Afferent Mechanisms Research Articles

Central command activation during exercise is essential for the bradycardic response to diving

Mammalian diving response evokes complex cardiovascular adjustments, including bradycardia during sustained muscular activity. This is intriguing because voluntary exercise involves the activation of central command and skeletal muscle afferents, known to provoke tachycardia by reducing vagal outflow and increasing cardiac sympathetic activity. Nonetheless, it is currently unknown how diving-induced bradycardia can override the exercise tachycardia. Given this, we aimed to test the hypothesis that central and peripheral afferent mechanisms interact to modulate this physiological phenomenon. In three visits, 32 healthy subjects (15 women; 22±3 yr) were exposed to trigeminal nerve stimulation (i.e., facial cooling; TGS) to partially activate the diving reflex at rest (semi-recumbent position) and under three protocols: 1) during voluntary light (resting heart rate+20 beats.min−1) and moderate (resting heart rate+50 beats.min−1) steady-state cycling exercise; 2) during isolation of peripheral afferent reflexes via passive exercise (muscle mechanoreceptors) and cold pressor test (nociceptors; CPT), and; 3) during CPT with concurrent light exercise. The exercise intensities were assumed to provide different levels of central command activation, while both passive exercise and CPT were used to provide insights into the contribution of central command to diving bradycardia. TGS was performed for at least 90 seconds in all conditions. Beat-to-beat heart rate (HR, by electrocardiography) and blood pressure (finger photoplethysmography) were continuously measured, and surface electromyography was used to ensure the lack of volitional component during passive exercise. TGS elicited significant bradycardia at rest (Δ-12±0.9 beats·min−1; P<0.001), and this response was increased during voluntary light exercise (Δ-15±1.2 beats·min−1; P=0.002), but unaffected during voluntary moderate exercise when compared to rest (Δ-11±1.3 beats·min−1; P=0.536). In contrast, compared to rest, the HR response to TGS during passive exercise was significantly attenuated (Δ-13±1.2 beats·min−1 vs. Δ-9±1.7 beats·min−1; P=0.039), whereas CPT completely abolish the diving bradycardic response (Δ0±1.6 beats·min−1; P<0.001). However, when the volitional component was restored during CPT with concurrent light exercise, TGS provoked a significant bradycardic response, when compared to CPT condition (Δ1±1.6 beats·min−1 vs. Δ-10±2.1 beats·min−1; P=0.004). Notably, our findings were not affected by sex. In conclusion, these findings suggest that 1) central command activation during cycling exercise is essential for the bradycardic response to diving; 2) isolated peripheral afferent reflexes exert inhibitory feedback to modulate diving-induced bradycardia, and; 3) central and peripheral afferent feedback are important mechanisms by which exercise modulates the dive response. CNPq 307764/2022-2; CAPES (001). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Potentiated respiratory metaboreflex in older males and females: afferent or efferent mechanisms?

Potentiated respiratory metaboreflex in older males and females: afferent or efferent mechanisms?

Modulation of Cerebral Function by Muscle Afferent Activity, with Reference to Intravenous Succinylcholine.

Cerebral Function and Muscle Afferent Activity Following Intravenous Succinylcholine in Dogs Anesthetized with Halothane: The Effects of Pretreatment with a Defasciculating Dose of Pancuronium. By WL Lanier, PA Iaizzo, and JH Milde. Anesthesiology 1989; 71:87-95. Reprinted with permission. By the mid-1980s, it was widely assumed that if the depolarizing muscle relaxant, succinylcholine, given IV, produced increases in intracranial pressure, it did so because fasciculations produced increases in intrathoracic and central venous pressures that were transferred to the brain; however, there was no direct evidence that this was true. In contrast, we explored the possibility that the succinylcholine effect on the brain was explained by the afferentation theory of cerebral arousal, which predicts that agents or maneuvers that stimulate muscle stretch receptors will tend to stimulate the brain. Our research in tracheally intubated, lightly anesthetized dogs discovered that IV succinylcholine (which does not cross the blood-brain barrier) produced a doubling of cerebral blood flow that lasted for 30 min and corresponded to activation of the electroencephalogram and increases in intracranial pressure. Later, in our Classic Paper, we were able to assess simultaneously cerebral physiology and afferent nerve traffic emanating from muscle stretch receptors (primarily muscle spindles). We affirmed that the cerebral arousal response to succinylcholine was indeed driven by muscle afferent traffic and was independent of fasciculations or increases in intrathoracic or central venous pressures. Later research in complementary models demonstrated that endogenous movement (e.g., coughing, hiccups) produced a cerebral response very similar to IV succinylcholine, apparently as a result of the same muscle afferent mechanisms, independent of intrathoracic and central venous pressures. Thus, the importance of afferentation theory as a driver of the cerebral state of arousal and cerebral physiology during anesthesia was affirmed.

Correlation between Mandarin acceptable noise level and cortical auditory evoked potential in young normal-hearing listeners

Objective:To investigate the correlation between Mandarin acceptable noise level （M-ANL） and cortical auditory evoked potential （CAEP）, and to explore the possible mechanism leading to individual differences in M-ANL values. Methods:Thirty listeners aged 22-33 years with normal hearing were selected as the study subjects, and the M-ANL test and CAEP test were performed respectively. The most comfortable level （MCL）, maximum background noise level （BNL）, M-ANL and CAEP values of each subject were recorded. The latency of each wave of P1, N1, P2, N2, P300 and the amplitude of P1-N1, P2-N2, P300 in CAEP were recorded for each subject. SPSS 25.0 was used for statistical analysis to explore the correlation between the MCL value, BNL value and M-ANL values and the latency of P1, N1, P2, N2, P300 and P1-N1, P2-N2, P300 amplitudes of CAEP. Results:①The MCL value and M-ANL value were positively correlated with the P2 latency of CAEP, and the correlation coefficients were 0.404 and 0.400, respectively, and the differences were statistically significant （P<0.05）. There was no correlation with P1, N1, N2, and P300 latencies of CAEP （P>0.05）. ②The MCL value, BNL value and M-ANL value had no significant difference with the CAEP wave amplitudes of P1-N1, P2-N2, and P300 （P>0.05）. Conclusion:There was a certain correlation between M-ANL and CAEP in young adults with normal hearing, suggesting that the central auditory cortex might play a potential regulatory role in the background noise tolerance. Individuals with a greater background noise acceptance might have stronger central efferent mechanisms and/or less active central afferent mechanisms.

The exercise pressor reflex: An update.

The exercise pressor reflex is a feedback mechanism engaged upon stimulation of mechano- and metabosensitive skeletal muscle afferents. Activation of these afferents elicits a reflex increase in heart rate, blood pressure, and ventilation in an intensity-dependent manner. Consequently, the exercise pressor reflex has been postulated to be one of the principal mediators of the cardiorespiratory responses to exercise. In this updated review, we will discuss classical and recent advancements in our understating of the exercise pressor reflex function in both human and animal models. Particular attention will be paid to the afferent mechanisms and pathways involved during its activation, its effects on different target organs, its potential role in the abnormal cardiovascular response to exercise in diseased states, and the impact of age and biological sex on these responses. Finally, we will highlight some unanswered questions in the literature that may inspire future investigations in the field.

Discriminant Analysis of the Coordinated Work Indicators of the Heart and Blood Vessels in Health and Disease

A discriminant method was proposed for modeling and quantifying the consistency of regulatory mechanisms in the cardiovascular system (CVS) of apparently healthy volunteers and those suffering from circulatory disorders associated with cervical spine osteochondrosis (OCS) and somatoform autonomic dysfunction (SAD). The congruence of the parameters of ECG intervalometry (DCI) and pulse wave duration (PWD) according to the volunteers’ photoplethysmograms (PPG) was established by calculating the disparity measure and deviations from the mean values using the coeffi cients of displacement, slope of the approximating straight line, as well as by comparing the reliability and correlation of the trend model with the initial data. We discovered gross violations of congruence in the work of efferent and afferent regulatory CVS mechanisms, mismatch and decrease in comparison with the norm of DCI and PWD, a signifi cant decrease in their approximation in the SAD volunteers. In volunteers with OCS, deviations in DCI and PWD from their mean values are much lower than in those with SAD, being inferior compared to healthy volunteers. Similar to SAD, these patients are inferior to healthy volunteers in terms of the disparity measure.

New Drugs on the Horizon for Functional and Motility Gastrointestinal Disorders

New Drugs on the Horizon for Functional and Motility Gastrointestinal Disorders

Sympathetic neural responses in heart failure during exercise and after exercise training.

The sympathetic nervous system coordinates the cardiovascular response to exercise. This regulation is impaired in both experimental and human heart failure with reduced ejection fraction (HFrEF), resulting in a state of sympathoexcitation which limits exercise capacity and contributes to adverse outcome. Exercise training can moderate sympathetic excess at rest. Recording sympathetic nerve firing during exercise is more challenging. Hence, data acquired during exercise are scant and results vary according to exercise modality. In this review we will: (1) describe sympathetic activity during various exercise modes in both experimental and human HFrEF and consider factors which influence these responses; and (2) summarise the effect of exercise training on sympathetic outflow both at rest and during exercise in both animal models and human HFrEF. We will particularly highlight studies in humans which report direct measurements of efferent sympathetic nerve traffic using intraneural recordings. Future research is required to clarify the neural afferent mechanisms which contribute to efferent sympathetic activation during exercise in HFrEF, how this may be altered by exercise training, and the impact of such attenuation on cardiac and renal function.

Relationship of motor mechanisms to gastroparesis symptoms: toward individualized treatment.

Following a classical paper by Dr. Keith A. Kelly published in this journal, and over the past 40 years, there has been increased understanding of the functions of different regions of the stomach, specifically the fundus, antrum, and pylorus. Several of the important physiological principles were based on in vivo animal studies that led to the appreciation of regional function and control mechanisms. These include the roles of the extrinsic parasympathetic vagal innervation, the gastric enteric nervous system and electrical syncytium consisting of pacemaker cells and smooth muscle cells, and duodenogastric reflexes providing feedback regulation following the arrival of food and hydrogen ions stimulating the release of hormones and vagal afferent mechanisms that inhibit gastric motility and stimulate pyloric contractility. Further insights on the role of regional motor functions in gastric emptying were obtained from observations in patients following diverse gastric surgeries or bariatric procedures, including fundoplication, Billroth I and sleeve gastrectomy, and sleeve gastroplasty. Antropyloroduodenal manometry and measurements of pyloric diameter and distensibility index provided important assessments of the role of antral hypomotility and pylorospasm, and these constitute specific targets for individualized treatment of patients with gastroparesis. Moreover, in patients with upper gastrointestinal symptoms suggestive of gastroparesis, the availability of measurements of gastric accommodation and pharmacological agents to reduce gastric sensitivity or enhance gastric accommodation provide additional specific targets for individualized treatment. It is anticipated that, in the future, such physiological measurements will be applied in patients to optimize choice of therapy, possibly including identifying the best candidate for pyloric interventions.

Purinergic receptor antagonism: A viable strategy for the management of autonomic dysreflexia?

The purinergic receptor ligand, ATP, may participate in reflex induced vasoconstriction through sympathetic efferent and sensory afferent mechanisms. However, the role of the purinergic system in contributing to autonomic dysreflexia following spinal cord injury is unclear. The present study investigates the involvement of P2X receptors in contributing to pressor responses during autonomic dysreflexia. Twenty rats were subjected to spinal cord injury and 24h later hemodynamic responses to colorectal distension were recorded. Animals were randomized to receive intravenous administration of the P2X receptor antagonist, NF023, or vehicle control. The data indicate that NF023 attenuates pressor responses to colorectal distension.

SPARC: Soft silicone electrode net for modulating bladder function

Bladder wall stimulation has been attempted for many decades to restore bladder function in people with spinal cord injury and other voiding dysfunctions. However, these efforts were limited by current spread to urethral structures, activation of the legs and co‐recruitment of other pelvic organs. Neural interfaces for the detrusor muscle itself face several challenges due to its unique structure and function. To directly modulate the bladder and urethra, we designed a stretchable electrode array that interfaces directly with the surface of these organs. With a stretchable electrode array that conforms to the bladder wall, we aim to create direct organ interface electrodes to stimulate and record from the bladder wall.Acute experiments in isoflurane‐anesthetized cats (n=9, 8 males, 1 female) were performed to characterize the functional and electromechanical properties of this polymer electrode. Nerve cuffs were placed bilaterally on the hypogastric and pelvic nerves to record neural activity during bladder wall stimulation. Fine wire electromyography (EMG) electrodes were placed in gluteal muscle as well as the external anal and urethral sphincters to measure current spread. A pressure catheter was placed transurethrally to record pressure and infuse saline into the bladder. Elastic electrodes were placed on the dorsal, ventral, and both lateral aspects of the bladder. In an isovolumetric bladder state, each electrode was stimulated (at amplitude: 2–8 mA, frequency: 3 – 33 Hz, pulse width: 1ms) while recording bladder pressure and compound action potentials in the instrumented nerves. To determine the mechanism of action, pelvic and hypogastric nerves were transected sequentially while measuring bladder pressure.We found that electrodes positioned near the bladder neck around the ureterovesical junction elicited the largest bladder contractions up to ~45 cmH2O while other locations such as the bladder dome generated significantly smaller contractions (~10 cmH2O). Bipolar stimulation on the bladder limited activation of the urethral sphincter and hind limbs through current spread compared to monopolar stimulation as shown by significant reduction in EMG activity with similar increases in bladder pressure. EMG recorded from the bladder wall had a directly proportional relation between frequency and volume thereby depicting detrusor muscle activity. Finally, we found that the passive mechanical effects of the silicone net around the bladder had a minimal impact (&lt; 5 cmH2O) on bladder pressure. Following nerve transection, single electrode stimulation on the ureterovesical junction resulted in smaller pressure increases compared to before transection, whereas there was no change in the pressures evoked by multi‐electrode stimulation.These soft silicone electrode nets can be used as a neural interface to generate bladder contractions in conditions where the bladder is underactive or atonic and enables continuous monitoring of detrusor EMG to monitor bladder state. Bladder wall stimulation acts through both direct‐efferent and reflex‐driven afferent mechanisms depending on stimulation location and charge.Support or Funding InformationNIH SPARC OT2OD025297

ТОНИЧЕСКАЯ АКТИВНОСТЬ И ГРАВИТАЦИОННЫЙ КОНТРОЛЬ ПОСТУРАЛЬНОЙ МЫШЦЫ

The review is an attempt to describe and give a meaning to the accumulated data about the mechanisms controlling the structure and functionality of the postural muscle the almost continuous work of which makes it possible for the humans and animals to exist actively on Earth's surface. A great bulk of these data was obtained, described and systematized by professor I.B. Kozlovskaya and her pupils. A body of the most interesting facts and regularities was documented in other laboratories and research centers, quite often under the influence of ideas suggested by I.B. Kozlovskaya. The concept of the tonic system, that is, an integral physiological apparatus comprising not only slow and fast muscular fibers and small controlling motoneurons but also a complex of the brain (up to and including the striatum and motor cortex) and sensory mechanisms, constitutes the most important parts of her theoretical legacy. The fundamental conclusion of this review is that the gravity-dependent tonic contracting activity of the postural muscle controlled by the nervous system and afferent mechanisms is key to maintaining its structure, signal pathways and mechanic properties crucial for its constant anti-gravity activity.

Abstract 044: High Sodium Intake Impairs Afferent Sympathodepressory Pathways in Rats

Afferent renal nerve pathways are likely involved the development of salt sensitive hypertension. We recently reported that intrarenal NaCl elicited a long-lasting sympatho-depression via a neuro-humoral TRPV1 dependent and tachykinin mediated renal afferent nerve pathway. We now wanted to test the hypothesis that high sodium intake impairs this afferent sympatho-depressory mechanism. Respective groups were put on tap water, 0.9 % saline for drinking or chow containing 8% NaCl. Cultured dorsal root ganglion neurons (DRG Th11-L2) of rats with renal afferents were investigated in current clamp mode to assess action potential generation during current injection. Rats were equipped with femoral catheters for blood pressure (BP) &amp; heart rate (HR) assessment, drug application, a renal arterial catheter for intrarenal administration (IRA) of NaCl boli (10 % NaCl, 10 μl) or Capsaicin (CAP 3.3, 6.6, 10, 33*10-7 M, 10 μl) and a bipolar electrode for renal sympathetic nerve activity (RSNA) recordings; eventually an intravenous (iv) bolus of the NK1-receptor blocker RP67580 (10*10-3M, 15 μl) was administered. Results are mean±SEM. In neurons from rats on high salt diet, but not on 0.9 % saline or controls the relation of tonic highly active neurons to less active neurons shifted towards less active units (tap water -tonic/phasic: 22/15; saline - tonic/phasic: 28/18; 8% high salt - tonic/phasic: 14/21* P&lt;0.05). However, cultured tonic renal neurons from rats on 0.9% saline or on high salt diet exhibited increased action potential (AP) production upon stimulation (control 13,3+/4 APs/600ms vs. saline 19,8+/-2,33* APs/600ms vs. high salt diet 22,2*+/-4,54 APs/600ms, control vs. experimental *p&lt;0.05, mean+/-SEM). ). 10% NaCl boli IRA induced decreases of RSNA from baseline 4.1±0.6 μV*sec to 2.2±0.8 μV*sec impaired in rats on 8% NaCl. (Suppressed RSNA unmasked in all groups by an i.v. NK1-inhibitor) In rats on high salt diet highly active tonic neurons with renal afferents in vitro decreased at the expense of less active phasic neurons in spite of tonic neurons producing more action potentials upon stimulation. The sodium inducible long-lasting sympatho-depression via a neuro-humoral tachykinin mediated afferent renal nerve pathway was eventually impaired.

Relationship Between Auditory and Visual Noise Acceptance in Normal-Hearing Listeners.

Research has shown that hearing aid acceptance is closely related to how well an individual tolerates background noise, regardless of improved speech understanding in background noise. The acceptable noise level (ANL) test was developed to quantify background noise acceptance. The ANL test measures a listener's willingness to listen to speech in noise rather than their ability to understand speech in noise, and is clinically valuable as a predictor of hearing aid success. Noise acceptance is thought to be mediated by central regions of the nervous system, but the underlying mechanism of noise acceptance is not well understood. Higher order central efferent mechanisms may be weaker and/or central afferent mechanisms are more active in listeners with large versus small ANLs. Noise acceptance, therefore, may not be limited to the auditory modality but observable across modalities. We designed a visual-ANL test, as a parallel of the auditory-ANL test, to examine the relations between auditory and visual noise acceptance. A correlational design. Thirty-seven adults between the ages of 21 and 30 years with normal hearing participated in this study. All participants completed the standard auditory-ANL task, the visual-ANL task developed for this study, reception thresholds for sentences using the hearing in noise test, and visual sentence recognition in noise using the text reception threshold test. Correlational analyses were performed to evaluate the relations between and among the ANL and perception tasks. Auditory- and Visual-ANLs were correlated; those who accepted more auditory noise were also those who accepted more visual noise. Auditory and visual perceptual measures were also correlated, demonstrating that both measures reflect common processes underlying the ability to recognize speech in noise. Finally, as expected, noise acceptance levels were unrelated to perception in noise across modalities. The results of this study support our hypothesis that noise acceptance may not be unique to the auditory modality, specifically, that the common variance shared between the two ANL tasks, may reflect a shared general perceptual or cognitive mechanism that is not specific to the auditory or visual domains. These findings also support that noise acceptance and speech recognition reflect different aspects of auditory and visual perception. Future work will relate these ANL measures with central tasks of inhibition and include hearing-impaired individuals to explore the mechanisms underlying noise acceptance.

Gentle Perineal Skin Stimulation for Control of Nocturia.

One of the major causes of nocturia is overactive bladder (OAB). Somatic afferent nerve stimuli are used for treating OAB. However, clinical evidence for the efficacy of this treatment is insufficient due to the lack of appropriate control stimuli. Studies on anesthetized animals, which eliminate emotional factors and placebo effects, have demonstrated an influence of somatic stimuli on urinary bladder functions and elucidated the underlying mechanisms. In general, the effects of somatic stimuli are dependent on the modality, location, and physical characteristics of the stimulus. Recently we showed that gentle stimuli applied to the perineal skin using a soft elastomer roller inhibited micturition contractions to a greater extent than a roller with a hard surface. Studies aiming to elucidate the neural mechanisms of gentle stimulation-induced inhibition reported that 1-10 Hz discharges of low-threshold cutaneous mechanoreceptive Aβ, Aδ, and C fibers evoked during stimulation with an elastomer roller inhibited the micturition reflex by activating the spinal cord opioid system, thereby reducing both ascending and descending transmission between bladder and pontine micturition center. The present review will provide a brief summary of (1) the effect of somatic electrical stimulation on the micturition reflex, (2) the effect of gentle mechanical skin stimulation on the micturition reflex, (3) the afferent, efferent, and central mechanisms underlying the effects of gentle stimulation, and (4) a translational clinical study demonstrating the efficacy of gentle skin stimuli for treating nocturia in the elderly with OAB by using the two roller types inducing distinct effects on rat micturition contractions. Anat Rec, 302:1824-1836, 2019. © 2019 American Association for Anatomy.

Cellular Responses of Human Postural Muscle to Dry Immersion.

Support withdrawal has been currently considered as one of the main factors involved in regulation of the human locomotor system. For last decades, several authors, including the authors of the present paper, have revealed afferent mechanisms of support perception and introduced the concept of the support afferentation system. The so-called “dry immersion” model which was developed in Russia allows for suspension of subjects in water providing the simulation of the mechanical support withdrawal. The present review is a summary of data allowing to appreciate the value of the “dry” immersion model for the purposes of studying cellular responses of human postural muscle to gravitational unloading. These studies corroborated our hypothesis that the removal of support afferentation inactivates the slow motor unit pool which leads to selective inactivation, and subsequent atony and atrophy, of muscle fibers expressing the slow isoform of myosin heavy chain (which constitutes the majority of soleus muscle fibers). Fibers that have lost a significant part of cytoskeletal molecules are incapable of effective actomyosin motor mobilization which leads to lower calcium sensitivity and lower range of maximal tension in permeabilized fibers. Support withdrawal also leads to lower efficiency of protective mechanisms (nitric oxide synthase) and decreased activity of AMP-activated protein kinase. Thus, “dry” immersion studies have already contributed considerably to the gravitational physiology of skeletal muscle.

Carotid chemoreflex activity restrains post-exercise cardiac autonomic control in healthy humans and in patients with pulmonary arterial hypertension.

Dysfunction of post-exercise cardiac autonomic control is associated with increased mortality risk in healthy adults and in patients with cardiorespiratory diseases. The afferent mechanisms that regulate the post-exercise cardiac autonomic control remain unclear. We found that afferent signals from carotid chemoreceptors restrain the post-exercise cardiac autonomic control in healthy adults and patients with pulmonary arterial hypertension (PAH). Patients with PAH had higher carotid chemoreflex sensitivity, and the magnitude of carotid chemoreceptor restraint of autonomic control was greater in patients with PAH as compared to healthy adults. The results demonstrate that the carotid chemoreceptors contribute to the regulation of post-exercise cardiac autonomic control, and suggest that the carotid chemoreceptors may be a potential target to treat post-exercise cardiac autonomic dysfunction in patients with PAH. Dysfunction of post-exercise cardiac autonomic control predicts mortality, but its underlying mechanisms remain unclear. We tested whether carotid chemoreflex activity restrains post-exercise cardiac autonomic control in healthy adults (HA), and whether such restraint is greater in patients with pulmonary arterial hypertension (PAH) who may have both altered carotid chemoreflex and altered post-exercise cardiac autonomic control. Twenty non-hypoxaemic patients with PAH and 13 age- and sex-matched HA pedalled until 90% of peak work rate observed in a symptom-limited ramp-incremental exercise test. Recovery consisted of unloaded pedalling for 5min followed by seated rest for 6min. During recovery, subjects randomly inhaled either 100% O2 (hyperoxia) to inhibit the carotid chemoreceptor activity, or 21% O2 (normoxia) as control. Post-exercise cardiac autonomic control was examined via heart rate (HR) recovery (HRR; HR change after 30, 60, 120 and 300s of recovery, using linear and non-linear regressions of HR decay) and HR variability (HRV; time and spectral domain analyses). As expected, the PAH group had higher carotid chemosensitivity and worse post-exercise HRR and HRV than HA. Hyperoxia increased HRR at 30, 60 and 120s and absolute spectral power HRV in both groups. Additionally, hyperoxia resulted in an accelerated linear HR decay and increased time domain HRV during active recovery only in the PAH group. In conclusion, the carotid chemoreceptors restrained recovery of cardiac autonomic control from exercise in HA and in patients with PAH, with the restraint greater for some autonomic indexes in patients with PAH.

A comprehensive review on Phyllanthus derived natural products as potential chemotherapeutic and immunomodulators for a wide range of human diseases

Abstract Treatment options for most cancers are still insufficient, despite developments and technology advancements. It has been postulated that the immune response to progressive tumors is insufficient due to a deficiency in afferent mechanisms responsible for the development of tumor-reactive T cells. Many patients treated for cancer will have their cancer recurrence, often after a long remission period. This suggests that there are a small number of tumor cells that remain alive after standard treatment(s) – alone or in combination and have been less effective in combating metastasis that represents the most elaborate hurdle to overcome in the cure of the disease. Therefore, any new effective and safe therapeutic agents will be highly demanded. To circumvent many plant extracts have attributed for their chemoprotective potentials and their influence on the human immune system. It is now well recognized that immunomodulation of immune response could provide an alternative or addition to conventional chemotherapy for a variety of disease conditions. However, many hurdles still exist. In recent years, there has been a tremendous interest either in harnessing the immune system or towards plant-derived immunomodulators as anticancer agents for their efficacy, safety and their targeted drug action and drug delivery mechanisms. This review discusses Phyllanthus Schum. & Thonn. their chemopreventive and immunomodulatory properties over the past few years. Although, as many as 500 important bioactive phytochemical compounds have been isolated from Phyllanthus their chemotherapeutic, immunomodulatory properties, molecular targets and modes of action are yet to be enlightened in detail. Hence, the theme of this review is very useful for further research on Phyllanthus species. because many phytochemicals from these plants have demonstrated preclinical therapeutic efficacy for a wide range of human diseases.

Distribution of physiological resources and effectivity of purposeful activity of patients with epilepsy

Aim: to study distribution of physiological resources in purposeful activity of patients with epilepsy.&#x0D; Materials and Methods. 70 Healthy individuals and 160 patients with epilepsy were examined. In the examined individuals purposeful activity was modeled with evaluation of its effectiveness using Schulte-Gorbov test. In the dynamics of the modeled activity, parameters of electroencephalogram, variability of heart rhythm were evaluated; in the initial condition (before Schulte-Gorbov test) parameters of evoked visual potentials, P300cognitive potentials and of a conditionally-negative deviation were estimated. Interrelations between parameters of electroencephalography and of variability of heart rhythm were studied using correlation analysis with Spearman rank correlation coefficient; the comparative analysis of variability of heart rhythm and characteristics of respiratory function was performed, and effectiveness of behavior of patients with epilepsy was predicted using logit-regression analysis.&#x0D; Results. Predomination of structural-metabolic forms of epilepsy was found in the group of patients with low effectiveness of the activity. The low-effective group of patients with epilepsy showed a higher correlation of physiological parameters and a high level of characteristics refecting activation of stress-realizing systems. For effective distribution of patients with epilepsy into groups with different effectiveness of behavior, it was necessary to include characteristics of visual evoked potential, P300 cognitive potential and conditionally-negative deviation into logit-regression model, that reflects the role of afferent and association mechanisms in this task. Increase in physiological «cost» and reduction in the effectiveness of activity in the group of patients with epilepsy is associated with prevalence of structural forms of epilepsy.&#x0D; Conclusion. Epileptogenic zones in patients with epilepsy are supposed to play a role not only in reduction of effectiveness of activity, but also in excessive mobilization of physiological resources and in increase in physiological cost of activity, that diminishes its effectiveness.

Attenuation of hypertension by C-fiber stimulation of the human median nerve and the concept-based novel device

High blood pressure (BP) is a highly controllable risk factor for cardiovascular diseases; however, awareness of this condition and the rates of controlled hypertension are low. Experimental animal studies have shown that stimulation of the median nerve or PC6 acupoint over the wrist has effects on cardiovascular activities, including reductions in systolic and diastolic BPs. A proof-of-concept study was conducted in humans to investigate whether stimulation of median nerve near PC6 acupoint decreased high BP, identify the optimal stimulation parameters for the BP-lowering effects of median nerve stimulation, and determine the specific peripheral nerves or types of afferent fibers mediating the BP-lowering effects. Median nerve stimulation was carried out bilaterally or unilaterally with different stimulation parameters, and the BP and heart rate were monitored. The afferent mechanisms underlying the effects of median nerve stimulation on hypertension were investigated via microneurography, A-fiber blocking experiments, and localized chemical or electrical stimulation. Bilateral median nerve stimulation at either low or high frequencies produced profound but transient reductions in systolic BP, which were elicited when median nerve stimulation was unilaterally applied at interelectrode distances of 2 and 4 cm. Systolic BP was also reduced by electrical stimulation of the thumb on the palm side. Although microneurographic recordings revealed the excitation of both A- and C-fibers following median nerve stimulation, the median nerve-mediated reductions in BP were not affected by A-fiber blockade, and they were mimicked by the activation of C-fibers with capsaicin. The present results indicate that activation of C-fibers in the median nerve generates BP-lowering effects in humans. Based on our clinical study, an optimized median nerve stimulator was built and combined with a wrist BP monitor for simultaneous BP measurements and median nerve stimulation.