are conducted in more congruent contexts. Nevertheless, the presented attributions are informative, directing future investigation to definitively elucidate RIF's pathoetiology. This study demonstrates an arguably comprehensive method of approaching known differential expression underlying a complex phenotype, to correlate feasible pathophysiology. Copyright © 2017 American Academy of Hospice and Palliative Medicine. All rights reserved.

Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure underpinning obesity

PubMed Central

Turcot, Valérie; Lu, Yingchang; Highland, Heather M; Schurmann, Claudia; Justice, Anne E; Fine, Rebecca S; Bradfield, Jonathan P; Esko, Tõnu; Giri, Ayush; Graff, Mariaelisa; Guo, Xiuqing; Hendricks, Audrey E; Karaderi, Tugce; Lempradl, Adelheid; Locke, Adam E; Mahajan, Anubha; Marouli, Eirini; Sivapalaratnam, Suthesh; Young, Kristin L; Alfred, Tamuno; Feitosa, Mary F; Masca, Nicholas GD; Manning, Alisa K; Medina-Gomez, Carolina; Mudgal, Poorva; Ng, Maggie CY; Reiner, Alex P; Vedantam, Sailaja; Willems, Sara M; Winkler, Thomas W; Abecasis, Goncalo; Aben, Katja K; Alam, Dewan S; Alharthi, Sameer E; Allison, Matthew; Amouyel, Philippe; Asselbergs, Folkert W; Auer, Paul L; Balkau, Beverley; Bang, Lia E; Barroso, Inês; Bastarache, Lisa; Benn, Marianne; Bergmann, Sven; Bielak, Lawrence F; Blüher, Matthias; Boehnke, Michael; Boeing, Heiner; Boerwinkle, Eric; Böger, Carsten A; Bork-Jensen, Jette; Bots, Michiel L; Bottinger, Erwin P; Bowden, Donald W; Brandslund, Ivan; Breen, Gerome; Brilliant, Murray H; Broer, Linda; Brumat, Marco; Burt, Amber A; Butterworth, Adam S; Campbell, Peter T; Cappellani, Stefania; Carey, David J; Catamo, Eulalia; Caulfield, Mark J; Chambers, John C; Chasman, Daniel I; Chen, Yii-Der Ida; Chowdhury, Rajiv; Christensen, Cramer; Chu, Audrey Y; Cocca, Massimiliano; Collins, Francis S; Cook, James P; Corley, Janie; Galbany, Jordi Corominas; Cox, Amanda J; Crosslin, David S; Cuellar-Partida, Gabriel; D'Eustacchio, Angela; Danesh, John; Davies, Gail; de Bakker, Paul IW; de Groot, Mark CH; de Mutsert, Renée; Deary, Ian J; Dedoussis, George; Demerath, Ellen W; den Heijer, Martin; den Hollander, Anneke I; den Ruijter, Hester M; Dennis, Joe G; Denny, Josh C; Di Angelantonio, Emanuele; Drenos, Fotios; Du, Mengmeng; Dubé, Marie-Pierre; Dunning, Alison M; Easton, Douglas F; Edwards, Todd L; Ellinghaus, David; Ellinor, Patrick T; Elliott, Paul; Evangelou, Evangelos; Farmaki, Aliki-Eleni; Farooqi, I. Sadaf; Faul, Jessica D; Fauser, Sascha; Feng, Shuang; Ferrannini, Ele; Ferrieres, Jean; Florez, Jose C; Ford, Ian; Fornage, Myriam; Franco, Oscar H; Franke, Andre; Franks, Paul W; Friedrich, Nele; Frikke-Schmidt, Ruth; Galesloot, Tessel E.; Gan, Wei; Gandin, Ilaria; Gasparini, Paolo; Gibson, Jane; Giedraitis, Vilmantas; Gjesing, Anette P; Gordon-Larsen, Penny; Gorski, Mathias; Grabe, Hans-Jörgen; Grant, Struan FA; Grarup, Niels; Griffiths, Helen L; Grove, Megan L; Gudnason, Vilmundur; Gustafsson, Stefan; Haessler, Jeff; Hakonarson, Hakon; Hammerschlag, Anke R; Hansen, Torben; Harris, Kathleen Mullan; Harris, Tamara B; Hattersley, Andrew T; Have, Christian T; Hayward, Caroline; He, Liang; Heard-Costa, Nancy L; Heath, Andrew C; Heid, Iris M; Helgeland, Øyvind; Hernesniemi, Jussi; Hewitt, Alex W; Holmen, Oddgeir L; Hovingh, G Kees; Howson, Joanna MM; Hu, Yao; Huang, Paul L; Huffman, Jennifer E; Ikram, M Arfan; Ingelsson, Erik; Jackson, Anne U; Jansson, Jan-Håkan; Jarvik, Gail P; Jensen, Gorm B; Jia, Yucheng; Johansson, Stefan; Jørgensen, Marit E; Jørgensen, Torben; Jukema, J Wouter; Kahali, Bratati; Kahn, René S; Kähönen, Mika; Kamstrup, Pia R; Kanoni, Stavroula; Kaprio, Jaakko; Karaleftheri, Maria; Kardia, Sharon LR; Karpe, Fredrik; Kathiresan, Sekar; Kee, Frank; Kiemeney, Lambertus A; Kim, Eric; Kitajima, Hidetoshi; Komulainen, Pirjo; Kooner, Jaspal S; Kooperberg, Charles; Korhonen, Tellervo; Kovacs, Peter; Kuivaniemi, Helena; Kutalik, Zoltán; Kuulasmaa, Kari; Kuusisto, Johanna; Laakso, Markku; Lakka, Timo A; Lamparter, David; Lange, Ethan M; Lange, Leslie A; Langenberg, Claudia; Larson, Eric B; Lee, Nanette R; Lehtimäki, Terho; Lewis, Cora E; Li, Huaixing; Li, Jin; Li-Gao, Ruifang; Lin, Honghuang; Lin, Keng-Hung; Lin, Li-An; Lin, Xu; Lind, Lars; Lindström, Jaana; Linneberg, Allan; Liu, Ching-Ti; Liu, Dajiang J; Liu, Yongmei; Lo, Ken Sin; Lophatananon, Artitaya; Lotery, Andrew J; Loukola, Anu; Luan, Jian'an; Lubitz, Steven A; Lyytikäinen, Leo-Pekka; Männistö, Satu; Marenne, Gaëlle; Mazul, Angela L; McCarthy, Mark I; McKean-Cowdin, Roberta; Medland, Sarah E; Meidtner, Karina; Milani, Lili; Mistry, Vanisha; Mitchell, Paul; Mohlke, Karen L; Moilanen, Leena; Moitry, Marie; Montgomery, Grant W; Mook-Kanamori, Dennis O; Moore, Carmel; Mori, Trevor A; Morris, Andrew D; Morris, Andrew P; Müller-Nurasyid, Martina; Munroe, Patricia B; Nalls, Mike A; Narisu, Narisu; Nelson, Christopher P; Neville, Matt; Nielsen, Sune F; Nikus, Kjell; Njølstad, Pål R; Nordestgaard, Børge G; Nyholt, Dale R; O'Connel, Jeffrey R; O’Donoghue, Michelle L.; Olde Loohuis, Loes M; Ophoff, Roel A; Owen, Katharine R; Packard, Chris J; Padmanabhan, Sandosh; Palmer, Colin NA; Palmer, Nicholette D; Pasterkamp, Gerard; Patel, Aniruddh P; Pattie, Alison; Pedersen, Oluf; Peissig, Peggy L; Peloso, Gina M; Pennell, Craig E; Perola, Markus; Perry, James A; Perry, John RB; Pers, Tune H; Person, Thomas N; Peters, Annette; Petersen, Eva RB; Peyser, Patricia A; Pirie, Ailith; Polasek, Ozren; Polderman, Tinca J; Puolijoki, Hannu; Raitakari, Olli T; Rasheed, Asif; Rauramaa, Rainer; Reilly, Dermot F; Renström, Frida; Rheinberger, Myriam; Ridker, Paul M; Rioux, John D; Rivas, Manuel A; Roberts, David J; Robertson, Neil R; Robino, Antonietta; Rolandsson, Olov; Rudan, Igor; Ruth, Katherine S; Saleheen, Danish; Salomaa, Veikko; Samani, Nilesh J; Sapkota, Yadav; Sattar, Naveed; Schoen, Robert E; Schreiner, Pamela J; Schulze, Matthias B; Scott, Robert A; Segura-Lepe, Marcelo P; Shah, Svati H; Sheu, Wayne H-H; Sim, Xueling; Slater, Andrew J; Small, Kerrin S; Smith, Albert Vernon; Southam, Lorraine; Spector, Timothy D; Speliotes, Elizabeth K; Starr, John M; Stefansson, Kari; Steinthorsdottir, Valgerdur; Stirrups, Kathleen E; Strauch, Konstantin; Stringham, Heather M; Stumvoll, Michael; Sun, Liang; Surendran, Praveen; Swift, Amy J; Tada, Hayato; Tansey, Katherine E; Tardif, Jean-Claude; Taylor, Kent D; Teumer, Alexander; Thompson, Deborah J; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Thuesen, Betina H; Tönjes, Anke; Tromp, Gerard; Trompet, Stella; Tsafantakis, Emmanouil; Tuomilehto, Jaakko; Tybjaerg-Hansen, Anne; Tyrer, Jonathan P; Uher, Rudolf; Uitterlinden, André G; Uusitupa, Matti; van der Laan, Sander W; van Duijn, Cornelia M; van Leeuwen, Nienke; van Setten, Jessica; Vanhala, Mauno; Varbo, Anette; Varga, Tibor V; Varma, Rohit; Velez Edwards, Digna R; Vermeulen, Sita H; Veronesi, Giovanni; Vestergaard, Henrik; Vitart, Veronique; Vogt, Thomas F; Völker, Uwe; Vuckovic, Dragana; Wagenknecht, Lynne E; Walker, Mark; Wallentin, Lars; Wang, Feijie; Wang, Carol A; Wang, Shuai; Wang, Yiqin; Ware, Erin B; Wareham, Nicholas J; Warren, Helen R; Waterworth, Dawn M; Wessel, Jennifer; White, Harvey D; Willer, Cristen J; Wilson, James G; Witte, Daniel R; Wood, Andrew R; Wu, Ying; Yaghootkar, Hanieh; Yao, Jie; Yao, Pang; Yerges-Armstrong, Laura M; Young, Robin; Zeggini, Eleftheria; Zhan, Xiaowei; Zhang, Weihua; Zhao, Jing Hua; Zhao, Wei; Zhao, Wei; Zhou, Wei; Zondervan, Krina T; Rotter, Jerome I; Pospisilik, John A; Rivadeneira, Fernando; Borecki, Ingrid B; Deloukas, Panos; Frayling, Timothy M; Lettre, Guillaume; North, Kari E; Lindgren, Cecilia M; Hirschhorn, Joel N; Loos, Ruth JF

2018-01-01

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, non-coding variants from which pinpointing causal genes remains challenging. Here, we combined data from 718,734 individuals to discover rare and low-frequency (MAF<5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which eight in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2, ZNF169) newly implicated in human obesity, two (MC4R, KSR2) previously observed in extreme obesity, and two variants in GIPR. Effect sizes of rare variants are ~10 times larger than of common variants, with the largest effect observed in carriers of an MC4R stop-codon (p.Tyr35Ter, MAF=0.01%), weighing ~7kg more than non-carriers. Pathway analyses confirmed enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically-supported therapeutic targets to treat obesity. PMID:29273807

Effect of hexamethonium on the vascular response to noradrenaline in man

PubMed Central

Hodge, R. L.; Whelan, R. F.

1962-01-01

Intra-arterial infusion of hexamethonium into the brachial artery had no potentiating effect on the constrictor response of the vessels of the forearm or hand to noradrenaline given by the same route. The response of the hand vessels to intravenous infusion of noradrenaline was enhanced after intra-arterial hexamethonium, but this was attributed to entry of the blocking agent into the general circulation resulting in blockade of baroreceptor reflexes since the potentiation was seen to an equal degree on both sides. It is concluded that if increased sensitivity to noradrenaline plays a part in the phenomenon of tolerance to hexamethonium this must be a slowly developing effect. PMID:13907950

[Aging and blood pressure].

PubMed

Mendes, Romeu; Themudo Barata, J L

2008-01-01

High blood pressure is a major risk factor of cardiovascular diseases and has a high prevalence in the older individuals becoming in a risk factor associated with high cardiovascular mortality and morbidity among these population. This study has the objective to analyze the changes in the cardiovascular system inherent to the aging process, that provoke the increase of blood pressure levels with the advance of age and that can origin hypertension. With the aging process, changes in the anatomy and cardiovascular physiology occur, even in the absence of illness. High blood pressure is characterized as a systemic condition that involves the presence of structural changes of the arteries and the myocardium, associated to an endotelial and baroreceptors dysfunction.

Mechanisms of Cardiopulmonary Adaptation to Microgravity. Part 1

NASA Technical Reports Server (NTRS)

1997-01-01

Session TA1 includes short reports covering: (1) Indices of Baroreceptor Reflex Sensitivity: The Use in Rehabilitation Medicine and Space Cardiology; (2) +Gz and +Gx Tolerance of Healthy Persons of Non-Flying Trades at Primary Selection of the Centrifuge; (3) Effect of Dry Immersion on Calf Blood Supply During Sustained Contraction and Upright Exercise in Man; (4) Cardiovascular and Valsalva Responses during Parabolic flight; (5) An Analysis of the Cardiovascular Responses under Hyper- and Hypo-Gravity Environments using a Mathematical model; (6) Effect of Very Gradual Onset Rate +Gz Exposures on the Cardiovascular System; and (7) NASA Specialized Center of Research and Training (NSCORT) in Integrated Physiology: Mechanisms of Physiological Adaptations to Microgravity.

Nitric oxide transport in blood: a third gas in the respiratory cycle.

PubMed

Doctor, Allan; Stamler, Jonathan S

2011-01-01

The trapping, processing, and delivery of nitric oxide (NO) bioactivity by red blood cells (RBCs) have emerged as a conserved mechanism through which regional blood flow is linked to biochemical cues of perfusion sufficiency. We present here an expanded paradigm for the human respiratory cycle based on the coordinated transport of three gases: NO, O₂, and CO₂. By linking O₂ and NO flux, RBCs couple vessel caliber (and thus blood flow) to O₂ availability in the lung and to O₂ need in the periphery. The elements required for regulated O₂-based signal transduction via controlled NO processing within RBCs are presented herein, including S-nitrosothiol (SNO) synthesis by hemoglobin and O₂-regulated delivery of NO bioactivity (capture, activation, and delivery of NO groups at sites remote from NO synthesis by NO synthase). The role of NO transport in the respiratory cycle at molecular, microcirculatory, and system levels is reviewed. We elucidate the mechanism through which regulated NO transport in blood supports O₂ homeostasis, not only through adaptive regulation of regional systemic blood flow but also by optimizing ventilation-perfusion matching in the lung. Furthermore, we discuss the role of NO transport in the central control of breathing and in baroreceptor control of blood pressure, which subserve O₂ supply to tissue. Additionally, malfunctions of this transport and signaling system that are implicated in a wide array of human pathophysiologies are described. Understanding the (dys)function of NO processing in blood is a prerequisite for the development of novel therapies that target the vasoactive capacities of RBCs. © 2011 American Physiological Society.

Plant-specific multisubunit RNA polymerase in gene silencing.

PubMed

Lahmy, Sylvie; Bies-Etheve, Natacha; Lagrange, Thierry

2010-01-01

In recent years, a major breakthrough in the study of epigenetic silencing in eukaryotes came with the discovery that the RNA-interference pathway (RNAi) is generally implicated in heterochromatin assembly and gene silencing. An important and paradoxical feature of the RNAi-mediated heterochromatin pathways is their requirement for some form of transcription. In fission yeast, Schizosaccharomyces pombe, centromeric siRNAs have been shown to derive from chromatin-bound nascent transcripts produced by RNA polymerase II (PolII) at the site of heterochromatin formation. Likewise, chromatin-bound nascent transcripts generated by a PolII-related DNA-dependent RNA polymerase, known as PolIVb/PolV, have recently been implicated in RNA-directed DNA methylation (RdDM), the prominent RNAi-mediated chromatin pathway in plants. In this review we discuss recent work on the plant-specific PolII variant enzymes and discuss the mechanistic convergences that have been observed in the role of these enzymes in their respective siRNA-mediated heterochromatin formation pathways.

Targeting Developmental Pathways: The Achilles Heel of Cancer?

PubMed

Dempke, Wolfram C M; Fenchel, Klaus; Uciechowski, Peter; Chevassut, Timothy

2017-01-01

Developmental pathways (e.g., Notch, Hippo, Hedgehog, Wnt, and TGF-β/BMP/FGF) are networks of genes that act co-ordinately to establish the body plan, and disruptions of genes in one pathway can have effects in related pathways and may result in serious dysmorphogenesis or cancer. Interestingly, all developmental pathways are highly conserved cell signalling systems present in almost all multicellular organisms. In addition, they have a crucial role in cell proliferation, apoptosis, differentiation, and finally in organ development. Of note, almost all of these pathways promote oncogenesis through synergistic associations with the Hippo signalling pathway, and several lines of evidence have also indicated that these pathways (e.g., Wnt/β-catenin) may be implicated in checkpoint inhibitor resistance (e.g., CTLA-4, PD-1, and PD-L1). Since Notch inhibition in vivo results in partial loss of its stemness features such as self-renewal, chemoresistance, invasive and migratory potential, and tumorigenesis, these highly conserved developmental pathways are regarded as being critical for regulation of self-renewal in both embryonic and adult stem cells and hence are likely to be implicated in the maintenance of cancer stem cells. Many small molecules are currently in preclinical and early clinical development, and only two compounds are approved for treatment of advanced or metastatic basal cell carcinoma (vismodegib and sonidegib). Furthermore, therapeutic targeting of cancer stem cells using drugs that disrupt activated developmental pathways may also represent an attractive strategy that is potentially relevant to many types of malignancy, notably blood cancers, where the evidence for leukaemia stem cells is well established. Future work will hopefully pave the way for the development of new strategies for targeting these pervasive oncogenic pathways. © 2017 S. Karger AG, Basel.

Catalase plays an important role in a genotoxic pathway of methylated arsenicals

EPA Science Inventory

Arsenic is a common contaminant of drinking water in many parts of the world. Consumption of arsenic-contaminated drinking water has been implicated in both cancerous and non-cancerous health conditions. However, the pathways that lead to arsenic-induced health conditions have no...

Impact of Diagenesis on Biosignature Preservation Potential in Playa Lake Evaporites of the Verde Formation, Arizona: Implications for Mars Exploration

NASA Astrophysics Data System (ADS)

Shkolyar, S.; Farmer, J. D.

2016-05-01

We studied evaporite subfacies in the Verde Fmn., AZ. We identified diagenetic pathways and assessed how diagenesis affected biosignature preservation potential (BPP) in each. Results revealed eight pathways, each with diverse impacts on BPP.

Activation of the MAPK/ERK Cell-Signaling Pathway in Uterine Smooth Muscle Cells of Women With Adenomyosis.

PubMed

Streuli, Isabelle; Santulli, Pietro; Chouzenoux, Sandrine; Chapron, Charles; Batteux, Frédéric

2015-12-01

We investigated whether the myometrium might be intrinsically different in women with adenomyosis. We studied whether the mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPKs/ERKs) and phosphoinositide 3-kinase/mammalian target of rapamycin/AKT (PI3K/mTOR/AKT) cell-signaling pathways, implicated in the pathogenesis of endometriosis, might also be activated in uterine smooth muscle cells (uSMCs) of women with adenomyosis and measured the production of reactive oxygen species (ROS), proinflammatory mediators that modulate cell proliferation and have been shown to activate the MAPK/ERK pathway in endometriosis. The uSMC cultures were derived from myometrium biopsies obtained during hysterectomy or myomectomy in women with adenomyosis and controls with leiomyoma. Proliferation of uSMCs and in vitro activation of the MAPK/ERK cell-signaling pathway were increased in women with adenomyosis compared to controls. The activation of the PI3K/mTOR/AKT pathway was not significant. The ROS production and ROS detoxification pathways were not different between uSMCs of women with adenomyosis and controls suggesting an ROS-independent activation of the MAPK/ERK pathway. Our results also provide evidence that protein kinase inhibitors and the rapanalogue temsirolimus can control proliferation of uSMCs in vitro suggesting an implication of the MAPK/ERK and the PI3K/mTOR/AKT pathways in proliferation of uSMCs in women with adenomyosis and leiomyomas. © The Author(s) 2015.

mRNA levels of enzymes and receptors implicated in arachidonic acid metabolism in gliomas.

PubMed

De Armas, Rafael; Durand, Karine; Guillaudeau, Angélique; Weinbreck, Nicolas; Robert, Sandrine; Moreau, Jean-Jacques; Caire, François; Acosta, Gisela; Pebet, Matias; Chaunavel, Alain; Marin, Benoît; Labrousse, François; Denizot, Yves

2010-07-01

Gliomas are tumors of the central nervous system derived from glial cells. They show cellular heterogeneity and lack specific diagnostic markers. Although a possible role for the eicosanoid cascade has been suggested in glioma tumorigenesis, the relationship between enzymes and receptors implicated in arachidonic acid metabolism, with histological tumor type has not yet been determined. Quantitative real-time reverse transcription-polymerase chain reaction was performed to measure and compare transcript levels of enzymes and receptors implicated in both lipoxygenase and cyclooxygenase pathways between oligodendrogliomas, astrocytomas, glioblastomas and mixed oligoastrocytomas. Arachidonic acid metabolism-related enzymes and receptor transcripts (i) were underexpressed in classical oligodendrogliomas compared to astrocytomas and/or glioblastomas, (ii) differed between astrocytomas and glioblastomas and (iii) had an intermediate expression in mixed oligoastrocytomas. mRNA levels of enzymes and receptors implicated both in lipoxygenase and cyclooxygenase pathways differed significantly in gliomas according to the histological type. Copyright 2010 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Phospholipase D and the Maintenance of Phosphatidic Acid Levels for Regulation of Mammalian Target of Rapamycin (mTOR)*

PubMed Central

Foster, David A.; Salloum, Darin; Menon, Deepak; Frias, Maria A.

2014-01-01

Phosphatidic acid (PA) is a critical metabolite at the heart of membrane phospholipid biosynthesis. However, PA also serves as a critical lipid second messenger that regulates several proteins implicated in the control of cell cycle progression and cell growth. Three major metabolic pathways generate PA: phospholipase D (PLD), diacylglycerol kinase (DGK), and lysophosphatidic acid acyltransferase (LPAAT). The LPAAT pathway is integral to de novo membrane phospholipid biosynthesis, whereas the PLD and DGK pathways are activated in response to growth factors and stress. The PLD pathway is also responsive to nutrients. A key target for the lipid second messenger function of PA is mTOR, the mammalian/mechanistic target of rapamycin, which integrates both nutrient and growth factor signals to control cell growth and proliferation. Although PLD has been widely implicated in the generation of PA needed for mTOR activation, it is becoming clear that PA generated via the LPAAT and DGK pathways is also involved in the regulation of mTOR. In this minireview, we highlight the coordinated maintenance of intracellular PA levels that regulate mTOR signals stimulated by growth factors and nutrients, including amino acids, lipids, glucose, and Gln. Emerging evidence indicates compensatory increases in one source of PA when another source is compromised, highlighting the importance of being able to adapt to stressful conditions that interfere with PA production. The regulation of PA levels has important implications for cancer cells that depend on PA and mTOR activity for survival. PMID:24990952

Phospholipase D and the maintenance of phosphatidic acid levels for regulation of mammalian target of rapamycin (mTOR).

PubMed

Foster, David A; Salloum, Darin; Menon, Deepak; Frias, Maria A

2014-08-15

Phosphatidic acid (PA) is a critical metabolite at the heart of membrane phospholipid biosynthesis. However, PA also serves as a critical lipid second messenger that regulates several proteins implicated in the control of cell cycle progression and cell growth. Three major metabolic pathways generate PA: phospholipase D (PLD), diacylglycerol kinase (DGK), and lysophosphatidic acid acyltransferase (LPAAT). The LPAAT pathway is integral to de novo membrane phospholipid biosynthesis, whereas the PLD and DGK pathways are activated in response to growth factors and stress. The PLD pathway is also responsive to nutrients. A key target for the lipid second messenger function of PA is mTOR, the mammalian/mechanistic target of rapamycin, which integrates both nutrient and growth factor signals to control cell growth and proliferation. Although PLD has been widely implicated in the generation of PA needed for mTOR activation, it is becoming clear that PA generated via the LPAAT and DGK pathways is also involved in the regulation of mTOR. In this minireview, we highlight the coordinated maintenance of intracellular PA levels that regulate mTOR signals stimulated by growth factors and nutrients, including amino acids, lipids, glucose, and Gln. Emerging evidence indicates compensatory increases in one source of PA when another source is compromised, highlighting the importance of being able to adapt to stressful conditions that interfere with PA production. The regulation of PA levels has important implications for cancer cells that depend on PA and mTOR activity for survival. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis.

PubMed

Timberlake, Andrew T; Furey, Charuta G; Choi, Jungmin; Nelson-Williams, Carol; Loring, Erin; Galm, Amy; Kahle, Kristopher T; Steinbacher, Derek M; Larysz, Dawid; Persing, John A; Lifton, Richard P

2017-08-29

Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent-offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, P = 2.4 × 10 -11 ). SMAD6 had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism. A common risk variant near BMP2 increased the penetrance of SMAD6 mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity.

Phase Synchronization of Hemodynamic Variables at Rest and after Deep Breathing Measured during the Course of Pregnancy

PubMed Central

Papousek, Ilona; Roessler, Andreas; Hinghofer-Szalkay, Helmut; Lang, Uwe; Kolovetsiou-Kreiner, Vassiliki

2013-01-01

Background The autonomic nervous system plays a central role in the functioning of systems critical for the homeostasis maintenance. However, its role in the cardiovascular adaptation to pregnancy-related demands is poorly understood. We explored the maternal cardiovascular systems throughout pregnancy to quantify pregnancy-related autonomic nervous system adaptations. Methodology Continuous monitoring of heart rate (R-R interval; derived from the 3-lead electrocardiography), blood pressure, and thoracic impedance was carried out in thirty-six women at six time-points throughout pregnancy. In order to quantify in addition to the longitudinal effects on baseline levels throughout gestation the immediate adaptive heart rate and blood pressure changes at each time point, a simple reflex test, deep breathing, was applied. Consequently, heart rate variability and blood pressure variability in the low (LF) and high (HF) frequency range, respiration and baroreceptor sensitivity were analyzed in resting conditions and after deep breathing. The adjustment of the rhythms of the R-R interval, blood pressure and respiration partitioned for the sympathetic and the parasympathetic branch of the autonomic nervous system were quantified by the phase synchronization index γ, which has been adopted from the analysis of weakly coupled chaotic oscillators. Results Heart rate and LF/HF ratio increased throughout pregnancy and these effects were accompanied by a continuous loss of baroreceptor sensitivity. The increases in heart rate and LF/HF ratio levels were associated with an increasing decline in the ability to flexibly respond to additional demands (i.e., diminished adaptive responses to deep breathing). The phase synchronization index γ showed that the observed effects could be explained by a decreased coupling of respiration and the cardiovascular system (HF components of heart rate and blood pressure). Conclusions/Significance The findings suggest that during the course of pregnancy the individual systems become increasingly independent to meet the increasing demands placed on the maternal cardiovascular and respiratory system. PMID:23577144

CHRONIC HYPERTENSION ENHANCES PRE-SYNAPTIC INHIBITION BY BACLOFEN IN THE NUCLEUS OF THE SOLITARY TRACT

PubMed Central

Zhang, Weirong; Mifflin, Steve

2010-01-01

The selective γ-aminobutyric acid B-subtype receptor agonist baclofen activates both pre- and post-synaptic receptors in the brain. Microinjection of baclofen into the nucleus of the solitary tract increases arterial pressure, heart rate and sympathetic nerve discharge consistent with inhibition of the arterial baroreflex. The magnitude of these responses is enhanced in hypertension and is associated with increased post-synaptic GABAB receptor function. We tested whether a pre-synaptic mechanism contributes to the enhanced baclofen inhibition in hypertension. Whole-cell recordings of second-order baroreceptor neurons, identified by 4-(4-(dihexadecylamino)styryl)-N-methylpyridinium iodide labeling of aortic nerve, were obtained in brainstem slices from normotensive control and renal-wrap hypertensive rats. After 4 weeks, arterial blood pressure was 162±9 mmHg in hypertensive (n=6) and 107±3 mmHg in control rats (n=6/11, p<0.001). Baclofen reduced the amplitude of excitatory post-synaptic currents evoked by solitary tract stimulation and the EC50 of this inhibition was greater in control (1.5±0.5 µmol/L, n=6) than hypertensive cells (0.6±0.1 µmol/L, n=9, p<0.05). Baclofen (1 µmol/L) elicited greater inhibition on evoked response in hypertensive (58±6%, n=9) than control cells (40±6%, n=8, p<0.05). Another index of pre-synaptic inhibition, the paired-pulse ratio (ratio of second to first evoked response amplitudes at stimulus intervals of 40 ms), was greater in hypertensive (0.60±0.08, n=8) than control cells (0.48±0.06. n=5, p<0.05). The results suggest that in renal-wrap hypertensive rats, baclofen causes an enhanced pre-synaptic inhibition of glutamate release from baroreceptor afferent terminals to second-order neurons in the nucleus of the solitary tract. This enhanced pre-synaptic inhibition could contribute to altered baroreflex function in hypertension. PMID:20038748

Mechanisms of blood pressure regulation that differ in men repeatedly exposed to high-G acceleration.

PubMed

Convertino, V A

2001-04-01

The purpose of this study was to test the hypothesis that repeated exposure to high acceleration (G) would be associated with enhanced functions of specific mechanisms of blood pressure regulation. We measured heart rate (HR), stroke volume (SV), cardiac output (), mean arterial blood pressure, central venous pressure, forearm and leg vascular resistance, catecholamines, and changes in leg volume (%DeltaLV) during various protocols of lower body negative pressure (LBNP), carotid stimulation, and infusions of adrenoreceptor agonists in 10 males after three training sessions on different days over a period of 5-7 days using a human centrifuge (G trained). These responses were compared with the same measurements in 10 males who were matched for height, weight, and fitness but did not undergo G training (controls). Compared with the control group, G-trained subjects demonstrated greater R-R interval response to equal carotid baroreceptor stimulation (7.3 +/- 1.2 vs. 3.9 +/- 0.4 ms/mmHg, P = 0.02), less vasoconstriction to equal low-pressure baroreceptor stimulation (-1.4 +/- 0.2 vs. -2.6 +/- 0.3 U/mmHg, P = 0.01), and higher HR (-1.2 +/- 0.2 vs. -0.5 +/- 0.1 beats. min(-1). mmHg(-1), P = 0.01) and alpha-adrenoreceptor response (32.8 +/- 3.4 vs. 19.5 +/- 4.7 U/mmHg, P = 0.04) to equal dose of phenylephrine. During graded LBNP, G-trained subjects had less decline in and SV, %DeltaLV, and elevation in thoracic impedance. G-trained subjects also had greater total blood (6,497 +/- 496 vs. 5,438 +/- 228 ml, P = 0.07) and erythrocyte (3,110 +/- 364 vs. 2,310 +/- 96 ml, P = 0.06) volumes. These results support the hypothesis that exposure to repeated high G is associated with increased capacities of mechanisms that underlie blood pressure regulation.

Low-Level But Not High-Level Baroreceptor Stimulation Inhibits Atrial Fibrillation in a Pig Model of Sleep Apnea.

PubMed

Linz, Dominik; Hohl, Mathias; Khoshkish, Shayan; Mahfoud, Felix; Ukena, Christian; Neuberger, Hans-Ruprecht; Wirth, Klaus; Böhm, Michael

2016-09-01

Obstructive sleep apnea (OSA) increases susceptibility to atrial fibrillation (AF) by a combined sympatho-vagal hyperactivation. The purpose of this study was to investigate the effect of autonomic nervous system modulation by low-level baroreceptor stimulation (LL-BRS) compared to high-level BRS (HL-BRS) on atrial arrhythmogenic changes in a pig model of OSA. Sixteen pigs received tracheotomy under general urethane/chloralose anesthesia. Group 1 pigs (n = 8) received LL-BRS (at 80% of that slowing sinus rate) for 3 hours and group 2 pigs (n = 8) received HL-BRS (slowing sinus rate). Changes in atrial effective refractory period (AERP) and AF-inducibility were determined during applied negative thoracic pressure (NTP) for 2 minutes before and at the end of the 3-hour stimulation protocol. Group 1: LL-BRS prolonged AERP from 150 ± 5 to 172 ± 19 milliseconds (P < 0.001). After 3 hours of LL-BRS, NTP-induced AERP-shortening was diminished from -51 ± 10 milliseconds (-34%) to -22 ± 4 milliseconds (-13%) (P < 0.01). AF-inducibility during NTP maneuvers decreased from 90% at baseline to 15% (P < 0.01). Group 2: HL-BRS shortened AERP from 150 ± 17 to 132 ± 8 milliseconds (P = 0.024). After 3 hours of HL-BRS, NTP-induced AERP-shortening was increased from -55 ± 7 milliseconds (-36%) to -72 ± 11 milliseconds (-54%) (P < 0.05) and AF-inducibility was not affected. NTP-induced changes in blood gases and blood pressure were not different between the groups. LL-BRS suppressed NTP-induced AERP-shortening and AF-inducibility. By contrast HL-BRS further perpetuated NTP-induced AERP-shortening and increased AF-inducibility. These findings support only the use of LL-BRS as a novel therapeutic modality to treat AF in OSA. © 2016 Wiley Periodicals, Inc.

Heart rate and blood pressure variabilities in salt-sensitive hypertension.

PubMed

Piccirillo, G; Bucca, C; Durante, M; Santagada, E; Munizzi, M R; Cacciafesta, M; Marigliano, V

1996-12-01

In salt-sensitive hypertension, a high sodium intake causes plasma catecholamines to rise and pulmonary baroreceptor plasticity to fall. In salt-sensitive and salt-resistant hypertensive subjects during low and high sodium intakes, we studied autonomic nervous system activity by power spectral analysis of heart rate and arterial pressure variabilities and baroreceptor sensitivity. In all subjects, high sodium intake significantly enhanced the low-frequency power of heart rate and arterial pressures at rest and after sympathetic stress. It also increased heart rate and arterial pressure variabilities. During high sodium intake, salt-sensitive hypertensive subjects had significantly higher low-frequency powers of systolic arterial pressure (7.5 mm Hg2, P < .05) and of heart rate at rest (59.2 +/- 2.4 normalized units [NU], P < .001) than salt-resistant subjects (6.6 +/- 0.3 mm Hg2, 55.0 +/- 3.2 NU) and normotensive control subjects (5.1 +/- 0.5 mm Hg2, 41.6 +/- 2.9 NU). In salt-sensitive subjects, low sodium intake significantly reduced low-frequency normalized units (P < .001) and the ratio of low- to high-power frequency (P < .001). High-sodium intake significantly increased baroreflex sensitivity in control subjects (from 10.0 +/- 0.7 to 17.5 +/- 0.7 ms/mm Hg, P < .001) and salt-resistant subjects (from 6.9 +/- 0.7 to 13.9 +/- 0.9, P < .05) but not in salt-sensitive subjects (7.4 +/- 0.3 to 7.9 +/- 0.4). In conclusion, a high sodium intake markedly enhances cardiac sympathetic activity in salt-sensitive and salt-resistant hypertension. In contrast, although reduced sodium intake lowers arterial pressure and sympathetic activity, it does so only in salt-sensitive subjects. Hence, in salt-resistant subjects, neither arterial pressure nor sympathetic activity depends on salt intake. During a high sodium intake in normotensive subjects and salt-resistant hypertensive subjects, increased sympathetic activity is probably compensated by enhanced baroreflex sensitivity.

The Neuroendocrinology of Thirst and Salt Appetite: Visceral Sensory Signals and Mechanisms of Central Integration

NASA Technical Reports Server (NTRS)

Johnson, Alan Kim; Thunhorst, Robert L.

1997-01-01

This review examines recent advances in the study of the behavioral responses to deficits of body water and body sodium that in humans are accompanied by the sensations of thirst and salt appetite. Thirst and salt appetite are satisfied by ingesting water and salty substances. These behavioral responses to losses of body fluids, together with reflex endocrine and neural responses, are critical for reestablishing homeostasis. Like their endocrine and neural counterparts, these behaviors are under the control of both excitatory and inhibitory influences arising from changes in osmolality, endocrine factors such as angiotensin and aldosterone, and neural signals from low and high pressure baroreceptors. The excitatory and inhibitory influences reaching the brain require the integrative capacity of a neural network which includes the structures of the lamina terminalis, the amygdala, the perifornical area, and the paraventricular nucleus in the forebrain, and the lateral parabrachial nucleus (LPBN), the nucleus tractus solitarius (NTS), and the area postrema in the hindbrain. These regions are discussed in terms of their roles in receiving afferent sensory input and in processing information related to hydromineral balance. Osmoreceptors controlling thirst are located in systemic Viscera and in central structures that lack the blood-brain barrier. Angiotensin and aldosterone act on and through structures of the lamina terminalis and the amygdala to stimulate thirst and sodium appetite under conditions of hypovolemia. The NTS and LPBN receive neural signals from baroreceptors and are responsible for inhibiting the ingestion of fluids under conditions of increased volume and pressure and for stimulating thirst under conditions of bypovolemia and hypotension. The interplay of multiple facilitory influences within the brain may take the form of interactions between descending angiotensinergic systems originating in the forebrain and ascending adrenergic systems emanating from the hindbrain. Oxytocin and serotonin are additional candidate neuro- chemicals with postulated inhibitory central actions and with essential roles in the overall integration of sensory input within the neural network devoted to maintaining hydromineral balance.

Rodent Studies of Cardiovascular Deconditioning

NASA Technical Reports Server (NTRS)

Shoukas, Artin A.

1999-01-01

Changes in blood pressure can occur for two reasons: 1) A decrease in cardiac output resulting from the altered contractility of the heart or through changes in venous filling pressure via the Frank Starling mechanism or; 2) A change in systemic vascular resistance. The observed changes in cardiac output and blood pressure after long term space flight cannot be entirely explained through changes in contractility or heart rate alone. Therefore, alterations in filling pressure mediated through changes in systemic venous capacitance and arterial resistance function may be important determinants of cardiac output and blood pressure after long term space flight. Our laboratory and previous studies have shown the importance of veno-constriction mediated by the carotid sinus baroreceptor reflex system on overall circulatory homeostasis and in the regulation of cardiac output. Our proposed experiments test the overall hypothesis that alterations in venous capacitance function and arterial resistance by the carotid sinus baroreceptor reflex system are an important determinant of the cardiac output and blood pressure response seen in astronauts after returning to earth from long term exposure to microgravity. This hypothesis is important to our overall understanding of circulatory adjustments made during long term space flight. It also provides a framework for investigating counter measures to reduce the incidence of orthostatic hypotension caused by an attenuation of cardiac output. We continue to use hind limb unweighted (HLU) rat model to simulate the patho physiological effects as they relate to cardiovascular deconditioning in microgravity. We have used this model to address the hypothesis that microgravity induced cardiovascular deconditioning results in impaired vascular responses and that these impaired vascular responses result from abnormal alpha-1 AR signaling. The impaired vascular reactivity results in attenuated blood pressure and cardiac output responses to an orthostatic challenge. We have used in vitro vascular reactivity assays to explore abnormalities in vascular responses in vessels from HLU animals and, cardiac output (CO), blood pressure (BP) and heart rate (HR) measurements to characterize changes in hemodynamics following HLU.

Aldosterone Contributes to Sympathoexcitation in Renovascular Hypertension.

PubMed

Lincevicius, Gisele S; Shimoura, Caroline G; Nishi, Erika E; Perry, Juliana C; Casarini, Dulce E; Gomes, Guiomar N; Bergamaschi, Cássia T; Campos, Ruy R

2015-09-01

Although angiotensin II (Ang II) is essential to the development of renovascular hypertension, aldosterone plays a role as well. Recent studies have demonstrated a cross-talk between Ang II type 1 and mineralocorticoid receptors in the brain and kidneys. However, the role of aldosterone in the autonomic and renal dysfunction of renovascular hypertension is not well understood. The current study evaluated whether aldosterone contributes to cardiovascular and renal dysfunction in the 2 kidney-1 clip (2K1C) model. Mean arterial pressure (MAP) and baroreceptor reflex for control of the heart rate were evaluated in 2K1C treated or not treated with spironolactone (200mg/kg/day, 7 days). Tonic and reflex control of renal sympathetic nerve activity (rSNA) were assessed in urethane-anaesthetized rats. Plasma renin activity (PRA), kidney renin protein expression, renal injury, and central AT1 receptor protein expression were assessed. Spiro reduced MAP (198±4 vs. 170±9mm Hg; P < 0.05), normalized rSNA (147±9 vs. 96±10 pps; P < 0.05), and increased renal baroreceptor reflex sensitivity in the 2K1C rats. Spiro reduced α-smooth muscle actin expression in the nonclipped kidney in the 2K1C group (5±0.6 vs. 1.1±0.2%; P < 0.05). There was no change in PRA; however, a decrease in renin protein expression in the nonclipped kidney was found in the 2K1C treated group (217±30 vs. 160±19%; P < 0.05). Spiro treatment decreased AT1 receptor in the central nervous system (CNS) only in 2K1C rats (138±10 vs. 84±12%; P < 0.05). Aldosterone contributes to autonomic dysfunction and intrarenal injury in 2K1C, these effects are mediated by the CNS. © American Journal of Hypertension, Ltd 2015. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Body height and arterial pressure in seated and supine young males during +2 G centrifugation.

PubMed

Arvedsen, Sine K; Eiken, Ola; Kölegård, Roger; Petersen, Lonnie G; Norsk, Peter; Damgaard, Morten

2015-11-01

It is known that arterial pressure correlates positively with body height in males, and it has been suggested that this is due to the increasing vertical hydrostatic gradient from the heart to the carotid baroreceptors. Therefore, we tested the hypothesis that a higher gravito-inertial stress induced by the use of a human centrifuge would increase mean arterial pressure (MAP) more in tall than in short males in the seated position. In short (162-171 cm; n = 8) and tall (194-203 cm; n = 10) healthy males (18-41 yr), brachial arterial pressure, heart rate (HR), and cardiac output were measured during +2G centrifugation, while they were seated upright with the legs kept horizontal (+2Gz). In a separate experiment, the same measurements were done with the subjects supine (+2Gx). During +2Gz MAP increased in the short (22 ± 2 mmHg, P < 0.0001) and tall (23 ± 2 mmHg, P < 0.0001) males, with no significant difference between the groups. HR increased more (P < 0.05) in the tall than in the short group (14 ± 2 vs. 7 ± 2 bpm). Stroke volume (SV) decreased in the short group (26 ± 4 ml, P = 0.001) and more so in the tall group (39 ± 5 ml, P < 0.0001; short vs. tall, P = 0.047). During +2Gx, systolic arterial pressure increased (P < 0.001) and SV (P = 0.012) decreased in the tall group only. In conclusion, during +2Gz, MAP increased in both short and tall males, with no difference between the groups. However, in the tall group, HR increased more during +2Gz, which could be caused by a larger hydrostatic pressure gradient from heart to head, leading to greater inhibition of the carotid baroreceptors. Copyright © 2015 the American Physiological Society.

Mechanisms of blood pressure regulation that differ in men repeatedly exposed to high-G acceleration

NASA Technical Reports Server (NTRS)

Convertino, V. A.

2001-01-01

The purpose of this study was to test the hypothesis that repeated exposure to high acceleration (G) would be associated with enhanced functions of specific mechanisms of blood pressure regulation. We measured heart rate (HR), stroke volume (SV), cardiac output (), mean arterial blood pressure, central venous pressure, forearm and leg vascular resistance, catecholamines, and changes in leg volume (%DeltaLV) during various protocols of lower body negative pressure (LBNP), carotid stimulation, and infusions of adrenoreceptor agonists in 10 males after three training sessions on different days over a period of 5-7 days using a human centrifuge (G trained). These responses were compared with the same measurements in 10 males who were matched for height, weight, and fitness but did not undergo G training (controls). Compared with the control group, G-trained subjects demonstrated greater R-R interval response to equal carotid baroreceptor stimulation (7.3 +/- 1.2 vs. 3.9 +/- 0.4 ms/mmHg, P = 0.02), less vasoconstriction to equal low-pressure baroreceptor stimulation (-1.4 +/- 0.2 vs. -2.6 +/- 0.3 U/mmHg, P = 0.01), and higher HR (-1.2 +/- 0.2 vs. -0.5 +/- 0.1 beats. min(-1). mmHg(-1), P = 0.01) and alpha-adrenoreceptor response (32.8 +/- 3.4 vs. 19.5 +/- 4.7 U/mmHg, P = 0.04) to equal dose of phenylephrine. During graded LBNP, G-trained subjects had less decline in and SV, %DeltaLV, and elevation in thoracic impedance. G-trained subjects also had greater total blood (6,497 +/- 496 vs. 5,438 +/- 228 ml, P = 0.07) and erythrocyte (3,110 +/- 364 vs. 2,310 +/- 96 ml, P = 0.06) volumes. These results support the hypothesis that exposure to repeated high G is associated with increased capacities of mechanisms that underlie blood pressure regulation.

Real-Time Growth Kinetics Measuring Hormone Mimicry for ToxCast Chemicals in T‑47D Human Ductal Carcinoma Cells

EPA Science Inventory

High-throughput screening (HTS) assays capable of profiling thousands of environmentally relevant chemicals for in vitro biological activity provide useful information on the potential for disrupting endocrine pathways. Disruption of the estrogen signaling pathway has been implic...

Adenosine receptor desensitization and trafficking.

PubMed

Mundell, Stuart; Kelly, Eamonn

2011-05-01

As with the majority of G-protein-coupled receptors, all four of the adenosine receptor subtypes are known to undergo agonist-induced regulation in the form of desensitization and trafficking. These processes can limit the ability of adenosine receptors to couple to intracellular signalling pathways and thus reduce the ability of adenosine receptor agonists as well as endogenous adenosine to produce cellular responses. In addition, since adenosine receptors couple to multiple signalling pathways, these pathways may desensitize differentially, while the desensitization of one pathway could even trigger signalling via another. Thus, the overall picture of adenosine receptor regulation can be complex. For all adenosine receptor subtypes, there is evidence to implicate arrestins in agonist-induced desensitization and trafficking, but there is also evidence for other possible forms of regulation, including second messenger-dependent kinase regulation, heterologous effects involving G proteins, and the involvement of non-clathrin trafficking pathways such as caveolae. In this review, the evidence implicating these mechanisms is summarized for each adenosine receptor subtype, and we also discuss those issues of adenosine receptor regulation that remain to be resolved as well as likely directions for future research in this field. Copyright © 2010 Elsevier B.V. All rights reserved.

The Hippo signaling pathway in stem cell biology and cancer

PubMed Central

Mo, Jung-Soon; Park, Hyun Woo; Guan, Kun-Liang

2014-01-01

The Hippo signaling pathway, consisting of a highly conserved kinase cascade (MST and Lats) and downstream transcription coactivators (YAP and TAZ), plays a key role in tissue homeostasis and organ size control by regulating tissue-specific stem cells. Moreover, this pathway plays a prominent role in tissue repair and regeneration. Dysregulation of the Hippo pathway is associated with cancer development. Recent studies have revealed a complex network of upstream inputs, including cell density, mechanical sensation, and G-protein-coupled receptor (GPCR) signaling, that modulate Hippo pathway activity. This review focuses on the role of the Hippo pathway in stem cell biology and its potential implications in tissue homeostasis and cancer. PMID:24825474

Disease implications of the Hippo/YAP pathway

PubMed Central

Plouffe, Steven W; Hong, Audrey W; Guan, Kun-Liang

2015-01-01

The Hippo signaling pathway is important for controlling organ size and tissue homeostasis. Originally identified in Drosophila melanogaster, the core components of the Hippo pathway are highly conserved in mammals. The Hippo pathway can be modulated by a wide range of stimuli, including G protein coupled receptor (GPCR) signaling, changes in the actin cytoskeleton, cell-cell contact, and cell polarity. When activated, the Hippo pathway functions as a tumor suppressor to limit cell growth. However, dysregulation by genetic inactivation of core pathway components, or amplification or gene fusion of its downstream effectors, results in increased cell proliferation and decreased apoptosis and differentiation. Not surprisingly, this can lead to tissue overgrowth, tumorigenesis, and many other diseases. PMID:25702974

The defence-arousal system and its relevance for circulatory and respiratory control.

PubMed

Hilton, S M

1982-10-01

It was proposed some fifty years ago that the visceral and hormonal changes accompanying fear and rage reactions can best be understood as adaptations which prepare an organism to cope with an emergency and specifically to perform the extreme muscular exertion of flight or attack. This is well exemplified by the pattern of cardiovascular response which is characteristic of the alerting stage of these reactions and consists of an increase in cardiac output directed mainly to the skeletal muscles. This group of behavioural responses has been collectively termed the defence reaction. The regions of the hypothalamus and brainstem which organize it have been mapped. They function as a reflex centre for the visceral components of the altering response as well as initiating the behavioural response. So far as the cardiovascular system is concerned, this is a preparatory reflex and not compatible with short-term homeostasis. Indeed, the baroreceptor reflex, which is homeostatic, is strongly inhibited. By contrast, the chemoreceptor reflex is facilitated. The input from peripheral chemoreceptors is itself an alerting stimulus. The visceral alerting response has been studied in most detail in the cat, but there is evidence for the same cardiovascular pattern and an accompanying group of respiratory changes in other mammalian species (rat, rabbit, dog, monkey and man). On the efferent pathway for the cardiovascular response pattern, there is a group of relay neurones near the ventral surface of the caudal medulla, which seem important for the maintenance of arterial blood pressure. The visceral alerting system may therefore be continually engaged to some extent in the awake state, as well as being acutely activated in response to novel, and especially to noxious, stimuli.

Exercise-induced neuronal plasticity in central autonomic networks: role in cardiovascular control.

PubMed

Michelini, Lisete C; Stern, Javier E

2009-09-01

It is now well established that brain plasticity is an inherent property not only of the developing but also of the adult brain. Numerous beneficial effects of exercise, including improved memory, cognitive function and neuroprotection, have been shown to involve an important neuroplastic component. However, whether major adaptive cardiovascular adjustments during exercise, needed to ensure proper blood perfusion of peripheral tissues, also require brain neuroplasticity, is presently unknown. This review will critically evaluate current knowledge on proposed mechanisms that are likely to underlie the continuous resetting of baroreflex control of heart rate during/after exercise and following exercise training. Accumulating evidence indicates that not only somatosensory afferents (conveyed by skeletal muscle receptors, baroreceptors and/or cardiopulmonary receptors) but also projections arising from central command neurons (in particular, peptidergic hypothalamic pre-autonomic neurons) converge into the nucleus tractus solitarii (NTS) in the dorsal brainstem, to co-ordinate complex cardiovascular adaptations during dynamic exercise. This review focuses in particular on a reciprocally interconnected network between the NTS and the hypothalamic paraventricular nucleus (PVN), which is proposed to act as a pivotal anatomical and functional substrate underlying integrative feedforward and feedback cardiovascular adjustments during exercise. Recent findings supporting neuroplastic adaptive changes within the NTS-PVN reciprocal network (e.g. remodelling of afferent inputs, structural and functional neuronal plasticity and changes in neurotransmitter content) will be discussed within the context of their role as important underlying cellular mechanisms supporting the tonic activation and improved efficacy of these central pathways in response to circulatory demand at rest and during exercise, both in sedentary and in trained individuals. We hope this review will stimulate more comprehensive studies aimed at understanding cellular and molecular mechanisms within CNS neuronal networks that contribute to exercise-induced neuroplasticity and cardiovascular adjustments.

Autism Spectrum Disorders and Drug Addiction: Common Pathways, Common Molecules, Distinct Disorders?

PubMed

Rothwell, Patrick E

2016-01-01

Autism spectrum disorders (ASDs) and drug addiction do not share substantial comorbidity or obvious similarities in etiology or symptomatology. It is thus surprising that a number of recent studies implicate overlapping neural circuits and molecular signaling pathways in both disorders. The purpose of this review is to highlight this emerging intersection and consider implications for understanding the pathophysiology of these seemingly distinct disorders. One area of overlap involves neural circuits and neuromodulatory systems in the striatum and basal ganglia, which play an established role in addiction and reward but are increasingly implicated in clinical and preclinical studies of ASDs. A second area of overlap relates to molecules like Fragile X mental retardation protein (FMRP) and methyl CpG-binding protein-2 (MECP2), which are best known for their contribution to the pathogenesis of syndromic ASDs, but have recently been shown to regulate behavioral and neurobiological responses to addictive drug exposure. These shared pathways and molecules point to common dimensions of behavioral dysfunction, including the repetition of behavioral patterns and aberrant reward processing. The synthesis of knowledge gained through parallel investigations of ASDs and addiction may inspire the design of new therapeutic interventions to correct common elements of striatal dysfunction.

Autism Spectrum Disorders and Drug Addiction: Common Pathways, Common Molecules, Distinct Disorders?

PubMed Central

Rothwell, Patrick E.

2016-01-01

Autism spectrum disorders (ASDs) and drug addiction do not share substantial comorbidity or obvious similarities in etiology or symptomatology. It is thus surprising that a number of recent studies implicate overlapping neural circuits and molecular signaling pathways in both disorders. The purpose of this review is to highlight this emerging intersection and consider implications for understanding the pathophysiology of these seemingly distinct disorders. One area of overlap involves neural circuits and neuromodulatory systems in the striatum and basal ganglia, which play an established role in addiction and reward but are increasingly implicated in clinical and preclinical studies of ASDs. A second area of overlap relates to molecules like Fragile X mental retardation protein (FMRP) and methyl CpG-binding protein-2 (MECP2), which are best known for their contribution to the pathogenesis of syndromic ASDs, but have recently been shown to regulate behavioral and neurobiological responses to addictive drug exposure. These shared pathways and molecules point to common dimensions of behavioral dysfunction, including the repetition of behavioral patterns and aberrant reward processing. The synthesis of knowledge gained through parallel investigations of ASDs and addiction may inspire the design of new therapeutic interventions to correct common elements of striatal dysfunction. PMID:26903789

[Interdisciplinary clinical pathway for colorectal cancer].

PubMed

Fischbach, W; Engemann, R

2006-07-01

Limited financial resources in public health care have led to the introduction of clinical pathways as a means to a better effectivity and efficacy. Colorectal cancer met the requirements for establishing such a pathway in a distinguished way: high patient volume, high costs, interdisciplinary multi-modal treatment concepts in a relevant frequency, and existing evidence based guidelines. This article gives an example of a clinical pathway for colorectal cancer as established in our hospital. The potential of such pathways to save costs as well as their implications on treatment results and patients' satisfaction will have to be critically analyzed in the future before their value can be definitely estimated.

Implications of State and Local Policy on Community College Transfer in California

ERIC Educational Resources Information Center

Neault, Lynn Ceresino; Piland, William E.

2014-01-01

Lower division transfer preparation for the university has been the primary mission of community colleges since their inception creating an important pathway to baccalaureate degree attainment for many students who may not otherwise have the opportunity for higher education. Once considered fairly straightforward, the transfer pathway has become…

Diversity in Pathways to Parenthood: Patterns, Implications, and Emerging Research Directions

ERIC Educational Resources Information Center

Smock, Pamela J.; Greenland, Fiona Rose

2010-01-01

This review examines and synthesizes recent research on pathways to parenthood. We begin by providing basic information about patterns, differentials, and trends and discussing adoption and new reproductive technologies. We next turn to several areas of inquiry that became particularly prominent in the last decade: the continued "decoupling" of…

Meaning Profiles of Dwellings, Pathways, and Metaphors in Design: Implications for Education

ERIC Educational Resources Information Center

Casakin, Hernan; Kreitler, Shulamith

2017-01-01

The study deals with the roles and interrelations of the meaning-based assessments of dwellings, pathways and metaphors in design performance. It is grounded in the Meaning Theory [Kreitler, S., and H. Kreitler. 1990. "The Cognitive Foundations of Personality Traits." New York: Plenum], which enables identifying the cognitive contents…

Target Deconvolution Efforts on Wnt Pathway Screen Reveal Dual Modulation of Oxidative Phosphorylation and SERCA2.

PubMed

Casás-Selves, Matias; Zhang, Andrew X; Dowling, James E; Hallén, Stefan; Kawatkar, Aarti; Pace, Nicholas J; Denz, Christopher R; Pontz, Timothy; Garahdaghi, Farzin; Cao, Qing; Sabirsh, Alan; Thakur, Kumar; O'Connell, Nichole; Hu, Jun; Cornella-Taracido, Iván; Weerapana, Eranthie; Zinda, Michael; Goodnow, Robert A; Castaldi, M Paola

2017-06-21

Wnt signaling is critical for development, cell proliferation and differentiation, and mutations in this pathway resulting in constitutive signaling have been implicated in various cancers. A pathway screen using a Wnt-dependent reporter identified a chemical series based on a 1,2,3-thiadiazole-5-carboxamide (TDZ) core with sub-micromolar potency. Herein we report a comprehensive mechanism-of-action deconvolution study toward identifying the efficacy target(s) and biological implication of this chemical series involving bottom-up quantitative chemoproteomics, cell biology, and biochemical methods. Through observing the effects of our probes on metabolism and performing confirmatory cellular and biochemical assays, we found that this chemical series inhibits ATP synthesis by uncoupling the mitochondrial potential. Affinity chemoproteomics experiments identified sarco(endo)plasmic reticulum Ca 2+ -dependent ATPase (SERCA2) as a binding partner of the TDZ series, and subsequent validation studies suggest that the TDZ series can act as ionophores through SERCA2 toward Wnt pathway inhibition. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Decoding the contribution of dopaminergic genes and pathways to autism spectrum disorder (ASD).

PubMed

Nguyen, Michael; Roth, Andrew; Kyzar, Evan J; Poudel, Manoj K; Wong, Keith; Stewart, Adam Michael; Kalueff, Allan V

2014-01-01

Autism spectrum disorder (ASD) is a debilitating brain illness causing social deficits, delayed development and repetitive behaviors. ASD is a heritable neurodevelopmental disorder with poorly understood and complex etiology. The central dopaminergic system is strongly implicated in ASD pathogenesis. Genes encoding various elements of this system (including dopamine receptors, the dopamine transporter or enzymes of synthesis and catabolism) have been linked to ASD. Here, we comprehensively evaluate known molecular interactors of dopaminergic genes, and identify their potential molecular partners within up/down-steam signaling pathways associated with dopamine. These in silico analyses allowed us to construct a map of molecular pathways, regulated by dopamine and involved in ASD. Clustering these pathways reveals groups of genes associated with dopamine metabolism, encoding proteins that control dopamine neurotransmission, cytoskeletal processes, synaptic release, Ca(2+) signaling, as well as the adenosine, glutamatergic and gamma-aminobutyric systems. Overall, our analyses emphasize the important role of the dopaminergic system in ASD, and implicate several cellular signaling processes in its pathogenesis. Copyright © 2014 Elsevier Ltd. All rights reserved.

Review of and Updates on Hypertension in Obstructive Sleep Apnea

PubMed Central

Ahmad, Masood; Makati, Devan

2017-01-01

Obstructive sleep apnea (OSA) is a prevalent sleep disorder as is hypertension (HTN) in the 21st century with the rising incidence of obesity. Numerous studies have shown a strong association of OSA with cardiovascular morbidity and mortality. There is overwhelming evidence supporting the relationship between OSA and hypertension (HTN). The pathophysiology of HTN in OSA is complex and dependent on various factors such as sympathetic tone, renin-angiotensin-aldosterone system, endothelial dysfunction, and altered baroreceptor reflexes. The treatment of OSA is multifactorial ranging from CPAP to oral appliances to lifestyle modifications to antihypertensive drugs. OSA and HTN both need prompt diagnosis and treatment to help address the growing cardiovascular morbidity and mortality due to these two entities. PMID:29147581

Interventional Therapies for Resistant Hypertension: A Brief Update

PubMed Central

Brandon, Lisa

2016-01-01

Resistant hypertension remains a clinical challenge with few management options beyond maximisation of medications. Catheter- based renal artery denervation (RDN) was proposed in 2009 as a possible therapy for resistant hypertension and early feasibility trials caused excitement among cardiologists and antihypertensive specialists, showing remarkable and sustained blood pressure reductions. In 2014, enthusiasm for RDN dampened following the SYMPLICITY 3 trial results, which showed no statistically significant difference in blood pressure between the intervention and control arms. However, hope remains for the improved management of resistant hypertension; procedural understanding, technological advancements and alternative targets – such as baroreceptor activation therapy and arteriovenous shunts – may aid the identification of those patients for whom specific interventional therapies will be effective. PMID:29588709

Genetic Variants in the Wnt/β-Catenin Signaling Pathway as Indicators of Bladder Cancer Risk.

PubMed

Pierzynski, Jeanne A; Hildebrandt, Michelle A; Kamat, Ashish M; Lin, Jie; Ye, Yuanqing; Dinney, Colin P N; Wu, Xifeng

2015-12-01

Genetic factors that influence bladder cancer risk remain largely unknown. Previous research has suggested that there is a strong genetic component underlying the risk of bladder cancer. The Wnt/β-catenin signaling pathway is a key modulator of cellular proliferation through its regulation of stem cell homeostasis. Furthermore, variants in the Wnt/β-catenin signaling pathway have been implicated in the development of other cancers, leading us to believe that this pathway may have a vital role in bladder cancer development. A total of 230 single nucleotide polymorphisms in 40 genes in the Wnt/β-catenin signaling pathway were genotyped in 803 bladder cancer cases and 803 healthy controls. A total of 20 single nucleotide polymorphisms were nominally significant for risk. Individuals with 2 variants of LRP6: rs10743980 were associated with a decreased risk of bladder cancer in the recessive model in the initial analysis (OR 0.76, 95% CI 0.58-0.99, p=0.039). This was validated using the bladder genome-wide association study chip (OR 0.51, 95% CI 0.27-1.00, p=0.049 and for combined analysis p=0.007). Together these findings implicate variants in the Wnt/β-catenin stem cell pathway as having a role in bladder cancer etiology. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Polluted Pathways: Mechanisms of Metabolic Disruption by Endocrine Disrupting Chemicals.

PubMed

Mimoto, Mizuho S; Nadal, Angel; Sargis, Robert M

2017-06-01

Environmental toxicants are increasingly implicated in the global decline in metabolic health. Focusing on diabetes, herein, the molecular and cellular mechanisms by which metabolism disrupting chemicals (MDCs) impair energy homeostasis are discussed. Emerging data implicate MDC perturbations in a variety of pathways as contributors to metabolic disease pathogenesis, with effects in diverse tissues regulating fuel utilization. Potentiation of traditional metabolic risk factors, such as caloric excess, and emerging threats to metabolism, such as disruptions in circadian rhythms, are important areas of current and future MDC research. Increasing evidence also implicates deleterious effects of MDCs on metabolic programming that occur during vulnerable developmental windows, such as in utero and early post-natal life as well as pregnancy. Recent insights into the mechanisms by which MDCs alter energy homeostasis will advance the field's ability to predict interactions with classical metabolic disease risk factors and empower studies utilizing targeted therapeutics to treat MDC-mediated diabetes.

Arabidopsis scaffold protein RACK1A modulates rare sugar D-allose regulated gibberellin signaling.

PubMed

Fennell, Herman; Olawin, Abdulquadri; Mizanur, Rahman M; Izumori, Ken; Chen, Jin-Gui; Ullah, Hemayet

2012-11-01

As energy sources and structural components, sugars are the central regulators of plant growth and development. In addition to the abundant natural sugars in plants, more than 50 different kinds of rare sugars exist in nature, several of which show distinct roles in plant growth and development. Recently, one of the rare sugars, D-allose, an epimer of D-glucose at C3, is found to suppress plant hormone gibberellin (GA) signaling in rice. Scaffold protein RACK1A in the model plant Arabidopsis is implicated in the GA pathway as rack1a knockout mutants show insensitivity to GA in GA-induced seed germination. Using genetic knockout lines and a reporter gene, the functional role of RACK1A in the D-allose pathway was investigated. It was found that the rack1a knockout seeds showed hypersensitivity to D-allose-induced inhibition of seed germination, implicating a role for RACK1A in the D-allose mediated suppression of seed germination. On the other hand, a functional RACK1A in the background of the double knockout mutations in the other two RACK1 isoforms, rack1b/rack1c, showed significant resistance to the D-allose induced inhibition of seed germination. The collective results implicate the RACK1A in the D-allose mediated seed germination inhibition pathway. Elucidation of the rare sugar signaling mechanism will help to advance understanding of this less studied but important cellular signaling pathway.

Arabidopsis scaffold protein RACK1A modulates rare sugar D-allose regulated gibberellin signaling

PubMed Central

Fennell, Herman; Olawin, Abdulquadri; Mizanur, Rahman M.; Izumori, Ken; Chen, Jin-Gui; Ullah, Hemayet

2012-01-01

As energy sources and structural components, sugars are the central regulators of plant growth and development. In addition to the abundant natural sugars in plants, more than 50 different kinds of rare sugars exist in nature, several of which show distinct roles in plant growth and development. Recently, one of the rare sugars, D-allose, an epimer of D-glucose at C3, is found to suppress plant hormone gibberellin (GA) signaling in rice. Scaffold protein RACK1A in the model plant Arabidopsis is implicated in the GA pathway as rack1a knockout mutants show insensitivity to GA in GA-induced seed germination. Using genetic knockout lines and a reporter gene, the functional role of RACK1A in the D-allose pathway was investigated. It was found that the rack1a knockout seeds showed hypersensitivity to D-allose-induced inhibition of seed germination, implicating a role for RACK1A in the D-allose mediated suppression of seed germination. On the other hand, a functional RACK1A in the background of the double knockout mutations in the other two RACK1 isoforms, rack1b/rack1c, showed significant resistance to the D-allose induced inhibition of seed germination. The collective results implicate the RACK1A in the D-allose mediated seed germination inhibition pathway. Elucidation of the rare sugar signaling mechanism will help to advance understanding of this less studied but important cellular signaling pathway. PMID:22951405

A Quantum Measurement Paradigm for Educational Predicates: Implications for Validity in Educational Measurement

ERIC Educational Resources Information Center

Cantley, Ian

2017-01-01

The outcomes of educational assessments undoubtedly have real implications for students, teachers, schools and education in the widest sense. Assessment results are, for example, used to award qualifications that determine future educational or vocational pathways of students. The results obtained by students in assessments are also used to gauge…

Clinical implications of parallel visual pathways.

PubMed

Bassi, C J; Lehmkuhle, S

1990-02-01

Visual information travels from the retina to visual cortical areas along at least two parallel pathways. In this paper, anatomical and physiological evidence is presented to demonstrate the existence of, and trace these two pathways throughout the visual systems of the cat, primate, and human. Physiological and behavioral experiments are discussed which establish that these two pathways are differentially sensitive to stimuli that vary in spatial and temporal frequency. One pathway (M-pathway) is more sensitive to coarse visual form that is modulated or moving at fast rates, whereas the other pathway (P-pathway) is more sensitive to spatial detail that is stationary or moving at slow rates. This difference between the M- and P-pathways is related to some spatial and temporal effects observed in humans. Furthermore, evidence is presented that certain diseases selectively comprise the functioning of M- or P-pathways (i.e., glaucoma, Alzheimer's disease, and anisometropic amblyopia), and some of the spatial and temporal deficits observed in these patients are presented within the context of the dysfunction of the M- or P-pathway.

Gaps and Pathways Project: driving pathways by diagnosis sheets.

PubMed

Touchinsky, Susan; Chew, Felicia; Davis, Elin Schold

2014-04-01

This paper describes the development and use of information sheets for occupational therapy practitioners to use as guides for evaluation and intervention planning to address their client's driving and community mobility needs. Called Driving Pathways by Diagnosis Sheets, the information assists therapists with direction to connect impairment to driving risk and incorporate intervention to client goals and priorities related to driving and community mobility. An example of one of the sheets for the diagnosis of arthritis is highlighted and implications for use are discussed.

Critical Pathways to School Readiness: Implications for First 5 Ventura County Strategic Planning, Funding and Evaluation

ERIC Educational Resources Information Center

Thompson, Lisa; Tullis, Ericka; Franke, Todd; Halfon, Neal

2005-01-01

The UCLA Center for Healthier Children, Families and Communities (CHCFC) has developed the School Readiness Critical Pathways (SRCPs) as an evidence-based conceptual model that links related outcomes and strategies. This helps to organize an array of broad and diffuse evidence regarding the strategies that produce school readiness outcomes for…

The New Juan Crow in Education: Revealing Panoptic Measures and Inequitable Resources That Hinder Latina/o Postsecondary Pathways

ERIC Educational Resources Information Center

Madrigal-Garcia, Yanira I.; Acevedo-Gil, Nancy

2016-01-01

This qualitative study examined the distribution of inequitable resources, a culture of control, and implications for postsecondary pathways for Latinas/os in five California high schools. This study integrated critical race theory in education, school culture, and the concept of "panopticon" to examine school structures, climate, and…

Post-traumatic stress disorder and opioid use disorder: A narrative review of conceptual models.

PubMed

Danovitch, Itai

2016-01-01

Post-traumatic stress disorder is highly prevalent among individuals who suffer from opioid use disorder. Compared to individuals with opioid use disorder alone, those with post-traumatic stress disorder have a worse course of illness, occupational functioning, and physical health. The neurobiological pathways underlying each disorder overlap substantially, and there are multiple pathways through which these disorders may interact. This narrative review explores evidence underpinning 3 explanatory perspectives on comorbid post-traumatic stress disorder and opioid use disorder: The opioid susceptibility model (a.k.a.: the Self-Medication Hypothesis), the post-traumatic stress disorder susceptibility model, and the common factors model. Diagnostic implications, treatment implications, and directions for future research are discussed.

Stress-induced EGFR trafficking: mechanisms, functions, and therapeutic implications

PubMed Central

Tan, Xiaojun; Lambert, Paul F.; Rapraeger, Alan C.; Anderson, Richard A.

2016-01-01

Epidermal growth factor receptor (EGFR) has fundamental roles in normal physiology and in cancer, making it a rational target for cancer therapy. Surprisingly, however, inhibitors that target canonical, ligand-stimulated EGFR signaling have proven to be largely ineffective in treating many EGFR-dependent cancers. Recent evidence indicates that both intrinsic and therapy-induced cellular stress triggers robust, non-canonical pathways of ligand-independent EGFR trafficking and signaling, which provides cancer cells with a survival advantage and resistance to therapeutics. Here we review the mechanistic regulation of non-canonical EGFR trafficking and signaling, the pathological and therapeutic stresses that activate it, and discuss the implications of this pathway in clinical treatment of EGFR-overexpressing cancers. PMID:26827089

Hypotensive effects of ghrelin receptor agonists mediated through a novel receptor

PubMed Central

Callaghan, Brid; Kosari, Samin; Pustovit, Ruslan V; Sartor, Daniela M; Ferens, Dorota; Ban, Kung; Baell, Jonathan; Nguyen, Trung V; Rivera, Leni R; Brock, James A; Furness, John B

2014-01-01

BACKGROUND AND PURPOSE Some agonists of ghrelin receptors cause rapid decreases in BP. The mechanisms by which they cause hypotension and the pharmacology of the receptors are unknown. EXPERIMENTAL APPROACH The effects of ligands of ghrelin receptors were investigated in rats in vivo, on isolated blood vessels and on cells transfected with the only molecularly defined ghrelin receptor, growth hormone secretagogue receptor 1a (GHSR1a). KEY RESULTS Three agonists of GHSR1a receptors, ulimorelin, capromorelin and CP464709, caused a rapid decrease in BP in the anaesthetized rat. The effect was not reduced by either of two GHSR1a antagonists, JMV2959 or YIL781, at doses that blocked effects on colorectal motility, in vivo. The rapid hypotension was not mimicked by ghrelin, unacylated ghrelin or the unacylated ghrelin receptor agonist, AZP531. The early hypotension preceded a decrease in sympathetic nerve activity. Early hypotension was not reduced by hexamethonium or by baroreceptor (sino-aortic) denervation. Ulimorelin also relaxed isolated segments of rat mesenteric artery, and, less potently, relaxed aorta segments. The vascular relaxation was not reduced by JMV2959 or YIL781. Ulimorelin, capromorelin and CP464709 activated GHSR1a in transfected HEK293 cells at nanomolar concentrations. JMV2959 and YIL781 both antagonized effects in these cells, with their pA2 values at the GHSR1a receptor being 6.55 and 7.84. CONCLUSIONS AND IMPLICATIONS Our results indicate a novel vascular receptor or receptors whose activation by ulimorelin, capromorelin and CP464709 lowered BP. This receptor is activated by low MW GHSR1a agonists, but is not activated by ghrelin. PMID:24670149

Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging

PubMed Central

Steelman, Linda S.; Chappell, William H.; Abrams, Stephen L.; Kempf, C. Ruth; Long, Jacquelyn; Laidler, Piotr; Mijatovic, Sanja; Maksimovic-Ivanic, Danijela; Stivala, Franca; Mazzarino, Maria C.; Donia, Marco; Fagone, Paolo; Malaponte, Graziella; Nicoletti, Ferdinando; Libra, Massimo; Milella, Michele; Tafuri, Agostino; Bonati, Antonio; Bäsecke, Jörg; Cocco, Lucio; Evangelisti, Camilla; Martelli, Alberto M.; Montalto, Giuseppe; Cervello, Melchiorre; McCubrey, James A.

2011-01-01

Dysregulated signaling through the Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways is often the result of genetic alterations in critical components in these pathways or upstream activators. Unrestricted cellular proliferation and decreased sensitivity to apoptotic-inducing agents are typically associated with activation of these pro-survival pathways. This review discusses the functions these pathways have in normal and neoplastic tissue growth and how they contribute to resistance to apoptotic stimuli. Crosstalk and commonly identified mutations that occur within these pathways that contribute to abnormal activation and cancer growth will also be addressed. Finally the recently described roles of these pathways in cancer stem cells, cellular senescence and aging will be evaluated. Controlling the expression of these pathways could ameliorate human health. PMID:21422497

Locally advanced and metastatic basal cell carcinoma: molecular pathways, treatment options and new targeted therapies.

PubMed

Ruiz Salas, Veronica; Alegre, Marta; Garcés, Joan Ramón; Puig, Lluis

2014-06-01

The hedgehog (Hh) signaling pathway has been identified as important to normal embryonic development in living organisms and it is implicated in processes including cell proliferation, differentiation and tissue patterning. Aberrant Hh pathway has been involved in the pathogenesis and chemotherapy resistance of different solid and hematologic malignancies. Basal cell carcinoma (BCC) and medulloblastoma are two well-recognized cancers with mutations in components of the Hh pathway. Vismodegib has recently approved as the first inhibitor of one of the components of the Hh pathway (smoothened). This review attempts to provide current data on the molecular pathways involved in the development of BCC and the therapeutic options available for the treatment of locally advanced and metastatic BCC, and the new targeted therapies in development.

Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

PubMed

Turcot, Valérie; Lu, Yingchang; Highland, Heather M; Schurmann, Claudia; Justice, Anne E; Fine, Rebecca S; Bradfield, Jonathan P; Esko, Tõnu; Giri, Ayush; Graff, Mariaelisa; Guo, Xiuqing; Hendricks, Audrey E; Karaderi, Tugce; Lempradl, Adelheid; Locke, Adam E; Mahajan, Anubha; Marouli, Eirini; Sivapalaratnam, Suthesh; Young, Kristin L; Alfred, Tamuno; Feitosa, Mary F; Masca, Nicholas G D; Manning, Alisa K; Medina-Gomez, Carolina; Mudgal, Poorva; Ng, Maggie C Y; Reiner, Alex P; Vedantam, Sailaja; Willems, Sara M; Winkler, Thomas W; Abecasis, Gonçalo; Aben, Katja K; Alam, Dewan S; Alharthi, Sameer E; Allison, Matthew; Amouyel, Philippe; Asselbergs, Folkert W; Auer, Paul L; Balkau, Beverley; Bang, Lia E; Barroso, Inês; Bastarache, Lisa; Benn, Marianne; Bergmann, Sven; Bielak, Lawrence F; Blüher, Matthias; Boehnke, Michael; Boeing, Heiner; Boerwinkle, Eric; Böger, Carsten A; Bork-Jensen, Jette; Bots, Michiel L; Bottinger, Erwin P; Bowden, Donald W; Brandslund, Ivan; Breen, Gerome; Brilliant, Murray H; Broer, Linda; Brumat, Marco; Burt, Amber A; Butterworth, Adam S; Campbell, Peter T; Cappellani, Stefania; Carey, David J; Catamo, Eulalia; Caulfield, Mark J; Chambers, John C; Chasman, Daniel I; Chen, Yii-Der I; Chowdhury, Rajiv; Christensen, Cramer; Chu, Audrey Y; Cocca, Massimiliano; Collins, Francis S; Cook, James P; Corley, Janie; Corominas Galbany, Jordi; Cox, Amanda J; Crosslin, David S; Cuellar-Partida, Gabriel; D'Eustacchio, Angela; Danesh, John; Davies, Gail; Bakker, Paul I W; Groot, Mark C H; Mutsert, Renée; Deary, Ian J; Dedoussis, George; Demerath, Ellen W; Heijer, Martin; Hollander, Anneke I; Ruijter, Hester M; Dennis, Joe G; Denny, Josh C; Di Angelantonio, Emanuele; Drenos, Fotios; Du, Mengmeng; Dubé, Marie-Pierre; Dunning, Alison M; Easton, Douglas F; Edwards, Todd L; Ellinghaus, David; Ellinor, Patrick T; Elliott, Paul; Evangelou, Evangelos; Farmaki, Aliki-Eleni; Farooqi, I Sadaf; Faul, Jessica D; Fauser, Sascha; Feng, Shuang; Ferrannini, Ele; Ferrieres, Jean; Florez, Jose C; Ford, Ian; Fornage, Myriam; Franco, Oscar H; Franke, Andre; Franks, Paul W; Friedrich, Nele; Frikke-Schmidt, Ruth; Galesloot, Tessel E; Gan, Wei; Gandin, Ilaria; Gasparini, Paolo; Gibson, Jane; Giedraitis, Vilmantas; Gjesing, Anette P; Gordon-Larsen, Penny; Gorski, Mathias; Grabe, Hans-Jörgen; Grant, Struan F A; Grarup, Niels; Griffiths, Helen L; Grove, Megan L; Gudnason, Vilmundur; Gustafsson, Stefan; Haessler, Jeff; Hakonarson, Hakon; Hammerschlag, Anke R; Hansen, Torben; Harris, Kathleen Mullan; Harris, Tamara B; Hattersley, Andrew T; Have, Christian T; Hayward, Caroline; He, Liang; Heard-Costa, Nancy L; Heath, Andrew C; Heid, Iris M; Helgeland, Øyvind; Hernesniemi, Jussi; Hewitt, Alex W; Holmen, Oddgeir L; Hovingh, G Kees; Howson, Joanna M M; Hu, Yao; Huang, Paul L; Huffman, Jennifer E; Ikram, M Arfan; Ingelsson, Erik; Jackson, Anne U; Jansson, Jan-Håkan; Jarvik, Gail P; Jensen, Gorm B; Jia, Yucheng; Johansson, Stefan; Jørgensen, Marit E; Jørgensen, Torben; Jukema, J Wouter; Kahali, Bratati; Kahn, René S; Kähönen, Mika; Kamstrup, Pia R; Kanoni, Stavroula; Kaprio, Jaakko; Karaleftheri, Maria; Kardia, Sharon L R; Karpe, Fredrik; Kathiresan, Sekar; Kee, Frank; Kiemeney, Lambertus A; Kim, Eric; Kitajima, Hidetoshi; Komulainen, Pirjo; Kooner, Jaspal S; Kooperberg, Charles; Korhonen, Tellervo; Kovacs, Peter; Kuivaniemi, Helena; Kutalik, Zoltán; Kuulasmaa, Kari; Kuusisto, Johanna; Laakso, Markku; Lakka, Timo A; Lamparter, David; Lange, Ethan M; Lange, Leslie A; Langenberg, Claudia; Larson, Eric B; Lee, Nanette R; Lehtimäki, Terho; Lewis, Cora E; Li, Huaixing; Li, Jin; Li-Gao, Ruifang; Lin, Honghuang; Lin, Keng-Hung; Lin, Li-An; Lin, Xu; Lind, Lars; Lindström, Jaana; Linneberg, Allan; Liu, Ching-Ti; Liu, Dajiang J; Liu, Yongmei; Lo, Ken S; Lophatananon, Artitaya; Lotery, Andrew J; Loukola, Anu; Luan, Jian'an; Lubitz, Steven A; Lyytikäinen, Leo-Pekka; Männistö, Satu; Marenne, Gaëlle; Mazul, Angela L; McCarthy, Mark I; McKean-Cowdin, Roberta; Medland, Sarah E; Meidtner, Karina; Milani, Lili; Mistry, Vanisha; Mitchell, Paul; Mohlke, Karen L; Moilanen, Leena; Moitry, Marie; Montgomery, Grant W; Mook-Kanamori, Dennis O; Moore, Carmel; Mori, Trevor A; Morris, Andrew D; Morris, Andrew P; Müller-Nurasyid, Martina; Munroe, Patricia B; Nalls, Mike A; Narisu, Narisu; Nelson, Christopher P; Neville, Matt; Nielsen, Sune F; Nikus, Kjell; Njølstad, Pål R; Nordestgaard, Børge G; Nyholt, Dale R; O'Connel, Jeffrey R; O'Donoghue, Michelle L; Olde Loohuis, Loes M; Ophoff, Roel A; Owen, Katharine R; Packard, Chris J; Padmanabhan, Sandosh; Palmer, Colin N A; Palmer, Nicholette D; Pasterkamp, Gerard; Patel, Aniruddh P; Pattie, Alison; Pedersen, Oluf; Peissig, Peggy L; Peloso, Gina M; Pennell, Craig E; Perola, Markus; Perry, James A; Perry, John R B; Pers, Tune H; Person, Thomas N; Peters, Annette; Petersen, Eva R B; Peyser, Patricia A; Pirie, Ailith; Polasek, Ozren; Polderman, Tinca J; Puolijoki, Hannu; Raitakari, Olli T; Rasheed, Asif; Rauramaa, Rainer; Reilly, Dermot F; Renström, Frida; Rheinberger, Myriam; Ridker, Paul M; Rioux, John D; Rivas, Manuel A; Roberts, David J; Robertson, Neil R; Robino, Antonietta; Rolandsson, Olov; Rudan, Igor; Ruth, Katherine S; Saleheen, Danish; Salomaa, Veikko; Samani, Nilesh J; Sapkota, Yadav; Sattar, Naveed; Schoen, Robert E; Schreiner, Pamela J; Schulze, Matthias B; Scott, Robert A; Segura-Lepe, Marcelo P; Shah, Svati H; Sheu, Wayne H-H; Sim, Xueling; Slater, Andrew J; Small, Kerrin S; Smith, Albert V; Southam, Lorraine; Spector, Timothy D; Speliotes, Elizabeth K; Starr, John M; Stefansson, Kari; Steinthorsdottir, Valgerdur; Stirrups, Kathleen E; Strauch, Konstantin; Stringham, Heather M; Stumvoll, Michael; Sun, Liang; Surendran, Praveen; Swift, Amy J; Tada, Hayato; Tansey, Katherine E; Tardif, Jean-Claude; Taylor, Kent D; Teumer, Alexander; Thompson, Deborah J; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Thuesen, Betina H; Tönjes, Anke; Tromp, Gerard; Trompet, Stella; Tsafantakis, Emmanouil; Tuomilehto, Jaakko; Tybjaerg-Hansen, Anne; Tyrer, Jonathan P; Uher, Rudolf; Uitterlinden, André G; Uusitupa, Matti; Laan, Sander W; Duijn, Cornelia M; Leeuwen, Nienke; van Setten, Jessica; Vanhala, Mauno; Varbo, Anette; Varga, Tibor V; Varma, Rohit; Velez Edwards, Digna R; Vermeulen, Sita H; Veronesi, Giovanni; Vestergaard, Henrik; Vitart, Veronique; Vogt, Thomas F; Völker, Uwe; Vuckovic, Dragana; Wagenknecht, Lynne E; Walker, Mark; Wallentin, Lars; Wang, Feijie; Wang, Carol A; Wang, Shuai; Wang, Yiqin; Ware, Erin B; Wareham, Nicholas J; Warren, Helen R; Waterworth, Dawn M; Wessel, Jennifer; White, Harvey D; Willer, Cristen J; Wilson, James G; Witte, Daniel R; Wood, Andrew R; Wu, Ying; Yaghootkar, Hanieh; Yao, Jie; Yao, Pang; Yerges-Armstrong, Laura M; Young, Robin; Zeggini, Eleftheria; Zhan, Xiaowei; Zhang, Weihua; Zhao, Jing Hua; Zhao, Wei; Zhao, Wei; Zhou, Wei; Zondervan, Krina T; Rotter, Jerome I; Pospisilik, John A; Rivadeneira, Fernando; Borecki, Ingrid B; Deloukas, Panos; Frayling, Timothy M; Lettre, Guillaume; North, Kari E; Lindgren, Cecilia M; Hirschhorn, Joel N; Loos, Ruth J F

2018-01-01

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

The Role of GABAA Receptors in the Development of Alcoholism

PubMed Central

Enoch, Mary-Anne

2008-01-01

Alcoholism is a common, heritable, chronic relapsing disorder. GABAA receptors undergo allosteric modulation by ethanol, anesthetics, benzodiazepines and neurosteroids and have been implicated in the acute as well as the chronic effects of ethanol including tolerance, dependence and withdrawal. Medications targeting GABAA receptors ameliorate the symptoms of acute withdrawal. Ethanol induces plasticity in GABAA receptors: tolerance is associated with generally decreased GABAA receptor activation and differentially altered subunit expression. The dopamine (DA) mesolimbic reward pathway originating in the ventral tegmental area (VTA), and interacting stress circuitry play an important role in the development of addiction. VTA GABAergic interneurons are the primary inhibitory regulators of DA neurons and a subset of VTA GABAA receptors may be implicated in the switch from heavy drinking to dependence. GABAA receptors modulate anxiety and response to stress; important elements of sustained drinking and relapse. The GABAA receptor subunit genes clustered on chromosome 4 are highly expressed in the reward pathway. Several recent studies have provided strong evidence that one of these genes, GABRA2, is implicated in alcoholism in humans. The influence of the interaction between ethanol and GABAA receptors in the reward pathway on the development of alcoholism together with genetic and epigenetic vulnerabilities will be explored in this review. PMID:18440057

The role of GABA(A) receptors in the development of alcoholism.

PubMed

Enoch, Mary-Anne

2008-07-01

Alcoholism is a common, heritable, chronic relapsing disorder. GABA(A) receptors undergo allosteric modulation by ethanol, anesthetics, benzodiazepines and neurosteroids and have been implicated in the acute as well as the chronic effects of ethanol including tolerance, dependence and withdrawal. Medications targeting GABA(A) receptors ameliorate the symptoms of acute withdrawal. Ethanol induces plasticity in GABA(A) receptors: tolerance is associated with generally decreased GABA(A) receptor activation and differentially altered subunit expression. The dopamine (DA) mesolimbic reward pathway originating in the ventral tegmental area (VTA), and interacting stress circuitry play an important role in the development of addiction. VTA GABAergic interneurons are the primary inhibitory regulators of DA neurons and a subset of VTA GABA(A) receptors may be implicated in the switch from heavy drinking to dependence. GABA(A) receptors modulate anxiety and response to stress; important elements of sustained drinking and relapse. The GABA(A) receptor subunit genes clustered on chromosome 4 are highly expressed in the reward pathway. Several recent studies have provided strong evidence that one of these genes, GABRA2, is implicated in alcoholism in humans. The influence of the interaction between ethanol and GABA(A) receptors in the reward pathway on the development of alcoholism together with genetic and epigenetic vulnerabilities will be explored in this review.

Dysregulation of Uterine Signaling Pathways in Progesterone Receptor-Cre Knockout of Dicer

PubMed Central

Andreu-Vieyra, Claudia V.; Kim, Tae Hoon; Jeong, Jae-Wook; Hodgson, Myles C.; Chen, Ruihong; Creighton, Chad J.; Lydon, John P.; Gunaratne, Preethi H.; DeMayo, Francesco J.; Matzuk, Martin M.

2012-01-01

Epithelial-stromal interactions in the uterus are required for normal uterine functions such as pregnancy, and multiple signaling pathways are essential for this process. Although Dicer and microRNA (miRNA) have been implicated in several reproductive processes, the specific roles of Dicer and miRNA in uterine development are not known. To address the roles of miRNA in the regulation of key uterine pathways, we generated a conditional knockout of Dicer in the postnatal uterine epithelium and stroma using progesterone receptor-Cre. These Dicer conditional knockout females are sterile with small uteri, which demonstrate significant defects, including absence of glandular epithelium and enhanced stromal apoptosis, beginning at approximately postnatal d 15, with coincident expression of Cre and deletion of Dicer. Specific miRNA (miR-181c, −200b, −101, let-7d) were down-regulated and corresponding predicted proapoptotic target genes (Bcl2l11, Aldh1a3) were up-regulated, reflecting the apoptotic phenomenon. Although these mice had normal serum hormone levels, critical uterine signaling pathways, including progesterone-responsive genes, Indian hedgehog signaling, and the Wnt/β-catenin canonical pathway, were dysregulated at the mRNA level. Importantly, uterine stromal cell proliferation in response to progesterone was absent, whereas uterine epithelial cell proliferation in response to estradiol was maintained in adult uteri. These data implicate Dicer and appropriate miRNA expression as essential players in the regulation of multiple uterine signaling pathways required for uterine development and appropriate function. PMID:22798293

Thermal convection currents in NMR: flow profiles and implications for coherence pathway selection

PubMed

Jerschow

2000-07-01

Rayleigh-Benard convection currents are visualized in a vertical cylindrical tube by means of magnetic resonance imaging. Axially antisymmetric flow, multiple vertical rolls, and twisted node planes are observed. The flow can also be induced by strong RF irradiation. Its effects on the coherence pathways in NMR experiments employing field gradients are discussed. Copyright 2000 Academic Press.

Meaning profiles of dwellings, pathways, and metaphors in design: implications for education

NASA Astrophysics Data System (ADS)

Casakin, Hernan; Kreitler, Shulamith

2017-11-01

The study deals with the roles and interrelations of the meaning-based assessments of dwellings, pathways and metaphors in design performance. It is grounded in the Meaning Theory [Kreitler, S., and H. Kreitler. 1990. The Cognitive Foundations of Personality Traits. New York: Plenum], which enables identifying the cognitive contents and processes underlying cognitive performance in different domains, thus rendering them more accessible to educational training. The objectives were to identify the components of the meaning profiles of dwellings, pathways, and metaphors as perceived by design students; to analyse their interrelations; and to examine which of the identified components of these constructs serve as best predictors of design performance aided by the use of metaphors. Participants were administered a design task and questionnaires about the Dimensional Profiles of Dwellings, Pathways, and Metaphors, based on the meaning system. Factors based on the factor analyses of the responses to the three questionnaires were used in regression analyses as predictors of the performance score in a design task. The following three factors of the dimensional meaning profiles of metaphors were significant predictors of design performance: sensory, functional, and structural evaluations. Implications for design education are discussed, primarily concerning the important role of metaphor in design problem-solving.

Profile of vismodegib and its potential in the treatment of advanced basal cell carcinoma.

PubMed

Macha, Muzafar A; Batra, Surinder K; Ganti, Apar Kishor

2013-01-01

Basal cell carcinoma (BCC) is the most common human malignancy. Recent advances in our understanding of the critical biologic pathways implicated in the development and progression of BCC have led to the development of the first molecular targeted therapy for this disease. The hedgehog pathway is mutated in virtually all patients with BCC and recent trials with vismodegib, an inhibitor of this pathway, have shown significant responses. This review will discuss the importance of the hedgehog pathway in the pathogenesis of BCC and describe in detail the pharmacology of vismodegib in relation to its activity in advanced BCC.

Profile of vismodegib and its potential in the treatment of advanced basal cell carcinoma

PubMed Central

Macha, Muzafar A; Batra, Surinder K; Ganti, Apar Kishor

2013-01-01

Basal cell carcinoma (BCC) is the most common human malignancy. Recent advances in our understanding of the critical biologic pathways implicated in the development and progression of BCC have led to the development of the first molecular targeted therapy for this disease. The hedgehog pathway is mutated in virtually all patients with BCC and recent trials with vismodegib, an inhibitor of this pathway, have shown significant responses. This review will discuss the importance of the hedgehog pathway in the pathogenesis of BCC and describe in detail the pharmacology of vismodegib in relation to its activity in advanced BCC. PMID:23940421

The Hippo pathway: regulators and regulations

PubMed Central

Yu, Fa-Xing; Guan, Kun-Liang

2013-01-01

Control of cell number is crucial in animal development and tissue homeostasis, and its dysregulation may result in tumor formation or organ degeneration. The Hippo pathway in both Drosophila and mammals regulates cell number by modulating cell proliferation, cell death, and cell differentiation. Recently, numerous upstream components involved in the Hippo pathway have been identified, such as cell polarity, mechanotransduction, and G-protein-coupled receptor (GPCR) signaling. Actin cytoskeleton or cellular tension appears to be the master mediator that integrates and transmits upstream signals to the core Hippo signaling cascade. Here, we review regulatory mechanisms of the Hippo pathway and discuss potential implications involved in different physiological and pathological conditions. PMID:23431053

The impact of perinatal stress on the functional maturation of prefronto-cortical synaptic circuits: implications for the pathophysiology of ADHD?

PubMed

Bock, Jörg; Braun, Katharina

2011-01-01

Enriched as well as impoverished or adverse perinatal environment plays an essential role in the development and refinement of neuronal pathways, which are the neural substrate of intellectual capacity and socioemotional competence. Perinatal experience and learning events continuously interact with the adaptive shaping of excitatory, inhibitory, and neuromodulatory synaptic as well as the endocrine stress systems, including the neuronal corticotropin-releasing factor (CRF) pathways. Adverse environments, such as stress and emotional deprivation can not only delay experience-dependent maturation of these pathways, but also induce permanent changes in prefronto-cortical wiring patterns. We assume that such dysfunctional connections are the neuronal basis for the development of psychosocially induced mental disorders during later life. The aim of this review is to focus on the impact of perinatal stress on the neuronal and synaptic reorganization during brain development and possible implications for the etiology and therapy of mental disorders such as ADHD. Copyright © 2011 Elsevier B.V. All rights reserved.

CREB-binding protein (CBP) regulates β-adrenoceptor (β-AR)−mediated apoptosis

PubMed Central

Lee, Y Y; Moujalled, D; Doerflinger, M; Gangoda, L; Weston, R; Rahimi, A; de Alboran, I; Herold, M; Bouillet, P; Xu, Q; Gao, X; Du, X-J; Puthalakath, H

2013-01-01

Catecholamines regulate the β-adrenoceptor/cyclic AMP-regulated protein kinase A (cAMP/PKA) pathway. Deregulation of this pathway can cause apoptotic cell death and is implicated in a range of human diseases, such as neuronal loss during aging, cardiomyopathy and septic shock. The molecular mechanism of this process is, however, only poorly understood. Here we demonstrate that the β-adrenoceptor/cAMP/PKA pathway triggers apoptosis through the transcriptional induction of the pro-apoptotic BH3-only Bcl-2 family member Bim in tissues such as the thymus and the heart. In these cell types, the catecholamine-mediated apoptosis is abrogated by loss of Bim. Induction of Bim is driven by the transcriptional co-activator CBP (CREB-binding protein) together with the proto-oncogene c-Myc. Association of CBP with c-Myc leads to altered histone acetylation and methylation pattern at the Bim promoter site. Our findings have implications for understanding pathophysiology associated with a deregulated neuroendocrine system and for developing novel therapeutic strategies for these diseases. PMID:23579242

Development of lower body negative pressure as a countermeasure for orthostatic intolerance

NASA Technical Reports Server (NTRS)

Fortney, Suzanne M.

1991-01-01

Exposure to prolonged (1-4 hr) lower body negative pressure (LBNP) is a countermeasure against postflight orthostatic intolerance which is used in the Soviet space program and planned for use in the American space program. LBNP in combination with fluid-loading is believed to act by promoting a transient positive fluid balance resulting in an increase in vascular, as well as extravascular fluid. Inflight LBNP also may provide beneficial orthostatic effects by restoring baroreceptor reflex functions and/or lower body venous compliance. Current research efforts at the Johnson Space Center are directed toward increasing the effectiveness and efficiency of the LBNP and saline countermeasure. A promising avenue may involve combining pharmacologic agents, such as inhaled anti-diuretic hormone, or mineralocorticoids, with mechanical stimuli such as LBNP.

Modelling of long-term and short-term mechanisms of arterial pressure control in the cardiovascular system: an object-oriented approach.

PubMed

Fernandez de Canete, J; Luque, J; Barbancho, J; Munoz, V

2014-04-01

A mathematical model that provides an overall description of both the short- and long-term mechanisms of arterial pressure regulation is presented. Short-term control is exerted through the baroreceptor reflex while renal elimination plays a role in long-term control. Both mechanisms operate in an integrated way over the compartmental model of the cardiovascular system. The whole system was modelled in MODELICA, which uses a hierarchical object-oriented modelling strategy, under the DYMOLA simulation environment. The performance of the controlled system was analysed by simulation in light of the existing hypothesis and validation tests previously performed with physiological data, demonstrating the effectiveness of both regulation mechanisms under physiological and pathological conditions. Copyright © 2014 Elsevier Ltd. All rights reserved.

Intravenous cannulation of adolescents does not affect the modulation of autonomic tone assessed by heart rate and blood pressure variability.

PubMed

Stewart, J M

2000-02-01

Invasive arterial monitoring alters autonomic tone. The effects of intravenous (i.v.) insertion are less clear. The author assessed the effects of i.v. insertion on autonomic activity in patients aged 11 to 19 years prior to head-up tilt by measuring heart rate, blood pressure, heart rate variability, blood pressure variability, and baroreceptor gain before and after i.v. insertion with continuous electrocardiography and arterial tonometry in patients with orthostatic tachycardia syndrome (OTS, N = 21), in patients who experienced simple fainting (N = 14), and in normal control subjects (N = 6). Five-minute samples were collected after 30 minutes supine. Fifteen minutes after i.v. insertion, data were collected again. These 5-minute samples were also collected in a separate control population without i.v. insertion after 30 minutes supine and again 30 minutes later. This population included 12 patients with OTS, 13 patients who experienced simple fainting, and 6 normal control subjects. Heart rate variability included the mean RR, the standard deviation of the RR interval (SDNN), and the root mean square of successive RR differences (RMSSD). Autoregressive spectral modeling was used. Low-frequency power (LFP, 0.04-0.15 Hz), high-frequency power (HFP, 0.15-0.40 Hz), and total power (TP, 0.01-0.40 Hz) were compared. Blood pressure variability included standard deviation of systolic blood pressure, LFP, and HFP. Baroreceptor gain at low frequency and high frequency was calculated from cross-spectral transfer function magnitudes when coherence was greater than 0.5. In patients with OTS, RR (790 +/- 50 msec), SDNN (54 +/- 6 msec), RMSSD (55 +/- 5 msec), LFP (422 +/- 200 ms2/Hz), HFP (846 +/- 400 ms2/Hz), and TP (1550 +/- 320 ms2/Hz) were less than in patients who experienced simple fainting (RR, 940 +/- 50 msec; SDNN, 84 +/- 10 msec; RMSSD, 91 +/- 7 msec; LFP, 880 +/- 342 ms2/Hz; HFP, 1720 +/- 210 ms2/Hz; and TP, 3228 +/- 490 ms2/Hz) or normal control subjects (RR, 920 +/- 30 msec; SDNN, 110 +/- 29 msec; RMSSD, 120 +/- 16 msec; LFP, 1600 +/- 331 ms2/Hz; HFP, 2700 +/- 526 ms2/Hz; and TP, 5400 +/- 1017 ms2/Hz). Blood pressure and blood pressure variability were not different in any group. Standard deviation, LFP, and HFP were, respectively, 5.24 +/- 0.8 mm Hg, 1.2 +/- 0.2, and 1.5 +/- 0.3 for patients with OTS; 4.6 +/- 0.4 mm Hg, 1.2 +/- 0.2, and 1.4 +/- 0.3 for patients who experienced simple fainting; and 5.55 +/- 1.0 mm Hg, 1.4 +/- 0.2, and 1.6 +/- 0.3 for normal control subjects. Baroreceptor gain at low frequency and high frequency in patients with OTS (16 +/- 4 msec/mm Hg, 17 +/- 5) was comparable to that in patients who experienced simple fainting (33 +/- 4, 32 +/- 3) and that in normal control subjects (31 +/- 8, 37 +/- 9). Heart rate variability differed between patients with OTS and patients who experienced simple fainting or normal control subjects, and blood pressure and blood pressure variability were not different, but no parameter changed after i.v. insertion. There were no differences from the groups that did not receive i.v. insertions. Data suggest, at most, a limited effect of i.v. insertion on autonomic function in adolescents.

The Hippo Pathway: Immunity and Cancer.

PubMed

Taha, Zaid; J Janse van Rensburg, Helena; Yang, Xiaolong

2018-03-28

Since its discovery, the Hippo pathway has emerged as a central signaling network in mammalian cells. Canonical signaling through the Hippo pathway core components (MST1/2, LATS1/2, YAP and TAZ) is important for development and tissue homeostasis while aberrant signaling through the Hippo pathway has been implicated in multiple pathologies, including cancer. Recent studies have uncovered new roles for the Hippo pathway in immunology. In this review, we summarize the mechanisms by which Hippo signaling in pathogen-infected or neoplastic cells affects the activities of immune cells that respond to these threats. We further discuss how Hippo signaling functions as part of an immune response. Finally, we review how immune cell-intrinsic Hippo signaling modulates the development/function of leukocytes and propose directions for future work.

'What' Is Happening in the Dorsal Visual Pathway.

PubMed

Freud, Erez; Plaut, David C; Behrmann, Marlene

2016-10-01

The cortical visual system is almost universally thought to be segregated into two anatomically and functionally distinct pathways: a ventral occipitotemporal pathway that subserves object perception, and a dorsal occipitoparietal pathway that subserves object localization and visually guided action. Accumulating evidence from both human and non-human primate studies, however, challenges this binary distinction and suggests that regions in the dorsal pathway contain object representations that are independent of those in ventral cortex and that play a functional role in object perception. We review here the evidence implicating dorsal object representations, and we propose an account of the anatomical organization, functional contributions, and origins of these representations in the service of perception. Copyright © 2016 Elsevier Ltd. All rights reserved.

Systemic leukotriene B4 receptor antagonism lowers arterial blood pressure and improves autonomic function in the spontaneously hypertensive rat

PubMed Central

Marvar, Paul J.; Hendy, Emma B.; Cruise, Thomas D.; Walas, Dawid; DeCicco, Danielle; Vadigepalli, Rajanikanth; Schwaber, James S.; Waki, Hidefumi; Murphy, David

2016-01-01

Key points Evidence indicates an association between hypertension and chronic systemic inflammation in both human hypertension and experimental animal models.Previous studies in the spontaneously hypertensive rat (SHR) support a role for leukotriene B4 (LTB4), a potent chemoattractant involved in the inflammatory response, but its mode of action is poorly understood.In the SHR, we observed an increase in T cells and macrophages in the brainstem; in addition, gene expression profiling data showed that LTB4 production, degradation and downstream signalling in the brainstem of the SHR are dynamically regulated during hypertension.When LTB4 receptor 1 (BLT1) receptors were blocked with CP‐105,696, arterial pressure was reduced in the SHR compared to the normotensive control and this reduction was associated with a significant decrease in systolic blood pressure (BP) indicators.These data provide new evidence for the role of LTB4 as an important neuro‐immune pathway in the development of hypertension and therefore may serve as a novel therapeutic target for the treatment of neurogenic hypertension. Abstract Accumulating evidence indicates an association between hypertension and chronic systemic inflammation in both human hypertension and experimental animal models. Previous studies in the spontaneously hypertensive rat (SHR) support a role for leukotriene B4 (LTB4), a potent chemoattractant involved in the inflammatory response. However, the mechanism for LTB4‐mediated inflammation in hypertension is poorly understood. Here we report in the SHR, increased brainstem infiltration of T cells and macrophages plus gene expression profiling data showing that LTB4 production, degradation and downstream signalling in the brainstem of the SHR are dynamically regulated during hypertension. Chronic blockade of the LTB4 receptor 1 (BLT1) receptor with CP‐105,696, reduced arterial pressure in the SHR compared to the normotensive control and this reduction was associated with a significant decrease in low and high frequency spectra of systolic blood pressure, and an increase in spontaneous baroreceptor reflex gain (sBRG). These data provide new evidence for the role of LTB4 as an important neuro‐immune pathway in the development of hypertension and therefore may serve as a novel therapeutic target for the treatment of neurogenic hypertension. PMID:27230966

Sharing, liking, commenting, and distressed? The pathway between Facebook interaction and psychological distress.

PubMed

Chen, Wenhong; Lee, Kye-Hyoung

2013-10-01

Studies on the mental health implications of social media have generated mixed results. Drawing on a survey of college students (N=513), this research uses structural equation modeling to assess the relationship between Facebook interaction and psychological distress and two underlying mechanisms: communication overload and self-esteem. It is the first study, to our knowledge, that examines how communication overload mediates the mental health implications of social media. Frequent Facebook interaction is associated with greater distress directly and indirectly via a two-step pathway that increases communication overload and reduces self-esteem. The research sheds light on new directions for understanding psychological well-being in an increasingly mediated social world as users share, like, and comment more and more.

Pathologic and Therapeutic Implications for the Cell Biology of Parkin

PubMed Central

Charan, Rakshita A.; LaVoie, Matthew J.

2015-01-01

Mutations in the E3 ligase parkin are the most common cause of autosomal recessive Parkinson's disease (PD), but it is believed that parkin dysfunction may also contribute to idiopathic PD. Since its discovery, parkin has been implicated in supporting multiple neuroprotective pathways, many revolving around the maintenance of mitochondrial health quality control and governance of cell survival. Recent advances across the structure, biochemistry, and cell biology of parkin have provided great insights into the etiology of parkin-linked and idiopathic PD and may ultimately generate novel therapeutic strategies to slow or halt disease progression. This review describes the various pathways in which parkin acts and the mechanisms by which parkin may be targeted for therapeutic intervention. PMID:25697646

C/EBPβ and Nuclear Factor of Activated T Cells Differentially Regulate Adamts-1 Induction by Stimuli Associated with Vascular Remodeling

PubMed Central

Oller, Jorge; Alfranca, Arántzazu; Méndez-Barbero, Nerea; Villahoz, Silvia; Lozano-Vidal, Noelia; Martín-Alonso, Mara; Arroyo, Alicia G.; Escolano, Amelia; Armesilla, Angel Luis

2015-01-01

Emerging evidence indicates that the metalloproteinase Adamts-1 plays a significant role in the pathophysiology of vessel remodeling, but little is known about the signaling pathways that control Adamts-1 expression. We show that vascular endothelial growth factor (VEGF), angiotensin-II, interleukin-1β, and tumor necrosis factor α, stimuli implicated in pathological vascular remodeling, increase Adamts-1 expression in endothelial and vascular smooth muscle cells. Analysis of the intracellular signaling pathways implicated in this process revealed that VEGF and angiotensin-II upregulate Adamts-1 expression via activation of differential signaling pathways that ultimately promote functional binding of the NFAT or C/EBPβ transcription factors, respectively, to the Adamts-1 promoter. Infusion of mice with angiotensin-II triggered phosphorylation and nuclear translocation of C/EBPβ proteins in aortic cells concomitantly with an increase in the expression of Adamts-1, further underscoring the importance of C/EBPβ signaling in angiotensin-II-induced upregulation of Adamts-1. Similarly, VEGF promoted NFAT activation and subsequent Adamts-1 induction in aortic wall in a calcineurin-dependent manner. Our results demonstrate that Adamts-1 upregulation by inducers of pathological vascular remodeling is mediated by specific signal transduction pathways involving NFAT or C/EBPβ transcription factors. Targeting of these pathways may prove useful in the treatment of vascular disease. PMID:26217013

Regulation of the Nampt-mediated NAD salvage pathway and its therapeutic implications in pancreatic cancer.

PubMed

Ju, Huai-Qiang; Zhuang, Zhuo-Nan; Li, Hao; Tian, Tian; Lu, Yun-Xin; Fan, Xiao-Qiang; Zhou, Hai-Jun; Mo, Hai-Yu; Sheng, Hui; Chiao, Paul J; Xu, Rui-Hua

2016-08-28

Nicotinamide adenine dinucleotide (NAD) is a crucial cofactor for the redox reactions in the metabolic pathways of cancer cells that have elevated aerobic glycolysis (Warburg effect). Cancer cells are reported to rely on NAD recycling and inhibition of the NAD salvage pathway causes metabolic collapse and cell death. However, the underlying regulatory mechanisms and clinical implications for the NAD salvage pathway in pancreatic ductal adenocarcinoma (PDAC) remain unclear. This study showed that the expression of Nampt, the rate-limiting enzyme of the NAD salvage pathway, was significantly increased in PDAC cells and PDAC tissues. Additionally, inhibition of Nampt impaired tumor growth in vitro and tumorigenesis in vivo, which was accompanied by a decreased cellular NAD level and glycolytic activity. Mechanistically, the Nampt expression was independent of Kras and p16 status, but it was directly regulated by miR-206, which was inversely correlated with the expression of Nampt in PDAC tissues. Importantly, pharmacological inhibition of Nampt by its inhibitor, FK866, significantly enhanced the antitumor activity of gemcitabine in PDAC cells and in orthotopic xenograft mouse models. In conclusion, the present study revealed a novel regulatory mechanism for Nampt in PDAC and suggested that Nampt inhibition may override gemcitabine resistance by decreasing the NAD level and suppressing glycolytic activity, warranting further clinical investigation for pancreatic cancer treatment. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Cell-autonomous inactivation of the Reelin pathway impairs adult neurogenesis in the hippocampus

PubMed Central

Teixeira, Catia M.; Kron, Michelle M.; Masachs, Nuria; Zhang, Helen; Lagace, Diane C.; Martinez, Albert; Reillo, Isabel; Duan, Xin; Bosch, Carles; Pujadas, Lluis; Brunso, Lucas; Song, Hongjun; Eisch, Amelia J.; Borrell, Victor; Howell, Brian W.; Parent, Jack M.; Soriano, Eduardo

2012-01-01

Adult hippocampal neurogenesis is thought to be essential for learning and memory and has been implicated in the pathogenesis of several disorders. Although recent studies have identified key factors regulating neuroprogenitor proliferation in the adult hippocampus, the mechanisms that control the migration and integration of adult-born neurons into circuits are largely unknown. Reelin is an extracellular matrix protein that is vital for neuronal development. Activation of the Reelin cascade leads to phosphorylation of disabled-1 (Dab1), an adaptor protein required for Reelin signaling. Here we used transgenic mouse and retroviral reporters along with Reelin signaling gain- and loss-of-function studies to show that the Reelin pathway regulates migration and dendritic development of adult-generated hippocampal neurons. Whereas overexpression of Reelin accelerated dendritic maturation, inactivation of the Reelin signaling pathway specifically in adult neuroprogenitor cells resulted in aberrant migration, decreased dendrite development, formation of ectopic dendrites in the hilus and the establishment of aberrant circuits. Our findings support a cell-autonomous and critical role for the Reelin pathway in regulating dendritic development and the integration of adult-generated granule cells and point to this pathway as a key regulator of adult neurogenesis. Moreover, our data reveal a novel role of the Reelin cascade in adult brain function with potential implications for the pathogenesis of several neurological and psychiatric disorders. PMID:22933789

The JAK/STAT pathway in obesity and diabetes.

PubMed

Gurzov, Esteban N; Stanley, William J; Pappas, Evan G; Thomas, Helen E; Gough, Daniel J

2016-08-01

Diabetes mellitus are complex, multi-organ metabolic pathologies characterized by hyperglycemia. Emerging evidence shows that the highly conserved and potent JAK/STAT signaling pathway is required for normal homeostasis, and, when dysregulated, contributes to the development of obesity and diabetes. In this review, we analyze the role of JAK/STAT activation in the brain, liver, muscle, fat and pancreas, and how this affects the course of the disease. We also consider the therapeutic implications of targeting the JAK/STAT pathway in treatment of obesity and diabetes. © 2016 Federation of European Biochemical Societies.

Believer-Skeptic Meets Actor-Critic: Rethinking the Role of Basal Ganglia Pathways during Decision-Making and Reinforcement Learning

PubMed Central

Dunovan, Kyle; Verstynen, Timothy

2016-01-01

The flexibility of behavioral control is a testament to the brain's capacity for dynamically resolving uncertainty during goal-directed actions. This ability to select actions and learn from immediate feedback is driven by the dynamics of basal ganglia (BG) pathways. A growing body of empirical evidence conflicts with the traditional view that these pathways act as independent levers for facilitating (i.e., direct pathway) or suppressing (i.e., indirect pathway) motor output, suggesting instead that they engage in a dynamic competition during action decisions that computationally captures action uncertainty. Here we discuss the utility of encoding action uncertainty as a dynamic competition between opposing control pathways and provide evidence that this simple mechanism may have powerful implications for bridging neurocomputational theories of decision making and reinforcement learning. PMID:27047328

Believer-Skeptic Meets Actor-Critic: Rethinking the Role of Basal Ganglia Pathways during Decision-Making and Reinforcement Learning.

PubMed

Dunovan, Kyle; Verstynen, Timothy

2016-01-01

The flexibility of behavioral control is a testament to the brain's capacity for dynamically resolving uncertainty during goal-directed actions. This ability to select actions and learn from immediate feedback is driven by the dynamics of basal ganglia (BG) pathways. A growing body of empirical evidence conflicts with the traditional view that these pathways act as independent levers for facilitating (i.e., direct pathway) or suppressing (i.e., indirect pathway) motor output, suggesting instead that they engage in a dynamic competition during action decisions that computationally captures action uncertainty. Here we discuss the utility of encoding action uncertainty as a dynamic competition between opposing control pathways and provide evidence that this simple mechanism may have powerful implications for bridging neurocomputational theories of decision making and reinforcement learning.

Therapeutic Efficacy of Suppressing the JAK/STAT Pathway in Multiple Models of EAE1

PubMed Central

Liu, Yudong; Holdbrooks, Andrew T.; De Sarno, Patrizia; Rowse, Amber L.; Yanagisawa, Lora L.; McFarland, Braden C.; Harrington, Laurie E.; Raman, Chander; Sabbaj, Steffanie; Benveniste, Etty N.; Qin, Hongwei

2014-01-01

Pathogenic T helper cells and myeloid cells are involved in the pathogenesis of Multiple Sclerosis (MS) and Experimental Autoimmune Encephalomyelitis (EAE), an animal model of MS. The JAK/STAT pathway is utilized by numerous cytokines for signaling, and is critical for development, regulation and termination of immune responses. Dysregulation of the JAK/STAT pathway has pathological implications in autoimmune and neuroinflammatory diseases. Many of the cytokines involved in MS/EAE, including IL-6, IL-12, IL-23, IFN-γ and GM-CSF, use the JAK/STAT pathway to induce biological responses. Thus, targeting JAKs has implications for treating autoimmune inflammation of the brain. We have utilized AZD1480, a JAK1/2 inhibitor, to investigate the therapeutic potential of inhibiting the JAK/STAT pathway in models of EAE. AZD1480 treatment inhibits disease severity in MOG-induced classical and atypical EAE models by preventing entry of immune cells into the brain, suppressing differentiation of Th1 and Th17 cells, deactivating myeloid cells, inhibiting STAT activation in the brain, and reducing expression of pro-inflammatory cytokines and chemokines. Treatment of SJL/J mice with AZD1480 delays disease onset of PLP-induced relapsing-remitting disease, reduces relapses and diminishes clinical severity. AZD1480 treatment was also effective in reducing ongoing paralysis induced by adoptive transfer of either pathogenic Th1 or Th17 cells. In vivo AZD1480 treatment impairs both the priming and expansion of T-cells, and attenuates antigen-presentation functions of myeloid cells. Inhibition of the JAK/STAT pathway has clinical efficacy in multiple pre-clinical models of MS, suggesting the feasibility of the JAK/STAT pathway as a target for neuroinflammatory diseases. PMID:24323580

Defining a Role for Acid Sphingomyelinase in the p38/Interleukin-6 Pathway*

PubMed Central

Perry, David M.; Newcomb, Benjamin; Adada, Mohamad; Wu, Bill X.; Roddy, Patrick; Kitatani, Kazuyuki; Siskind, Leah; Obeid, Lina M.; Hannun, Yusuf A.

2014-01-01

Acid sphingomyelinase (ASM) is one of the key enzymes involved in regulating the metabolism of the bioactive sphingolipid ceramide in the sphingolipid salvage pathway, yet defining signaling pathways by which ASM exerts its effects has proven difficult. Previous literature has implicated sphingolipids in the regulation of cytokines such as interleukin-6 (IL-6), but the specific sphingolipid pathways and mechanisms involved in inflammatory signaling need to be further elucidated. In this work, we sought to define the role of ASM in IL-6 production because our previous work showed that a parallel pathway of ceramide metabolism, acid β-glucosidase 1, negatively regulates IL-6. First, silencing ASM with siRNA abrogated IL-6 production in response to the tumor promoter, 4β-phorbol 12-myristate 13-acetate (PMA), in MCF-7 cells, in distinction to acid β-glucosidase 1 and acid ceramidase, suggesting specialization of the pathways. Moreover, treating cells with siRNA to ASM or with the indirect pharmacologic inhibitor desipramine resulted in significant inhibition of TNFα- and PMA-induced IL-6 production in MDA-MB-231 and HeLa cells. Knockdown of ASM was found to significantly inhibit PMA-dependent IL-6 induction at the mRNA level, probably ruling out mechanisms of translation or secretion of IL-6. Further, ASM knockdown or desipramine blunted p38 MAPK activation in response to TNFα, revealing a key role for ASM in activating p38, a signaling pathway known to regulate IL-6 induction. Last, knockdown of ASM dramatically blunted invasion of HeLa and MDA-MB-231 cells through Matrigel. Taken together, these results demonstrate that ASM plays a critical role in p38 signaling and IL-6 synthesis with implications for tumor pathobiology. PMID:24951586

Comprehensive gene- and pathway-based analysis of depressive symptoms in older adults.

PubMed

Nho, Kwangsik; Ramanan, Vijay K; Horgusluoglu, Emrin; Kim, Sungeun; Inlow, Mark H; Risacher, Shannon L; McDonald, Brenna C; Farlow, Martin R; Foroud, Tatiana M; Gao, Sujuan; Callahan, Christopher M; Hendrie, Hugh C; Niculescu, Alexander B; Saykin, Andrew J

2015-01-01

Depressive symptoms are common in older adults and are particularly prevalent in those with or at elevated risk for dementia. Although the heritability of depression is estimated to be substantial, single nucleotide polymorphism-based genome-wide association studies of depressive symptoms have had limited success. In this study, we performed genome-wide gene- and pathway-based analyses of depressive symptom burden. Study participants included non-Hispanic Caucasian subjects (n = 6,884) from three independent cohorts, the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Health and Retirement Study (HRS), and the Indiana Memory and Aging Study (IMAS). Gene-based meta-analysis identified genome-wide significant associations (ANGPT4 and FAM110A, q-value = 0.026; GRM7-AS3 and LRFN5, q-value = 0.042). Pathway analysis revealed enrichment of association in 105 pathways, including multiple pathways related to ERK/MAPK signaling, GSK3 signaling in bipolar disorder, cell development, and immune activation and inflammation. GRM7, ANGPT4, and LRFN5 have been previously implicated in psychiatric disorders, including the GRM7 region displaying association with major depressive disorder. The ERK/MAPK signaling pathway is a known target of antidepressant drugs and has important roles in neuronal plasticity, and GSK3 signaling has been previously implicated in Alzheimer's disease and as a promising therapeutic target for depression. Our results warrant further investigation in independent and larger cohorts and add to the growing understanding of the genetics and pathobiology of depressive symptoms in aging and neurodegenerative disorders. In particular, the genes and pathways demonstrating association with depressive symptoms may be potential therapeutic targets for these symptoms in older adults.

Evolution of Retinoid and Steroid Signaling: Vertebrate Diversification from an Amphioxus Perspective

PubMed Central

Albalat, Ricard; Brunet, Frédéric; Laudet, Vincent; Schubert, Michael

2011-01-01

Although the physiological relevance of retinoids and steroids in vertebrates is very well established, the origin and evolution of the genetic machineries implicated in their metabolic pathways is still very poorly understood. We investigated the evolution of these genetic networks by conducting an exhaustive survey of components of the retinoid and steroid pathways in the genome of the invertebrate chordate amphioxus (Branchiostoma floridae). Due to its phylogenetic position at the base of chordates, amphioxus is a very useful model to identify and study chordate versus vertebrate innovations, both on a morphological and a genomic level. We have characterized more than 220 amphioxus genes evolutionarily related to vertebrate components of the retinoid and steroid pathways and found that, globally, amphioxus has orthologs of most of the vertebrate components of these two pathways, with some very important exceptions. For example, we failed to identify a vertebrate-like machinery for retinoid storage, transport, and delivery in amphioxus and were also unable to characterize components of the adrenal steroid pathway in this invertebrate chordate. The absence of these genes from the amphioxus genome suggests that both an elaboration and a refinement of the retinoid and steroid pathways took place at the base of the vertebrate lineage. In stark contrast, we also identified massive amplifications in some amphioxus gene families, most extensively in the short-chain dehydrogenase/reductase superfamily, which, based on phylogenetic and genomic linkage analyses, were likely the result of duplications specific to the amphioxus lineage. In sum, this detailed characterization of genes implicated in retinoid and steroid signaling in amphioxus allows us not only to reconstruct an outline of these pathways in the ancestral chordate but also to discuss functional innovations in retinoid homeostasis and steroid-dependent regulation in both cephalochordate and vertebrate evolution. PMID:21856648

Neurophysiology and itch pathways.

PubMed

Schmelz, Martin

2015-01-01

As we all can easily differentiate the sensations of itch and pain, the most straightforward neurophysiologic concept would consist of two specific pathways that independently encode itch and pain. Indeed, a neuronal pathway for histamine-induced itch in the peripheral and central nervous system has been described in animals and humans, and recently several non-histaminergic pathways for itch have been discovered in rodents that support a dichotomous concept differentiated into a pain and an itch pathway, with both pathways being composed of different "flavors." Numerous markers and mediators have been found that are linked to itch processing pathways. Thus, the delineation of neuronal pathways for itch from pain pathways seemingly proves that all sensory aspects of itch are based on an itch-specific neuronal pathway. However, such a concept is incomplete as itch can also be induced by the activation of the pain pathway in particular when the stimulus is applied in a highly localized spatial pattern. These opposite views reflect the old dispute between specificity and pattern theories of itch. Rather than only being of theoretic interest, this conceptual problem has key implication for the strategy to treat chronic itch as key therapeutic targets would be either itch-specific pathways or unspecific nociceptive pathways.

The Implications of Temperature-Mediated Plasticity in Larval Instar Number for Development within a Marine Invertebrate, the Shrimp Palaemonetes varians

PubMed Central

Oliphant, Andrew; Hauton, Chris; Thatje, Sven

2013-01-01

Variations in larval instar number are common among arthropods. Here, we assess the implications of temperature-mediated variations in larval instar number for larval development time, larval growth rates, and juvenile dry weight within the palaemonid shrimp, Palaemonetes varians. In contrast with previous literature, which focuses on terrestrial arthropods, particularly model and pest species often of laboratory lines, we use wild shrimp, which differ in their life history from previous models. Newly-hatched P. varians larvae were first reared at 5, 10, 17, 25, and 30°C to assess their thermal scope for development. Larvae developed at 17, 25, and 30°C. At higher temperatures, larvae developed through fewer larval instars. Two dominant developmental pathways were observed; a short pathway of four instars and a long pathway of five instars. Longer developmental pathways of six to seven instars were rarely observed (mostly at lower temperatures) and consisted of additional instars as ‘repeat’ instars; i.e. little developmental advance over the preceding instar. To assess the implications of temperature-mediated variation in larval instar number, newly-hatched larvae were then reared at 15, 20, and 25°C. Again, the proportion of larvae developing through four instars increased with temperature. At all temperatures, larval development time and juvenile dry weight were greater for larvae developing through five instars. Importantly, because of the increasing proportion of larvae developing through four instars with increasing temperature, larval traits associated with this pathway (reduced development time and juvenile dry weight) became more dominant. As a consequence of increasing growth rate with temperature, and the shift in the proportion of larvae developing through four instars, juvenile dry weight was greatest at intermediate temperatures (20°C). We conclude that at settlement P. varians juveniles do not follow the temperature-size rule; this is of importance for life-history ecology in response to environmental change, as well as for aquaculture applications. PMID:24069450

The implications of temperature-mediated plasticity in larval instar number for development within a marine invertebrate, the shrimp Palaemonetes varians.

PubMed

Oliphant, Andrew; Hauton, Chris; Thatje, Sven

2013-01-01

Variations in larval instar number are common among arthropods. Here, we assess the implications of temperature-mediated variations in larval instar number for larval development time, larval growth rates, and juvenile dry weight within the palaemonid shrimp, Palaemonetes varians. In contrast with previous literature, which focuses on terrestrial arthropods, particularly model and pest species often of laboratory lines, we use wild shrimp, which differ in their life history from previous models. Newly-hatched P. varians larvae were first reared at 5, 10, 17, 25, and 30 °C to assess their thermal scope for development. Larvae developed at 17, 25, and 30 °C. At higher temperatures, larvae developed through fewer larval instars. Two dominant developmental pathways were observed; a short pathway of four instars and a long pathway of five instars. Longer developmental pathways of six to seven instars were rarely observed (mostly at lower temperatures) and consisted of additional instars as 'repeat' instars; i.e. little developmental advance over the preceding instar. To assess the implications of temperature-mediated variation in larval instar number, newly-hatched larvae were then reared at 15, 20, and 25 °C. Again, the proportion of larvae developing through four instars increased with temperature. At all temperatures, larval development time and juvenile dry weight were greater for larvae developing through five instars. Importantly, because of the increasing proportion of larvae developing through four instars with increasing temperature, larval traits associated with this pathway (reduced development time and juvenile dry weight) became more dominant. As a consequence of increasing growth rate with temperature, and the shift in the proportion of larvae developing through four instars, juvenile dry weight was greatest at intermediate temperatures (20 °C). We conclude that at settlement P. varians juveniles do not follow the temperature-size rule; this is of importance for life-history ecology in response to environmental change, as well as for aquaculture applications.

Pathway-Specific Striatal Substrates for Habitual Behavior.

PubMed

O'Hare, Justin K; Ade, Kristen K; Sukharnikova, Tatyana; Van Hooser, Stephen D; Palmeri, Mark L; Yin, Henry H; Calakos, Nicole

2016-02-03

The dorsolateral striatum (DLS) is implicated in habit formation. However, the DLS circuit mechanisms underlying habit remain unclear. A key role for DLS is to transform sensorimotor cortical input into firing of output neurons that project to the mutually antagonistic direct and indirect basal ganglia pathways. Here we examine whether habit alters this input-output function. By imaging cortically evoked firing in large populations of pathway-defined striatal projection neurons (SPNs), we identify features that strongly correlate with habitual behavior on a subject-by-subject basis. Habitual behavior correlated with strengthened DLS output to both pathways as well as a tendency for action-promoting direct pathway SPNs to fire before indirect pathway SPNs. In contrast, habit suppression correlated solely with a weakened direct pathway output. Surprisingly, all effects were broadly distributed in space. Together, these findings indicate that the striatum imposes broad, pathway-specific modulations of incoming activity to render learned motor behaviors habitual. Copyright © 2016 Elsevier Inc. All rights reserved.

Molecular Pathways: Translational and Therapeutic Implications of the Notch Signaling Pathway in Cancer

PubMed Central

Previs, Rebecca A.; Coleman, Robert L.; Harris, Adrian L.; Sood, Anil K.

2014-01-01

Over 100 years have passed since the first observation of the notched wing phenotype in Drosophila melanogaster, and significant progress has been made to characterize the role of the Notch receptor, its ligands, downstream targets, and crosstalk with other signaling pathways. The canonical Notch pathway with four Notch receptors (Notch1-4) and five ligands (DLL1, 3–4, Jagged 1–2) is an evolutionarily conserved cell signaling pathway that plays critical roles in cell-fate determination, differentiation, development, tissue patterning, cell proliferation, and death. In cancer, these roles have a critical impact on tumor behavior and response to therapy. Since the role of Notch remains tissue and context dependent, alterations within this pathway may lead to tumor suppressive or oncogenic phenotypes. Although no FDA approved therapies currently exist for the Notch pathway, multiple therapeutics (e.g., demcizumab, tarextumab, GSI MK0752, R04929097, and PF63084014) have been developed to target different aspects of this pathway for both hematologic and solid malignancies. Understanding the context-specific effects of the Notch pathway will be important for individualized therapies targeting this pathway. PMID:25388163

Regulation of sympathetic nervous system function after cardiovascular deconditioning

NASA Technical Reports Server (NTRS)

Hasser, E. M.; Moffitt, J. A.

2001-01-01

Humans subjected to prolonged periods of bed rest or microgravity undergo deconditioning of the cardiovascular system, characterized by resting tachycardia, reduced exercise capability, and a predisposition for orthostatic intolerance. These changes in cardiovascular function are likely due to a combination of factors, including changes in control of body fluid balance or cardiac alterations resulting in inadequate maintenance of stroke volume, altered arterial or venous vascular function, reduced activation of cardiovascular hormones, and diminished autonomic reflex function. There is evidence indicating a role for each of these mechanisms. Diminished reflex activation of the sympathetic nervous system and subsequent vasoconstriction appear to play an important role. Studies utilizing the hindlimb-unloaded (HU) rat, an animal model of deconditioning, evaluated the potential role of altered arterial baroreflex control of the sympathetic nervous system. These studies indicate that HU results in blunted baroreflex-mediated activation of both renal and lumbar sympathetic nerve activity in response to a hypotensive stimulus. HU rats are less able to maintain arterial pressure during hemorrhage, suggesting that diminished ability to increase sympathetic activity has functional consequences for the animal. Reflex control of vasopressin secretion appears to be enhanced following HU. Blunted baroreflex-mediated sympathoexcitation appears to involve altered central nervous system function. Baroreceptor afferent activity in response to changes in arterial pressure is unaltered in HU rats. However, increases in efferent sympathetic nerve activity for a given decrease in afferent input are blunted after HU. This altered central nervous system processing of baroreceptor inputs appears to involve an effect at the rostral ventrolateral medulla (RVLM). Specifically, it appears that tonic GABAA-mediated inhibition of the RVLM is enhanced after HU. Augmented inhibition apparently arises from sources other than the caudal ventrolateral medulla. If similar alterations in control of the sympathetic nervous system occur in humans in response to cardiovascular deconditioning, it is likely that they play an important role in the observed tendency for orthostatic intolerance. Combined with potential changes in vascular function, cardiac function, and hypovolemia, the predisposition for orthostatic intolerance following cardiovascular deconditioning would be markedly enhanced by blunted ability to reflexly activate the sympathetic nervous system.

α-Adrenergic effects on low-frequency oscillations in blood pressure and R-R intervals during sympathetic activation.

PubMed

Kiviniemi, Antti M; Frances, Maria F; Tiinanen, Suvi; Craen, Rosemary; Rachinsky, Maxim; Petrella, Robert J; Seppänen, Tapio; Huikuri, Heikki V; Tulppo, Mikko P; Shoemaker, J Kevin

2011-08-01

The present study was designed to address the contribution of α-adrenergic modulation to the genesis of low-frequency (LF; 0.04-0.15 Hz) oscillations in R-R interval (RRi), blood pressure (BP) and muscle sympathetic nerve activity (MSNA) during different sympathetic stimuli. Blood pressure and RRi were measured continuously in 12 healthy subjects during 5 min periods each of lower body negative pressure (LBNP; -40 mmHg), static handgrip exercise (HG; 20% of maximal force) and postexercise forearm circulatory occlusion (PECO) with and without α-adrenergic blockade by phentolamine. Muscle sympathetic nerve activity was recorded in five subjects during LBNP and in six subjects during HG and PECO. Low-frequency powers and median frequencies of BP, RRi and MSNA were calculated from power spectra. Low-frequency power during LBNP was lower with phentolamine versus without for both BP and RRi oscillations (1.6 ± 0.6 versus 1.2 ± 0.7 ln mmHg(2), P = 0.049; and 6.9 ± 0.8 versus 5.4 ± 0.9 ln ms(2), P = 0.001, respectively). In contrast, the LBNP with phentolamine increased the power of high-frequency oscillations (0.15-0.4 Hz) in BP and MSNA (P < 0.01 for both), which was not observed during saline infusion. Phentolamine also blunted the increases in the LBNP-induced increase in frequency of LF oscillations in BP and RRi. Phentolamine decreased the LF power of RRi during HG (P = 0.015) but induced no other changes in LF powers or frequencies during HG. Phentolamine resulted in decreased frequency of LF oscillations in RRi (P = 0.004) during PECO, and a similar tendency was observed in BP and MSNA. The power of LF oscillation in MSNA did not change during any intervention. We conclude that α-adrenergic modulation contributes to LF oscillations in BP and RRi during baroreceptor unloading (LBNP) but not during static exercise. Also, α-adrenergic modulation partly explains the shift to a higher frequency of LF oscillations during baroreceptor unloading and muscle metaboreflex activation.

Responses of aortic depressor nerve-evoked neurones in rat nucleus of the solitary tract to changes in blood pressure

PubMed Central

Zhang, Jing; Mifflin, Steven W

2000-01-01

Using electrophysiological techniques, the discharge of neurones in the nucleus of the solitary tract (NTS) receiving aortic depressor nerve (ADN) inputs was examined during blood pressure changes induced by I.V. phenylephrine or nitroprusside in anaesthetized, paralysed and artificially ventilated rats. Various changes in discharge rate were observed during phenylephrine-induced blood pressure elevations: an increase (n = 38), a decrease (n = 5), an increase followed by a decrease (n = 4) and no response (n = 11). In cells receiving a monosynaptic ADN input (MSNs), the peak discharge frequency response was correlated to the rate of increase in mean arterial pressure (P < 0.01) but was not correlated to the absolute increase in blood pressure. The peak discharge frequency response of cells receiving a polysynaptic ADN input (PSNs) was correlated to neither the absolute increase in blood pressure nor the rate of increase in mean arterial pressure. Diverse changes in discharge rate were observed during nitroprusside-induced reductions in blood pressure: an increase (n = 3), a decrease (n = 10), an increase followed by a decrease (n = 3) and no response (n = 6). Reductions in pressure of 64 ± 2 mmHg produced weak reductions in spontaneous discharge of 1.3 ± 0.9 Hz and only totally abolished spontaneous discharge in one neurone. These response patterns of NTS neurones during changes in arterial pressure suggest that baroreceptor inputs are integrated differently in MSNs compared to PSNs. The sensitivity of MSNs to the rate of change of pressure provides a mechanism for the rapid regulation of cardiovascular function. The lack of sensitivity to the mean level of a pressure increase in both MSNs and PSNs suggests that steady-state changes in pressure are encoded by the number of active neurones and not graded changes in the discharge of individual neurones. Both MSNs and PSNs receive tonic excitatory inputs from the arterial baroreceptors; however, these tonic inputs appear to be insufficient to totally account for their spontaneous discharge. PMID:11101652

Non-clinical and Pre-clinical Testing to Demonstrate Safety of the Barostim Neo Electrode for Activation of Carotid Baroreceptors in Chronic Human Implants

PubMed Central

Wilks, Seth J.; Hara, Seth A.; Ross, Erika K.; Nicolai, Evan N.; Pignato, Paul A.; Cates, Adam W.; Ludwig, Kip A.

2017-01-01

The Barostim neo™ electrode was developed by CVRx, Inc.to deliver baroreflex activation therapy (BAT)™ to treat hypertension and heart failure. The neo electrode concept was designed to deliver electrical stimulation to the baroreceptors within the carotid sinus bulb, while minimizing invasiveness of the implant procedure. This device is currently CE marked in Europe, and in a Pivotal (akin to Phase III) Trial in the United States. Here we present the in vitro and in vivo safety testing that was completed in order to obtain necessary regulatory approval prior to conducting human studies in Europe, as well as an FDA Investigational Device Exemption (IDE) to conduct a Pivotal Trial in the United States. Stimulated electrodes (10 mA, 500 μs, 100 Hz) were compared to unstimulated electrodes using optical microscopy and several electrochemical techniques over the course of 27 weeks. Electrode dissolution was evaluated by analyzing trace metal content of solutions in which electrodes were stimulated. Lastly, safety testing under Good Laboratory Practice guidelines was conducted in an ovine animal model over a 12 and 24 week time period, with results processed and evaluated by an independent histopathologist. Long-term stimulation testing indicated that the neo electrode with a sputtered iridium oxide coating can be stimulated at maximal levels for the lifetime of the implant without clinically significant dissolution of platinum or iridium, and without increasing the potential at the electrode interface to cause hydrolysis or significant tissue damage. Histological examination of tissue that was adjacent to the neo electrodes indicated no clinically significant signs of increased inflammation and no arterial stenosis as a result of 6 months of continuous stimulation. The work presented here involved rigorous characterization and evaluation testing of the neo electrode, which was used to support its safety for chronic implantation. The testing strategies discussed provide a starting point and proven framework for testing new neuromodulation electrode concepts to support regulatory approval for clinical studies. PMID:28824361

Assessing the relevance of light for fungi: Implications and insights into the network of signal transmission.

PubMed

Schmoll, Monika

2011-01-01

Light represents an important environmental cue, which provides information enabling fungi to prepare and react to the different ambient conditions between day and night. This adaptation requires both anticipation of the changing conditions, which is accomplished by daily rhythmicity of gene expression brought about by the circadian clock, and reaction to sudden illumination. Besides perception of the light signal, also integration of this signal with other environmental cues, most importantly nutrient availability, necessitates light-dependent regulation of signal transduction pathways and metabolic pathways. An influence of light and/or the circadian clock is known for the cAMP pathway, heterotrimeric G-protein signaling, mitogen-activated protein kinases, two-component phosphorelays, and Ca(2+) signaling. Moreover, also the target of rapamycin signaling pathway and reactive oxygen species as signal transducing elements are assumed to be connected to the light-response pathway. The interplay of the light-response pathway with signaling cascades results in light-dependent regulation of primary and secondary metabolism, morphology, development, biocontrol activity, and virulence. The frequent use of fungi in biotechnology as well as analysis of fungi in the artificial environment of a laboratory therefore requires careful consideration of still operative evolutionary heritage of these organisms. This review summarizes the diverse effects of light on fungi and the mechanisms they apply to deal both with the information content and with the harmful properties of light. Additionally, the implications of the reaction of fungi to light in a laboratory environment for experimental work and industrial applications are discussed. Copyright © 2011 Elsevier Inc. All rights reserved.

Genetic Susceptibility to Head and Neck Squamous Cell Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lacko, Martin; Braakhuis, Boudewijn J.M.; Sturgis, Erich M.

2014-05-01

Head-and-neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and its incidence is growing. Although environmental carcinogens and carcinogenic viruses are the main etiologic factors, genetic predisposition obviously plays a risk-modulating role, given that not all individuals exposed to these carcinogens experience the disease. This review highlights some aspects of genetic susceptibility to HNSCC: among others, genetic polymorphisms in biotransformation enzymes, DNA repair pathway, apoptotic pathway, human papillomavirus-related pathways, mitochondrial polymorphisms, and polymorphism related to the bilirubin-metabolized pathway. Furthermore, epigenetic variations, familial forms of HNSCC, functional assays for HNSCC risk assessment, and the implications and perspectives ofmore » research on genetic susceptibility in HNSCC are discussed.« less

The Hippo Pathway: Immunity and Cancer

PubMed Central

J. Janse van Rensburg, Helena

2018-01-01

Since its discovery, the Hippo pathway has emerged as a central signaling network in mammalian cells. Canonical signaling through the Hippo pathway core components (MST1/2, LATS1/2, YAP and TAZ) is important for development and tissue homeostasis while aberrant signaling through the Hippo pathway has been implicated in multiple pathologies, including cancer. Recent studies have uncovered new roles for the Hippo pathway in immunology. In this review, we summarize the mechanisms by which Hippo signaling in pathogen-infected or neoplastic cells affects the activities of immune cells that respond to these threats. We further discuss how Hippo signaling functions as part of an immune response. Finally, we review how immune cell-intrinsic Hippo signaling modulates the development/function of leukocytes and propose directions for future work. PMID:29597279

Cell Signaling Pathways that Regulate Ag Presentation

PubMed Central

Brutkiewicz, Randy R.

2016-01-01

Cell signaling pathways regulate much in the life of a cell: from shuttling cargo through intracellular compartments and onto the cell surface, how it should respond to stress, protecting itself from harm (environmental insults or infections), to ultimately, death by apoptosis. These signaling pathways are important for various aspects of the immune response as well. However, not much is known in terms of the participation of cell signaling pathways in Ag presentation--a necessary first step in the activation of innate and adaptive T cells. In this brief review, I will discuss the known signaling molecules (and pathways) that regulate how Ags are presented to T cells and the mechanism(s) if identified. Studies in this area have important implications in vaccine development and new treatment paradigms against infectious diseases, autoimmunity and cancer. PMID:27824592

Frontier of Epilepsy Research - mTOR signaling pathway

PubMed Central

2011-01-01

Studies of epilepsy have mainly focused on the membrane proteins that control neuronal excitability. Recently, attention has been shifting to intracellular proteins and their interactions, signaling cascades and feedback regulation as they relate to epilepsy. The mTOR (mammalian target of rapamycin) signal transduction pathway, especially, has been suggested to play an important role in this regard. These pathways are involved in major physiological processes as well as in numerous pathological conditions. Here, involvement of the mTOR pathway in epilepsy will be reviewed by presenting; an overview of the pathway, a brief description of key signaling molecules, a summary of independent reports and possible implications of abnormalities of those molecules in epilepsy, a discussion of the lack of experimental data, and questions raised for the understanding its epileptogenic mechanism. PMID:21467839

Estradiol regulates the insulin-like growth factor-I (IGF-I) signalling pathway: A crucial role of phosphatidylinositol 3-kinase (PI 3-kinase) in estrogens requirement for growth of MCF-7 human breast carcinoma cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bernard, Laurence; Legay, Christine; Adriaenssens, Eric

2006-12-01

Estrogens can stimulate the proliferation of estrogen-responsive breast cancer cells by increasing their proliferative response to insulin-like growth factors. With a view to investigating the molecular mechanisms implicated, we studied the effect of estradiol on the expression of proteins implicated in the insulin-like growth factor signalling pathway. Estradiol dose- and time-dependently increased the expression of insulin receptor substrate-1 and the p85/p110 subunits of phosphatidylinositol 3-kinase but did not change those of ERK2 and Akt/PKB. ICI 182,780 did not inhibit estradiol-induced IRS-1 and p85 expression. Moreover, two distinct estradiol-BSA conjugate compounds were as effective as estradiol in inducing IRS-1 and p85/p110more » expression indicating the possible implication of an estradiol membrane receptor. Comparative analysis of steroids-depleted and steroids-treated cells showed that IGF-I only stimulates cell growth in the latter condition. Nevertheless, expression of a constitutively active form of PI 3-kinase in steroid-depleted cells triggers proliferation. These results demonstrate that estradiol positively regulates essential proteins of the IGF signalling pathway and put in evidence that phosphatidylinositol 3-kinase plays a central role in the synergistic pro-proliferative action of estradiol and IGF-I.« less

Gastrointestinal disorders associated with migraine: A comprehensive review

PubMed Central

Cámara-Lemarroy, Carlos R; Rodriguez-Gutierrez, Rene; Monreal-Robles, Roberto; Marfil-Rivera, Alejandro

2016-01-01

Migraine is a recurrent and commonly disabling primary headache disorder that affects over 17% of women and 5%-8% of men. Migraine susceptibility is multifactorial with genetic, hormonal and environmental factors all playing an important role. The physiopathology of migraine is complex and still not fully understood. Many different neuropeptides, neurotransmitters and brain pathways have been implicated. In connection with the myriad mechanisms and pathways implicated in migraine, a variety of multisystemic comorbidities (e.g., cardiovascular, psychiatric and other neurological conditions) have been found to be closely associated with migraine. Recent reports demonstrate an increased frequency of gastrointestinal (GI) disorders in patients with migraine compared with the general population. Helicobacter pylori infection, irritable bowel syndrome, gastroparesis, hepatobiliary disorders, celiac disease and alterations in the microbiota have been linked to the occurrence of migraine. Several mechanisms involving the gut-brain axis, such as a chronic inflammatory response with inflammatory and vasoactive mediators passing to the circulatory system, intestinal microbiota modulation of the enteric immunological milieu and dysfunction of the autonomic and enteric nervous system, have been postulated to explain these associations. However, the precise mechanisms and pathways related to the gut-brain axis in migraine need to be fully elucidated. In this review, we survey the available literature linking migraine with GI disorders. We discuss the possible physiopathological mechanisms, and clinical implications as well as several future areas of interest for research. PMID:27688656

Gastrointestinal disorders associated with migraine: A comprehensive review.

PubMed

Cámara-Lemarroy, Carlos R; Rodriguez-Gutierrez, Rene; Monreal-Robles, Roberto; Marfil-Rivera, Alejandro

2016-09-28

Migraine is a recurrent and commonly disabling primary headache disorder that affects over 17% of women and 5%-8% of men. Migraine susceptibility is multifactorial with genetic, hormonal and environmental factors all playing an important role. The physiopathology of migraine is complex and still not fully understood. Many different neuropeptides, neurotransmitters and brain pathways have been implicated. In connection with the myriad mechanisms and pathways implicated in migraine, a variety of multisystemic comorbidities (e.g., cardiovascular, psychiatric and other neurological conditions) have been found to be closely associated with migraine. Recent reports demonstrate an increased frequency of gastrointestinal (GI) disorders in patients with migraine compared with the general population. Helicobacter pylori infection, irritable bowel syndrome, gastroparesis, hepatobiliary disorders, celiac disease and alterations in the microbiota have been linked to the occurrence of migraine. Several mechanisms involving the gut-brain axis, such as a chronic inflammatory response with inflammatory and vasoactive mediators passing to the circulatory system, intestinal microbiota modulation of the enteric immunological milieu and dysfunction of the autonomic and enteric nervous system, have been postulated to explain these associations. However, the precise mechanisms and pathways related to the gut-brain axis in migraine need to be fully elucidated. In this review, we survey the available literature linking migraine with GI disorders. We discuss the possible physiopathological mechanisms, and clinical implications as well as several future areas of interest for research.

Pathways to Firesetting for Mentally Disordered Offenders: A Preliminary Examination.

PubMed

Tyler, Nichola; Gannon, Theresa A

2017-06-01

The current study aimed to investigate the specific pathways in the offence process for mentally disordered firesetters. In a previous study, an offence chain model was constructed (i.e., the Firesetting Offence Chain for Mentally Disordered Offenders, FOC-MD) using offence descriptions obtained from 23 mentally disordered firesetters, detailing the sequence of contextual, behavioural, affective, and cognitive factors that precipitate an incidence of firesetting for this population. The current study examines the prevalence of the specific pathways to firesetting for the original 23 mentally disordered firesetters and a further sample of 13 mentally disordered firesetters. Three distinct pathways to firesetting are identified within the FOC-MD: fire interest-childhood mental health, no fire interest-adult mental health, fire interest-adult mental health. In this article, we describe these three pathways in detail using illustrative case studies. The practice implications of these identified pathways are also discussed.

Targeting the Interleukin-6/Jak/Stat Pathway in Human Malignancies

PubMed Central

Sansone, Pasquale; Bromberg, Jacqueline

2012-01-01

The Janus kinase/signal transducer and activator of transcription (Jak/Stat) pathway was discovered 20 years ago as a mediator of cytokine signaling. Since this time, more than 2,500 articles have been published demonstrating the importance of this pathway in virtually all malignancies. Although there are dozens of cytokines and cytokine receptors, four Jaks, and seven Stats, it seems that interleukin-6–mediated activation of Stat3 is a principal pathway implicated in promoting tumorigenesis. This transcription factor regulates the expression of numerous critical mediators of tumor formation and metastatic progression. This review will examine the relative importance and function of this pathway in nonmalignant conditions as well as malignancies (including tumor intrinsic and extrinsic), the influence of other Stats, the development of inhibitors to this pathway, and the potential role of inhibitors in controlling or eradicating cancers. PMID:22355058

Overlapping 16p13.11 deletion and gain of copies variations associated with childhood onset psychosis include genes with mechanistic implications for autism associated pathways: Two case reports.

PubMed

Brownstein, Catherine A; Kleiman, Robin J; Engle, Elizabeth C; Towne, Meghan C; D'Angelo, Eugene J; Yu, Timothy W; Beggs, Alan H; Picker, Jonathan; Fogler, Jason M; Carroll, Devon; Schmitt, Rachel C O; Wolff, Robert R; Shen, Yiping; Lip, Va; Bilguvar, Kaya; Kim, April; Tembulkar, Sahil; O'Donnell, Kyle; Gonzalez-Heydrich, Joseph

2016-05-01

Copy number variability at 16p13.11 has been associated with intellectual disability, autism, schizophrenia, epilepsy, and attention-deficit hyperactivity disorder. Adolescent/adult- onset psychosis has been reported in a subset of these cases. Here, we report on two children with CNVs in 16p13.11 that developed psychosis before the age of 7. The genotype and neuropsychiatric abnormalities of these patients highlight several overlapping genes that have possible mechanistic relevance to pathways previously implicated in Autism Spectrum Disorders, including the mTOR signaling and the ubiquitin-proteasome cascades. A careful screening of the 16p13.11 region is warranted in patients with childhood onset psychosis. © 2016 Wiley Periodicals, Inc.

Overlapping 16p13.11 Deletion and Gain of Copies Variations Associated with Childhood Onset Psychosis Include Genes with Mechanistic Implications for Autism Associated Pathways: Two Case Reports

PubMed Central

Brownstein, Catherine A.; Kleiman, Robin J.; Engle, Elizabeth C.; Towne, Meghan C.; D’Angelo, Eugene J.; Yu, Timothy W.; Beggs, Alan H.; Picker, Jonathan; Fogler, Jason M.; Carroll, Devon; Schmitt, Rachel C. O.; Wolff, Robert R.; Shen, Yiping; Lip, Va; Bilguvar, Kaya; Kim, April; Tembulkar, Sahil; O’Donnell, Kyle; Gonzalez-Heydrich, Joseph

2016-01-01

Copy number variability at 16p13.11 has been associated with intellectual disability, autism, schizophrenia, epilepsy and attention-deficit hyperactivity disorder. Adolescent/adult- onset psychosis has been reported in a subset of these cases. Here, we report on two children with CNVs in 16p13.11 that developed psychosis before the age of 7. The genotype and neuropsychiatric abnormalities of these patients highlight several overlapping genes that have possible mechanistic relevance to pathways previously implicated in Autism Spectrum Disorders, including the mTOR signaling and the ubiquitin-proteasome cascades. A careful screening of the 16p13.11 region is warranted in patients with childhood onset psychosis. PMID:26887912

Vitamin D and its effects on cardiovascular diseases: a comprehensive review.

PubMed

Pérez-Hernández, Nonanzit; Aptilon-Duque, Gad; Nostroza-Hernández, María Cristina; Vargas-Alarcón, Gilberto; Rodríguez-Pérez, José Manuel; Blachman-Braun, Ruben

2016-11-01

Vitamin D is a molecule that is actively involved in multiple metabolic pathways. It is mostly known for its implications related to calcium metabolism. It has also been determined that it actively participates in the cardiovascular system, influencing blood pressure, coronary artery disease and other vascular diseases, such as heart failure and atrial fibrillation. Furthermore, it has been established that this vitamin is extensively involved in the regulation of both the renin angiotensin aldosterone system and the immune system. In this review, we present the different vitamin D metabolic pathways associated with the cardiovascular pathophysiology, and we include studies in animal and human models, as well as some of the controversies found in the literature. This review also incorporates an overview of the implications in the molecular biology and public health fields.

Sequencing the head and neck cancer genome: implications for therapy

PubMed Central

Sun, Wenyue; Califano, Joseph A.

2015-01-01

Head and neck squamous cell carcinoma (HNSCC) is a disease with significant morbidity and mortality. The advancement of next-generation sequencing technologies now enables the landscape of genetic alterations in HNSCCs to be deciphered. In this review, we describe the mutation spectrum discovered in HNSCCs, especially human papilloma virus (HPV)- and/or tobacco smoke exposure–associated HNSCCs. We also describe related research from two independent investigators and from the Cancer Genome Atlas (TCGA). Emphasis is placed on the therapeutic implications of genes frequently altered in HNSCCs (i.e., TP53, PIK3CA, and NOTCH1) and their corresponding pathways, with a particular focus on recent findings of NOTCH pathway activation in HNSCC. We also discuss the application of integrated genomic pathway–based analysis for precision cancer therapy in HNSCC. PMID:25440877

Mechanisms to Control Rereplication and Implications for Cancer

PubMed Central

Hook, Sara S.; Lin, Jie Jessie; Dutta, Anindya

2007-01-01

Recent advances in the replication field have highlighted how the replication initiator proteins are negatively regulated by inhibitor proteins and ubiquitin-mediated degradation in mammalian cells to prevent rereplication. When these regulatory pathways go awry, uncontrolled rereplication ensues and a G2/M checkpoint is evoked to prevent cellular death. Many components of the checkpoints activated by rereplicaton are important for cancer prevention by facilitating DNA damage repair processes. The pathways that prevent rereplication themselves have also recently been implicated in preventing tumorigenesis. Studies from patient tumors, genetically altered mice, and mammalian cell culture suggest that deregulation of replication licensing proteins results in an increase in aneuploidy, chromosomal fusions, and DNA breaks. These studies provide a framework to address how regulators of replication function to maintain genomic stability. PMID:18053699

Programs of Study as a State Policy Mandate: A Longitudinal Study of the South Carolina Personal Pathways to Success Initiative. Final Technical Report: Major Findings and Implications

ERIC Educational Resources Information Center

Hammond, Cathy; Drew, Sam F.; Withington, Cairen; Griffith, Cathy; Swiger, Caroline M.; Mobley, Catherine; Sharp, Julia L.; Stringfield, Samuel C.; Stipanovic, Natalie; Daugherty, Lindsay

2013-01-01

This is the final technical report from the National Research Center for Career and Technical Education's (NRCCTE's) five-year longitudinal study of South Carolina's Personal Pathway to Success initiative, which was authorized by the state's Education and Economic Development Act (EEDA) in 2005. NRCCTE-affiliated researchers at the National…

The dark side of hippo signaling: A cancer promoter role.

PubMed

Dunn, Brandon; Ma, Xianjue

2017-10-02

The Hippo signaling pathway regulates organ size and tissue homeostasis. Given this role it is unsurprising that dysregulation of this pathway has implications for cancer progression. A convincing body of literature shows that the Hippo pathway serves a tumor suppressive function with its inactivation leading to massive overgrowth. However, additional studies have also shown that activation of Hippo signaling can promote tumor progression. It remains unknown how a single pathway can produce such diametrically opposed effects. This lack of knowledge is in part due to our inability to make meaningful comparisons from studies which have taken place in a variety of cell types, tissues, and organisms. Recently however, we have published 2 studies using the Drosophila wing disk to study the Hippo pathway and have found that Hippo pathway activation can promote cell migration and invasion while Hippo pathway inactivation leads to overgrowth. Thus we propose here that Drosophila can provide a research platform with which to begin addressing how the Hippo pathway can both enhance and suppress tumor progression due to published pro- and anti-tumor functionalities of the Hippo pathway in the same tissue.

Pro-Inflammatory and Pro-Oxidant Status of Pancreatic Islet In Vitro Is Controlled by TLR-4 and HO-1 Pathways

PubMed Central

Vivot, Kevin; Langlois, Allan; Bietiger, William; Dal, Stéphanie; Seyfritz, Elodie; Pinget, Michel; Jeandidier, Nathalie; Maillard, Elisa; Gies, Jean-Pierre; Sigrist, Séverine

2014-01-01

Since their isolation until implantation, pancreatic islets suffer a major stress leading to the activation of inflammatory reactions. The maintenance of controlled inflammation is essential to preserve survival and function of the graft. Identification and targeting of pathway(s) implicated in post-transplant detrimental inflammatory events, is mandatory to improve islet transplantation success. We sought to characterize the expression of the pro-inflammatory and pro-oxidant mediators during islet culture with a focus on Heme oxygenase (HO-1) and Toll-like receptors-4 signaling pathways. Rat pancreatic islets were isolated and pro-inflammatory and pro-oxidant status were evaluated after 0, 12, 24 and 48 hours of culture through TLR-4, HO-1 and cyclooxygenase-2 (COX-2) expression, CCL-2 and IL-6 secretion, ROS (Reactive Oxygen Species) production (Dihydroethidine staining, DHE) and macrophages migration. To identify the therapeutic target, TLR4 inhibition (CLI-095) and HO-1 activation (cobalt protoporphyrin,CoPP) was performed. Activation of NFκB signaling pathway was also investigated. After isolation and during culture, pancreatic islet exhibited a proinflammatory and prooxidant status (increase levels of TLR-4, COX-2, CCL-2, IL-6, and ROS). Activation of HO-1 or inhibition of TLR-4 decreased inflammatory status and oxidative stress of islets. Moreover, the overexpression of HO-1 induced NFκB phosphorylation while the inhibition of TLR-4 had no effect NFκB activation. Finally, inhibition of pro-inflammatory pathway induced a reduction of macrophages migration. These data demonstrated that the TLR-4 signaling pathway is implicated in early inflammatory events leading to a pro-inflammatory and pro-oxidant status of islets in vitro. Moreover, these results provide the mechanism whereby the benefits of HO-1 target in TLR-4 signaling pathway. HO-1 could be then an interesting target to protect islets before transplantation. PMID:25343247

Plasticity in Glutamatergic NTS Neurotransmission

PubMed Central

Kline, David D.

2008-01-01

Changes in the physiological state of an animal or human can result in alterations in the cardiovascular and respiratory system in order to maintain homeostasis. Accordingly, the cardiovascular and respiratory systems are not static but readily adapt under a variety of circumstances. The same can be said for the brainstem circuits that control these systems. The nucleus tractus solitarius (NTS) is the central integration site of baroreceptor and chemoreceptor sensory afferent fibers. This central nucleus, and in particular the synapse between the sensory afferent and second-order NTS cell, possesses a remarkable degree of plasticity in response to a variety of stimuli, both acute and chronic. This brief review is intended to describe the plasticity observed in the NTS as well as the locus and mechanisms as they are currently understood. The functional consequence of NTS plasticity is also discussed. PMID:18524694

Preclinical safety assessments of nano-sized constructs on cardiovascular system toxicity: A case for telemetry.

PubMed

Cheah, Hoay Yan; Kiew, Lik Voon; Lee, Hong Boon; Japundžić-Žigon, Nina; Vicent, Marίa J; Hoe, See Ziau; Chung, Lip Yong

2017-11-01

While nano-sized construct (NSC) use in medicine has grown significantly in recent years, reported unwanted side effects have raised safety concerns. However, the toxicity of NSCs to the cardiovascular system (CVS) and the relative merits of the associated evaluation methods have not been thoroughly studied. This review discusses the toxicological profiles of selected NSCs and provides an overview of the assessment methods, including in silico, in vitro, ex vivo and in vivo models and how they are related to CVS toxicity. We conclude the review by outlining the merits of telemetry coupled with spectral analysis, baroreceptor reflex sensitivity analysis and echocardiography as an appropriate integrated strategy for the assessment of the acute and chronic impact of NSCs on the CVS. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Cerebellar pressor response in the dog

NASA Technical Reports Server (NTRS)

Dormer, K. J.; Stone, H. L.

1976-01-01

A fastigial pressor response has been elicited in the anesthetized mongrel dog. Stimulation within the rostral portions of this nucleus results in mean arterial pressure rises up to 150 mmHg above control. A proportional tachycardia is simultaneously evoked which may rapidly attain heart rates of 190 beats/min above control levels. Peak tachycardias immediately subside and often the heart rate declines below control values during stimulation while arterial pressure remains elevated. When either the carotid sinuses were isolated by ligation or a bilateral vagotomy was performed, the fastigial tachycardia was sustained. The response could still be attained when submaximal doses of alpha-chloralose anesthesia or high levels of barbiturates (30-40 mg/kg) were given. Both portions of the response result from widespread sympathetic activation; however, buffering of the response through the baroreceptor reflexes is only demonstrated in the cardiac segment of the response.

The Caenorhabditis elegans EGL-15 Signaling Pathway Implicates a DOS-Like Multisubstrate Adaptor Protein in Fibroblast Growth Factor Signal Transduction

PubMed Central

Schutzman, Jennifer L.; Borland, Christina Z.; Newman, John C.; Robinson, Matthew K.; Kokel, Michelle; Stern, Michael J.

2001-01-01

EGL-15 is a fibroblast growth factor receptor in the nematode Caenorhabditis elegans. Components that mediate EGL-15 signaling have been identified via mutations that confer a Clear (Clr) phenotype, indicative of hyperactivity of this pathway, or a suppressor-of-Clr (Soc) phenotype, indicative of reduced pathway activity. We have isolated a gain-of-function allele of let-60 ras that confers a Clr phenotype and implicated both let-60 ras and components of a mitogen-activated protein kinase cascade in EGL-15 signaling by their Soc phenotype. Epistasis analysis indicates that the gene soc-1 functions in EGL-15 signaling by acting either upstream of or independently of LET-60 RAS. soc-1 encodes a multisubstrate adaptor protein with an amino-terminal pleckstrin homology domain that is structurally similar to the DOS protein in Drosophila and mammalian GAB1. DOS is known to act with the cytoplasmic tyrosine phosphatase Corkscrew (CSW) in signaling pathways in Drosophila. Similarly, the C. elegans CSW ortholog PTP-2 was found to be involved in EGL-15 signaling. Structure-function analysis of SOC-1 and phenotypic analysis of single and double mutants are consistent with a model in which SOC-1 and PTP-2 act together in a pathway downstream of EGL-15 and the Src homology domain 2 (SH2)/SH3-adaptor protein SEM-5/GRB2 contributes to SOC-1-independent activities of EGL-15. PMID:11689700

Molecular mechanism of TGF-β signaling pathway in colon carcinogenesis and status of curcumin as chemopreventive strategy.

PubMed

Ramamoorthi, Ganesan; Sivalingam, Nageswaran

2014-08-01

Colon cancer is one of the third most common cancer in man, the second most common cancer in women worldwide, and the second leading cause of mortality in the USA. There are a number of molecular pathways that have been implicated in colon carcinogenesis, including TGF-β/Smad signaling pathway. TGF-β (transforming growth factor-beta) signaling pathway has the potential to regulate various biological processes including cell growth, differentiation, apoptosis, extracellular matrix modeling, and immune response. TGF-β signaling pathway acts as a tumor suppressor, but alterations in TGF-β signaling pathway promotes colon cancer cell growth, migration, invasion, angiogenesis, and metastasis. Here we review the role of TGF-β signaling cascade in colon carcinogenesis and multiple molecular targets of curcumin in colon carcinogenesis. Elucidation of the molecular mechanism of curcumin on TGF-β signaling pathway-induced colon carcinogenesis may ultimately lead to novel and more effective treatments for colon cancer.

The genetic makeup of the Drosophila piRNA pathway.

PubMed

Handler, Dominik; Meixner, Katharina; Pizka, Manfred; Lauss, Kathrin; Schmied, Christopher; Gruber, Franz Sebastian; Brennecke, Julius

2013-06-06

The piRNA (PIWI-interacting RNA) pathway is a small RNA silencing system that acts in animal gonads and protects the genome against the deleterious influence of transposons. A major bottleneck in the field is the lack of comprehensive knowledge of the factors and molecular processes that constitute this pathway. We conducted an RNAi screen in Drosophila and identified ~50 genes that strongly impact the ovarian somatic piRNA pathway. Many identified genes fall into functional categories that indicate essential roles for mitochondrial metabolism, RNA export, the nuclear pore, transcription elongation, and chromatin regulation in the pathway. Follow-up studies on two factors demonstrate that components acting at distinct hierarchical levels of the pathway were identified. Finally, we define CG2183/Gasz as an essential primary piRNA biogenesis factor in somatic and germline cells. Based on the similarities between insect and vertebrate piRNA pathways, our results have far-reaching implications for the understanding of this conserved genome defense system. Copyright © 2013 Elsevier Inc. All rights reserved.

Novel strategies targeting cancer stem cells through phytochemicals and their analogs

PubMed Central

Dandawate, Prasad; Padhye, Subhash; Ahmad, Aamir

2013-01-01

Cancer stem cells (CSCs) are cells that exist within a tumor with a capacity of self-renewal and an ability to differentiate, giving rise to heterogeneous populations of cancer cells. These cells are increasingly being implicated in resistance to conventional therapeutics and have also been implicated in tumor recurrence. Several cellular signaling pathways including Notch, Wnt, phosphoinositide-3-kinase–Akt–mammalian target of rapamycin pathways, and known markers such as CD44, CD133, CD166, ALDH, etc. have been associated with CSCs. Here, we have reviewed our current understanding of self-renewal pathways and factors that help in the survival of CSCs with special emphasis on those that have been documented to be modulated by well characterized natural agents such as curcumin, sulforaphane, resveratrol, genistein, and epigallocatechin gallate. With the inclusion of a novel derivative of curcumin, CDF, we showcase how natural agents can be effectively modified to increase their efficacy, particularly against CSCs. We hope that this article will generate interest among researchers for further mechanistic and clinical studies exploiting the cancer preventive and therapeutic role of nutraceuticals by targeted elimination of CSCs. PMID:24076568

Enhanced Functional Genomic Screening Identifies Novel Mediators of Dual Leucine Zipper Kinase-Dependent Injury Signaling in Neurons.

PubMed

Welsbie, Derek S; Mitchell, Katherine L; Jaskula-Ranga, Vinod; Sluch, Valentin M; Yang, Zhiyong; Kim, Jessica; Buehler, Eugen; Patel, Amit; Martin, Scott E; Zhang, Ping-Wu; Ge, Yan; Duan, Yukan; Fuller, John; Kim, Byung-Jin; Hamed, Eman; Chamling, Xitiz; Lei, Lei; Fraser, Iain D C; Ronai, Ze'ev A; Berlinicke, Cynthia A; Zack, Donald J

2017-06-21

Dual leucine zipper kinase (DLK) has been implicated in cell death signaling secondary to axonal damage in retinal ganglion cells (RGCs) and other neurons. To better understand the pathway through which DLK acts, we developed enhanced functional genomic screens in primary RGCs, including use of arrayed, whole-genome, small interfering RNA libraries. Explaining why DLK inhibition is only partially protective, we identify leucine zipper kinase (LZK) as cooperating with DLK to activate downstream signaling and cell death in RGCs, including in a mouse model of optic nerve injury, and show that the same pathway is active in human stem cell-derived RGCs. Moreover, we identify four transcription factors, JUN, activating transcription factor 2 (ATF2), myocyte-specific enhancer factor 2A (MEF2A), and SRY-Box 11 (SOX11), as being the major downstream mediators through which DLK/LZK activation leads to RGC cell death. Increased understanding of the DLK pathway has implications for understanding and treating neurodegenerative diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

CpG Island Methylator Phenotype-High Colorectal Cancers and Their Prognostic Implications and Relationships with the Serrated Neoplasia Pathway.

PubMed

Rhee, Ye-Young; Kim, Kyung-Ju; Kang, Gyeong Hoon

2017-01-15

The concept of a CpG island methylator phenotype (CIMP) was first introduced by Toyota and Issa to describe a subset of colorectal cancers (CRCs) with concurrent hypermethylation of multiple CpG island loci. The concept of CIMP as a molecular carcinogenesis mechanism was consolidated by the identification of the serrated neoplasia pathway, in which CIMP participates in the initiation and progression of serrated adenomas. Distinct clinicopathological and molecular features of CIMP-high (CIMP-H) CRCs have been characterized, including proximal colon location, older age of onset, female preponderance, and frequent associations of high-level microsatellite instability and BRAF mutations. CIMP-H CRCs arise in sessile or traditional serrated adenomas and thus tend to display the morphological characteristics of serrated adenomas, including epithelial serration, vesicular nuclei, and abundant cytoplasm. Both the frequent association of CIMP and poor prognosis and different responses of CRCs to adjuvant therapy depending on CIMP status indicate clinical implications. In this review, we present an overview of the literature documenting the relevant findings of CIMP-H CRCs and their relationships with the serrated neoplasia pathway.

IL-1β, RAGE and FABP4: targeting the dynamic trio in metabolic inflammation and related pathologies

PubMed Central

Hardaway, Aimalie L; Podgorski, Izabela

2013-01-01

Within the past decade, inflammatory and lipid mediators, such as IL-1β, FABP4 and RAGE, have emerged as important contributors to metabolic dysfunction. As growing experimental and clinical evidence continues to tie obesity-induced chronic inflammation with dysregulated lipid, insulin signaling and related pathologies, IL-1β, FABP4 and RAGE each are being independently implicated as culprits in these events. There are also convincing data that molecular pathways driven by these molecules are interconnected in exacerbating metabolic consequences of obesity. This article highlights the roles of IL-1β, FABP4 and RAGE in normal physiology as well as focusing specifically on their contribution to inflammation, insulin resistance, atherosclerosis, Type 2 diabetes and cancer. Studies implicating the interconnection between these pathways, current and emerging therapeutics, and their use as potential biomarkers are also discussed. Evidence of impact of IL-1β, FABP4 and RAGE pathways on severity of metabolic dysfunction underlines the strong links between inflammatory events, lipid metabolism and insulin regulation, and offers new intriguing approaches for future therapies of obesity-driven pathologies. PMID:23795967

IL-1β, RAGE and FABP4: targeting the dynamic trio in metabolic inflammation and related pathologies.

PubMed

Hardaway, Aimalie L; Podgorski, Izabela

2013-06-01

Within the past decade, inflammatory and lipid mediators, such as IL-1β, FABP4 and RAGE, have emerged as important contributors to metabolic dysfunction. As growing experimental and clinical evidence continues to tie obesity-induced chronic inflammation with dysregulated lipid, insulin signaling and related pathologies, IL-1β, FABP4 and RAGE each are being independently implicated as culprits in these events. There are also convincing data that molecular pathways driven by these molecules are interconnected in exacerbating metabolic consequences of obesity. This article highlights the roles of IL-1β, FABP4 and RAGE in normal physiology as well as focusing specifically on their contribution to inflammation, insulin resistance, atherosclerosis, Type 2 diabetes and cancer. Studies implicating the interconnection between these pathways, current and emerging therapeutics, and their use as potential biomarkers are also discussed. Evidence of impact of IL-1β, FABP4 and RAGE pathways on severity of metabolic dysfunction underlines the strong links between inflammatory events, lipid metabolism and insulin regulation, and offers new intriguing approaches for future therapies of obesity-driven pathologies.

The role of MAPK signal transduction pathways in the response to oxidative stress in the fungal pathogen Candida albicans: implications in virulence.

PubMed

de Dios, Carmen Herrero; Román, Elvira; Monge, Rebeca Alonso; Pla, Jesús

2010-12-01

In recent years, Mitogen-Activated Protein Kinase (MAPK) pathways have emerged as major regulators of cellular physiology. In the fungal pathogen Candida albicans, three different MAPK pathways have been characterized in the last years. The HOG pathway is mainly a stress response pathway that is activated in response to osmotic and oxidative stress and also participates regulating other pathways. The SVG pathway (or mediated by the Cek1 MAPK) is involved in cell wall formation under vegetative and filamentous growth, while the Mkc1-mediated pathway is involved in cell wall integrity. Oxidative stress is one of the types of stress that every fungal cell has to face during colonization of the host, where the cell encounters both hypoxia niches (i.e. gut) and high concentrations of reactive oxygen species (upon challenge with immune cells). Two pathways have been shown to be activated in response to oxidative stress: the HOG pathway and the MKC1-mediated pathway while the third, the Cek1 pathway is deactivated. The timing, kinetics, stimuli and functional responses generated upon oxidative stress differ among them; however, they have essential functional consequences that severely influence pathogenesis. MAPK pathways are, therefore, valuable targets to be explored in antifungal research.

Redesigning metabolism based on orthogonality principles

PubMed Central

Pandit, Aditya Vikram; Srinivasan, Shyam; Mahadevan, Radhakrishnan

2017-01-01

Modifications made during metabolic engineering for overproduction of chemicals have network-wide effects on cellular function due to ubiquitous metabolic interactions. These interactions, that make metabolic network structures robust and optimized for cell growth, act to constrain the capability of the cell factory. To overcome these challenges, we explore the idea of an orthogonal network structure that is designed to operate with minimal interaction between chemical production pathways and the components of the network that produce biomass. We show that this orthogonal pathway design approach has significant advantages over contemporary growth-coupled approaches using a case study on succinate production. We find that natural pathways, fundamentally linked to biomass synthesis, are less orthogonal in comparison to synthetic pathways. We suggest that the use of such orthogonal pathways can be highly amenable for dynamic control of metabolism and have other implications for metabolic engineering. PMID:28555623

It's all connected: Pathways in visual object recognition and early noun learning.

PubMed

Smith, Linda B

2013-11-01

A developmental pathway may be defined as the route, or chain of events, through which a new structure or function forms. For many human behaviors, including object name learning and visual object recognition, these pathways are often complex and multicausal and include unexpected dependencies. This article presents three principles of development that suggest the value of a developmental psychology that explicitly seeks to trace these pathways and uses empirical evidence on developmental dependencies among motor development, action on objects, visual object recognition, and object name learning in 12- to 24-month-old infants to make the case. The article concludes with a consideration of the theoretical implications of this approach. (PsycINFO Database Record (c) 2013 APA, all rights reserved).

Major Developments in the Design of Inhibitors along the Kynurenine Pathway

PubMed Central

Jacobs, Kelly R.; Castellano-González, Gloria; Guillemin, Gilles J.; Lovejoy, David B.

2017-01-01

Disrupted kynurenine pathway (KP) metabolism has been implicated in the progression of neurodegenerative disease, psychiatric disorders and cancer. Modulation of enzyme activity along this pathway may therefore offer potential new therapeutic strategies for these conditions. Considering their prominent positions in the KP, the enzymes indoleamine 2,3-dioxygenase, kynurenine 3-monooxygenase and kynurenine aminotransferase, appear the most attractive targets. Already, increasing interest in this pathway has led to the identification of a number of potent and selective enzyme inhibitors with promising pre-clinical data and the elucidation of several enzyme crystal structures provides scope to rationalize the molecular mechanisms of inhibitor activity. The field seems poised to yield one or more inhibitors that should find clinical utility. PMID:28464785

A common pathway for charge transport through voltage-sensing domains.

PubMed

Chanda, Baron; Bezanilla, Francisco

2008-02-07

Voltage-gated ion channels derive their voltage sensitivity from the movement of specific charged residues in response to a change in transmembrane potential. Several studies on mechanisms of voltage sensing in ion channels support the idea that these gating charges move through a well-defined permeation pathway. This gating pathway in a voltage-gated ion channel can also be mutated to transport free cations, including protons. The recent discovery of proton channels with sequence homology to the voltage-sensing domains suggests that evolution has perhaps exploited the same gating pathway to generate a bona fide voltage-dependent proton transporter. Here we will discuss implications of these findings on the mechanisms underlying charge (and ion) transport by voltage-sensing domains.

Redox imbalance stress in diabetes mellitus: Role of the polyol pathway.

PubMed

Yan, Liang-Jun

2018-03-01

In diabetes mellitus, the polyol pathway is highly active and consumes approximately 30% glucose in the body. This pathway contains 2 reactions catalyzed by aldose reductase (AR) and sorbitol dehydrogenase, respectively. AR reduces glucose to sorbitol at the expense of NADPH, while sorbitol dehydrogenase converts sorbitol to fructose at the expense of NAD + , leading to NADH production. Consumption of NADPH, accumulation of sorbitol, and generation of fructose and NADH have all been implicated in the pathogenesis of diabetes and its complications. In this review, the roles of this pathway in NADH/NAD + redox imbalance stress and oxidative stress in diabetes are highlighted. A potential intervention using nicotinamide riboside to restore redox balance as an approach to fighting diabetes is also discussed.

Genistein and daidzein: different molecular effects on prostate cancer.

PubMed

Adjakly, Mawussi; Ngollo, Marjolaine; Boiteux, Jean-Paul; Bignon, Yves-Jean; Guy, Laurent; Bernard-Gallon, Dominique

2013-01-01

Diet is believed to play an important role in cancer. It has been revealed by epidemiological studies that Asian populations, who consume phytoestrogens in large amounts, have a lower incidence of prostate cancer in comparison with the Western world, where consumption of soy is lower. Genistein and daidzein, the soy phytoestrogens most widely studied, are believed to be potent anticancer agents and have been shown to possess anticancer properties. It has been shown that these compounds inhibit the growth of cancer cells through the modulation of genes controlling cell-cycle progression. Genistein inhibits the activation of the kappa light polypeptide gene enhancer in B-cells (NF-κB), signaling pathway, which is implicated in the balance between cell survival and programmed cell death (apoptosis). Antioxidant and antiangiogenesis properties of genistein have been also described. Soy isoflavones are also implicated in reversion of epigenetic events observed in prostate cancer. Significant advances have been made for understanding how soy isoflavones are implicated in protection against prostate cancer. However, more studies are needed to better-understand and elucidate all pathways mobilized by genistein and daidzein, in order to fully exploit their anticancer properties.

Pathway Analysis in Attention Deficit Hyperactivity Disorder: An Ensemble Approach

PubMed Central

Mooney, Michael A.; McWeeney, Shannon K.; Faraone, Stephen V.; Hinney, Anke; Hebebrand, Johannes; Nigg, Joel T.; Wilmot, Beth

2016-01-01

Despite a wealth of evidence for the role of genetics in attention deficit hyperactivity disorder (ADHD), specific and definitive genetic mechanisms have not been identified. Pathway analyses, a subset of gene-set analyses, extend the knowledge gained from genome-wide association studies (GWAS) by providing functional context for genetic associations. However, there are numerous methods for association testing of gene sets and no real consensus regarding the best approach. The present study applied six pathway analysis methods to identify pathways associated with ADHD in two GWAS datasets from the Psychiatric Genomics Consortium. Methods that utilize genotypes to model pathway-level effects identified more replicable pathway associations than methods using summary statistics. In addition, pathways implicated by more than one method were significantly more likely to replicate. A number of brain-relevant pathways, such as RhoA signaling, glycosaminoglycan biosynthesis, fibroblast growth factor receptor activity, and pathways containing potassium channel genes, were nominally significant by multiple methods in both datasets. These results support previous hypotheses about the role of regulation of neurotransmitter release, neurite outgrowth and axon guidance in contributing to the ADHD phenotype and suggest the value of cross-method convergence in evaluating pathway analysis results. PMID:27004716

How might contact with nature promote human health? Promising mechanisms and a possible central pathway.

PubMed

Kuo, Ming

2015-01-01

How might contact with nature promote human health? Myriad studies have linked the two; at this time the task of identifying the mechanisms underlying this link is paramount. This article offers: (1) a compilation of plausible pathways between nature and health; (2) criteria for identifying a possible central pathway; and (3) one promising candidate for a central pathway. The 21 pathways identified here include environmental factors, physiological and psychological states, and behaviors or conditions, each of which has been empirically tied to nature and has implications for specific physical and mental health outcomes. While each is likely to contribute to nature's impacts on health to some degree and under some circumstances, this paper explores the possibility of a central pathway by proposing criteria for identifying such a pathway and illustrating their use. A particular pathway is more likely to be central if it can account for the size of nature's impacts on health, account for nature's specific health outcomes, and subsume other pathways. By these criteria, enhanced immune functioning emerges as one promising candidate for a central pathway between nature and health. There may be others.

Liver-brain interactions in inflammatory liver diseases: implications for fatigue and mood disorders.

PubMed

D'Mello, Charlotte; Swain, Mark G

2014-01-01

Chronic inflammatory liver diseases are often accompanied by behavior alterations including fatigue, mood disorders, cognitive dysfunction and sleep disturbances. These altered behaviors can adversely affect patient quality of life. The communication pathways between the inflamed liver and the brain that mediate changes in central neural activity leading to behavior alterations during liver inflammation are poorly understood. Neural and humoral communication pathways have been most commonly implicated as driving peripheral inflammation to brain signaling. Classically, the cytokines TNFα, IL-1β and IL-6 have received the greatest scientific attention as potential mediators of this communication pathway. In mice with liver inflammation we have identified a novel immune-mediated liver-to-brain communication pathway whereby CCR2(+) monocytes found within the peripheral circulation transmigrate into the brain parenchyma in response to MCP-1/CCL2 expressing activated microglia. Inhibition of cerebral monocyte infiltration in these mice significantly improved liver inflammation associated sickness behaviors. Importantly, in recent work we have found that at an earlier time point, when cerebral monocyte infiltration is not evident in mice with liver inflammation, increased monocyte:cerebral endothelial cell adhesive interactions are observed using intravital microscopy of the brain. These monocyte:cerebral endothelial cell adhesive interactions are P-selectin mediated, and inhibition of these interactions attenuated microglial activation and sickness behavior development. Delineating the pathways that the periphery uses to communicate with the brain during inflammatory liver diseases, and the central neurotransmitter systems that are altered through these communication pathways (e.g., serotonin, corticotrophin releasing hormone) to give rise to liver inflammation-associated sickness behaviors, will allow for the identification of novel therapeutic targets to decrease the burden of debilitating symptoms in these patients. Copyright © 2013 Elsevier Inc. All rights reserved.

Hyperglycaemia-induced resistance to Docetaxel is negated by metformin: a role for IGFBP-2.

PubMed

Biernacka, K M; Persad, R A; Bahl, A; Gillatt, D; Holly, J M P; Perks, C M

2017-01-01

The incidence of many common cancers varies between different populations and appears to be affected by a Western lifestyle. Highly proliferative malignant cells require sufficient levels of nutrients for their anabolic activity. Therefore, targeting genes and pathways involved in metabolic pathways could yield future therapeutics. A common pathway implicated in energetic and nutritional requirements of a cell is the LKB1/AMPK pathway. Metformin is a widely studied anti-diabetic drug, which improves glycaemia in patients with type 2 diabetes by targeting this pathway. We investigated the effect of metformin on prostate cancer cell lines and evaluated its mechanism of action using DU145, LNCaP, PC3 and VCaP prostate cancer cell lines. Trypan blue dye-exclusion assay was used to assess levels of cell death. Western immunoblotting was used to determine the abundance of proteins. Insulin-like growth factor-binding protein-2 (IGFBP-2) and AMPK genes were silenced using siRNA. Effects on cell morphology were visualised using microscopy. IGFBP-2 gene expression was assessed using real-time RT-PCR. With DU145 and LNCaP cells metformin alone induced cell death, but this was reduced in hyperglycaemic conditions. Hyperglycaemia also reduced the sensitivity to Docetaxel, but this was countered by co-treatment with metformin. LKB1 was required for the activation of AMPK but was not essential to mediate the induction of cell death. An alternative pathway by which metformin exerted its action was through downregulation of IGFBP-2 in DU145 and LNCaP cells, independently of AMPK. This finding could have important implications in relation to therapeutic strategies in prostate cancer patients presenting with diabetes. © 2017 The authors.

GABA and Glutamate Pathways Are Spatially and Developmentally Affected in the Brain of Mecp2-Deficient Mice

PubMed Central

Matagne, Valérie; Ghata, Adeline; Villard, Laurent; Roux, Jean-Christophe

2014-01-01

Proper brain functioning requires a fine-tuning between excitatory and inhibitory neurotransmission, a balance maintained through the regulation and release of glutamate and GABA. Rett syndrome (RTT) is a rare genetic disorder caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene affecting the postnatal brain development. Dysfunctions in the GABAergic and glutamatergic systems have been implicated in the neuropathology of RTT and a disruption of the balance between excitation and inhibition, together with a perturbation of the electrophysiological properties of GABA and glutamate neurons, were reported in the brain of the Mecp2-deficient mouse. However, to date, the extent and the nature of the GABA/glutamate deficit affecting the Mecp2-deficient mouse brain are unclear. In order to better characterize these deficits, we simultaneously analyzed the GABA and glutamate levels in Mecp2-deficient mice at 2 different ages (P35 and P55) and in several brain areas. We used a multilevel approach including the quantification of GABA and glutamate levels, as well as the quantification of the mRNA and protein expression levels of key genes involved in the GABAergic and glutamatergic pathways. Our results show that Mecp2-deficient mice displayed regional- and age-dependent variations in the GABA pathway and, to a lesser extent, in the glutamate pathway. The implication of the GABA pathway in the RTT neuropathology was further confirmed using an in vivo treatment with a GABA reuptake inhibitor that significantly improved the lifespan of Mecp2-deficient mice. Our results confirm that RTT mouse present a deficit in the GABAergic pathway and suggest that GABAergic modulators could be interesting therapeutic agents for this severe neurological disorder. PMID:24667344

A geographically-diverse collection of 418 human gut microbiome pathway genome databases

PubMed Central

Hahn, Aria S.; Altman, Tomer; Konwar, Kishori M.; Hanson, Niels W.; Kim, Dongjae; Relman, David A.; Dill, David L.; Hallam, Steven J.

2017-01-01

Advances in high-throughput sequencing are reshaping how we perceive microbial communities inhabiting the human body, with implications for therapeutic interventions. Several large-scale datasets derived from hundreds of human microbiome samples sourced from multiple studies are now publicly available. However, idiosyncratic data processing methods between studies introduce systematic differences that confound comparative analyses. To overcome these challenges, we developed GutCyc, a compendium of environmental pathway genome databases (ePGDBs) constructed from 418 assembled human microbiome datasets using MetaPathways, enabling reproducible functional metagenomic annotation. We also generated metabolic network reconstructions for each metagenome using the Pathway Tools software, empowering researchers and clinicians interested in visualizing and interpreting metabolic pathways encoded by the human gut microbiome. For the first time, GutCyc provides consistent annotations and metabolic pathway predictions, making possible comparative community analyses between health and disease states in inflammatory bowel disease, Crohn’s disease, and type 2 diabetes. GutCyc data products are searchable online, or may be downloaded and explored locally using MetaPathways and Pathway Tools. PMID:28398290

Orexin: a Missing Link Between Sleep Disorders and Heart Failure?

PubMed

Pan, Stephen; Cabral, Carolina S; Ashley, Euan A; Perez, Marco V

2017-04-01

Sleep disorders represent a significant comorbidity in the heart failure population, and there is mounting evidence that treatment of sleep disorders such as obstructive sleep apnea can significantly improve cardiac function. However, the link between these two disorders is still not entirely clear. Recently, a novel neurohormonal pathway has been elucidated involving signaling molecules now collectively known as the orexins, which have been implicated in regulating autonomic function during sleep/wake cycles. Further evidence has mounted that orexin signaling is deeply perturbed in the setting of sleep disorders, and furthermore that abnormal orexin signaling may be implicated in the pathology of heart failure. The orexin signaling pathway represents an enticing novel target for both the treatment of sleep disorders as well as heart failure, and may represent one facet of the "missing link" between these two prevalent and often comorbid diseases.

Vitamin D and its effects on cardiovascular diseases: a comprehensive review

PubMed Central

Pérez-Hernández, Nonanzit; Aptilon-Duque, Gad; Nostroza-Hernández, María Cristina; Vargas-Alarcón, Gilberto; Rodríguez-Pérez, José Manuel; Blachman-Braun, Ruben

2016-01-01

Vitamin D is a molecule that is actively involved in multiple metabolic pathways. It is mostly known for its implications related to calcium metabolism. It has also been determined that it actively participates in the cardiovascular system, influencing blood pressure, coronary artery disease and other vascular diseases, such as heart failure and atrial fibrillation. Furthermore, it has been established that this vitamin is extensively involved in the regulation of both the renin angiotensin aldosterone system and the immune system. In this review, we present the different vitamin D metabolic pathways associated with the cardiovascular pathophysiology, and we include studies in animal and human models, as well as some of the controversies found in the literature. This review also incorporates an overview of the implications in the molecular biology and public health fields. PMID:27117316

Ras signaling in aging and metabolic regulation.

PubMed

Slack, Cathy

2017-12-07

Aberrant signal transduction downstream of the Ras GTPase has a well-established role in tumorigenesis. Mutations that result in hyperactivation of Ras are responsible for a third of all human cancers. Hence, small molecule inhibitors of the Ras signal transduction cascade have been under intense focus as potential cancer treatments. In both invertebrate and mammalian models, emerging evidence has also implicated components of the Ras signaling pathway in aging and metabolic regulation. Here, I review the current evidence for Ras signaling in these newly discovered roles highlighting the interactions between the Ras pathway and other longevity assurance mechanisms. Defining the role of Ras signaling in maintaining age-related health may have important implications for the development of interventions that could not only increase lifespan but also delay the onset and/or progression of age-related functional decline.

Genes and gene networks implicated in aggression related behaviour.

PubMed

Malki, Karim; Pain, Oliver; Du Rietz, Ebba; Tosto, Maria Grazia; Paya-Cano, Jose; Sandnabba, Kenneth N; de Boer, Sietse; Schalkwyk, Leonard C; Sluyter, Frans

2014-10-01

Aggressive behaviour is a major cause of mortality and morbidity. Despite of moderate heritability estimates, progress in identifying the genetic factors underlying aggressive behaviour has been limited. There are currently three genetic mouse models of high and low aggression created using selective breeding. This is the first study to offer a global transcriptomic characterization of the prefrontal cortex across all three genetic mouse models of aggression. A systems biology approach has been applied to transcriptomic data across the three pairs of selected inbred mouse strains (Turku Aggressive (TA) and Turku Non-Aggressive (TNA), Short Attack Latency (SAL) and Long Attack Latency (LAL) mice and North Carolina Aggressive (NC900) and North Carolina Non-Aggressive (NC100)), providing novel insight into the neurobiological mechanisms and genetics underlying aggression. First, weighted gene co-expression network analysis (WGCNA) was performed to identify modules of highly correlated genes associated with aggression. Probe sets belonging to gene modules uncovered by WGCNA were carried forward for network analysis using ingenuity pathway analysis (IPA). The RankProd non-parametric algorithm was then used to statistically evaluate expression differences across the genes belonging to modules significantly associated with aggression. IPA uncovered two pathways, involving NF-kB and MAPKs. The secondary RankProd analysis yielded 14 differentially expressed genes, some of which have previously been implicated in pathways associated with aggressive behaviour, such as Adrbk2. The results highlighted plausible candidate genes and gene networks implicated in aggression-related behaviour.

Vascular dysfunctions following spinal cord injury

PubMed Central

Popa, F; Grigorean, VT; Onose, G; Sandu, AM; Popescu, M; Burnei, G; Strambu, V; Sinescu, C

2010-01-01

The aim of this article is to analyze the vascular dysfunctions occurring after spinal cord injury (SCI). Vascular dysfunctions are common complications of SCI. Cardiovascular disturbances are the leading causes of morbidity and mortality in both acute and chronic stages of SCI. Neuroanatomy and physiology of autonomic nervous system, sympathetic and parasympathetic, is reviewed. SCI implies disruption of descendent pathways from central centers to spinal sympathetic neurons, originating in intermediolateral nuclei of T1–L2 cord segments. Loss of supraspinal control over sympathetic nervous system results in reduced overall sympathetic activity below the level of injury and unopposed parasympathetic outflow through intact vagal nerve. SCI associates significant vascular dysfunction. Spinal shock occurs during the acute phase following SCI and it is a transitory suspension of function and reflexes below the level of the injury. Neurogenic shock, part of spinal shock, consists of severe arterial hypotension and bradycardia. Autonomic dysreflexia appears during the chronic phase, after spinal shock resolution, and it is a life–threatening syndrome of massive imbalanced reflex sympathetic discharge occurring in patients with SCI above the splanchnic sympathetic outflow (T5–T6). Arterial hypotension with orthostatic hypotension occurs in both acute and chronic phases. The etiology is multifactorial. We described a few factors influencing the orthostatic hypotension occurrence in SCI: sympathetic nervous system dysfunction, low plasma catecholamine levels, rennin–angiotensin–aldosterone activity, peripheral alpha–adrenoceptor hyperresponsiveness, impaired function of baroreceptors, hyponatremia and low plasmatic volume, cardiovascular deconditioning, morphologic changes in sympathetic neurons, plasticity within spinal circuits, and motor deficit leading to loss of skeletal muscle pumping activity. Additional associated cardiovascular concerns in SCI, such as deep vein thrombosis and long–term risk for coronary heart disease and systemic atherosclerosis are also described. Proper prophylaxis, including non–pharmacologic and pharmacological strategies, diminishes the occurrence of the vascular dysfunction following SCI. Each vascular disturbance requires a specific treatment. PMID:20945818

Neuropeptide Y-mediated sex- and afferent-specific neurotransmissions contribute to sexual dimorphism of baroreflex afferent function.

PubMed

Liu, Yang; Wu, Di; Qu, Mei-Yu; He, Jian-Li; Yuan, Mei; Zhao, Miao; Wang, Jian-Xin; He, Jian; Wang, Lu-Qi; Guo, Xin-Jing; Zuo, Meng; Zhao, Shu-Yang; Ma, Mei-Na; Li, Jun-Nan; Shou, Weinian; Qiao, Guo-Fen; Li, Bai-Yan

2016-10-04

Molecular and cellular mechanisms of neuropeptide-Y (NPY)-mediated gender-difference in blood pressure (BP) regulation are largely unknown. Baroreceptor sensitivity (BRS) was evaluated by measuring the response of BP to phenylephrine/nitroprusside. Serum NPY concentration was determined using ELISA. The mRNA and protein expression of NPY receptors were assessed in tissue and single-cell by RT-PCR, immunoblot, and immunohistochemistry. NPY was injected into the nodose while arterial pressure was monitored. Electrophysiological recordings were performed on nodose neurons from rats by patch-clamp technique. The BRS was higher in female than male and ovariectomized rats, while serum NPY concentration was similar among groups. The sex-difference was detected in Y1R, not Y2R protein expression, however, both were upregulated upon ovariectomy and canceled by estrogen replacement. Immunostaining confirmed Y1R and Y2R expression in myelinated and unmyelinated afferents. Single-cell PCR demonstrated that Y1R expression/distribution was identical between A- and C-types, whereas, expressed level of Y2R was ~15 and ~7 folds higher in Ah- and C-types than A-types despite similar distribution. Activation of Y1R in nodose elevated BP, while activation of Y2R did the opposite. Activation of Y1R did not alter action potential duration (APD) of A-types, but activation of Y2R- and Y1R/Y2R in Ah- and C-types frequency-dependently prolonged APD. N-type ICa was reduced in A-, Ah- and C-types when either Y1R, Y2R, or both were activated. The sex-difference in Y1R expression was also observed in NTS. Sex- and afferent-specific expression of Neuropeptide-Y receptors in baroreflex afferent pathway may contribute to sexual-dimorphic neurocontrol of BP regulation.

Compliance to clinical pathways in the management of suspected pulmonary embolus: are there cost implications?

PubMed

Rehman, Ata; Yelf, Eric; Pearson, Jacqueline; Yeo, Wilf

2017-04-01

This study investigated the cost implications of poor compliance to established guidelines for management of suspected pulmonary embolism (PE) in two NSW public hospitals. A retrospective audit showed that the prevalence of PE overall was 9.9% (4.3% in the low-risk groups) in 436 patients. An estimated total of $32 454 (14%) was spent on unnecessary tests. © 2017 Royal Australasian College of Physicians.

Raft-mediated trafficking of apical resident proteins occurs in both direct and transcytotic pathways in polarized hepatic cells: role of distinct lipid microdomains.

PubMed

Slimane, Tounsia Aït; Trugnan, Germain; Van IJzendoorn, Sven C D; Hoekstra, Dick

2003-02-01

In polarized hepatic cells, pathways and molecular principles mediating the flow of resident apical bile canalicular proteins have not yet been resolved. Herein, we have investigated apical trafficking of a glycosylphosphatidylinositol-linked and two single transmembrane domain proteins on the one hand, and two polytopic proteins on the other in polarized HepG2 cells. We demonstrate that the former arrive at the bile canalicular membrane via the indirect transcytotic pathway, whereas the polytopic proteins reach the apical membrane directly, after Golgi exit. Most importantly, cholesterol-based lipid microdomains ("rafts") are operating in either pathway, and protein sorting into such domains occurs in the biosynthetic pathway, largely in the Golgi. Interestingly, rafts involved in the direct pathway are Lubrol WX insoluble but Triton X-100 soluble, whereas rafts in the indirect pathway are both Lubrol WX and Triton X-100 insoluble. Moreover, whereas cholesterol depletion alters raft-detergent insolubility in the indirect pathway without affecting apical sorting, protein missorting occurs in the direct pathway without affecting raft insolubility. The data implicate cholesterol as a traffic direction-determining parameter in the direct apical pathway. Furthermore, raft-cargo likely distinguishing single vs. multispanning membrane anchors, rather than rafts per se (co)determine the sorting pathway.

Raft-mediated Trafficking of Apical Resident Proteins Occurs in Both Direct and Transcytotic Pathways in Polarized Hepatic Cells: Role of Distinct Lipid Microdomains

PubMed Central

Slimane, Tounsia Aït; Trugnan, Germain; van IJzendoorn, Sven C.D.; Hoekstra, Dick

2003-01-01

In polarized hepatic cells, pathways and molecular principles mediating the flow of resident apical bile canalicular proteins have not yet been resolved. Herein, we have investigated apical trafficking of a glycosylphosphatidylinositol-linked and two single transmembrane domain proteins on the one hand, and two polytopic proteins on the other in polarized HepG2 cells. We demonstrate that the former arrive at the bile canalicular membrane via the indirect transcytotic pathway, whereas the polytopic proteins reach the apical membrane directly, after Golgi exit. Most importantly, cholesterol-based lipid microdomains (“rafts”) are operating in either pathway, and protein sorting into such domains occurs in the biosynthetic pathway, largely in the Golgi. Interestingly, rafts involved in the direct pathway are Lubrol WX insoluble but Triton X-100 soluble, whereas rafts in the indirect pathway are both Lubrol WX and Triton X-100 insoluble. Moreover, whereas cholesterol depletion alters raft-detergent insolubility in the indirect pathway without affecting apical sorting, protein missorting occurs in the direct pathway without affecting raft insolubility. The data implicate cholesterol as a traffic direction-determining parameter in the direct apical pathway. Furthermore, raft-cargo likely distinguishing single vs. multispanning membrane anchors, rather than rafts per se (co)determine the sorting pathway. PMID:12589058

Mechanisms underlying caloric restriction and life span regulation: implications for vascular aging

PubMed Central

Ungvari, Zoltan; Parrado-Fernandez, Cristina; Csiszar, Anna; de Cabo, Rafael

2008-01-01

This review focuses on the emerging evidence that attenuation of the production of reactive oxygen species (ROS) and inhibition of inflammatory pathways play a central role in the anti-aging cardiovascular effects of caloric restriction (CR). Particular emphasis is placed on the potential role of the plasma membrane redox system in CR-induced pathways responsible for sensing oxidative stress and increasing cellular oxidative stress resistance. We propose that CR increases bioavailability of NO, decreases vascular ROS generation, activates the Nrf2/ARE pathway inducing ROS detoxification systems, exerts anti-inflammatory effects and, thereby, suppresses initiation/progression of vascular disease that accompany aging. PMID:18340017

New Insights into Glomerular Parietal Epithelial Cell Activation and Its Signaling Pathways in Glomerular Diseases

PubMed Central

Su, Hua; Chen, Shan; He, Fang-Fang; Wang, Yu-Mei; Bondzie, Philip; Zhang, Chun

2015-01-01

The glomerular parietal epithelial cells (PECs) have aroused an increasing attention recently. The proliferation of PECs is the main feature of crescentic glomerulonephritis; besides that, in the past decade, PEC activation has been identified in several types of noninflammatory glomerulonephropathies, such as focal segmental glomerulosclerosis, diabetic glomerulopathy, and membranous nephropathy. The pathogenesis of PEC activation is poorly understood; however, a few studies delicately elucidate the potential mechanisms and signaling pathways implicated in these processes. In this review we will focus on the latest observations and concepts about PEC activation in glomerular diseases and the newest identified signaling pathways in PEC activation. PMID:25866774

Developmental Pathways from Parental Substance Use to Childhood Academic Achievement

PubMed Central

Brook, Judith S.; Saar, Naomi S.; Brook, David W.

2010-01-01

This cross-sectional study examined the pathways to childhood academic achievement in 209 African American and Puerto Rican children and their mothers. There were three pathways to childhood academic achievement: (a) the mother-child relationship and the child’s personality mediated between parental substance use and childhood academic achievement; (b) the child’s personality mediated between parental education and childhood academic achievement; and (c) there was a direct relationship between the child’s gender and childhood academic achievement. Policy and clinical implications suggest the importance of increasing educational opportunities for all parents, providing substance use treatment and self-esteem workshops, and altering the school curriculum. PMID:20525035

Modeling of coupled differential equations for cellular chemical signaling pathways: Implications for assay protocols utilized in cellular engineering.

PubMed

O'Clock, George D

2016-08-01

Cellular engineering involves modification and control of cell properties, and requires an understanding of fundamentals and mechanisms of action for cellular derived product development. One of the keys to success in cellular engineering involves the quality and validity of results obtained from cell chemical signaling pathway assays. The accuracy of the assay data cannot be verified or assured if the effect of positive feedback, nonlinearities, and interrelationships between cell chemical signaling pathway elements are not understood, modeled, and simulated. Nonlinearities and positive feedback in the cell chemical signaling pathway can produce significant aberrations in assay data collection. Simulating the pathway can reveal potential instability problems that will affect assay results. A simulation, using an electrical analog for the coupled differential equations representing each segment of the pathway, provides an excellent tool for assay validation purposes. With this approach, voltages represent pathway enzyme concentrations and operational amplifier feedback resistance and input resistance values determine pathway gain and rate constants. The understanding provided by pathway modeling and simulation is strategically important in order to establish experimental controls for assay protocol structure, time frames specified between assays, and assay concentration variation limits; to ensure accuracy and reproducibility of results.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ma, Xiang; Zhang, Shuai; Jiao, Fang

Two-step nucleation pathways in which disordered, amorphous, or dense liquid states precede appearance of crystalline phases have been reported for a wide range of materials, but the dynamics of such pathways are poorly understood. Moreover, whether these pathways are general features of crystallizing systems or a consequence of system-specific structural details that select for direct vs two-step processes is unknown. Using atomic force microscopy to directly observe crystallization of sequence-defined polymers, we show that crystallization pathways are indeed sequence dependent. When a short hydrophobic region is added to a sequence that directly forms crystalline particles, crystallization instead follows a two-stepmore » pathway that begins with creation of disordered clusters of 10-20 molecules and is characterized by highly non-linear crystallization kinetics in which clusters transform into ordered structures that then enter the growth phase. The results shed new light on non-classical crystallization mechanisms and have implications for design of self-assembling polymer systems.« less

Electronic patient information systems and care pathways: the organisational challenges of implementation and integration.

PubMed

Dent, Mike; Tutt, Dylan

2014-09-01

Our interest here is with the 'marriage' of e-patient information systems with care pathways in order to deliver integrated care. We report on the development and implementation of four such pathways within two National Health Service primary care trusts in England: (a) frail elderly care, (b) stroke care, (c) diabetic retinopathy screening and (d) intermediate care. The pathways were selected because each represents a different type of information and data 'couplings', in terms of task interdependency with some pathways/systems reflecting more complex coordinating patterns than others. Our aim here is identify and explain how health professionals and information specialists in two organisational National Health Service primary care trusts organisationally construct and use such systems and, in particular, the implications this has for issues of professional and managerial control and autonomy. The article is informed by an institutionalist analysis. © The Author(s) 2013.

SCFSlmb E3 ligase-mediated degradation of Expanded is inhibited by the Hippo pathway in Drosophila

PubMed Central

Zhang, Hongtao; Li, Changqing; Chen, Hanqing; Wei, Chuanxian; Dai, Fei; Wu, Honggang; Dui, Wen; Deng, Wu-Min; Jiao, Renjie

2015-01-01

Deregulation of the evolutionarily conserved Hippo pathway has been implicated in abnormal development of animals and in several types of cancer. One mechanism of Hippo pathway regulation is achieved by controlling the stability of its regulatory components. However, the executive E3 ligases that are involved in this process, and how the process is regulated, remain poorly defined. In this study, we identify, through a genetic candidate screen, the SCFSlmb E3 ligase as a novel negative regulator of the Hippo pathway in Drosophila imaginal tissues via mediation of the degradation of Expanded (Ex). Mechanistic study shows that Slmb-mediated degradation of Ex is inhibited by the Hippo signaling. Considering the fact that Hippo signaling suppresses the transcription of ex, we propose that the Hippo pathway employs a double security mechanism to ensure fine-tuned homeostasis during development. PMID:25522691

Shh pathway in wounds in non-diabetic Shh-Cre-eGFP/Ptch1-LacZ mice treated with MAA beads.

PubMed

Lisovsky, Alexandra; Sefton, Michael V

2016-09-01

Previously, poly(methacrylic acid-co-methyl methacrylate) (MAA) beads were shown to improve vessel formation with a concomitant increase in the expression of the sonic hedgehog (Shh) gene, a pleiotropic factor implicated in vascularization. The aim of this study was to follow up on this observation in the absence of the confounding factors of diabetes in non-diabetic Shh-Cre-eGFP/Ptch1-LacZ mice; in this mouse, expression of GFP and β-Gal is consistent with the transcription patterns of Shh and its receptor patched 1 (Ptch1), respectively. In agreement with studies in diabetic males, MAA beads improved vascularization in large (15 mm × 15 mm) wounds in non-diabetic males at day 7. Shh pathway activation was suggested, as the numbers of GFP+ (Shh) and β-Gal+ (Ptch1, a target of the pathway) cells increased in the granulation tissue. Shh signaling pathway modulation was also suggested in the healthy skin surrounding the wound bed, as evidenced by an increase in the number of GFP+ and β-Gal+ cells in males at day 4. Gene expression analysis of the wounds confirmed increase in Ptch1 and showed the upregulation of a downstream transcription factor Gli3, involved in the vascular effect of the Shh pathway, implicating the pathway in the effect of MAA beads. The efficacy of MAA beads was also investigated in females; MAA beads modulated the Shh pathway within granulation tissue similarly as in males, but had no enhancement effect on the healthy skin and on vascularization. We believe that understanding the molecular and cellular mechanisms of MAA-based biomaterials and testing the efficacy of therapeutics in both sexes will inform the development of novel therapeutic biomaterials. Copyright © 2016 Elsevier Ltd. All rights reserved.

Molecular Targeting of Prostate Cancer During Androgen Ablation: Inhibition of CHES1/FOXN3

DTIC Science & Technology

2010-05-10

target of rapamycin ( mTOR ) and hypoxia-inducible factor-1α (HIF-1α) target genes (12). Additionally, transcriptional activation of Bcl-2 by NF-κB...in resistance to hormone therapy (19). Elevated expression of genes encoding PI3K/Akt/ mTOR pathway components has also been implicated in androgen... mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med, 10

Preventing Early Child Maltreatment: Implications from a Longitudinal Study of Maternal Abuse History, Substance Use Problems, and Offspring Victimization

PubMed Central

Appleyard, Karen; Berlin, Lisa J.; Rosanbalm, Katherine D.; Dodge, Kenneth A.

2013-01-01

In the interest of improving child maltreatment prevention science, this longitudinal, community based study of 499 mothers and their infants tested the hypothesis that mothers’ childhood history of maltreatment would predict maternal substance use problems, which in turn would predict offspring victimization. Mothers (35% White/non-Latina, 34% Black/non-Latina, 23% Latina, 7% other) were recruited and interviewed during pregnancy, and child protective services records were reviewed for the presence of the participants’ target infants between birth and age 26 months. Mediating pathways were examined through structural equation modeling and tested using the products of the coefficients approach. The mediated pathway from maternal history of sexual abuse to substance use problems to offspring victimization was significant (standardized mediated path [ab]=.07, 95% CI [.02, .14]; effect size=.26), as was the mediated pathway from maternal history of physical abuse to substance use problems to offspring victimization (standardized mediated path [ab]=.05, 95% CI [.01, .11]; effect size =.19). There was no significant mediated pathway from maternal history of neglect. Findings are discussed in terms of specific implications for child maltreatment prevention, including the importance of assessment and early intervention for maternal history of maltreatment and substance use problems, targeting women with maltreatment histories for substance use services, and integrating child welfare and parenting programs with substance use treatment. PMID:21240556

Transmembrane protein OSTA-1 shapes sensory cilia morphology via regulation of intracellular membrane trafficking in C. elegans.

PubMed

Olivier-Mason, Anique; Wojtyniak, Martin; Bowie, Rachel V; Nechipurenko, Inna V; Blacque, Oliver E; Sengupta, Piali

2013-04-01

The structure and function of primary cilia are critically dependent on intracellular trafficking pathways that transport ciliary membrane and protein components. The mechanisms by which these trafficking pathways are regulated are not fully characterized. Here we identify the transmembrane protein OSTA-1 as a new regulator of the trafficking pathways that shape the morphology and protein composition of sensory cilia in C. elegans. osta-1 encodes an organic solute transporter alpha-like protein, mammalian homologs of which have been implicated in membrane trafficking and solute transport, although a role in regulating cilia structure has not previously been demonstrated. We show that mutations in osta-1 result in altered ciliary membrane volume, branch length and complexity, as well as defects in localization of a subset of ciliary transmembrane proteins in different sensory cilia types. OSTA-1 is associated with transport vesicles, localizes to a ciliary compartment shown to house trafficking proteins, and regulates both retrograde and anterograde flux of the endosome-associated RAB-5 small GTPase. Genetic epistasis experiments with sensory signaling, exocytic and endocytic proteins further implicate OSTA-1 as a crucial regulator of ciliary architecture via regulation of cilia-destined trafficking. Our findings suggest that regulation of transport pathways in a cell type-specific manner contributes to diversity in sensory cilia structure and might allow dynamic remodeling of ciliary architecture via multiple inputs.

Genetic architecture for human aggression: A study of gene-phenotype relationship in OMIM.

PubMed

Zhang-James, Yanli; Faraone, Stephen V

2016-07-01

Genetic studies of human aggression have mainly focused on known candidate genes and pathways regulating serotonin and dopamine signaling and hormonal functions. These studies have taught us much about the genetics of human aggression, but no genetic locus has yet achieved genome-significance. We here present a review based on a paradoxical hypothesis that studies of rare, functional genetic variations can lead to a better understanding of the molecular mechanisms underlying complex multifactorial disorders such as aggression. We examined all aggression phenotypes catalogued in Online Mendelian Inheritance in Man (OMIM), an Online Catalog of Human Genes and Genetic Disorders. We identified 95 human disorders that have documented aggressive symptoms in at least one individual with a well-defined genetic variant. Altogether, we retrieved 86 causal genes. Although most of these genes had not been implicated in human aggression by previous studies, the most significantly enriched canonical pathways had been previously implicated in aggression (e.g., serotonin and dopamine signaling). Our findings provide strong evidence to support the causal role of these pathways in the pathogenesis of aggression. In addition, the novel genes and pathways we identified suggest additional mechanisms underlying the origins of human aggression. Genome-wide association studies with very large samples will be needed to determine if common variants in these genes are risk factors for aggression. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

Preventing early child maltreatment: implications from a longitudinal study of maternal abuse history, substance use problems, and offspring victimization.

PubMed

Appleyard, Karen; Berlin, Lisa J; Rosanbalm, Katherine D; Dodge, Kenneth A

2011-06-01

In the interest of improving child maltreatment prevention science, this longitudinal, community based study of 499 mothers and their infants tested the hypothesis that mothers' childhood history of maltreatment would predict maternal substance use problems, which in turn would predict offspring victimization. Mothers (35% White/non-Latina, 34% Black/non-Latina, 23% Latina, 7% other) were recruited and interviewed during pregnancy, and child protective services records were reviewed for the presence of the participants' target infants between birth and age 26 months. Mediating pathways were examined through structural equation modeling and tested using the products of the coefficients approach. The mediated pathway from maternal history of sexual abuse to substance use problems to offspring victimization was significant (standardized mediated path [ab] = .07, 95% CI [.02, .14]; effect size = .26), as was the mediated pathway from maternal history of physical abuse to substance use problems to offspring victimization (standardized mediated path [ab] = .05, 95% CI [.01, .11]; effect size = .19). There was no significant mediated pathway from maternal history of neglect. Findings are discussed in terms of specific implications for child maltreatment prevention, including the importance of assessment and early intervention for maternal history of maltreatment and substance use problems, targeting women with maltreatment histories for substance use services, and integrating child welfare and parenting programs with substance use treatment.

Opposite Interplay Between the Canonical WNT/β-Catenin Pathway and PPAR Gamma: A Potential Therapeutic Target in Gliomas.

PubMed

Vallée, Alexandre; Lecarpentier, Yves; Guillevin, Rémy; Vallée, Jean-Noël

2018-06-01

In gliomas, the canonical Wingless/Int (WNT)/β-catenin pathway is increased while peroxisome proliferator-activated receptor gamma (PPAR-γ) is downregulated. The two systems act in an opposite manner. This review focuses on the interplay between WNT/β-catenin signaling and PPAR-γ and their metabolic implications as potential therapeutic target in gliomas. Activation of the WNT/β-catenin pathway stimulates the transcription of genes involved in proliferation, invasion, nucleotide synthesis, tumor growth, and angiogenesis. Activation of PPAR-γ agonists inhibits various signaling pathways such as the JAK/STAT, WNT/β-catenin, and PI3K/Akt pathways, which reduces tumor growth, cell proliferation, cell invasiveness, and angiogenesis. Nonsteroidal anti-inflammatory drugs, curcumin, antipsychotic drugs, adiponectin, and sulforaphane downregulate the WNT/β-catenin pathway through the upregulation of PPAR-γ and thus appear to provide an interesting therapeutic approach for gliomas. Temozolomide (TMZ) is an antiangiogenic agent. The downstream action of this opposite interplay may explain the TMZ-resistance often reported in gliomas.

Characterization of Hippo Pathway Components by Gene Inactivation.

PubMed

Plouffe, Steven W; Meng, Zhipeng; Lin, Kimberly C; Lin, Brian; Hong, Audrey W; Chun, Justin V; Guan, Kun-Liang

2016-12-01

The Hippo pathway is important for regulating tissue homeostasis, and its dysregulation has been implicated in human cancer. However, it is not well understood how the Hippo pathway becomes dysregulated because few mutations in core Hippo pathway components have been identified. Therefore, much work in the Hippo field has focused on identifying upstream regulators, and a complex Hippo interactome has been identified. Nevertheless, it is not always clear which components are the most physiologically relevant in regulating YAP/TAZ. To provide an overview of important Hippo pathway components, we created knockout cell lines for many of these components and compared their relative contributions to YAP/TAZ regulation in response to a wide range of physiological signals. By this approach, we provide an overview of the functional importance of many Hippo pathway components and demonstrate NF2 and RHOA as important regulators of YAP/TAZ and TAOK1/3 as direct kinases for LATS1/2. Copyright © 2016 Elsevier Inc. All rights reserved.

p53 regulates the mevalonate pathway in human glioblastoma multiforme

PubMed Central

Laezza, C; D'Alessandro, A; Di Croce, L; Picardi, P; Ciaglia, E; Pisanti, S; Malfitano, A M; Comegna, M; Faraonio, R; Gazzerro, P; Bifulco, M

2015-01-01

The mevalonate (MVA) pathway is an important metabolic pathway implicated in multiple aspects of tumorigenesis. In this study, we provided evidence that p53 induces the expression of a group of enzymes of the MVA pathway including 3′-hydroxy-3′-methylglutaryl-coenzyme A reductase, MVA kinase, farnesyl diphosphate synthase and farnesyl diphosphate farnesyl transferase 1, in the human glioblastoma multiforme cell line, U343 cells, and in normal human astrocytes, NHAs. Genetic and pharmacologic perturbation of p53 directly influences the expression of these genes. Furthermore, p53 is recruited to the gene promoters in designated p53-responsive elements, thereby increasing their transcription. Such effect was abolished by site-directed mutagenesis in the p53-responsive element of promoter of the genes. These findings highlight another aspect of p53 functions unrelated to tumor suppression and suggest p53 as a novel regulator of the MVA pathway providing insight into the role of this pathway in cancer progression. PMID:26469958

Cell signaling pathways in the adrenal cortex: Links to stem/progenitor biology and neoplasia.

PubMed

Penny, Morgan K; Finco, Isabella; Hammer, Gary D

2017-04-15

The adrenal cortex is a dynamic tissue responsible for the synthesis of steroid hormones, including mineralocorticoids, glucocorticoids, and androgens in humans. Advances have been made in understanding the role of adrenocortical stem/progenitor cell populations in cortex homeostasis and self-renewal. Recently, large molecular profiling studies of adrenocortical carcinoma (ACC) have given insights into proteins and signaling pathways involved in normal tissue homeostasis that become dysregulated in cancer. These data provide an impetus to examine the cellular pathways implicated in adrenocortical disease and study connections, or lack thereof, between adrenal homeostasis and tumorigenesis, with a particular focus on stem and progenitor cell pathways. In this review, we discuss evidence for stem/progenitor cells in the adrenal cortex, proteins and signaling pathways that may regulate these cells, and the role these proteins play in pathologic and neoplastic conditions. In turn, we also examine common perturbations in adrenocortical tumors (ACT) and how these proteins and pathways may be involved in adrenal homeostasis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

A chloroplast pathway for the de novo biosynthesis of triacylglycerol in Chlamydomonas reinhardtii

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fan, J.; Xu, C.; Andre, C.

2011-06-23

Neutral lipid metabolism has been extensively studied in yeast, plants and mammals. In contrast, little information is available regarding the biochemical pathway, enzymes and regulatory factors involved in the biosynthesis of triacylglycerol (TAG) in microalgae. In the conventional TAG biosynthetic pathway widely accepted for yeast, plants and mammals, TAG is assembled in the endoplasmic reticulum (ER) from its immediate precursor diacylglycerol (DAG) made by ER-specific acyltransferases, and is deposited exclusively in lipid droplets in the cytosol. Here, we demonstrated that the unicellular microalga Chlamydomonas reinhardtii employs a distinct pathway that uses DAG derived almost exclusively from the chloroplast to producemore » TAG. This unique TAG biosynthesis pathway is largely dependent on de novo fatty acid synthesis, and the TAG formed in this pathway is stored in lipid droplets in both the chloroplast and the cytosol. These findings have wide implications for understanding TAG biosynthesis and storage and other areas of lipid metabolism in microalgae and other organisms.« less

Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array.

PubMed

Saunders, Edward J; Dadaev, Tokhir; Leongamornlert, Daniel A; Al Olama, Ali Amin; Benlloch, Sara; Giles, Graham G; Wiklund, Fredrik; Gronberg, Henrik; Haiman, Christopher A; Schleutker, Johanna; Nordestgaard, Borge G; Travis, Ruth C; Neal, David; Pasayan, Nora; Khaw, Kay-Tee; Stanford, Janet L; Blot, William J; Thibodeau, Stephen N; Maier, Christiane; Kibel, Adam S; Cybulski, Cezary; Cannon-Albright, Lisa; Brenner, Hermann; Park, Jong Y; Kaneva, Radka; Batra, Jyotsna; Teixeira, Manuel R; Pandha, Hardev; Govindasami, Koveela; Muir, Ken; Easton, Douglas F; Eeles, Rosalind A; Kote-Jarai, Zsofia

2016-04-12

Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated risk, whereas two of B100 common, low-penetrance PrCa susceptibility variants identified so far by genome-wide association studies implicate RAD51B and RAD23B. Genotype data from the iCOGS array were imputed to the 1000 genomes phase 3 reference panel for 21 780 PrCa cases and 21 727 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. We subsequently performed single variant, gene and pathway-level analyses using 81 303 SNPs within 20 Kb of a panel of 179 DNA-repair genes. Single SNP analyses identified only the previously reported association with RAD51B. Gene-level analyses using the SKAT-C test from the SNP-set (Sequence) Kernel Association Test (SKAT) identified a significant association with PrCa for MSH5. Pathway-level analyses suggested a possible role for the translesion synthesis pathway in PrCa risk and Homologous recombination/Fanconi Anaemia pathway for PrCa aggressiveness, even though after adjustment for multiple testing these did not remain significant. MSH5 is a novel candidate gene warranting additional follow-up as a prospective PrCa-risk locus. MSH5 has previously been reported as a pleiotropic susceptibility locus for lung, colorectal and serous ovarian cancers.

PI3K pathway inhibitors: potential prospects as adjuncts to vaccine immunotherapy for glioblastoma.

PubMed

Oh, Taemin; Ivan, Michael E; Sun, Matthew Z; Safaee, Michael; Fakurnejad, Shayan; Clark, Aaron J; Sayegh, Eli T; Bloch, Orin; Parsa, Andrew T

2014-01-01

Constitutive activation of the PI3K pathway has been implicated in glioblastoma (GBM) pathogenesis. Pharmacologic inhibition can both inhibit tumor survival and downregulate expression of programmed death ligand-1, a protein highly expressed on glioma cells that strongly contributes to cancer immunosuppression. In that manner, PI3K pathway inhibitors can help optimize GBM vaccine immunotherapy. In this review, we describe and assess the potential integration of various classes of PI3K pathway inhibitors into GBM immunotherapy. While early-generation inhibitors have a wide range of immunosuppressive effects that could negate their antitumor potency, further work should better characterize how contemporary inhibitors affect the immune response. This will help determine if these inhibitors are truly a therapeutic avenue with a strong future in GBM immunotherapy.

Effect of posture on arterial baroreflex control of heart rate in humans

NASA Technical Reports Server (NTRS)

Harrison, M. H.; Rittenhouse, D.; Greenleaf, J. E.

1986-01-01

The effects of blood-volume redistribution induced by postural changes on baroreflex activity are investigated. The central blood volume and baroreceptor functions of ten males between 23-51 years old were examined while they were in the head-up tilt (HUT), head-down tilt (HDT), and supine positions. It is observed that during HDT at 15 deg the pulse interval over the first five cardiac cycles following neck suction onset is 51 + or - 18 ms longer, at 30 deg it is 61 + or - 20 ms longer, and at 45 deg it is 74 + or - 35 ms longer than at supine; during HUT at 15 deg the pulse interval is 25 + or - 9 ms shorter than when supine, but for the 30 and 45 deg there is no significant difference in pulse interval detected. The data reveal that posture does modify arterial baroreflex control of heart rate.

Left ventricular function during lower body negative pressure

NASA Technical Reports Server (NTRS)

Ahmad, M.; Blomqvist, C. G.; Mullins, C. B.; Willerson, J. T.

1977-01-01

The response of the human left ventricle to lower body negative pressure (LBNP) and the relation between left ventricular function and hemodynamic response were investigated. Ventricular function curves relating stroke volume to end-diastolic volume were obtained in 12 normal men. Volume data were derived from echocardiographic measurements of left ventricular end-systolic and end-diastolic diameters at rest and during lower body negative pressure (LBNP) at minus 40 mm Hg. End-diastolic volume decreased by 19% and stroke volume by 22%. There were no significant changes in heart rate, arterial blood pressure, or end-systolic volume. Thus, moderate levels of LBNP significantly reduce preload and stroke volume without affecting contractile state. The absence of significant changes in heart rate and arterial blood pressure in the presence of a significant reduction in stroke volume is consistent with an increase in systemic peripheral resistance mediated by low-pressure baroreceptors.

[Urban individual exposure to cadmium and baroreceptor response to posture].

PubMed

Sancini, A; Sinibaldi, F; Loreti, B; De Sio, S; Casale, T; Sacco, C; Scala, B; Monti, C; Chighine, A; Bonomi, S; Cirelli, P; Massimi, R; Giubilati, R; Tomei, F; Rosati, M V

2014-01-01

Outdoor workers are daily exposed to urban pollutants. The aim of the study is to evaluate the relationship between the values of environmental monitoring collected by personal dosimetries and changes in blood pressure due to posture in outdoor workers. 32 subjects of both sexes were enrolled in the study, we evaluated the values of environmental monitoring of breathable dust, nickel, arsenic, cadmium, lead, benzene, toluene, xylene and 16 PAHs. Blood pressure in supine and standing positions was measured in all subjects. The multiple linear regression analysis showed a significant reduction of orthostatic response of diastolic blood pressure in non-smoking outdoor workers occupationally exposed to cadmium. The results of our study let us to believe that exposure to low doses of urban polluted cadmium may affect the response of diastolic blood pressure to orthostatism, as per a paraphysiological condition of sympathetic down-regulation.

The autonomic nervous system at high altitude

PubMed Central

Drinkhill, Mark J.; Rivera-Chira, Maria

2007-01-01

The effects of hypobaric hypoxia in visitors depend not only on the actual elevation but also on the rate of ascent. Sympathetic activity increases and there are increases in blood pressure and heart rate. Pulmonary vasoconstriction leads to pulmonary hypertension, particularly during exercise. The sympathetic excitation results from hypoxia, partly through chemoreceptor reflexes and partly through altered baroreceptor function. High pulmonary arterial pressures may also cause reflex systemic vasoconstriction. Most permanent high altitude dwellers show excellent adaptation although there are differences between populations in the extent of the ventilatory drive and the erythropoiesis. Some altitude dwellers, particularly Andeans, may develop chronic mountain sickness, the most prominent characteristic of which being excessive polycythaemia. Excessive hypoxia due to peripheral chemoreceptor dysfunction has been suggested as a cause. The hyperviscous blood leads to pulmonary hypertension, symptoms of cerebral hypoperfusion, and eventually right heart failure and death. PMID:17264976

The history and regulatory mechanism of the Hippo pathway

PubMed Central

Kim, Wantae; Jho, Eek-hoon

2018-01-01

How the organ size is adjusted to the proper size during development and how organs know that they reach the original size during regeneration remain long-standing questions. Based on studies using multiple model organisms and approaches for over 20 years, a consensus has been established that the Hippo pathway plays crucial roles in controlling organ size and maintaining tissue homeostasis. Given the significance of these processes, the dysregulation of the Hippo pathway has also implicated various diseases, such as tissue degeneration and cancer. By regulating the downstream transcriptional coactivators YAP and TAZ, the Hippo pathway coordinates cell proliferation and apoptosis in response to a variety of signals including cell contact inhibition, polarity, mechanical sensation and soluble factors. Since the core components and their functions of the Hippo pathway are evolutionarily conserved, this pathway serves as a global regulator of organ size control. Therefore, further investigation of the regulatory mechanisms will provide physiological insights to better understand tissue homeostasis. In this review, the historical developments and current understandings of the regulatory mechanism of Hippo signaling pathway are discussed. PMID:29397869

Identification of a novel trafficking pathway exporting a replication protein, Orc2 to nucleus via classical secretory pathway in Plasmodium falciparum.

PubMed

Sharma, Rahul; Sharma, Bhumika; Gupta, Ashish; Dhar, Suman Kumar

2018-05-01

Malaria parasites use an extensive secretory pathway to traffic a number of proteins within itself and beyond. In higher eukaryotes, Endoplasmic Reticulum (ER) membrane bound transcription factors such as SREBP are reported to get processed en route and migrate to nucleus under the influence of specific cues. However, a protein constitutively trafficked to the nucleus via classical secretory pathway has not been reported. Herein, we report the presence of a novel trafficking pathway in an apicomplexan, Plasmodium falciparum where a homologue of an Origin Recognition Complex 2 (Orc2) goes to the nucleus following its association with the ER. Our work highlights the unconventional role of ER in protein trafficking and reports for the first time an ORC homologue getting trafficked through such a pathway to the nucleus where it may be involved in DNA replication and other ancillary functions. Such trafficking pathways may have a profound impact on the cell biology of a malaria parasite and have significant implications in strategizing new antimalarials. Copyright © 2018 Elsevier B.V. All rights reserved.

Sonic Hedgehog Signaling in Thyroid Cancer

PubMed Central

Xu, Xiulong; Lu, Yurong; Li, Yi; Prinz, Richard A.

2017-01-01

Thyroid cancer is the most common malignancy of the endocrine system. The initiation of thyroid cancer is often triggered by a genetic mutation in the phosphortidylinositol-3 kinase (PI3K) or mitogen-activated protein kinase (MAPK) pathway, such as RAS and BRAF, or by the rearrangement of growth factor receptor tyrosine kinase genes such as RET/PTC. The sonic hedgehog (Shh) pathway is evolutionarily conserved and plays an important role in the embryonic development of normal tissues and organs. Gene mutations in the Shh pathway are involved in basal cell carcinomas (BCC). Activation of the Shh pathway due to overexpression of the genes encoding the components of this pathway stimulates the growth and spread of a wide range of cancer types. The Shh pathway also plays an important role in cancer stem cell (CSC) self-renewal. GDC-0449 and LDE-225, two inhibitors of this pathway, have been approved for treating BCC and are being tested as a single agent or in combination with other drugs for treating various other cancers. Here, we review the recent findings on activation of the Shh pathway in thyroid cancer and its role in maintaining thyroid CSC self-renewal. We also summarize the recent developments on crosstalk of the Shh pathway with the MAPK and PI3K oncogenic pathways, and its implications for combination therapy. PMID:29163356

Policy Implications of Deep Decarbonization in the United States

NASA Astrophysics Data System (ADS)

Williams, J.

2015-12-01

Independent research teams from sixteen of the largest greenhouse gas (GHG) emitting countries have participated in a collaborative two-year project developing emission reduction scenarios for their own countries consistent with limiting anthropogenic warming to 2 C or less. This talk discusses the policy implications of the work done by the Deep Decarbonization Pathways Project (DDPP) at the US federal and international levels, including new ways of informing decision makers about the requirements of an energy system transformation.

FTO associations with obesity and telomere length.

PubMed

Zhou, Yuling; Hambly, Brett D; McLachlan, Craig S

2017-09-01

This review examines the biology of the Fat mass- and obesity-associated gene (FTO), and the implications of genetic association of FTO SNPs with obesity and genetic aging. Notably, we focus on the role of FTO in the regulation of methylation status as possible regulators of weight gain and genetic aging. We present a theoretical review of the FTO gene with a particular emphasis on associations with UCP2, AMPK, RBL2, IRX3, CUX1, mTORC1 and hormones involved in hunger regulation. These associations are important for dietary behavior regulation and cellular nutrient sensing via amino acids. We suggest that these pathways may also influence telomere regulation. Telomere length (TL) attrition may be influenced by obesity-related inflammation and oxidative stress, and FTO gene-involved pathways. There is additional emerging evidence to suggest that telomere length and obesity are bi-directionally associated. However, the role of obesity risk-related genotypes and associations with TL are not well understood. The FTO gene may influence pathways implicated in regulation of TL, which could help to explain some of the non-consistent relationship between weight phenotype and telomere length that is observed in population studies investigating obesity.

CpG Island Methylator Phenotype-High Colorectal Cancers and Their Prognostic Implications and Relationships with the Serrated Neoplasia Pathway

PubMed Central

Rhee, Ye-Young; Kim, Kyung-Ju; Kang, Gyeong Hoon

2017-01-01

The concept of a CpG island methylator phenotype (CIMP) was first introduced by Toyota and Issa to describe a subset of colorectal cancers (CRCs) with concurrent hypermethylation of multiple CpG island loci. The concept of CIMP as a molecular carcinogenesis mechanism was consolidated by the identification of the serrated neoplasia pathway, in which CIMP participates in the initiation and progression of serrated adenomas. Distinct clinicopathological and molecular features of CIMP-high (CIMP-H) CRCs have been characterized, including proximal colon location, older age of onset, female preponderance, and frequent associations of high-level microsatellite instability and BRAF mutations. CIMP-H CRCs arise in sessile or traditional serrated adenomas and thus tend to display the morphological characteristics of serrated adenomas, including epithelial serration, vesicular nuclei, and abundant cytoplasm. Both the frequent association of CIMP and poor prognosis and different responses of CRCs to adjuvant therapy depending on CIMP status indicate clinical implications. In this review, we present an overview of the literature documenting the relevant findings of CIMP-H CRCs and their relationships with the serrated neoplasia pathway. PMID:27885175

The Fanconi anemia pathway and ICL repair: implications for cancer therapy

PubMed Central

Wang, Lily C; Gautier, Jean

2011-01-01

Fanconi anemia (FA) is an inherited disease caused by mutations in at least 13 genes and characterized by genomic instability. In addition to displaying strikingly heterogenous clinical phenotypes, FA patients are exquisitely sensitive to treatments with crosslinking agents that create interstrand crosslinks (ICL). In contrast to bacteria and yeast, in which ICLs are repaired through replication-dependent and –independent mechanisms, it is thought that ICLs are repaired primarily during DNA replication in vertebrates (Moldovan and D’Andrea, 2009). However, recent data indicate that replication-independent ICL repair also operates in vertebrates. While the precise role of the FA pathway in ICL repair remains elusive, increasing evidence suggests that FA proteins function at different steps in the sensing, recognition and processing of ICLs, as well as in signaling from these very toxic lesions, which can be generated by a wide variety of cancer chemotherapeutic drugs. Here, we discuss some of the recent findings that have shed light on the role of the FA pathway in ICL repair with special emphasis on the implications of these findings for cancer therapy since disruption of FA genes have been associated with cancer predisposition. PMID:20807115

Arsenic degrades PML or PML-RARalpha through a SUMO-triggered RNF4/ubiquitin-mediated pathway.

PubMed

Lallemand-Breitenbach, Valérie; Jeanne, Marion; Benhenda, Shirine; Nasr, Rihab; Lei, Ming; Peres, Laurent; Zhou, Jun; Zhu, Jun; Raught, Brian; de Thé, Hugues

2008-05-01

In acute promyelocytic leukaemia (APL), arsenic trioxide induces degradation of the fusion protein encoded by the PML-RARA oncogene, differentiation of leukaemic cells and produces clinical remissions. SUMOylation of its PML moiety was previously implicated, but the nature of the degradation pathway involved and the role of PML-RARalpha catabolism in the response to therapy have both remained elusive. Here, we demonstrate that arsenic-induced PML SUMOylation triggers its Lys 48-linked polyubiquitination and proteasome-dependent degradation. When exposed to arsenic, SUMOylated PML recruits RNF4, the human orthologue of the yeast SUMO-dependent E3 ubiquitin-ligase, as well as ubiquitin and proteasomes onto PML nuclear bodies. Arsenic-induced differentiation is impaired in cells transformed by a non-degradable PML-RARalpha SUMOylation mutant or in APL cells transduced with a dominant-negative RNF4, directly implicating PML-RARalpha catabolism in the therapeutic response. We thus identify PML as the first protein degraded by SUMO-dependent polyubiquitination. As PML SUMOylation recruits not only RNF4, ubiquitin and proteasomes, but also many SUMOylated proteins onto PML nuclear bodies, these domains could physically integrate the SUMOylation, ubiquitination and degradation pathways.

Ceramide Is Metabolized to Acylceramide and Stored in Lipid Droplets.

PubMed

Senkal, Can E; Salama, Mohamed F; Snider, Ashley J; Allopenna, Janet J; Rana, Nadia A; Koller, Antonius; Hannun, Yusuf A; Obeid, Lina M

2017-03-07

In an approach aimed at defining interacting partners of ceramide synthases (CerSs), we found that fatty acyl-CoA synthase ACSL5 interacts with all CerSs. We demonstrate that ACSL5-generated FA-CoA was utilized with de novo ceramide for the generation of acylceramides, poorly studied ceramide metabolites. Functionally, inhibition of ceramide channeling to acylceramide enhanced accumulation of de novo ceramide and resulted in augmentation of ceramide-mediated apoptosis. Mechanistically, we show that acylceramide generation is catalyzed by diacylglycerol acyltransferase 2 (DGAT2) on lipid droplets. In summary, this study identifies a metabolic pathway of acylceramide generation and its sequestration in LDs in cells and in livers of mice on a high-fat diet. The study also implicates this pathway in ceramide-mediated apoptosis, and has implications in co-regulation of triglyceride and sphingolipid metabolisms. Published by Elsevier Inc.

Epidemiological transition of colorectal cancer in developing countries: Environmental factors, molecular pathways, and opportunities for prevention

PubMed Central

Bishehsari, Faraz; Mahdavinia, Mahboobeh; Vacca, Michele; Malekzadeh, Reza; Mariani-Costantini, Renato

2014-01-01

Colorectal cancer (CRC) is one of the leading causes of cancer and cancer-related mortality worldwide. The disease has been traditionally a major health problem in industrial countries, however the CRC rates are increasing in the developing countries that are undergoing economic growth. Several environmental risk factors, mainly changes in diet and life style, have been suggested to underlie the rise of CRC in these populations. Diet and lifestyle impinge on nuclear receptors, on the intestinal microbiota and on crucial molecular pathways that are implicated in intestinal carcinogenesis. In this respect, the epidemiological transition in several regions of the world offers a unique opportunity to better understand CRC carcinogenesis by studying the disease phenotypes and their environmental and molecular associations in different populations. The data from these studies may have important implications for the global prevention and treatment of CRC. PMID:24876728

Tissue and cellular rigidity and mechanosensitive signaling activation in Alexander disease.

PubMed

Wang, Liqun; Xia, Jing; Li, Jonathan; Hagemann, Tracy L; Jones, Jeffrey R; Fraenkel, Ernest; Weitz, David A; Zhang, Su-Chun; Messing, Albee; Feany, Mel B

2018-05-15

Glial cells have increasingly been implicated as active participants in the pathogenesis of neurological diseases, but critical pathways and mechanisms controlling glial function and secondary non-cell autonomous neuronal injury remain incompletely defined. Here we use models of Alexander disease, a severe brain disorder caused by gain-of-function mutations in GFAP, to demonstrate that misregulation of GFAP leads to activation of a mechanosensitive signaling cascade characterized by activation of the Hippo pathway and consequent increased expression of A-type lamin. Importantly, we use genetics to verify a functional role for dysregulated mechanotransduction signaling in promoting behavioral abnormalities and non-cell autonomous neurodegeneration. Further, we take cell biological and biophysical approaches to suggest that brain tissue stiffness is increased in Alexander disease. Our findings implicate altered mechanotransduction signaling as a key pathological cascade driving neuronal dysfunction and neurodegeneration in Alexander disease, and possibly also in other brain disorders characterized by gliosis.

Carbon dioxide-sensing in organisms and its implications for human disease

PubMed Central

Cummins, Eoin P.; Selfridge, Andrew C.; Sporn, Peter H.; Sznajder, Jacob I.; Taylor, Cormac T.

2013-01-01

The capacity of organisms to sense changes in the levels of internal and external gases and to respond accordingly is central to a range of physiologic and pathophysiologic processes. Carbon dioxide, a primary product of oxidative metabolism is one such gas that can be sensed by both prokaryotic and eukaryotic cells and in response to altered levels, elicit the activation of multiple adaptive pathways. The outcomes of activating CO2-sensitive pathways in various species include increased virulence of fungal and bacterial pathogens, prey-seeking behavior in insects as well as taste perception, lung function, and the control of immunity in mammals. In this review, we discuss what is known about the mechanisms underpinning CO2 sensing across a range of species and consider the implications of this for physiology, disease progression, and the possibility of developing new therapeutics for inflammatory and infectious disease. PMID:24045706

Traumatogenic Processes and Pathways to Mental Health Outcomes for Sexual Minorities Exposed to Bias Crime Information.

PubMed

Lannert, Brittany K

2015-07-01

Vicarious traumatization of nonvictim members of communities targeted by bias crimes has been suggested by previous qualitative studies and often dominates public discussion following bias events, but proximal and distal responses of community members have yet to be comprehensively modeled, and quantitative research on vicarious responses is scarce. This comprehensive review integrates theoretical and empirical literatures in social, clinical, and physiological psychology in the development of a model of affective, cognitive, and physiological responses of lesbian, gay, and bisexual individuals upon exposure to information about bias crimes. Extant qualitative research in vicarious response to bias crimes is reviewed in light of theoretical implications and methodological limitations. Potential pathways to mental health outcomes are outlined, including accumulative effects of anticipatory defensive responding, multiplicative effects of minority stress, and putative traumatogenic physiological and cognitive processes of threat. Methodological considerations, future research directions, and clinical implications are also discussed. © The Author(s) 2014.

Infection control implications of heterogeneous resistance mechanisms in carbapenem-resistant Enterobacteriaceae (CRE).

PubMed

Goodman, K E; Simner, P J; Tamma, P D; Milstone, A M

2016-01-01

The Centers for Disease Control and Prevention (CDC) defines carbapenem-resistant Enterobacteriaceae (CRE) based upon a phenotypic demonstration of carbapenem resistance. However, considerable heterogeneity exists within this definitional umbrella. CRE may mechanistically differ by whether they do or do not produce carbapenemases. Moreover, patients can acquire CRE through multiple pathways: endogenously through antibiotic selective pressure on intestinal microbiota, exogenously through horizontal transmission or through a combination of these factors. Some evidence suggests that non-carbapenemase-producing CRE may be more frequently acquired by antibiotic exposure and carbapenemase-producing CRE via horizontal transmission, but definitive data are lacking. This review examines types of CRE resistance mechanisms, antibiotic exposure and horizontal transmission pathways of CRE acquisition, and the implications of these heterogeneities to the development of evidence-based CRE healthcare epidemiology policies. In our Expert Commentary & Five-Year View, we outline specific nosocomial CRE knowledge gaps and potential methodological approaches for their resolution.

Towards a Genetic Definition of Cancer-Associated Inflammation

PubMed Central

Prendergast, George C.; Metz, Richard; Muller, Alexander J.

2010-01-01

Chronic inflammation drives the development of many cancers, but a genetic definition of what constitutes ‘cancer-associated’ inflammation has not been determined. Recently, a mouse genetic study revealed a critical role for the immune escape mediator indoleamine 2,3-dioxygenase (IDO) in supporting inflammatory skin carcinogenesis. IDO is generally regarded as being immunosuppressive; however, there was no discernable difference in generalized inflammatory processes in IDO-null mice under conditions where tumor development was significantly suppressed, implicating IDO as key to establishing the pathogenic state of ‘cancer-associated’ inflammation. Here we review recent findings and their potential implications to understanding the relationship between immune escape and inflammation in cancer. Briefly, we propose that genetic pathways of immune escape in cancer are synonymous with pathways that define ‘cancer-associated’ inflammation and that these processes may be identical rather than distinct, as generally presumed, in terms of their genetic definition. PMID:20228228

Early Life Stress Effects on Glucocorticoid—BDNF Interplay in the Hippocampus

PubMed Central

Daskalakis, Nikolaos P.; De Kloet, Edo Ronald; Yehuda, Rachel; Malaspina, Dolores; Kranz, Thorsten M.

2015-01-01

Early life stress (ELS) is implicated in the etiology of multiple psychiatric disorders. Important biological effects of ELS are manifested in stress-susceptible regions of the hippocampus and are partially mediated by long-term effects on glucocorticoid (GC) and/or neurotrophin signaling pathways. GC-signaling mediates the regulation of stress response to maintain homeostasis, while neurotrophin signaling plays a key role in neuronal outgrowth and is crucial for axonal guidance and synaptic integrity. The neurotrophin and GC-signaling pathways co-exist throughout the central nervous system (CNS), particularly in the hippocampus, which has high expression levels of glucocorticoid-receptors (GR) and mineralocorticoid-receptors (MR) as well as brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase receptor B (TrkB). This review addresses the effects of ELS paradigms on GC- and BDNF-dependent mechanisms and their crosstalk in the hippocampus, including potential implications for the pathogenesis of common stress-related disorders. PMID:26635521

Reelin Regulates the Maturation of Dendritic Spines, Synaptogenesis and Glial Ensheathment of Newborn Granule Cells

PubMed Central

Bosch, Carles; Masachs, Nuria; Exposito-Alonso, David; Martínez, Albert; Teixeira, Cátia M.; Fernaud, Isabel; Pujadas, Lluís; Ulloa, Fausto; Comella, Joan X.; DeFelipe, Javier; Merchán-Pérez, Angel; Soriano, Eduardo

2016-01-01

The Reelin pathway is essential for both neural migration and for the development and maturation of synaptic connections. However, its role in adult synaptic formation and remodeling is still being investigated. Here, we investigated the impact of the Reelin/Dab1 pathway on the synaptogenesis of newborn granule cells (GCs) in the young-adult mouse hippocampus. We show that neither Reelin overexpression nor the inactivation of its intracellular adapter, Dab1, substantially alters dendritic spine numbers in these neurons. In contrast, 3D-electron microscopy (focused ion beam milling/scanning electron microscope) revealed that dysregulation of the Reelin/Dab1 pathway leads to both transient and permanent changes in the types and morphology of dendritic spines, mainly altering mushroom, filopodial, and branched GC spines. We also found that the Reelin/Dab1 pathway controls synaptic configuration of presynaptic boutons in the dentate gyrus, with its dysregulation leading to a substantial decrease in multi-synaptic bouton innervation. Lastly, we show that the Reelin/Dab1 pathway controls astroglial ensheathment of synapses. Thus, the Reelin pathway is a key regulator of adult-generated GC integration, by controlling dendritic spine types and shapes, their synaptic innervation patterns, and glial ensheathment. These findings may help to better understanding of hippocampal circuit alterations in neurological disorders in which the Reelin pathway is implicated. Significance Statement The extracellular protein Reelin has an important role in neurological diseases, including epilepsy, Alzheimer's disease and psychiatric diseases, targeting hippocampal circuits. Here we address the role of Reelin in the development of synaptic contacts in adult-generated granule cells (GCs), a neuronal population that is crucial for learning and memory and implicated in neurological and psychiatric diseases. We found that the Reelin pathway controls the shapes, sizes, and types of dendritic spines, the complexity of multisynaptic innervations and the degree of the perisynaptic astroglial ensheathment that controls synaptic homeostasis. These findings show a pivotal role of Reelin in GC synaptogenesis and provide a foundation for structural circuit alterations caused by Reelin deregulation that may occur in neurological and psychiatric disorders. PMID:27624722

Mechanisms of Resistance to Chemotherapies Targeting BRCA-Mutant Breast Cancer

DTIC Science & Technology

2015-12-01

limiting for mutagenic NHEJ but not for physiological CSR. An implication of our results is that deregulation of the RNF168/53BP1 pathway could alter the...resistance in BRCA-deficient tumors. We have also observed that deregulation of the RNF168/53BP1 pathway can alter the chemosensitivity of BRCA1 deficient...FASEB Summer Research Conference. Big Sky, Montana, 2015 g. Invited Speaker, Conference "Chromatin and Cell Fate", Essen, Germany , 2015 h. Invited

Alternative Splicing in the Hippo Pathway—Implications for Disease and Potential Therapeutic Targets

PubMed Central

Porazinski, Sean; Ladomery, Michael

2018-01-01

Alternative splicing is a well-studied gene regulatory mechanism that produces biological diversity by allowing the production of multiple protein isoforms from a single gene. An involvement of alternative splicing in the key biological signalling Hippo pathway is emerging and offers new therapeutic avenues. This review discusses examples of alternative splicing in the Hippo pathway, how deregulation of these processes may contribute to disease and whether these processes offer new potential therapeutic targets. PMID:29534050

The Atypical MAP Kinase SWIP-13/ERK8 Regulates Dopamine Transporters through a Rho-Dependent Mechanism

PubMed Central

Bermingham, Daniel P.; Snider, Sam L.; Miller, David M.

2017-01-01

The neurotransmitter dopamine (DA) regulates multiple behaviors across phylogeny, with disrupted DA signaling in humans associated with addiction, attention-deficit/ hyperactivity disorder, schizophrenia, and Parkinson's disease. The DA transporter (DAT) imposes spatial and temporal limits on DA action, and provides for presynaptic DA recycling to replenish neurotransmitter pools. Molecular mechanisms that regulate DAT expression, trafficking, and function, particularly in vivo, remain poorly understood, though recent studies have implicated rho-linked pathways in psychostimulant action. To identify genes that dictate the ability of DAT to sustain normal levels of DA clearance, we pursued a forward genetic screen in Caenorhabditis elegans based on the phenotype swimming-induced paralysis (Swip), a paralytic behavior observed in hermaphrodite worms with loss-of-function dat-1 mutations. Here, we report the identity of swip-13, which encodes a highly conserved ortholog of the human atypical MAP kinase ERK8. We present evidence that SWIP-13 acts presynaptically to insure adequate levels of surface DAT expression and DA clearance. Moreover, we provide in vitro and in vivo evidence supporting a conserved pathway involving SWIP-13/ERK8 activation of Rho GTPases that dictates DAT surface expression and function. SIGNIFICANCE STATEMENT Signaling by the neurotransmitter dopamine (DA) is tightly regulated by the DA transporter (DAT), insuring efficient DA clearance after release. Molecular networks that regulate DAT are poorly understood, particularly in vivo. Using a forward genetic screen in the nematode Caenorhabditis elegans, we implicate the atypical mitogen activated protein kinase, SWIP-13, in DAT regulation. Moreover, we provide in vitro and in vivo evidence that SWIP-13, as well as its human counterpart ERK8, regulate DAT surface availability via the activation of Rho proteins. Our findings implicate a novel pathway that regulates DA synaptic availability and that may contribute to risk for disorders linked to perturbed DA signaling. Targeting this pathway may be of value in the development of therapeutics in such disorders. PMID:28842414

Alcohol resistance in Drosophila is modulated by the Toll innate immune pathway.

PubMed

Troutwine, B R; Ghezzi, A; Pietrzykowski, A Z; Atkinson, N S

2016-04-01

A growing body of evidence has shown that alcohol alters the activity of the innate immune system and that changes in innate immune system activity can influence alcohol-related behaviors. Here, we show that the Toll innate immune signaling pathway modulates the level of alcohol resistance in Drosophila. In humans, a low level of response to alcohol is correlated with increased risk of developing an alcohol use disorder. The Toll signaling pathway was originally discovered in, and has been extensively studied in Drosophila. The Toll pathway is a major regulator of innate immunity in Drosophila, and mammalian Toll-like receptor signaling has been implicated in alcohol responses. Here, we use Drosophila-specific genetic tools to test eight genes in the Toll signaling pathway for effects on the level of response to ethanol. We show that increasing the activity of the pathway increases ethanol resistance whereas decreasing the pathway activity reduces ethanol resistance. Furthermore, we show that gene products known to be outputs of innate immune signaling are rapidly induced following ethanol exposure. The interaction between the Toll signaling pathway and ethanol is rooted in the natural history of Drosophila melanogaster. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Targeting disease through novel pathways of apoptosis and autophagy.

PubMed

Maiese, Kenneth; Chong, Zhao Zhong; Shang, Yan Chen; Wang, Shaohui

2012-12-01

Apoptosis and autophagy impact cell death in multiple systems of the body. Development of new therapeutic strategies that target these processes must address their complex role during developmental cell growth as well as during the modulation of toxic cellular environments. Novel signaling pathways involving Wnt1-inducible signaling pathway protein 1 (WISP1), phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), β-catenin and mammalian target of rapamycin (mTOR) govern apoptotic and autophagic pathways during oxidant stress that affect the course of a broad spectrum of disease entities including Alzheimer's disease, Parkinson's disease, myocardial injury, skeletal system trauma, immune system dysfunction and cancer progression. Implications of potential biological and clinical outcome for these signaling pathways are presented. The CCN family member WISP1 and its intimate relationship with canonical and non-canonical wingless signaling pathways of PI3K, Akt1, β-catenin and mTOR offer an exciting approach for governing the pathways of apoptosis and autophagy especially in clinical disorders that are currently without effective treatments. Future studies that can elucidate the intricate role of these cytoprotective pathways during apoptosis and autophagy can further the successful translation and development of these cellular targets into robust and safe clinical therapeutic strategies.

The Hippo signaling functions through the Notch signaling to regulate intrahepatic bile duct development in mammals.

PubMed

Wu, Nan; Nguyen, Quy; Wan, Ying; Zhou, Tiaohao; Venter, Julie; Frampton, Gabriel A; DeMorrow, Sharon; Pan, Duojia; Meng, Fanyin; Glaser, Shannon; Alpini, Gianfranco; Bai, Haibo

2017-07-01

The Hippo signaling pathway and the Notch signaling pathway are evolutionary conserved signaling cascades that have important roles in embryonic development of many organs. In murine liver, disruption of either pathway impairs intrahepatic bile duct development. Recent studies suggested that the Notch signaling receptor Notch2 is a direct transcriptional target of the Hippo signaling pathway effector YAP, and the Notch signaling is a major mediator of the Hippo signaling in maintaining biliary cell characteristics in adult mice. However, it remains to be determined whether the Hippo signaling pathway functions through the Notch signaling in intrahepatic bile duct development. We found that loss of the Hippo signaling pathway tumor suppressor Nf2 resulted in increased expression levels of the Notch signaling pathway receptor Notch2 in cholangiocytes but not in hepatocytes. When knocking down Notch2 on the background of Nf2 deficiency in mouse livers, the excessive bile duct development induced by Nf2 deficiency was suppressed by heterozygous and homozygous deletion of Notch2 in a dose-dependent manner. These results implicated that Notch signaling is one of the downstream effectors of the Hippo signaling pathway in regulating intrahepatic bile duct development.

Emerging evidence on the role of the Hippo/YAP pathway in liver physiology and cancer.

PubMed

Yimlamai, Dean; Fowl, Brendan H; Camargo, Fernando D

2015-12-01

The Hippo pathway and its regulatory target, YAP, has recently emerged as an important biochemical signaling pathway that tightly governs epithelial tissue growth. Initially defined in Drosophilia, this pathway has shown remarkable conservation in vertebrate systems with many components of the Hippo/YAP pathway showing biochemical and functional conservation. The liver is particularly sensitive to changes in Hippo/YAP signaling with rapid increases in liver size becoming manifest on the order of days to weeks after perturbation. The first identified direct targets of Hippo/YAP signaling were pro-proliferative and anti-apoptotic gene programs, but recent work has now implicated this pathway in cell fate choice, stem cell maintenance/renewal, epithelial to mesenchymal transition, and oncogenesis. The mechanisms by which Hippo/YAP signaling is changed endogenously are beginning to come to light as well as how this pathway interacts with other signaling pathways, and important details for designing new therapeutic interventions. This review focuses on the known roles for Hippo/YAP signaling in the liver and promising avenues for future study. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

The Hippo signaling functions through the Notch signaling to regulate intrahepatic bile duct development in mammals

PubMed Central

Wu, Nan; Nguyen, Quy; Wan, Ying; Zhou, Tiaohao; Venter, Julie; Frampton, Gabriel A; DeMorrow, Sharon; Pan, Duojia; Meng, Fanyin; Glaser, Shannon; Alpini, Gianfranco; Bai, Haibo

2018-01-01

The Hippo signaling pathway and the Notch signaling pathway are evolutionary conserved signaling cascades that have important roles in embryonic development of many organs. In murine liver, disruption of either pathway impairs intrahepatic bile duct development. Recent studies suggested that the Notch signaling receptor Notch2 is a direct transcriptional target of the Hippo signaling pathway effector YAP, and the Notch signaling is a major mediator of the Hippo signaling in maintaining biliary cell characteristics in adult mice. However, it remains to be determined whether the Hippo signaling pathway functions through the Notch signaling in intrahepatic bile duct development. We found that loss of the Hippo signaling pathway tumor suppressor Nf2 resulted in increased expression levels of the Notch signaling pathway receptor Notch2 in cholangiocytes but not in hepatocytes. When knocking down Notch2 on the background of Nf2 deficiency in mouse livers, the excessive bile duct development induced by Nf2 deficiency was suppressed by heterozygous and homozygous deletion of Notch2 in a dose-dependent manner. These results implicated that Notch signaling is one of the downstream effectors of the Hippo signaling pathway in regulating intrahepatic bile duct development. PMID:28581486

Central nervous system regulation of intestinal lipid and lipoprotein metabolism.

PubMed

Farr, Sarah; Taher, Jennifer; Adeli, Khosrow

2016-02-01

In response to nutrient availability, the small intestine and brain closely communicate to modulate energy homeostasis and metabolism. The gut-brain axis involves complex nutrient sensing mechanisms and an integration of neuronal and hormonal signaling. This review summarizes recent evidence implicating the gut-brain axis in regulating lipoprotein metabolism, with potential implications for the dyslipidemia of insulin resistant states. The intestine and brain possess distinct mechanisms for sensing lipid availability, which triggers subsequent regulation of feeding, glucose homeostasis, and adipose tissue metabolism. More recently, central receptors, neuropeptides, and gut hormones that communicate with the brain have been shown to modulate hepatic and intestinal lipoprotein metabolism via parasympathetic and sympathetic signaling. Gut-derived glucagon-like peptides appear to be particularly important in modulating the intestinal secretion of chylomicron particles via a novel brain-gut axis. Dysregulation of these pathways may contribute to postprandial diabetic dyslipidemia. Emerging evidence implicates the central and enteric nervous systems in controlling many aspects of lipid and lipoprotein metabolism. Bidirectional communication between the gut and brain involving neuronal pathways and gut peptides is critical for regulating feeding and metabolism, and forms a neuroendocrine circuit to modulate dietary fat absorption and intestinal production of atherogenic chylomicron particles.

White matter pathways in persistent developmental stuttering: Lessons from tractography.

PubMed

Kronfeld-Duenias, Vered; Civier, Oren; Amir, Ofer; Ezrati-Vinacour, Ruth; Ben-Shachar, Michal

2018-03-01

Fluent speech production relies on the coordinated processing of multiple brain regions. This highlights the role of neural pathways that connect distinct brain regions in producing fluent speech. Here, we aim to investigate the role of the white matter pathways in persistent developmental stuttering (PDS), where speech fluency is disrupted. We use diffusion weighted imaging and tractography to compare the white matter properties between adults who do and do not stutter. We compare the diffusion properties along 18 major cerebral white matter pathways. We complement the analysis with an overview of the methodology and a roadmap of the pathways implicated in PDS according to the existing literature. We report differences in the microstructural properties of the anterior callosum, the right inferior longitudinal fasciculus and the right cingulum in people who stutter compared with fluent controls. Persistent developmental stuttering is consistently associated with differences in bilateral distributed networks. We review evidence showing that PDS involves differences in bilateral dorsal fronto-temporal and fronto-parietal pathways, in callosal pathways, in several motor pathways and in basal ganglia connections. This entails an important role for long range white matter pathways in this disorder. Using a wide-lens analysis, we demonstrate differences in additional, right hemispheric pathways, which go beyond the replicable findings in the literature. This suggests that the affected circuits may extend beyond the known language and motor pathways. Copyright © 2017 Elsevier Inc. All rights reserved.

Rapid Evolution of piRNA Pathway in the Teleost Fish: Implication for an Adaptation to Transposon Diversity

PubMed Central

Yi, Minhan; Chen, Feng; Luo, Majing; Cheng, Yibin; Zhao, Huabin; Cheng, Hanhua; Zhou, Rongjia

2014-01-01

The Piwi-interacting RNA (piRNA) pathway is responsible for germline specification, gametogenesis, transposon silencing, and genome integrity. Transposable elements can disrupt genome and its functions. However, piRNA pathway evolution and its adaptation to transposon diversity in the teleost fish remain unknown. This article unveils evolutionary scene of piRNA pathway and its association with diverse transposons by systematically comparative analysis on diverse teleost fish genomes. Selective pressure analysis on piRNA pathway and miRNA/siRNA (microRNA/small interfering RNA) pathway genes between teleosts and mammals showed an accelerated evolution of piRNA pathway genes in the teleost lineages, and positive selection on functional PAZ (Piwi/Ago/Zwille) and Tudor domains involved in the Piwi–piRNA/Tudor interaction, suggesting that the amino acid substitutions are adaptive to their functions in piRNA pathway in the teleost fish species. Notably five piRNA pathway genes evolved faster in the swamp eel, a kind of protogynous hermaphrodite fish, than the other teleosts, indicating a differential evolution of piRNA pathway between the swamp eel and other gonochoristic fishes. In addition, genome-wide analysis showed higher diversity of transposons in the teleost fish species compared with mammals. Our results suggest that rapidly evolved piRNA pathway in the teleost fish is likely to be involved in the adaption to transposon diversity. PMID:24846630

Suicide by people in a community justice pathway: population-based nested case–control study

PubMed Central

King, Carlene; Senior, Jane; Webb, Roger T.; Millar, Tim; Piper, Mary; Pearsall, Alison; Humber, Naomi; Appleby, Louis; Shaw, Jenny

2015-01-01

The elevated risk of suicide in prison and after release is a well-recognised and serious problem. Despite this, evidence concerning community-based offenders' suicide risk is sparse. We conducted a population-based nested case–control study of all people in a community justice pathway in England and Wales. Our data show 13% of general population suicides were in community justice pathways before death. Suicide risks were highest among individuals receiving police cautions, and those having recent, or impending prosecution for sexual offences. Findings have implications for the training and practice of clinicians identifying and assessing suicidality, and offering support to those at elevated risk. PMID:26159602

On the levels of enzymatic substrate specificity: Implications for the early evolution of metabolic pathways

NASA Technical Reports Server (NTRS)

Lazcano, A.; Diaz-Villagomez, E.; Mills, T.; Oro, J.

1995-01-01

The most frequently invoked explanation for the origin of metabolic pathways is the retrograde evolution hypothesis. In contrast, according to the so-called 'patchwork' theory, metabolism evolved by the recruitment of relatively inefficient small enzymes of broad specificity that could react with a wide range of chemically related substrates. In this paper it is argued that both sequence comparisons and experimental results on enzyme substrate specificity support the patchwork assembly theory. The available evidence supports previous suggestions that gene duplication events followed by a gradual neoDarwinian accumulation of mutations and other minute genetic changes lead to the narrowing and modification of enzyme function in at least some primordial metabolic pathways.

Melatonin and Hippo Pathway: Is There Existing Cross-Talk?

PubMed

Lo Sardo, Federica; Muti, Paola; Blandino, Giovanni; Strano, Sabrina

2017-09-06

Melatonin is an indolic hormone that regulates a plethora of functions ranging from the regulation of circadian rhythms and antioxidant properties to the induction and maintenance of tumor suppressor pathways. It binds to specific receptors as well as to some cytosolic proteins, leading to several cellular signaling cascades. Recently, the involvement of melatonin in cancer insurgence and progression has clearly been demonstrated. In this review, we will first describe the structure and functions of melatonin and its receptors, and then discuss both molecular and epidemiological evidence on melatonin anticancer effects. Finally, we will shed light on potential cross-talk between melatonin signaling and the Hippo signaling pathway, along with the possible implications for cancer therapy.

Heart rate complexity in sinoaortic-denervated mice.

PubMed

Silva, Luiz Eduardo V; Rodrigues, Fernanda Luciano; de Oliveira, Mauro; Salgado, Hélio Cesar; Fazan, Rubens

2015-02-01

What is the central question of this study? New measurements for cardiovascular complexity, such as detrended fluctuation analysis (DFA) and multiscale entropy (MSE), have been shown to predict cardiovascular outcomes. Given that cardiovascular diseases are accompanied by autonomic imbalance and decreased baroreflex sensitivity, the central question is: do baroreceptors contribute to cardiovascular complexity? What is the main finding and its importance? Sinoaortic denervation altered both DFA scaling exponents and MSE, indicating that both short- and long-term mechanisms of complexity are altered in sinoaortic denervated mice, resulting in a loss of physiological complexity. These results suggest that the baroreflex is a key element in the complex structures involved in heart rate variability regulation. Recently, heart rate (HR) oscillations have been recognized as complex behaviours derived from non-linear processes. Physiological complexity theory is based on the idea that healthy systems present high complexity, i.e. non-linear, fractal variability at multiple scales, with long-range correlations. The loss of complexity in heart rate variability (HRV) has been shown to predict adverse cardiovascular outcomes. Based on the idea that most cardiovascular diseases are accompanied by autonomic imbalance and a decrease in baroreflex sensitivity, we hypothesize that the baroreflex plays an important role in complex cardiovascular behaviour. Mice that had been subjected to sinoaortic denervation (SAD) were implanted with catheters in the femoral artery and jugular vein 5 days prior to the experiment. After recording the baseline arterial pressure (AP), pulse interval time series were generated from the intervals between consecutive values of diastolic pressure. The complexity of the HRV was determined using detrended fluctuation analysis and multiscale entropy. The detrended fluctuation analysis α1 scaling exponent (a short-term index) was remarkably decreased in the SAD mice (0.79 ± 0.06 versus 1.13 ± 0.04 for the control mice), whereas SAD slightly increased the α2 scaling exponent (a long-term index; 1.12 ± 0.03 versus 1.04 ± 0.02 for control mice). In the SAD mice, the total multiscale entropy was decreased (13.2 ± 1.3) compared with the control mice (18.9 ± 1.4). In conclusion, fractal and regularity structures of HRV are altered in SAD mice, affecting both short- and long-term mechanisms of complexity, suggesting that the baroreceptors play a considerable role in the complex structure of HRV. © 2014 The Authors. Experimental Physiology © 2014 The Physiological Society.

Varieties of preschool hyperactivity: multiple pathways from risk to disorder.

PubMed

Sonuga-Barke, Edmund J S; Auerbach, Judith; Campbell, Susan B; Daley, David; Thompson, Margaret

2005-03-01

In this paper we examine the characteristics of preschool attention deficit hyperactivity disorder (ADHD) from both mental disorder and developmental psychopathology points of view. The equivalence of preschool and school-aged hyperactivity as a behavioral dimension is highlighted together with the potential value of extending the use of the ADHD diagnostic category to the preschool period where these behaviours take an extreme and impairing form (assuming age appropriate diagnostic items and thresholds can be developed). At the same time, the importance of identifying pathways between risk and later ADHD is emphasized. Developmental discontinuity and heterogeneity are identified as major characteristics of these pathways. We argue that models that distinguish among different developmental types of early-emerging problems are needed. An illustrative taxonomy of four developmental pathways implicating preschool hyperactivity is presented to provide a framework for future research.

Signal Transduction in the Chronic Leukemias: Implications for Targeted Therapies

PubMed Central

Ahmed, Wesam; Van Etten, Richard A.

2013-01-01

The chronic leukemias, including chronic myeloid leukemia (CML), the Philadelphia-negative myeloproliferative neoplasms (MPNs), and chronic lymphocytic leukemia (CLL), have been characterized extensively for abnormalities of cellular signaling pathways. This effort has led to the elucidation of the central role of dysregulated tyrosine kinase signaling in the chronic myeloid neoplasms and of constitutive B-cell receptor signaling in CLL. This, in turn, has stimulated the development of small molecule inhibitors of these signaling pathways for therapy of chronic leukemia. Although the field is still in its infancy, the clinical results with these agents have ranged from encouraging (CLL) to spectacular (CML). In this review, we summarize recent studies that have helped to define the signaling pathways critical to the pathogenesis of the chronic leukemias. We also discuss correlative studies emerging from clinical trials of drugs targeting these pathways. PMID:23307472

Activation of the yeast Hippo pathway by phosphorylation-dependent assembly of signaling complexes.

PubMed

Rock, Jeremy M; Lim, Daniel; Stach, Lasse; Ogrodowicz, Roksana W; Keck, Jamie M; Jones, Michele H; Wong, Catherine C L; Yates, John R; Winey, Mark; Smerdon, Stephen J; Yaffe, Michael B; Amon, Angelika

2013-05-17

Scaffold-assisted signaling cascades guide cellular decision-making. In budding yeast, one such signal transduction pathway called the mitotic exit network (MEN) governs the transition from mitosis to the G1 phase of the cell cycle. The MEN is conserved and in metazoans is known as the Hippo tumor-suppressor pathway. We found that signaling through the MEN kinase cascade was mediated by an unusual two-step process. The MEN kinase Cdc15 first phosphorylated the scaffold Nud1. This created a phospho-docking site on Nud1, to which the effector kinase complex Dbf2-Mob1 bound through a phosphoserine-threonine binding domain, in order to be activated by Cdc15. This mechanism of pathway activation has implications for signal transmission through other kinase cascades and might represent a general principle in scaffold-assisted signaling.

Synthetic Small Molecule Inhibitors of Hh Signaling As Anti-Cancer Chemotherapeutics

PubMed Central

Maschinot, C.A.; Pace, J.R.; Hadden, M.K.

2016-01-01

The hedgehog (Hh) pathway is a developmental signaling pathway that is essential to the proper embryonic development of many vertebrate systems. Dysregulation of Hh signaling has been implicated as a causative factor in the development and progression of several forms of human cancer. As such, the development of small molecule inhibitors of Hh signaling as potential anti-cancer chemotherapeutics has been a major area of research interest in both academics and industry over the past ten years. Through these efforts, synthetic small molecules that target multiple components of the Hh pathway have been identified and advanced to preclinical or clinical development. The goal of this review is to provide an update on the current status of several synthetic small molecule Hh pathway inhibitors and explore the potential of several recently disclosed inhibitory scaffolds. PMID:26310919

An Evaluation of Active Learning Causal Discovery Methods for Reverse-Engineering Local Causal Pathways of Gene Regulation

PubMed Central

Ma, Sisi; Kemmeren, Patrick; Aliferis, Constantin F.; Statnikov, Alexander

2016-01-01

Reverse-engineering of causal pathways that implicate diseases and vital cellular functions is a fundamental problem in biomedicine. Discovery of the local causal pathway of a target variable (that consists of its direct causes and direct effects) is essential for effective intervention and can facilitate accurate diagnosis and prognosis. Recent research has provided several active learning methods that can leverage passively observed high-throughput data to draft causal pathways and then refine the inferred relations with a limited number of experiments. The current study provides a comprehensive evaluation of the performance of active learning methods for local causal pathway discovery in real biological data. Specifically, 54 active learning methods/variants from 3 families of algorithms were applied for local causal pathways reconstruction of gene regulation for 5 transcription factors in S. cerevisiae. Four aspects of the methods’ performance were assessed, including adjacency discovery quality, edge orientation accuracy, complete pathway discovery quality, and experimental cost. The results of this study show that some methods provide significant performance benefits over others and therefore should be routinely used for local causal pathway discovery tasks. This study also demonstrates the feasibility of local causal pathway reconstruction in real biological systems with significant quality and low experimental cost. PMID:26939894

Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development.

PubMed

Fukami, Maki; Homma, Keiko; Hasegawa, Tomonobu; Ogata, Tsutomu

2013-04-01

We review the current knowledge about the "backdoor" pathway for the biosynthesis of dihydrotestosterone (DHT). While DHT is produced from cholesterol through the conventional "frontdoor" pathway via testosterone, recent studies have provided compelling evidence for the presence of an alternative "backdoor" pathway to DHT without testosterone intermediacy. This backdoor pathway is known to exist in the tammar wallaby pouch young testis and the immature mouse testis, and has been suggested to be present in the human as well. Indeed, molecular analysis has identified pathologic mutations of genes involved in the backdoor pathway in genetic male patients with undermasculinized external genitalia, and urine steroid profile analysis has argued for the relevance of the activated backdoor pathway to abnormal virilization in genetic females with cytochrome P450 oxidoreductase deficiency and 21-hydroxylase deficiency. It is likely that the backdoor pathway is primarily operating in the fetal testis in a physiological condition to produce a sufficient amount of DHT for male sex development, and that the backdoor pathway is driven with a possible interaction between fetal and permanent adrenals in pathologic conditions with increased 17-hydroxyprogesterone levels. These findings provide novel insights into androgen biosynthesis in both physiological and pathological conditions. Copyright © 2012 Wiley Periodicals, Inc., a Wiley company.

Comparison of tumor related signaling pathways with known compounds to determine potential agents for lung adenocarcinoma.

PubMed

Xu, Song; Liu, Renwang; Da, Yurong

2018-06-05

This study compared tumor-related signaling pathways with known compounds to determine potential agents for lung adenocarcinoma (LUAD) treatment. Kyoto Encyclopedia of Genes and Genomes signaling pathway analyses were performed based on LUAD differentially expressed genes from The Cancer Genome Atlas (TCGA) project and genotype-tissue expression controls. These results were compared to various known compounds using the Connectivity Mapping dataset. The clinical significance of the hub genes identified by overlapping pathway enrichment analysis was further investigated using data mining from multiple sources. A drug-pathway network for LUAD was constructed, and molecular docking was carried out. After the integration of 57 LUAD-related pathways and 35 pathways affected by small molecules, five overlapping pathways were revealed. Among these five pathways, the p53 signaling pathway was the most significant, with CCNB1, CCNB2, CDK1, CDKN2A, and CHEK1 being identified as hub genes. The p53 signaling pathway is implicated as a risk factor for LUAD tumorigenesis and survival. A total of 88 molecules significantly inhibiting the five LUAD-related oncogenic pathways were involved in the LUAD drug-pathway network. Daunorubicin, mycophenolic acid, and pyrvinium could potentially target the hub gene CHEK1 directly. Our study highlights the critical pathways that should be targeted in the search for potential LUAD treatments, most importantly, the p53 signaling pathway. Some compounds, such as ciclopirox and AG-028671, may have potential roles for LUAD treatment but require further experimental verification. © 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

Oxidative Stress, Amyloid-β Peptide, and Altered Key Molecular Pathways in the Pathogenesis and Progression of Alzheimer’s Disease

PubMed Central

Butterfield, D. Allan; Boyd-Kimball, Debra

2018-01-01

Oxidative stress is implicated in the pathogenesis and progression of Alzheimer’s disease (AD) and its earlier stage, amnestic mild cognitive impairment (aMCI). One source of oxidative stress in AD and aMCI brains is that associated with amyloid-β peptide, Aβ1-42 oligomers. Our laboratory first showed in AD elevated oxidative stress occurred in brain regions rich in Aβ1-42, but not in Aβ1-42-poor regions, and was among the first to demonstrate Aβ peptides led to lipid peroxidation (indexed by HNE) in AD and aMCI brains. Oxidatively modified proteins have decreased function and contribute to damaged key biochemical and metabolic pathways in which these proteins normally play a role. Identification of oxidatively modified brain proteins by the methods of redox proteomics was pioneered in the Butterfield laboratory. Four recurring altered pathways secondary to oxidative damage in brain from persons with AD, aMCI, or Down syndrome with AD are interrelated and contribute to neuronal death. This “Quadrilateral of Neuronal Death” includes altered: glucose metabolism, mTOR activation, proteostasis network, and protein phosphorylation. Some of these pathways are altered even in brains of persons with preclinical AD. We opine that targeting these pathways pharmacologically and with lifestyle changes potentially may provide strategies to slow or perhaps one day, prevent, progression or development of this devastating dementing disorder. This invited review outlines both in vitro and in vivo studies from the Butterfield laboratory related to Aβ1-42 and AD and discusses the importance and implications of some of the major achievements of the Butterfield laboratory in AD research. PMID:29562527

MEK-ERK inhibition corrects the defect in VLDL assembly in HepG2 cells: potential role of ERK in VLDL-ApoB100 particle assembly.

PubMed

Tsai, Julie; Qiu, Wei; Kohen-Avramoglu, Rita; Adeli, Khosrow

2007-01-01

Hepatic VLDL assembly is defective in HepG2 cells, resulting in the secretion of immature triglyceride-poor LDL-sized apoB particles. We investigated the mechanisms underlying defective VLDL assembly in HepG2 and have obtained evidence implicating the MEK-ERK pathway. HepG2 cells exhibited considerably higher levels of the ERK1/2 mass and activity compared with primary hepatocytes. Inhibition of ERK1/2 using the MEK1/MEK2 inhibitor, U0126 (but not the inactive analogue) led to a significant increase in apoB secretion. In the presence of oleic acid, ERK1/2 inhibition caused a major shift in the lipoprotein distribution with a majority of particles secreted as VLDL, an effect independent of insulin. In contrast, overexpression of constitutively active MEK1 decreased apoB and large VLDL secretion. MEK1/2 inhibition significantly increased both cellular and microsomal TG mass, and mRNA levels for DGAT-1 and DGAT-2. In contrast to ERK, modulation of the PI3-K pathway or inhibition of the p38 MAP kinase, had no effect on lipoprotein density profile. Modulation of the MEK-ERK pathway in primary hamster hepatocytes led to changes in apoB secretion and altered the density profile of apoB-containing lipoproteins. Inhibition of the overactive ras-MEK-ERK pathway in HepG2 cells can correct the defect in VLDL assembly leading to the secretion of large, VLDL-sized particles, similar to primary hepatocytes, implicating the MEK-ERK cascade in VLDL assembly in the HepG2 model. Modulation of this pathway in primary hepatocytes also regulates apoB secretion and appears to alter the formation of VLDL-1 sized particles.

Pathway-Based Analysis of Genome-Wide siRNA Screens Reveals the Regulatory Landscape of App Processing

PubMed Central

Camargo, Luiz Miguel; Zhang, Xiaohua Douglas; Loerch, Patrick; Caceres, Ramon Miguel; Marine, Shane D.; Uva, Paolo; Ferrer, Marc; de Rinaldis, Emanuele; Stone, David J.; Majercak, John; Ray, William J.; Yi-An, Chen; Shearman, Mark S.; Mizuguchi, Kenji

2015-01-01

The progressive aggregation of Amyloid-β (Aβ) in the brain is a major trait of Alzheimer's Disease (AD). Aβ is produced as a result of proteolytic processing of the β-amyloid precursor protein (APP). Processing of APP is mediated by multiple enzymes, resulting in the production of distinct peptide products: the non-amyloidogenic peptide sAPPα and the amyloidogenic peptides sAPPβ, Aβ40, and Aβ42. Using a pathway-based approach, we analyzed a large-scale siRNA screen that measured the production of different APP proteolytic products. Our analysis identified many of the biological processes/pathways that are known to regulate APP processing and have been implicated in AD pathogenesis, as well as revealing novel regulatory mechanisms. Furthermore, we also demonstrate that some of these processes differentially regulate APP processing, with some mechanisms favouring production of certain peptide species over others. For example, synaptic transmission having a bias towards regulating Aβ40 production over Aβ42 as well as processes involved in insulin and pancreatic biology having a bias for sAPPβ production over sAPPα. In addition, some of the pathways identified as regulators of APP processing contain genes (CLU, BIN1, CR1, PICALM, TREM2, SORL1, MEF2C, DSG2, EPH1A) recently implicated with AD through genome wide association studies (GWAS) and associated meta-analysis. In addition, we provide supporting evidence and a deeper mechanistic understanding of the role of diabetes in AD. The identification of these processes/pathways, their differential impact on APP processing, and their relationships to each other, provide a comprehensive systems biology view of the “regulatory landscape” of APP. PMID:25723573

Small RNA profiling of Dengue virus-mosquito interactions implicates the PIWI RNA pathway in anti-viral defense

PubMed Central

2011-01-01

Background Small RNA (sRNA) regulatory pathways (SRRPs) are important to anti-viral defence in mosquitoes. To identify critical features of the virus infection process in Dengue serotype 2 (DENV2)-infected Ae. aegypti, we deep-sequenced small non-coding RNAs. Triplicate biological replicates were used so that rigorous statistical metrics could be applied. Results In addition to virus-derived siRNAs (20-23 nts) previously reported for other arbovirus-infected mosquitoes, we show that PIWI pathway sRNAs (piRNAs) (24-30 nts) and unusually small RNAs (usRNAs) (13-19 nts) are produced in DENV-infected mosquitoes. We demonstrate that a major catalytic enzyme of the siRNA pathway, Argonaute 2 (Ago2), co-migrates with a ~1 megadalton complex in adults prior to bloodfeeding. sRNAs were cloned and sequenced from Ago2 immunoprecipitations. Viral sRNA patterns change over the course of infection. Host sRNAs were mapped to the published aedine transcriptome and subjected to analysis using edgeR (Bioconductor). We found that sRNA profiles are altered early in DENV2 infection, and mRNA targets from mitochondrial, transcription/translation, and transport functional categories are affected. Moreover, small non-coding RNAs (ncRNAs), such as tRNAs, spliceosomal U RNAs, and snoRNAs are highly enriched in DENV-infected samples at 2 and 4 dpi. Conclusions These data implicate the PIWI pathway in anti-viral defense. Changes to host sRNA profiles indicate that specific cellular processes are affected during DENV infection, such as mitochondrial function and ncRNA levels. Together, these data provide important progress in understanding the DENV2 infection process in Ae. aegypti. PMID:21356105

Autism and the synapse: emerging mechanisms and mechanism-based therapies.

PubMed

Ebrahimi-Fakhari, Darius; Sahin, Mustafa

2015-04-01

Recent studies have implicated hundreds of genetic variants in the cause of autism spectrum disorder (ASD). Genes involved in 'monogenic' forms of syndromic ASD converge on common pathways that are involved in synaptic development, plasticity and signaling. In this review, we discuss how these 'developmental synaptopathies' inform our understanding of the molecular disease in ASD and highlight promising approaches that have bridged the gap between the bench and the clinic. Accumulating evidence suggests that synaptic deficits in syndromic and nonsyndromic ASD can be mapped to gene mutations in pathways that control synaptic protein synthesis and degradation, postsynaptic scaffold architecture and neurotransmitter receptors. This is recapitulated in models of Fragile X syndrome (FXS), Tuberous Sclerosis Complex (TSC), Angelman syndrome and Phelan-McDermid syndrome (PMS), all of which cause syndromic ASD. Important recent advances include the development of mouse models and patient-derived induced pluripotent stem cell (iPSC) lines that enable a detailed investigation of synaptic deficits and the identification of potential targets for therapy. Examples of the latter include mGluR5 antagonists in FXS, mTOR inhibitors in TSC and insulin-like growth factor 1 (IGF-1) in PMS. Identifying converging pathways in syndromic forms of ASD will uncover novel therapeutic targets for non-syndromic ASD. Insights into developmental synaptopathies will lead to rational development of mechanism-based therapies and clinical trials that may provide a blueprint for other common pathways implicated in the molecular neuropathology of ASD.

Arabidopsis DRB4, AGO1, AGO7, and RDR6 participate in a DCL4-initiated antiviral RNA silencing pathway negatively regulated by DCL1.

PubMed

Qu, Feng; Ye, Xiaohong; Morris, T Jack

2008-09-23

Plant RNA silencing machinery enlists four primary classes of proteins to achieve sequence-specific regulation of gene expression and mount an antiviral defense. These include Dicer-like ribonucleases (DCLs), Argonaute proteins (AGOs), dsRNA-binding proteins (DRBs), and RNA-dependent RNA polymerases (RDRs). Although at least four distinct endogenous RNA silencing pathways have been thoroughly characterized, a detailed understanding of the antiviral RNA silencing pathway is just emerging. In this report, we have examined the role of four DCLs, two AGOs, one DRB, and one RDR in controlling viral RNA accumulation in infected Arabidopsis plants by using a mutant virus lacking its silencing suppressor. Our results show that all four DCLs contribute to antiviral RNA silencing. We confirm previous reports implicating both DCL4 and DCL2 in this process and establish a minor role for DCL3. Surprisingly, we found that DCL1 represses antiviral RNA silencing through negatively regulating the expression of DCL4 and DCL3. We also implicate DRB4 in antiviral RNA silencing. Finally, we show that both AGO1 and AGO7 function to ensure efficient clearance of viral RNAs and establish that AGO1 is capable of targeting viral RNAs with more compact structures, whereas AGO7 and RDR6 favor less structured RNA targets. Our results resolve several key steps in the antiviral RNA silencing pathway and provide a basis for further in-depth analysis.

Inhibition of Histone Deacetylases Permits Lipopolysaccharide-Mediated Secretion of Bioactive IL-1β via a Caspase-1-Independent Mechanism.

PubMed

Stammler, Dominik; Eigenbrod, Tatjana; Menz, Sarah; Frick, Julia S; Sweet, Matthew J; Shakespear, Melanie R; Jantsch, Jonathan; Siegert, Isabel; Wölfle, Sabine; Langer, Julian D; Oehme, Ina; Schaefer, Liliana; Fischer, Andre; Knievel, Judith; Heeg, Klaus; Dalpke, Alexander H; Bode, Konrad A

2015-12-01

Histone deacetylase (HDAC) inhibitors (HDACi) are clinically approved anticancer drugs that have important immune-modulatory properties. We report the surprising finding that HDACi promote LPS-induced IL-1β processing and secretion in human and murine dendritic cells and murine macrophages. HDACi/LPS-induced IL-1β maturation and secretion kinetics differed completely from those observed upon inflammasome activation. Moreover, this pathway of IL-1β secretion was dependent on caspase-8 but was independent of the inflammasome components NACHT, LRR, and PYD domains-containing protein 3, apoptosis-associated speck-like protein containing a carboxyl-terminal caspase-recruitment domain, and caspase-1. Genetic studies excluded HDAC6 and HDAC10 as relevant HDAC targets in this pathway, whereas pharmacological inhibitor studies implicated the involvement of HDAC11. Treatment of mice with HDACi in a dextran sodium sulfate-induced colitis model resulted in a strong increase in intestinal IL-1β, confirming that this pathway is also operative in vivo. Thus, in addition to the conventional inflammasome-dependent IL-1β cleavage pathway, dendritic cells and macrophages are capable of generating, secreting, and processing bioactive IL-1β by a novel, caspase-8-dependent mechanism. Given the widespread interest in the therapeutic targeting of IL-1β, as well as the use of HDACi for anti-inflammatory applications, these findings have substantial clinical implications. Copyright © 2015 by The American Association of Immunologists, Inc.

Implications of Cancer Stem Cell Theory for Cancer Chemoprevention by Natural Dietary Compounds

PubMed Central

Li, Yanyan; Wicha, Max S.; Schwartz, Steven J.; Sun, Duxin

2011-01-01

The emergence of cancer stem cell theory has profound implications for cancer chemoprevention and therapy. Cancer stem cells give rise to the tumor bulk through continuous self-renewal and differentiation. Understanding the mechanisms that regulate self-renewal is of greatest importance for discovery of anti-cancer drugs targeting cancer stem cells. Naturally-occurring dietary compounds have received increasing attention in cancer chemoprevention. The anti-cancer effects of many dietary components have been reported for both in vitro and in vivo studies. Recently, a number of studies have found that several dietary compounds can directly or indirectly affect cancer stem cell self-renewal pathways. Herein we review the current knowledge of most common natural dietary compounds for their impact on self-renewal pathways and potential effect against cancer stem cells. Three pathways (Wnt/β-catenin, Hedgehog, and Notch) are summarized for their functions in self-renewal of cancer stem cells. The dietary compounds, including curcumin, sulforaphane, soy isoflavone, epigallocatechin-3-gallate, resveratrol, lycopene, piperine, and vitamin D3, are discussed for their direct or indirect effect on these self-renewal pathways. Curcumin and piperine have been demonstrated to target breast cancer stem cells. Sulforaphane has been reported to inhibit pancreatic tumor initiating cells and breast cancer stem cells. These studies provide a basis for preclinical and clinical evaluation of dietary compounds for chemoprevention of cancer stem cells. This may enable us to discover more preventive strategies for cancer management by reducing cancer resistance and recurrence and improving patient survival. PMID:21295962

Hydroxyhydroperoxide (HHP) Formation From H2O2 Addition to Carbonyls in the Aqueous Phase and Its Environmental Implications

NASA Astrophysics Data System (ADS)

Zhao, R.; Soong, R.; Simpson, A. J.; Abbatt, J.

2012-12-01

Organic peroxides are major components of secondary organic aerosol (SOA), affecting the toxicity of SOA and its oxidative capacity. Hydroxyhydroperoxide (HHP) is a class of organic peroxide observed in ambient air, rain water, and cloud water. However, the formation pathway of HHPs remains under debate, with one potential path via reaction of water with Criegee Intermediates. The current study focuses on a formation mechanism involving reversible nucleophilic addition of H2O2 to aldehydes. This formation pathway of HHPs has been known for decades, but has long been considered as a minor reaction. This is because HHPs were observed to decompose rapidly into H2O2 and the corresponding aldehydes in dilute aqueous solutions. In the current study, proton transfer reaction mass spectrometry (PTR-MS) and proton nuclear magnetic resonance (1H NMR) spectrometry were employed to determine the equilibrium constants (Keq) of H2O2 addition to a variety of atmospherically relevant carbonyls in the aqueous phase. HHP formation was insignificant from ketones and methacrolein, but was significant from formaldehyde, acetaldehyde and propionaldehyde. The Keq values ranged from 80 to 150 M-1 at 25 °C. Based on these values, the environmental implications of HHP formation via this pathway suggest that HHP formation is unlikely to be significant in cloud water. However, in aerosol liquid water, where the concentrations of aldehydes and H2O2 can be at the mM level, this pathway may be significant.

Synaptic plasticity in the hippocampal area CA1-subiculum projection: implications for theories of memory.

PubMed

O'Mara, S M; Commins, S; Anderson, M

2000-01-01

This paper reviews investigations of synaptic plasticity in the major, and underexplored, pathway from hippocampal area CA1 to the subiculum. This brain area is the major synaptic relay for the majority of hippocampal area CA1 neurons, making the subiculum the last relay of the hippocampal formation prior to the cortex. The subiculum thus has a very major role in mediating hippocampal-cortical interactions. We demonstrate that the projection from hippocampal area CA1 to the subiculum sustains plasticity on a number of levels. We show that this pathway is capable of undergoing both long-term potentiation (LTP) and paired-pulse facilitation (PPF, a short-term plastic effect). Although we failed to induce long-term depression (LTD) of this pathway with low-frequency stimulation (LFS) and two-pulse stimulation (TPS), both protocols can induce a "late-developing" potentiation of synaptic transmission. We further demonstrate that baseline synaptic transmission can be dissociated from paired-pulse stimulation of the same pathway; we also show that it is possible, using appropriate protocols, to change PPF to paired-pulse depression, thus revealing subtle and previously undescribed mechanisms which regulate short-term synaptic plasticity. Finally, we successfully recorded from individual subicular units in the freely-moving animal, and provide a description of the characteristics of such neurons in a pellet-chasing task. We discuss the implications of these findings in relation to theories of the biological consolidation of memory.

Behavioral Approach in ADHD: Testing a Motivational Dysfunction Hypothesis

ERIC Educational Resources Information Center

Mitchell, John T.

2010-01-01

Objective: Etiological models of attention-deficit hyperactivity disorder (ADHD) increasingly support the role of a motivational dysfunction pathway, particularly for hyperactive-impulsive symptoms. Overactive behavioral approach tendencies are implicated among these motivational accounts. However, other externalizing disorder symptoms, such as…

The chemistry side of AOP: implications for toxicity extrapolation

EPA Science Inventory

An adverse outcome pathway (AOP) is a structured representation of the biological events that lead to adverse impacts following a molecular initiating event caused by chemical interaction with a macromolecule. AOPs have been proposed to facilitate toxicity extrapolation across s...

Pathways into prostitution among female jail detainees and their implications for mental health services.

PubMed

McClanahan, S F; McClelland, G M; Abram, K M; Teplin, L A

1999-12-01

To explore the service needs of women in jail, the authors examined three pathways into prostitution: childhood sexual victimization, running away, and drug use. Studies typically have explored only one or two of these pathways, and the relationships among the three points of entry remain unclear. Data on 1,142 female jail detainees were used to examine the effects of childhood sexual victimization, running away, and drug use on entry into prostitution and their differential effects over the life course. Two distinct pathways into prostitution were identified. Running away had a dramatic effect on entry into prostitution in early adolescence, but little effect later in the life course. Childhood sexual victimization, by contrast, nearly doubled the odds of entry into prostitution throughout the lives of women. Although the prevalence of drug use was significantly higher among prostitutes than among nonprostitutes, drug abuse did not explain entry into prostitution. Running away and childhood sexual victimization provide distinct pathways into prostitution. The findings suggest that women wishing to leave prostitution may benefit from different mental health service strategies depending on which pathway to prostitution they experienced.

Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome.

PubMed

Marti, Nesa; Galván, José A; Pandey, Amit V; Trippel, Mafalda; Tapia, Coya; Müller, Michel; Perren, Aurel; Flück, Christa E

2017-02-05

Recently, dihydrotestosterone biosynthesis through the backdoor pathway has been implicated for the human testis in addition to the classic pathway for testosterone (T) synthesis. In the human ovary, androgen precursors are crucial for estrogen synthesis and hyperandrogenism in pathologies such as the polycystic ovary syndrome is partially due to ovarian overproduction. However, a role for the backdoor pathway is only established for the testis and the adrenal, but not for the human ovary. To investigate whether the backdoor pathway exists in normal and PCOS ovaries, we performed specific gene and protein expression studies on ovarian tissues. We found aldo-keto reductases (AKR1C1-1C4), 5α-reductases (SRD5A1/2) and retinol dehydrogenase (RoDH) expressed in the human ovary, indicating that the ovary might produce dihydrotestosterone via the backdoor pathway. Immunohistochemical studies showed specific localization of these proteins to the theca cells. PCOS ovaries show enhanced expression, what may account for the hyperandrogenism. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Sterol homeostasis requires regulated degradation of squalene monooxygenase by the ubiquitin ligase Doa10/Teb4

PubMed Central

Foresti, Ombretta; Ruggiano, Annamaria; Hannibal-Bach, Hans K; Ejsing, Christer S; Carvalho, Pedro

2013-01-01

Sterol homeostasis is essential for the function of cellular membranes and requires feedback inhibition of HMGR, a rate-limiting enzyme of the mevalonate pathway. As HMGR acts at the beginning of the pathway, its regulation affects the synthesis of sterols and of other essential mevalonate-derived metabolites, such as ubiquinone or dolichol. Here, we describe a novel, evolutionarily conserved feedback system operating at a sterol-specific step of the mevalonate pathway. This involves the sterol-dependent degradation of squalene monooxygenase mediated by the yeast Doa10 or mammalian Teb4, a ubiquitin ligase implicated in a branch of the endoplasmic reticulum (ER)-associated protein degradation (ERAD) pathway. Since the other branch of ERAD is required for HMGR regulation, our results reveal a fundamental role for ERAD in sterol homeostasis, with the two branches of this pathway acting together to control sterol biosynthesis at different levels and thereby allowing independent regulation of multiple products of the mevalonate pathway. DOI: http://dx.doi.org/10.7554/eLife.00953.001 PMID:23898401

Oxytocin Pathways in the Intergenerational Transmission of Maternal Early Life Stress

PubMed Central

Toepfer, Philipp; Heim, Christine; Entringer, Sonja; Binder, Elisabeth; Wadhwa, Pathik; Buss, Claudia

2017-01-01

Severe stress in early life, such as childhood abuse and neglect, constitutes a major risk factor in the etiology of psychiatric disorders and somatic diseases. Importantly, these long-term effects may impact the next generation. The intergenerational transmission of maternal early life stress (ELS) may occur via pre-and postnatal pathways, such as alterations in maternal-fetal-placental stress physiology, maternal depression during pregnancy and postpartum, as well as impaired mother-offspring interactions. The neuropeptide oxytocin (OT) has gained considerable attention for its role in modulating all of these assumed transmission pathways. Moreover, central and peripheral OT signaling pathways are highly sensitive to environmental exposures and may be compromised by ELS with implications for these putative transmission mechanisms. Together, these data suggest that OT pathways play an important role in the intergenerational transmission of maternal ELS in humans. By integrating recent studies on gene-environment interactions and epigenetic modifications in OT pathway genes, the present review aims to develop a conceptual framework of intergenerational transmission of maternal ELS that emphasizes the role of OT. PMID:28027955

A Systematic Review of Known Mechanisms of Hydroxyurea-induced Foetal Haemoglobin for Treatment of Sickle Cell Disease

PubMed Central

Pule, Gift D.; Mowla, Shaheen; Novitzky, Nicolas; Wiysonge, Charles S.; Wonkam, Ambroise

2016-01-01

Aims To report on molecular mechanisms of foetal haemoglobin (HbF) induction by hydroxyurea (HU) for the treatment of Sickle Cell Disease (SCD). Study Design Systematic review. Results Studies have provided consistent associations between genomic variations in HbF-promoting loci and variable HbF level in response to HU. Numerous signal transduction pathways have been implicated, through the identification of key genomic variants in BCL11A, HBS1L-MYB, SAR1 or XmnI polymorphism that predispose the response to the treatment, and signal transduction pathways, that modulate γ-globin expression (cAMP/cGMP; Giα/JNK/Jun; methylation and microRNA). Three main molecular pathways have been reported: 1) Epigenetic modifications, transcriptional events and signalling pathways involved in HU-mediated response, 2) Signalling pathways involving HU-mediated response and 3) Post-transcriptional pathways (regulation by microRNAs). Conclusions The complete picture of HU-mediated mechanisms of HbF production in SCD remains elusive. Research on post-transcriptional mechanisms could lead to therapeutic targets that may minimize alterations to the cellular transcriptome. PMID:26327494

A systematic review of known mechanisms of hydroxyurea-induced fetal hemoglobin for treatment of sickle cell disease.

PubMed

Pule, Gift D; Mowla, Shaheen; Novitzky, Nicolas; Wiysonge, Charles S; Wonkam, Ambroise

2015-10-01

To report on molecular mechanisms of fetal hemoglobin (HbF) induction by hydroxyurea (HU) for the treatment of sickle cell disease. Systematic review. Studies have provided consistent associations between genomic variations in HbF-promoting loci and variable HbF level in response to HU. Numerous signal transduction pathways have been implicated, through the identification of key genomic variants in BCL11A, HBS1L-MYB, SAR1 or XmnI polymorphism that predispose the response to the treatment, and signal transduction pathways that modulate γ-globin expression (cAMP/cGMP; Giα/c-Jun N-terminal kinase/Jun; methylation and miRNA). Three main molecular pathways have been reported: i) Epigenetic modifications, transcriptional events and signaling pathways involved in HU-mediated response, ii) Signaling pathways involving HU-mediated response and iii) Post-transcriptional pathways (regulation by miRNAs). The complete picture of HU-mediated mechanisms of HbF production in Sickle Cell Disease remains elusive. Research on post-transcriptional mechanisms could lead to therapeutic targets that may minimize alterations to the cellular transcriptome.

Human blindsight is mediated by an intact geniculo-extrastriate pathway

PubMed Central

Ajina, Sara; Pestilli, Franco; Rokem, Ariel; Kennard, Christopher; Bridge, Holly

2015-01-01

Although damage to the primary visual cortex (V1) causes hemianopia, many patients retain some residual vision; known as blindsight. We show that blindsight may be facilitated by an intact white-matter pathway between the lateral geniculate nucleus and motion area hMT+. Visual psychophysics, diffusion-weighted magnetic resonance imaging and fibre tractography were applied in 17 patients with V1 damage acquired during adulthood and 9 age-matched controls. Individuals with V1 damage were subdivided into blindsight positive (preserved residual vision) and negative (no residual vision) according to psychophysical performance. All blindsight positive individuals showed intact geniculo-hMT+ pathways, while this pathway was significantly impaired or not measurable in blindsight negative individuals. Two white matter pathways previously implicated in blindsight: (i) superior colliculus to hMT+ and (ii) between hMT+ in each hemisphere were not consistently present in blindsight positive cases. Understanding the visual pathways crucial for residual vision may direct future rehabilitation strategies for hemianopia patients. DOI: http://dx.doi.org/10.7554/eLife.08935.001 PMID:26485034

Ubiquitin-protein ligases in muscle wasting: multiple parallel pathways?

NASA Technical Reports Server (NTRS)

Lecker, Stewart H.; Goldberg, A. L. (Principal Investigator)

2003-01-01

PURPOSE OF REVIEW: Studies in a wide variety of animal models of muscle wasting have led to the concept that increased protein breakdown via the ubiquitin-proteasome pathway is responsible for the loss of muscle mass seen as muscle atrophy. The complexity of the ubiquitination apparatus has hampered our understanding of how this pathway is activated in atrophying muscles and which ubiquitin-conjugating enzymes in muscle are responsible. RECENT FINDINGS: Recent experiments have shown that two newly identified ubiquitin-protein ligases (E3s), atrogin-1/MAFbx and MURF-1, are critical in the development of muscle atrophy. Other in-vitro studies also implicated E2(14k) and E3alpha, of the N-end rule pathway, as playing an important role in the process. SUMMARY: It seems likely that multiple pathways of ubiquitin conjugation are activated in parallel in atrophying muscle, perhaps to target for degradation specific classes of muscle proteins. The emerging challenge will be to define the protein targets for, as well as inhibitors of, these E3s.

Genetic dissection of cardiac growth control pathways

NASA Technical Reports Server (NTRS)

MacLellan, W. R.; Schneider, M. D.

2000-01-01

Cardiac muscle cells exhibit two related but distinct modes of growth that are highly regulated during development and disease. Cardiac myocytes rapidly proliferate during fetal life but exit the cell cycle irreversibly soon after birth, following which the predominant form of growth shifts from hyperplastic to hypertrophic. Much research has focused on identifying the candidate mitogens, hypertrophic agonists, and signaling pathways that mediate these processes in isolated cells. What drives the proliferative growth of embryonic myocardium in vivo and the mechanisms by which adult cardiac myocytes hypertrophy in vivo are less clear. Efforts to answer these questions have benefited from rapid progress made in techniques to manipulate the murine genome. Complementary technologies for gain- and loss-of-function now permit a mutational analysis of these growth control pathways in vivo in the intact heart. These studies have confirmed the importance of suspected pathways, have implicated unexpected pathways as well, and have led to new paradigms for the control of cardiac growth.

Insights into the origin and evolution of the plant hormone signaling machinery.

PubMed

Wang, Chunyang; Liu, Yang; Li, Si-Shen; Han, Guan-Zhu

2015-03-01

Plant hormones modulate plant growth, development, and defense. However, many aspects of the origin and evolution of plant hormone signaling pathways remain obscure. Here, we use a comparative genomic and phylogenetic approach to investigate the origin and evolution of nine major plant hormone (abscisic acid, auxin, brassinosteroid, cytokinin, ethylene, gibberellin, jasmonate, salicylic acid, and strigolactone) signaling pathways. Our multispecies genome-wide analysis reveals that: (1) auxin, cytokinin, and strigolactone signaling pathways originated in charophyte lineages; (2) abscisic acid, jasmonate, and salicylic acid signaling pathways arose in the last common ancestor of land plants; (3) gibberellin signaling evolved after the divergence of bryophytes from land plants; (4) the canonical brassinosteroid signaling originated before the emergence of angiosperms but likely after the split of gymnosperms and angiosperms; and (5) the origin of the canonical ethylene signaling pathway postdates shortly the emergence of angiosperms. Our findings might have important implications in understanding the molecular mechanisms underlying the emergence of land plants. © 2015 American Society of Plant Biologists. All Rights Reserved.

Regulation of Tissue Growth by the Mammalian Hippo Signaling Pathway

PubMed Central

Watt, Kevin I.; Harvey, Kieran F.; Gregorevic, Paul

2017-01-01

The integrative control of diverse biological processes such as proliferation, differentiation, apoptosis and metabolism is essential to maintain cellular and tissue homeostasis. Disruption of these underlie the development of many disease states including cancer and diabetes, as well as many of the complications that arise as a consequence of aging. These biological outputs are governed by many cellular signaling networks that function independently, and in concert, to convert changes in hormonal, mechanical and metabolic stimuli into alterations in gene expression. First identified in Drosophila melanogaster as a powerful mediator of cell division and apoptosis, the Hippo signaling pathway is a highly conserved regulator of mammalian organ size and functional capacity in both healthy and diseased tissues. Recent studies have implicated the pathway as an effector of diverse physiological cues demonstrating an essential role for the Hippo pathway as an integrative component of cellular homeostasis. In this review, we will: (a) outline the critical signaling elements that constitute the mammalian Hippo pathway, and how they function to regulate Hippo pathway-dependent gene expression and tissue growth, (b) discuss evidence that shows this pathway functions as an effector of diverse physiological stimuli and (c) highlight key questions in this developing field. PMID:29225579

Lens fibre cell differentiation and organelle loss: many paths lead to clarity

PubMed Central

Wride, Michael A.

2011-01-01

The programmed removal of organelles from differentiating lens fibre cells contributes towards lens transparency through formation of an organelle-free zone (OFZ). Disruptions in OFZ formation are accompanied by the persistence of organelles in lens fibre cells and can contribute towards cataract. A great deal of work has gone into elucidating the nature of the mechanisms and signalling pathways involved. It is apparent that multiple, parallel and redundant pathways are involved in this process and that these pathways form interacting networks. Furthermore, it is possible that the pathways can functionally compensate for each other, for example in mouse knockout studies. This makes sense given the importance of lens clarity in an evolutionary context. Apoptosis signalling and proteolytic pathways have been implicated in both lens fibre cell differentiation and organelle loss, including the Bcl-2 and inhibitor of apoptosis families, tumour necrosis factors, p53 and its regulators (such as Mdm2) and proteolytic enzymes, including caspases, cathepsins, calpains and the ubiquitin–proteasome pathway. Ongoing approaches being used to dissect the molecular pathways involved, such as transgenics, lens-specific gene deletion and zebrafish mutants, are discussed here. Finally, some of the remaining unresolved issues and potential areas for future studies are highlighted. PMID:21402582

RhoA, Rho kinase, JAK2, and STAT3 may be the intracellular determinants of longevity implicated in the progeric influence of obesity: Insulin, IGF-1, and leptin may all conspire to promote stem cell exhaustion.

PubMed

Tapia, Patrick C

2006-01-01

The aging process in higher mammals is increasingly being shown to feature a potentially substantial contribution from the longitudinal deterioration of normative stem cell dynamics seen with the passage of time. The precise mechanistic sequence producing this phenomenon is not entirely understood, but recent evidence has strongly implicated intracellular downstream effectors of endocrinologic pathways thought to be engaged by the obese state, specifically the insulin, IGF-1, and leptin signaling pathways. Among the intracellular effectors of these signals, a uniquely potent influence on stem cell dynamics may be attributable to Rho/ROCK, JAK kinase activity and STAT3 activity. In particular, it has already been shown that specific tyrosine kinase activities, such as that seen with Rho kinase, are presently thought to be associated with adverse health outcomes in numerous clinical contexts. Furthermore, the Rho GTPase is thought to be contributing to end-stage renal disease. However, in addition to its contribution to organ system dysfunction, the Rho/ROCK pathway has recently been shown to be activated by insulin and IGF-1, providing a tantalizing connection to nutrition and aging science. The JAK-STAT pathway, in contrast, has long been associated with pro-inflammatory cytokines, but has recently been implicated in leptin signaling as well. Importantly, JAK-STAT signaling has, similarly to Rho/ROCK signaling, been implicated as capable of accelerating stem cell proliferation. The implications of these recent determinations, in light of the recent finding of telomere attrition in humans associated with obesity, are that the intracellular determinants of aging may already be known, and the known common influence of these signaling elements on longitudinal stem cell dynamics is a pronounced induction of proliferation, an elevation that has been linked to the pathologic evolution of longitudinal organ-level dysfunction and the organismal-level physiologic decline seen with the inexorable passage of time. Besides the obvious utility for the management for human age-related dysfunction that investigation of pharmacologic inhibitors of these proteins would provide, interventions such as caloric restriction and possibly intermittent fasting may beneficially influence stem cell proliferation dynamics and reduce intracellular correlates of mitogenic drive. Integrating the findings present in the present body of research may reveal endocrinological states that are compatible with longevity, and will also provide novel insight into the specific proteomic determinants of age-related physiologic decline, ushering in a new epoch of medicine that fosters the management of the "pre-etiopathology" of chronic disease and disability of aging, therefore mitigating the suffering widely thought to be inherent in the latter stages of life.

β-Adrenergic induced SR Ca2+ leak is mediated by an Epac-NOS pathway.

PubMed

Pereira, Laëtitia; Bare, Dan J; Galice, Samuel; Shannon, Thomas R; Bers, Donald M

2017-07-01

Cardiac β-adrenergic receptors (β-AR) and Ca 2+ -Calmodulin dependent protein kinase (CaMKII) regulate both physiological and pathophysiological Ca 2+ signaling. Elevated diastolic Ca 2+ leak from the sarcoplasmic reticulum (SR) contributes to contractile dysfunction in heart failure and to arrhythmogenesis. β-AR activation is known to increase SR Ca 2+ leak via CaMKII-dependent phosphorylation of the ryanodine receptor. Two independent and reportedly parallel pathways have been implicated in this β-AR-CaMKII cascade, one involving exchange protein directly activated by cAMP (Epac2) and another involving nitric oxide synthase 1 (NOS1). Here we tested whether Epac and NOS function in a single series pathway to increase β-AR induced and CaMKII-dependent SR Ca 2+ leak. Leak was measured as both Ca 2+ spark frequency and tetracaine-induced shifts in SR Ca 2+ , in mouse and rabbit ventricular myocytes. Direct Epac activation by 8-CPT (8-(4-chlorophenylthio)-2'-O-methyl-cAMP) mimicked β-AR-induced SR Ca 2+ leak, and both were blocked by NOS inhibition. The same was true for myocyte CaMKII activation (assessed via a FRET-based reporter) and ryanodine receptor phosphorylation. Inhibitor and phosphorylation studies also implicated phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt) downstream of Epac and above NOS activation in this pathway. We conclude that these two independently characterized parallel pathways function mainly via a single series arrangement (β-AR-cAMP-Epac-PI3K-Akt-NOS1-CaMKII) to mediate increased SR Ca 2+ leak. Thus, for β-AR activation the cAMP-PKA branch effects inotropy and lusitropy (by effects on Ca 2+ current and SR Ca 2+ -ATPase), this cAMP-Epac-NOS pathway increases pathological diastolic SR Ca 2+ leak. This pathway distinction may allow novel SR Ca 2+ leak therapeutic targeting in treatment of arrhythmias in heart failure that spare the inotropic and lusitropic effects of the PKA branch. Copyright © 2017 Elsevier Ltd. All rights reserved.

Expression of the Kynurenine Pathway in Human Peripheral Blood Mononuclear Cells: Implications for Inflammatory and Neurodegenerative Disease.

PubMed

Jones, Simon P; Franco, Nunzio F; Varney, Bianca; Sundaram, Gayathri; Brown, David A; de Bie, Josien; Lim, Chai K; Guillemin, Gilles J; Brew, Bruce J

2015-01-01

The kynurenine pathway is a fundamental mechanism of immunosuppression and peripheral tolerance. It is increasingly recognized as playing a major role in the pathogenesis of a wide variety of inflammatory, neurodegenerative and malignant disorders. However, the temporal dynamics of kynurenine pathway activation and metabolite production in human immune cells is currently unknown. Here we report the novel use of flow cytometry, combined with ultra high-performance liquid chromatography and gas chromatography-mass spectrometry, to sensitively quantify the intracellular expression of three key kynurenine pathway enzymes and the main kynurenine pathway metabolites in a time-course study. This is the first study to show that up-regulation of indoleamine 2,3-dioxygenase (IDO-1), kynurenine 3-monoxygenase (KMO) and quinolinate phosphoribosyltransferase (QPRT) is lacking in lymphocytes treated with interferon gamma. In contrast, peripheral monocytes showed a significant elevation of kynurenine pathway enzymes and metabolites when treated with interferon gamma. Expression of IDO-1, KMO and QPRT correlated significantly with activation of the kynurenine pathway (kynurenine:tryptophan ratio), quinolinic acid concentration and production of the monocyte derived, pro-inflammatory immune response marker: neopterin. Our results also describe an original and sensitive methodological approach to quantify kynurenine pathway enzyme expression in cells. This has revealed further insights into the potential role of these enzymes in disease processes.

Altering the Mitochondrial Fatty Acid Synthesis (mtFASII) Pathway Modulates Cellular Metabolic States and Bioactive Lipid Profiles as Revealed by Metabolomic Profiling

PubMed Central

Clay, Hayley B.; Parl, Angelika K.; Mitchell, Sabrina L.; Singh, Larry; Bell, Lauren N.; Murdock, Deborah G.

2016-01-01

Despite the presence of a cytosolic fatty acid synthesis pathway, mitochondria have retained their own means of creating fatty acids via the mitochondrial fatty acid synthesis (mtFASII) pathway. The reason for its conservation has not yet been elucidated. Therefore, to better understand the role of mtFASII in the cell, we used thin layer chromatography to characterize the contribution of the mtFASII pathway to the fatty acid composition of selected mitochondrial lipids. Next, we performed metabolomic analysis on HeLa cells in which the mtFASII pathway was either hypofunctional (through knockdown of mitochondrial acyl carrier protein, ACP) or hyperfunctional (through overexpression of mitochondrial enoyl-CoA reductase, MECR). Our results indicate that the mtFASII pathway contributes little to the fatty acid composition of mitochondrial lipid species examined. Additionally, loss of mtFASII function results in changes in biochemical pathways suggesting alterations in glucose utilization and redox state. Interestingly, levels of bioactive lipids, including lysophospholipids and sphingolipids, directly correlate with mtFASII function, indicating that mtFASII may be involved in the regulation of bioactive lipid levels. Regulation of bioactive lipid levels by mtFASII implicates the pathway as a mediator of intracellular signaling. PMID:26963735

Dysregulation of Wnt/β-catenin Signaling in Gastrointestinal Cancers

PubMed Central

White, Bryan D.; Chien, Andy J.; Dawson, David W.

2012-01-01

Aberrant Wnt/β-catenin signaling is widely implicated in numerous malignancies, including cancers of the gastrointestinal (GI) tract. Dysregulation of signaling is traditionally attributed to mutations in Axin, APC (adenomatous polyposis coli), and β-catenin that lead to constitutive hyperactivation of the pathway. However, Wnt/β-catenin signaling is also modulated through various other mechanisms in cancer, including crosstalk with other altered signaling pathways. A more complex view of Wnt/β-catenin signaling and its role in GI cancers is now emerging as divergent phenotypic outcomes are found to be dictated by temporospatial context and relative levels of pathway activation. This review summarizes the dysregulation of Wnt/β-catenin signaling in colorectal carcinoma, hepatocellular carcinoma, and pancreatic ductal adenocarcinoma, with particular emphasis on the latter two. We conclude by addressing some of the major challenges faced in attempting to target the pathway in the clinic. PMID:22155636

Outdoor Ambient Air Pollution and Neurodegenerative Diseases: the Neuroinflammation Hypothesis.

PubMed

Jayaraj, Richard L; Rodriguez, Eric A; Wang, Yi; Block, Michelle L

2017-06-01

Accumulating research indicates that ambient outdoor air pollution impacts the brain and may affect neurodegenerative diseases, yet the potential underlying mechanisms are poorly understood. The neuroinflammation hypothesis holds that elevation of cytokines and reactive oxygen species in the brain mediates the deleterious effects of urban air pollution on the central nervous system (CNS). Studies in human and animal research document that neuroinflammation occurs in response to several inhaled pollutants. Microglia are a prominent source of cytokines and reactive oxygen species in the brain, implicated in the progressive neuron damage in diverse neurodegenerative diseases, and activated by inhaled components of urban air pollution through both direct and indirect pathways. The MAC1-NOX2 pathway has been identified as a mechanism through which microglia respond to different forms of air pollution, suggesting a potential common deleterious pathway. Multiple direct and indirect pathways in response to air pollution exposure likely interact in concert to exert CNS effects.

mTOR Inhibitors in Children: Current Indications and Future Directions in Neurology.

PubMed

Jeong, Anna; Wong, Michael

2016-12-01

The mammalian/mechanistic target of rapamycin (mTOR) pathway is a key signaling pathway that has been implicated in genetic epilepsy syndromes, neurodegenerative diseases, and conditions associated with autism spectrum disorder and cognitive impairment. The mTOR pathway has become an exciting treatment target for these various disorders, with mTOR inhibitors such as rapamycin being studied for their potential therapeutic applications. In particular, tuberous sclerosis complex (TSC) is a genetic disorder resulting from overactivation of the mTOR pathway, and pharmacologic therapy with mTOR inhibitors has emerged as a viable treatment option for the systemic manifestations of the disease. In this review, we discuss the approved indications for mTOR inhibitors in TSC, the potential future applications of mTOR inhibitors in TSC and other neurological conditions, and the safety considerations applicable to mTOR therapy in the pediatric population.

International scientists’ priorities for research on pharmaceutical and personal care products in the environment

EPA Science Inventory

Pharmaceuticals and personal care products (PPCPs) are widely discharged into the environment via diverse pathways. The effects of PPCPs in the environment have potentially important human and ecosystem health implications, so credible, salient, and legitimate scientific evidence...

Defective downregulation of receptor tyrosine kinases in cancer

PubMed Central

Bache, Kristi G; Slagsvold, Thomas; Stenmark, Harald

2004-01-01

Most growth factors control cellular functions by activating specific receptor tyrosine kinases (RTKs). While overactivation of RTK signalling pathways is strongly associated with carcinogenesis, it is becoming increasingly clear that impaired deactivation of RTKs may also be a mechanism in cancer. A major deactivation pathway, receptor downregulation, involves ligand-induced endocytosis of the RTK and subsequent degradation in lysosomes. A complex molecular machinery that uses the small protein ubiquitin as a key regulator assures proper endocytosis and degradation of RTKs. Here we discuss evidence that implicates deregulation of this machinery in cancer. PMID:15229652

Rapid evolution of piRNA pathway in the teleost fish: implication for an adaptation to transposon diversity.

PubMed

Yi, Minhan; Chen, Feng; Luo, Majing; Cheng, Yibin; Zhao, Huabin; Cheng, Hanhua; Zhou, Rongjia

2014-05-19

The Piwi-interacting RNA (piRNA) pathway is responsible for germline specification, gametogenesis, transposon silencing, and genome integrity. Transposable elements can disrupt genome and its functions. However, piRNA pathway evolution and its adaptation to transposon diversity in the teleost fish remain unknown. This article unveils evolutionary scene of piRNA pathway and its association with diverse transposons by systematically comparative analysis on diverse teleost fish genomes. Selective pressure analysis on piRNA pathway and miRNA/siRNA (microRNA/small interfering RNA) pathway genes between teleosts and mammals showed an accelerated evolution of piRNA pathway genes in the teleost lineages, and positive selection on functional PAZ (Piwi/Ago/Zwille) and Tudor domains involved in the Piwi-piRNA/Tudor interaction, suggesting that the amino acid substitutions are adaptive to their functions in piRNA pathway in the teleost fish species. Notably five piRNA pathway genes evolved faster in the swamp eel, a kind of protogynous hermaphrodite fish, than the other teleosts, indicating a differential evolution of piRNA pathway between the swamp eel and other gonochoristic fishes. In addition, genome-wide analysis showed higher diversity of transposons in the teleost fish species compared with mammals. Our results suggest that rapidly evolved piRNA pathway in the teleost fish is likely to be involved in the adaption to transposon diversity. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Plants Used in the Management of Diabetic Complications

PubMed Central

Dodda, D.; Ciddi, V.

2014-01-01

Diabetes is a disease, which has assumed vital public health importance because of the complications associated with it. Various mechanisms including polyol pathway along with a complex integrating paradigm have been implicated in glucose-mediated complications. Though polyol pathway was established as a major mechanism, precise pathogenesis of these complications is not yet completely elucidated. Thus research focus was shifted towards key enzyme, aldose reductase in the pathway. Even though various compounds with aldose reductase inhibitory activity were synthesised, a very few compounds are under clinical use. However, studies on these compounds were always under conflicting results and an attempt has been made to review various natural substances with aldose reductase inhibitory activity and their role in management of diabetic complications. PMID:24843182

Unphosphorylated STATs go nuclear.

PubMed

Brown, Stephen; Zeidler, Martin P

2008-10-01

The JAK/STAT signal transduction pathway has traditionally been viewed as a cytokine-stimulated activator of gene expression consisting of a straightforward receptor/JAK kinase/STAT transcription factor cascade. Recent studies in Drosophila, have, however consistently identified a range of chromatin-remodelling factors as regulators of in vivo JAK/STAT signalling. Now, the detailed analysis of one of these, heterochromatin protein 1 (HP1), has provided an insight into an unexpected non-canonical in vivo role for STAT. In this model, unphosphorylated STATs associate with and maintain the stability of transcriptionally repressed heterochromatin--an effect countered by the recruitment of STAT to the canonical pathway. We examine the background of this new model and its implications for JAK/STAT pathway requirements in stem cell maintenance and cancer.

Genetics and the Placebo Effect: the Placebome

PubMed Central

Hall, Kathryn T.; Loscalzo, Joseph; Kaptchuk, Ted J.

2015-01-01

Placebos are indispensable controls in randomized clinical trials (RCTs), and placebo responses significantly contribute to routine clinical outcomes. Recent neurophysiological studies reveal neurotransmitter pathways that mediate placebo effects. Evidence that genetic variations in these pathways can modify placebo effects raises the possibility of using genetic screening to identify placebo responders and thereby increase RCT efficacy and improve therapeutic care. Furthermore, the possibility of interaction between placebo and drug molecular pathways warrants consideration in RCT design. The study of genomic effects on placebo response, “the placebome”, is in its infancy. Here, we review evidence from placebo studies and RCTs to identify putative genes in the placebome, examine evidence for placebo-drug interactions, and discuss implications for RCTs and clinical care. PMID:25883069

Criegee intermediate-hydrogen sulfide chemistry at the air/water interface.

PubMed

Kumar, Manoj; Zhong, Jie; Francisco, Joseph S; Zeng, Xiao C

2017-08-01

We carry out Born-Oppenheimer molecular dynamic simulations to show that the reaction between the smallest Criegee intermediate, CH 2 OO, and hydrogen sulfide (H 2 S) at the air/water interface can be observed within few picoseconds. The reaction follows both concerted and stepwise mechanisms with former being the dominant reaction pathway. The concerted reaction proceeds with or without the involvement of one or two nearby water molecules. An important implication of the simulation results is that the Criegee-H 2 S reaction can provide a novel non-photochemical pathway for the formation of a C-S linkage in clouds and could be a new oxidation pathway for H 2 S in terrestrial, geothermal and volcanic regions.

Dissecting the hypothalamic pathways that underlie innate behaviors.

PubMed

Zha, Xi; Xu, Xiaohong

2015-12-01

Many complex behaviors that do not require learning are displayed and are termed innate. Although traditionally the subject matter of ethology, innate behaviors offer a unique entry point for neuroscientists to dissect the physiological mechanisms governing complex behaviors. Since the last century, converging evidence has implicated the hypothalamus as the central brain area that controls innate behaviors. Recent studies using cutting-edge tools have revealed that genetically-defined populations of neurons residing in distinct hypothalamic nuclei and their associated neural pathways regulate the initiation and maintenance of diverse behaviors including feeding, sleep, aggression, and parental care. Here, we review the newly-defined hypothalamic pathways that regulate each innate behavior. In addition, emerging general principles of the neural control of complex behaviors are discussed.

Immune pathways and defence mechanisms in honey bees Apis mellifera

PubMed Central

Evans, J D; Aronstein, K; Chen, Y P; Hetru, C; Imler, J-L; Jiang, H; Kanost, M; Thompson, G J; Zou, Z; Hultmark, D

2006-01-01

Social insects are able to mount both group-level and individual defences against pathogens. Here we focus on individual defences, by presenting a genome-wide analysis of immunity in a social insect, the honey bee Apis mellifera. We present honey bee models for each of four signalling pathways associated with immunity, identifying plausible orthologues for nearly all predicted pathway members. When compared to the sequenced Drosophila and Anopheles genomes, honey bees possess roughly one-third as many genes in 17 gene families implicated in insect immunity. We suggest that an implied reduction in immune flexibility in bees reflects either the strength of social barriers to disease, or a tendency for bees to be attacked by a limited set of highly coevolved pathogens. PMID:17069638

Crosstalk between p38, Hsp25 and Akt in spinal motor neurons after sciatic nerve injury

NASA Technical Reports Server (NTRS)

Murashov, A. K.; Ul Haq, I.; Hill, C.; Park, E.; Smith, M.; Wang, X.; Wang, X.; Goldberg, D. J.; Wolgemuth, D. J.

2001-01-01

The p38 stress-activated protein kinase pathway is involved in regulation of phosphorylation of Hsp25, which in turn regulates actin filament dynamic in non-neuronal cells. We report that p38, Hsp25 and Akt signaling pathways were specifically activated in spinal motor neurons after sciatic nerve axotomy. The activation of the p38 kinase was required for induction of Hsp25 expression. Furthermore, Hsp25 formed a complex with Akt, a member of PI-3 kinase pathway that prevents neuronal cell death. Together, our observations implicate Hsp25 as a central player in a complex system of signaling that may both promote regeneration of nerve fibers and prevent neuronal cell death in the injured spinal cord.

Regulation of DNA Alkylation Damage Repair: Lessons and Therapeutic Opportunities

PubMed Central

Soll, Jennifer M.; Sobol, Robert W.; Mosammaparast, Nima

2016-01-01

Alkylation chemotherapy is one of the most widely used systemic therapies for cancer. While somewhat effective, clinical responses and toxicities of these agents are highly variable. A major contributing factor for this variability is the numerous distinct lesions that are created upon alkylation damage. These adducts activate multiple repair pathways. There is mounting evidence that the individual pathways function cooperatively, suggesting that coordinated regulation of alkylation repair is critical to prevent toxicity. Furthermore, some alkylating agents produce adducts that overlap with newly discovered methylation marks, making it difficult to distinguish between bona fide damaged bases and so called ‘epigenetic’ adducts. We discuss new efforts aimed at deciphering the mechanisms that regulate these repair pathways, emphasizing their implications for cancer chemotherapy. PMID:27816326

Novel and ultra-rare damaging variants in neuropeptide signaling are associated with disordered eating behaviors

PubMed Central

Bahl, Ethan; Hannah, Claire; Hofammann, Dabney; Acevedo, Summer; Cui, Huxing; McAdams, Carrie J.

2017-01-01

Objective Eating disorders develop through a combination of genetic vulnerability and environmental stress, however the genetic basis of this risk is unknown. Methods To understand the genetic basis of this risk, we performed whole exome sequencing on 93 unrelated individuals with eating disorders (38 restricted-eating and 55 binge-eating) to identify novel damaging variants. Candidate genes with an excessive burden of predicted damaging variants were then prioritized based upon an unbiased, data-driven bioinformatic analysis. One top candidate pathway was empirically tested for therapeutic potential in a mouse model of binge-like eating. Results An excessive burden of novel damaging variants was identified in 186 genes in the restricted-eating group and 245 genes in the binge-eating group. This list is significantly enriched (OR = 4.6, p<0.0001) for genes involved in neuropeptide/neurotrophic pathways implicated in appetite regulation, including neurotensin-, glucagon-like peptide 1- and BDNF-signaling. Administration of the glucagon-like peptide 1 receptor agonist exendin-4 significantly reduced food intake in a mouse model of ‘binge-like’ eating. Conclusions These findings implicate ultra-rare and novel damaging variants in neuropeptide/neurotropic factor signaling pathways in the development of eating disorder behaviors and identify glucagon-like peptide 1-receptor agonists as a potential treatment for binge eating. PMID:28846695

The Emerging Role of Insulin and Insulin-Like Growth Factor Signaling in Cancer Stem Cells

PubMed Central

Malaguarnera, Roberta; Belfiore, Antonino

2014-01-01

Cancer cells frequently exploit the IGF signaling, a fundamental pathway mediating development, cell growth, and survival. As a consequence, several components of the IGF signaling are deregulated in cancer and sustain cancer progression. However, specific targeting of IGF-IR in humans has resulted efficacious only in small subsets of cancers, making researches wondering whether IGF system targeting is still worth pursuing in the clinical setting. Although no definite answer is yet available, it has become increasingly clear that other components of the IGF signaling pathway, such as IR-A, may substitute for the lack of IGF-IR, and induce cancer resistance and/or clonal selection. Moreover, accumulating evidence now indicates that IGF signaling is a central player in the induction/maintenance of epithelial mesenchymal transition (EMT) and cell stemness, two strictly related programs, which play a key role in metastatic spread and resistance to cancer treatments. Here we review the evidences indicating that IGF signaling enhances the expression of transcription factors implicated in the EMT program and has extensive cross-talk with specific pathways involved in cell pluripotency and stemness maintenance. In turn, EMT and cell stemness activate positive feed-back mechanisms causing up-regulation of various IGF signaling components. These findings may have novel translational implications. PMID:24550888

Molecular biology of anal squamous cell carcinoma: implications for future research and clinical intervention.

PubMed

Bernardi, Maria-Pia; Ngan, Samuel Y; Michael, Michael; Lynch, A Craig; Heriot, Alexander G; Ramsay, Robert G; Phillips, Wayne A

2015-12-01

Anal squamous cell carcinoma is a human papillomavirus-related disease, in which no substantial advances in treatment have been made in over 40 years, especially for those patients who develop disease relapse and for whom no surgical options exist. HPV can evade the immune system and its role in disease progression can be exploited in novel immunotherapy platforms. Although several studies have investigated the expression and inactivation (through loss of heterozygosity) of tumour suppressor genes in the pathways to cancer, no clinically valuable biomarkers have emerged. Regulators of apoptosis, including survivin, and agents targeting the PI3K/AKT pathway, offer opportunities for targeted therapy, although robust data are scarce. Additionally, antibody therapy targeting EGFR may prove effective, although its safety profile in combination with standard chemoradiotherapy has proven to be suboptimal. Finally, progress in the treatment of anal cancer has remained stagnant due to a lack of preclinical models, including cell lines and mouse models. In this Review, we discuss the molecular biology of anal squamous cell carcinoma, clinical trials in progress, and implications for novel therapeutic targets. Future work should focus on preclinical models to provide a resource for investigation of new molecular pathways and for testing novel targets. Copyright © 2015 Elsevier Ltd. All rights reserved.

Dopamine and oxytocin interactions underlying behaviors: potential contributions to behavioral disorders.

PubMed

Baskerville, Tracey A; Douglas, Alison J

2010-06-01

Dopamine is an important neuromodulator that exerts widespread effects on the central nervous system (CNS) function. Disruption in dopaminergic neurotransmission can have profound effects on mood and behavior and as such is known to be implicated in various neuropsychiatric behavioral disorders including autism and depression. The subsequent effects on other neurocircuitries due to dysregulated dopamine function have yet to be fully explored. Due to the marked social deficits observed in psychiatric patients, the neuropeptide, oxytocin is emerging as one particular neural substrate that may be influenced by the altered dopamine levels subserving neuropathologic-related behavioral diseases. Oxytocin has a substantial role in social attachment, affiliation and sexual behavior. More recently, it has emerged that disturbances in peripheral and central oxytocin levels have been detected in some patients with dopamine-dependent disorders. Thus, oxytocin is proposed to be a key neural substrate that interacts with central dopamine systems. In addition to psychosocial improvement, oxytocin has recently been implicated in mediating mesolimbic dopamine pathways during drug addiction and withdrawal. This bi-directional role of dopamine has also been implicated during some components of sexual behavior. This review will discuss evidence for the existence dopamine/oxytocin positive interaction in social behavioral paradigms and associated disorders such as sexual dysfunction, autism, addiction, anorexia/bulimia, and depression. Preliminary findings suggest that whilst further rigorous testing has to be conducted to establish a dopamine/oxytocin link in human disorders, animal models seem to indicate the existence of broad and integrated brain circuits where dopamine and oxytocin interactions at least in part mediate socio-affiliative behaviors. A profound disruption to these pathways is likely to underpin associated behavioral disorders. Central oxytocin pathways may serve as a potential therapeutic target to improve mood and socio-affiliative behaviors in patients with profound social deficits and/or drug addiction.

Modeling economic implications of alternative treatment strategies for acute bacterial skin and skin structure infections.

PubMed

Revankar, Nikhil; Ward, Alexandra J; Pelligra, Christopher G; Kongnakorn, Thitima; Fan, Weihong; LaPensee, Kenneth T

2014-10-01

The economic implications from the US Medicare perspective of adopting alternative treatment strategies for acute bacterial skin and skin structure infections (ABSSSIs) are substantial. The objective of this study is to describe a modeling framework that explores the impact of decisions related to both the location of care and switching to different antibiotics at discharge. A discrete event simulation (DES) was developed to model the treatment pathway of each patient through various locations (emergency department [ED], inpatient, and outpatient) and the treatments prescribed (empiric antibiotic, switching to a different antibiotic at discharge, or a second antibiotic). Costs are reported in 2012 USD. The mean number of days on antibiotic in a cohort assigned to a full course of vancomycin was 11.2 days, with 64% of the treatment course being administered in the outpatient setting. Mean total costs per patient were $8671, with inpatient care accounting for 58% of the costs accrued. The majority of outpatient costs were associated with parenteral administration rather than drug acquisition or monitoring. Scenarios modifying the treatment pathway to increase the proportion of patients receiving the first dose in the ED, and then managing them in the outpatient setting or prescribing an oral antibiotic at discharge to avoid the cost associated with administering parenteral therapy, therefore have a major impact and lower the typical cost per patient by 11-20%. Since vancomycin is commonly used as empiric therapy in clinical practice, based on these analyses, a shift in treatment practice could result in substantial savings from the Medicare perspective. The choice of antibiotic and location of care influence the costs and resource use associated with the management of ABSSSIs. The DES framework presented here can provide insight into the potential economic implications of decisions that modify the treatment pathway.

Prioritization of Epilepsy Associated Candidate Genes by Convergent Analysis

PubMed Central

Jia, Peilin; Ewers, Jeffrey M.; Zhao, Zhongming

2011-01-01

Background Epilepsy is a severe neurological disorder affecting a large number of individuals, yet the underlying genetic risk factors for epilepsy remain unclear. Recent studies have revealed several recurrent copy number variations (CNVs) that are more likely to be associated with epilepsy. The responsible gene(s) within these regions have yet to be definitively linked to the disorder, and the implications of their interactions are not fully understood. Identification of these genes may contribute to a better pathological understanding of epilepsy, and serve to implicate novel therapeutic targets for further research. Methodology/Principal Findings In this study, we examined genes within heterozygous deletion regions identified in a recent large-scale study, encompassing a diverse spectrum of epileptic syndromes. By integrating additional protein-protein interaction data, we constructed subnetworks for these CNV-region genes and also those previously studied for epilepsy. We observed 20 genes common to both networks, primarily concentrated within a small molecular network populated by GABA receptor, BDNF/MAPK signaling, and estrogen receptor genes. From among the hundreds of genes in the initial networks, these were designated by convergent evidence for their likely association with epilepsy. Importantly, the identified molecular network was found to contain complex interrelationships, providing further insight into epilepsy's underlying pathology. We further performed pathway enrichment and crosstalk analysis and revealed a functional map which indicates the significant enrichment of closely related neurological, immune, and kinase regulatory pathways. Conclusions/Significance The convergent framework we proposed here provides a unique and powerful approach to screening and identifying promising disease genes out of typically hundreds to thousands of genes in disease-related CNV-regions. Our network and pathway analysis provides important implications for the underlying molecular mechanisms for epilepsy. The strategy can be applied for the study of other complex diseases. PMID:21390307

Prioritization of epilepsy associated candidate genes by convergent analysis.

PubMed

Jia, Peilin; Ewers, Jeffrey M; Zhao, Zhongming

2011-02-24

Epilepsy is a severe neurological disorder affecting a large number of individuals, yet the underlying genetic risk factors for epilepsy remain unclear. Recent studies have revealed several recurrent copy number variations (CNVs) that are more likely to be associated with epilepsy. The responsible gene(s) within these regions have yet to be definitively linked to the disorder, and the implications of their interactions are not fully understood. Identification of these genes may contribute to a better pathological understanding of epilepsy, and serve to implicate novel therapeutic targets for further research. In this study, we examined genes within heterozygous deletion regions identified in a recent large-scale study, encompassing a diverse spectrum of epileptic syndromes. By integrating additional protein-protein interaction data, we constructed subnetworks for these CNV-region genes and also those previously studied for epilepsy. We observed 20 genes common to both networks, primarily concentrated within a small molecular network populated by GABA receptor, BDNF/MAPK signaling, and estrogen receptor genes. From among the hundreds of genes in the initial networks, these were designated by convergent evidence for their likely association with epilepsy. Importantly, the identified molecular network was found to contain complex interrelationships, providing further insight into epilepsy's underlying pathology. We further performed pathway enrichment and crosstalk analysis and revealed a functional map which indicates the significant enrichment of closely related neurological, immune, and kinase regulatory pathways. The convergent framework we proposed here provides a unique and powerful approach to screening and identifying promising disease genes out of typically hundreds to thousands of genes in disease-related CNV-regions. Our network and pathway analysis provides important implications for the underlying molecular mechanisms for epilepsy. The strategy can be applied for the study of other complex diseases.

Signaling intermediates (MAPK and PI3K) as therapeutic targets in NSCLC.

PubMed

Ciuffreda, Ludovica; Incani, Ursula Cesta; Steelman, Linda S; Abrams, Stephen L; Falcone, Italia; Curatolo, Anais Del; Chappell, William H; Franklin, Richard A; Vari, Sabrina; Cognetti, Francesco; McCubrey, James A; Milella, Michele

2014-01-01

The RAS/RAF/MEK/ ERK and the PI3K/AKT/mTOR pathways govern fundamental physiological processes, such as cell proliferation, differentiation, metabolism, cytoskeleton reorganization and cell death and survival. Constitutive activation of these signal transduction pathways is a required hallmark of cancer and dysregulation, on either genetic or epigenetic grounds, of these pathways has been implicated in the initiation, progression and metastastic spread of lung cances. Targeting components of the MAPK and PI3K cascades is thus an attractive strategy in the development of novel therapeutic approaches to treat lung cancer, although the use of single pathway inhibitors has met with limited clinical success so far. Indeed, the presence of intra- and inter-pathway compensatory loops that re-activate the very same cascade, either upstream or downstream the point of pharmacological blockade, or activate the alternate pathway following the blockade of one signaling cascade has been demonstrated, potentially driving preclinical (and possibly clinical) resistance. Therefore, the blockade of both pathways with combinations of signaling inhibitors might result in a more efficient anti-tumor effect, and thus potentially overcome and/or delay clinical resistance, as compared with single agent. The current review aims at summarizing the current status of preclinical and clinical research with regard to pathway crosstalks between the MAPK and PI3K cascades in NSCLC and the rationale for combined therapeutic pathway targeting.

Representing Carbon Capture and Storage in MARKAL EPAUS9r16a

EPA Science Inventory

Energy system models are used to evaluate the energy and environmental implications of alternative pathways for producing and using energy. Many such models include representations of the costs and capacities of carbon capture and sequestration (CCS). In this presentation, Dan Lo...

Mitigation of formalin-induced RNA damage to advance whole transcriptomic analyses of archival tissues

EPA Science Inventory

Leveraging the use of biorepository samples for genomic analyses holds huge implications for human health, including applications in pathway identification, biomarker discovery, and tumor profiling for precision medicine. However, there is a need for better ways to reduce nucleic...

Neurogenetic and Neurodevelopmental Pathways to Learning Disabilities.

ERIC Educational Resources Information Center

Mazzocco, Michele M. M.; And Others

1997-01-01

This paper reviews ongoing research designed to specify the cognitive, behavioral, and neuroanatomical phenotypes of specific genetic etiologies of learning disability. The genetic disorders at the focus of the research include reading disability, neurofibromatosis type 1, Tourette syndrome, and fragile X syndrome. Implications for identifying…

LASSO-ing Potential Nuclear Receptor Agonists and Antagonists: A New Computational Method for Database Screening

EPA Science Inventory

Nuclear receptors (NRs) are important biological macromolecular transcription factors that are implicated in multiple biological pathways and may interact with other xenobiotics that are endocrine disruptors present in the environment. Examples of important NRs include the androg...

Differential programming of p53-deficient embryonic cells during rotenone block

EPA Science Inventory

Mitochondrial dysfunction has been implicated in chemical toxicities. The present study used an in vitro model to investigate the differential expression of metabolic pathways during cellular stress in p53- efficient embryonic fibroblasts compared to p53-deficient cells. These c...

The long tail of oncogenic drivers in prostate cancer.

PubMed

Armenia, Joshua; Wankowicz, Stephanie A M; Liu, David; Gao, Jianjiong; Kundra, Ritika; Reznik, Ed; Chatila, Walid K; Chakravarty, Debyani; Han, G Celine; Coleman, Ilsa; Montgomery, Bruce; Pritchard, Colin; Morrissey, Colm; Barbieri, Christopher E; Beltran, Himisha; Sboner, Andrea; Zafeiriou, Zafeiris; Miranda, Susana; Bielski, Craig M; Penson, Alexander V; Tolonen, Charlotte; Huang, Franklin W; Robinson, Dan; Wu, Yi Mi; Lonigro, Robert; Garraway, Levi A; Demichelis, Francesca; Kantoff, Philip W; Taplin, Mary-Ellen; Abida, Wassim; Taylor, Barry S; Scher, Howard I; Nelson, Peter S; de Bono, Johann S; Rubin, Mark A; Sawyers, Charles L; Chinnaiyan, Arul M; Schultz, Nikolaus; Van Allen, Eliezer M

2018-05-01

Comprehensive genomic characterization of prostate cancer has identified recurrent alterations in genes involved in androgen signaling, DNA repair, and PI3K signaling, among others. However, larger and uniform genomic analysis may identify additional recurrently mutated genes at lower frequencies. Here we aggregate and uniformly analyze exome sequencing data from 1,013 prostate cancers. We identify and validate a new class of E26 transformation-specific (ETS)-fusion-negative tumors defined by mutations in epigenetic regulators, as well as alterations in pathways not previously implicated in prostate cancer, such as the spliceosome pathway. We find that the incidence of significantly mutated genes (SMGs) follows a long-tail distribution, with many genes mutated in less than 3% of cases. We identify a total of 97 SMGs, including 70 not previously implicated in prostate cancer, such as the ubiquitin ligase CUL3 and the transcription factor SPEN. Finally, comparing primary and metastatic prostate cancer identifies a set of genomic markers that may inform risk stratification.

The role of genetics and antibodies in sepsis

PubMed Central

Giamarellos-Bourboulis, Evangelos J.

2016-01-01

During the course of sepsis when immunosuppression predominates, the concentrations of circulating immunoglobulins (IGs) are decreased and this is associated with adverse outcomes. The production of IGs as response to invasive bacterial pathogens takes place through a complex pathway starting from the recognition of the antigen (Ag) by innate immune cells that process and present Ags to T cells. The orchestration of T-helper (Th) lymphocyte responses directs specific B cells and ends with the production of IGs by plasma cells. All molecules implicated in this process are encoded by genes bearing single nucleotide polymorphisms (SNPs). Meta-analysis of case-control studies have shown that the carriage of minor frequency SNPs of CD14, TLR2 and TNF is associated with increased sepsis risk. The ambiguity of results of clinical trials studying the clinical efficacy of exogenous IG administration in sepsis suggests that efficacy of treatment should be considered after adjustment for SNPs of all implicated genes in the pathway of IG production. PMID:27713886

The role of genetics and antibodies in sepsis.

PubMed

Giamarellos-Bourboulis, Evangelos J; Opal, Steven M

2016-09-01

During the course of sepsis when immunosuppression predominates, the concentrations of circulating immunoglobulins (IGs) are decreased and this is associated with adverse outcomes. The production of IGs as response to invasive bacterial pathogens takes place through a complex pathway starting from the recognition of the antigen (Ag) by innate immune cells that process and present Ags to T cells. The orchestration of T-helper (Th) lymphocyte responses directs specific B cells and ends with the production of IGs by plasma cells. All molecules implicated in this process are encoded by genes bearing single nucleotide polymorphisms (SNPs). Meta-analysis of case-control studies have shown that the carriage of minor frequency SNPs of CD14 , TLR2 and TNF is associated with increased sepsis risk. The ambiguity of results of clinical trials studying the clinical efficacy of exogenous IG administration in sepsis suggests that efficacy of treatment should be considered after adjustment for SNPs of all implicated genes in the pathway of IG production.

A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance.

PubMed

Manning, Alisa K; Hivert, Marie-France; Scott, Robert A; Grimsby, Jonna L; Bouatia-Naji, Nabila; Chen, Han; Rybin, Denis; Liu, Ching-Ti; Bielak, Lawrence F; Prokopenko, Inga; Amin, Najaf; Barnes, Daniel; Cadby, Gemma; Hottenga, Jouke-Jan; Ingelsson, Erik; Jackson, Anne U; Johnson, Toby; Kanoni, Stavroula; Ladenvall, Claes; Lagou, Vasiliki; Lahti, Jari; Lecoeur, Cecile; Liu, Yongmei; Martinez-Larrad, Maria Teresa; Montasser, May E; Navarro, Pau; Perry, John R B; Rasmussen-Torvik, Laura J; Salo, Perttu; Sattar, Naveed; Shungin, Dmitry; Strawbridge, Rona J; Tanaka, Toshiko; van Duijn, Cornelia M; An, Ping; de Andrade, Mariza; Andrews, Jeanette S; Aspelund, Thor; Atalay, Mustafa; Aulchenko, Yurii; Balkau, Beverley; Bandinelli, Stefania; Beckmann, Jacques S; Beilby, John P; Bellis, Claire; Bergman, Richard N; Blangero, John; Boban, Mladen; Boehnke, Michael; Boerwinkle, Eric; Bonnycastle, Lori L; Boomsma, Dorret I; Borecki, Ingrid B; Böttcher, Yvonne; Bouchard, Claude; Brunner, Eric; Budimir, Danijela; Campbell, Harry; Carlson, Olga; Chines, Peter S; Clarke, Robert; Collins, Francis S; Corbatón-Anchuelo, Arturo; Couper, David; de Faire, Ulf; Dedoussis, George V; Deloukas, Panos; Dimitriou, Maria; Egan, Josephine M; Eiriksdottir, Gudny; Erdos, Michael R; Eriksson, Johan G; Eury, Elodie; Ferrucci, Luigi; Ford, Ian; Forouhi, Nita G; Fox, Caroline S; Franzosi, Maria Grazia; Franks, Paul W; Frayling, Timothy M; Froguel, Philippe; Galan, Pilar; de Geus, Eco; Gigante, Bruna; Glazer, Nicole L; Goel, Anuj; Groop, Leif; Gudnason, Vilmundur; Hallmans, Göran; Hamsten, Anders; Hansson, Ola; Harris, Tamara B; Hayward, Caroline; Heath, Simon; Hercberg, Serge; Hicks, Andrew A; Hingorani, Aroon; Hofman, Albert; Hui, Jennie; Hung, Joseph; Jarvelin, Marjo-Riitta; Jhun, Min A; Johnson, Paul C D; Jukema, J Wouter; Jula, Antti; Kao, W H; Kaprio, Jaakko; Kardia, Sharon L R; Keinanen-Kiukaanniemi, Sirkka; Kivimaki, Mika; Kolcic, Ivana; Kovacs, Peter; Kumari, Meena; Kuusisto, Johanna; Kyvik, Kirsten Ohm; Laakso, Markku; Lakka, Timo; Lannfelt, Lars; Lathrop, G Mark; Launer, Lenore J; Leander, Karin; Li, Guo; Lind, Lars; Lindstrom, Jaana; Lobbens, Stéphane; Loos, Ruth J F; Luan, Jian'an; Lyssenko, Valeriya; Mägi, Reedik; Magnusson, Patrik K E; Marmot, Michael; Meneton, Pierre; Mohlke, Karen L; Mooser, Vincent; Morken, Mario A; Miljkovic, Iva; Narisu, Narisu; O'Connell, Jeff; Ong, Ken K; Oostra, Ben A; Palmer, Lyle J; Palotie, Aarno; Pankow, James S; Peden, John F; Pedersen, Nancy L; Pehlic, Marina; Peltonen, Leena; Penninx, Brenda; Pericic, Marijana; Perola, Markus; Perusse, Louis; Peyser, Patricia A; Polasek, Ozren; Pramstaller, Peter P; Province, Michael A; Räikkönen, Katri; Rauramaa, Rainer; Rehnberg, Emil; Rice, Ken; Rotter, Jerome I; Rudan, Igor; Ruokonen, Aimo; Saaristo, Timo; Sabater-Lleal, Maria; Salomaa, Veikko; Savage, David B; Saxena, Richa; Schwarz, Peter; Seedorf, Udo; Sennblad, Bengt; Serrano-Rios, Manuel; Shuldiner, Alan R; Sijbrands, Eric J G; Siscovick, David S; Smit, Johannes H; Small, Kerrin S; Smith, Nicholas L; Smith, Albert Vernon; Stančáková, Alena; Stirrups, Kathleen; Stumvoll, Michael; Sun, Yan V; Swift, Amy J; Tönjes, Anke; Tuomilehto, Jaakko; Trompet, Stella; Uitterlinden, Andre G; Uusitupa, Matti; Vikström, Max; Vitart, Veronique; Vohl, Marie-Claude; Voight, Benjamin F; Vollenweider, Peter; Waeber, Gerard; Waterworth, Dawn M; Watkins, Hugh; Wheeler, Eleanor; Widen, Elisabeth; Wild, Sarah H; Willems, Sara M; Willemsen, Gonneke; Wilson, James F; Witteman, Jacqueline C M; Wright, Alan F; Yaghootkar, Hanieh; Zelenika, Diana; Zemunik, Tatijana; Zgaga, Lina; Wareham, Nicholas J; McCarthy, Mark I; Barroso, Ines; Watanabe, Richard M; Florez, Jose C; Dupuis, Josée; Meigs, James B; Langenberg, Claudia

2012-05-13

Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.