Changes in parotid acinar cells accompanying salivary secretion in rats on sympathetic or parasympathetic nerve stimulation

Morphological and secretory effects of stimulating autonomic nerves have been studied in parotid glands of rats. Sympathetic stimulation evoked a slow flow of saliva which had a high concentration of amylase. After long term sympathetic stimulation secretory granules were heavily depleted from the parotid acinar cells. Parasympathetic stimulation evoked a copious flow of saliva with a low concentration of amylase. However, at high frequency stimulation the total amount of amylase secreted on parasympathetic stimulation was as great or even greater than on symphatetic stimulation, nevertheless, any loss of secretory granules from the acinar cells was very small. It is concluded that secretion of parotid acinar granules in the rat is prinicipally a sympathetic function. Secretion of fluid is more effectively produced by parasympathetic stimulation and much of the amylase in such saliva appears to have arisen from sources other than the secretory granules.     

Amygdaloid-induced jaw opening and facilitation or inhibition of the trigeminal motoneurons in the rat

1. Repetitive stimulation of the rat'se central amygdaloid (CAm) nucleus induced rhythmic masticatory jaw movements or continuous jaw opening. Both types of jaw movements were accompanied by coincidental activities of the mylohyoid (Myl) nerve. 2. The effects of CAm stimulation were examined on activities of bilateral Myl and masseteric (Mass) nerves or their motoneurons (Myl-Dig and Mass, respectively). 3. CAm stimulation induced contralaterally dominant facilitation of the Myl nerve activity as well as Myl-Dig motoneurons. These facilitatory effects were caused by EPSPs seen in Myl-Dig motoneurons. 4. One third of the Mass motoneurons were inhibited or hyperpolarized by contralateral CAm stimulation, while a few were facilitated and the majority unaffected.     

Chloride concentration of rat parotid saliva evoked by electrical stimulation of parasympathetic or sympathetic nerves with or without antagonists

Chloride (Cl) of saliva evoked by electrical stimulation of the parasympathetic nerve to parotid gland was from two to seven times higher than that elicited with sympathetic nerve stimulation; [Cl] remained elevated (125-135 mEq/liter) for 60 min of parasympathetic nerve stimulation, whereas Cl of sympathetically evoked saliva decreased from high levels of 58 to 15 to 20 mEq/liter. The administration of propranolol, the beta-adrenergic antagonist, 20 min prior to initiation of sympathetic nerve stimulation resulted in saliva with Cl of 100 mEq/liter; when phentolamine, the alpha-adrenergic antagonist was administered prior to sympathetic nerve stimulation, [Cl] was 48-35 mEq/liter. Values with the beta-agonist, isoproterenol, were about 35 mEq/liter, whereas phenylephrine, an alpha-adrenergic agonist, evoked saliva with Cl ranging from 113 to 85 mEq/liter. Flow rate was very high with parasympathetic nerve stimulation and low with sympathetic nerve stimulation, but [Cl] with beta-blockade was not flow dependent: flow was very low but Cl high. Cl secretion is principally regulated by activation of cholinergic and alpha-adrenergic receptors.     

Beneficial effects of moderate,early loading and adverse effects of delayed or excessive loading on bone healing

Fracture healing involves the differentiation and proliferation of cells in the callus and the synthesis and degradation of connective, cartilage and bone tissue. These processes are initiated and tightly regulated by growth factors and by the mechanical environment in the callus. In this work we incorporated the effects of mechanical stimulation on cell differentiation and ossification into a previously developed temporal-spatial model of growth factor mediated fracture healing. In particular, the stimulatory and inhibitory effects of dilatational and deviatoric strains were modeled. This predictive model was then calibrated and validated using well-defined in vivo experiments from the literature. As in the experiments, the results of the model demonstrated the beneficial and adverse effects of moderate and excessive loading, respectively, as well as the negative effects of delaying mechanical stimulation of rigidly fixed calluses. In addition, the model examined loading conditions and time points beyond those used in the experiments, providing a more complete and mechanistic characterization of the effects of loading in the biological tissue response associated with fracture healing.     

Differential alterations in cardiac adrenergic signaling in chronic hypoxia or norepinephrine infusion

Norepinephrine (NE)-induced desensitization of the adrenergic receptor pathway may mimic the effects of hypoxia on cardiac adrenoceptors. The mechanisms involved in this desensitization were evaluated in male Wistar rats kept in a hypobaric chamber (380 Torr) and in rats infused with NE (0.3 mg. kg(-1). h(-1)) for 21 days. Because NE treatment resulted in left ventricular (LV) hypertrophy, whereas hypoxia resulted in right (RV) hypertrophy, the selective hypertrophic response of hypoxia and NE was also evaluated. In hypoxia, alpha(1)-adrenergic receptors (AR) density increased by 35%, only in the LV. In NE, alpha(1)-AR density decreased by 43% in the RV. Both hypoxia and NE decreased beta-AR density. No difference was found in receptor apparent affinity. Stimulated maximal activity of adenylate cyclase decreased in both ventricles with hypoxia (LV, 41%; RV, 36%) but only in LV with NE infusion (42%). The functional activities of G(i) and G(s) proteins in cardiac membranes were assessed by incubation with pertussis toxin (PT) and cholera toxin (CT). PT had an important effect in abolishing the decrease in isoproterenol-induced stimulation of adenylate cyclase in hypoxia; however, pretreatment of the NE ventricle cells with PT failed to restore this stimulation. Although CT attenuates the basal activity of adenylate cyclase in the RV and the isoproterenol-stimulated activity in the LV, pretreatment of NE or hypoxic cardiac membranes with CT has a less clear effect on the adenylate cyclase pathway. The present study has demonstrated that 1) NE does not mimic the effects of hypoxia at the cellular level, i.e., hypoxia has specific effects on cardiac adrenergic signaling, and 2) changes in alpha- and beta-adrenergic pathways are chamber specific and may depend on the type of stimulation (hypoxia or adrenergic).     

Effects of 22K or 20K human growth hormone on lipolysis, leptin production in adipocytes in the presence and absence of human growth hormone binding protein.

OBJECTIVE AND METHOD: We studied the effects of human growth hormone (hGH) on leptin production and lipolysis stimulation in the presence or absence of human growth hormone binding protein (hGHBP) using 3T3- L1-hGHR adipocytes which efficiently express human growth hormone receptor. RESULTS AND CONCLUSION: It was clarified that (1) hGH decreases leptin secretion after hGH-induced lipolysis stimulation, and (2) the reduction of leptin production and lipolysis stimulation by 22K hGH was attenuated with hGHBP, whereas that by 20K hGH, which is a naturally occurring isoform of 22K hGH, was not affected with hGHBP.     

Effect of cytochalasin B on lymphocyte stimulation induced by concanavalin A or periodate

The effects of cytochalasin B on lymphocyte stimulation induced by concanavalin A (Con A) and by periodate were investigated. At low concentrations (0.1 – 1 μg/ml) cytochalosin B greatly potentiated the responses to these two mitogens. Cytochalasin B was most effective when added with the mitogens at the beginning of incubation. The action of cytochalasin B at low concentration was suggested to be on an early process of DNA synthesis induced by these mitogens.     

Delay of sexual maturation in female house mice by exposure to grouped females or urine from grouped females

The experiments examined the timing, duration and possible enhancement effects of group contact on the delay of sexual maturation produced in prepubertal female house mice by urine from grouped females. One or three days of pheromone stimulation at specified ages during the first 2 weeks after weaning was not sufficient to delay puberty in females caged singly. However, pheromone treatment for 7 days, beginning during the first week after weaning, did significantly delay the onset of first vaginal oestrus relative to control females treated with water. Both the timing and duration of pheromone stimulation appear to be critical factors affecting pheromone-induced delay of sexual maturation. Mean ages at first oestrus for females housed with a group of 7 other females, for 3 or 7 days at specified ages during the first 2 weeks after weaning, did not differ from mean ages recorded with urine stimulation only. Contact with other females does not appear to alter or enhance the delay-of-maturation effect achieved with urine stimulation. In all these respects the maturation-delay pheromone of grouped female mice appears to differ from the puberty-accelerating pheromone of male mice.     

Right or left ear reference changes the voltage of frontal and parietal somatosensory evoked potentials

Short-latency cortical somatosensory evoked potentials (SEPs) to left median nerve stimulation were recorded with either the left or right earlobe as reference. With a right earlobe reference the voltage of the parietal N20 and P27 was reduced while the voltage of the frontal P20 and N30 was enhanced. The effects were consistent, but their size varied with the SEP component considered and also among the subjects. Analysis of SEPs at different scalp sites and at either earlobe suggested that the ear contralateral to the side stimulated picked up transient potential differences, depending a.o. on side asymmetry and geometry of the neural generators as disclosed in topographic mapping. For example, the right ear potential can be shifted negatively by the right N20 field evoked by left median nerve stimulation. The changes involve the absolute potential values, but not the time features of the gradients of potential fields. Scalp current density (SCD) maps are not affected. The results are pertinent for current discussions about which reference to use and document the practical recommendation of recording short-latency cortical SEPs with a reference at the ear ipsilateral (not contralateral) to the side of stimulation.     

Electromagnetic fields act via activation of voltage‐gated calcium channels to produce beneficial or adverse effects

The direct targets of extremely low and microwave frequency range electromagnetic fields (EMFs) in producing non‐thermal effects have not been clearly established. However, studies in the literature, reviewed here, provide substantial support for such direct targets. Twenty‐three studies have shown that voltage‐gated calcium channels (VGCCs) produce these and other EMF effects, such that the L‐type or other VGCC blockers block or greatly lower diverse EMF effects. Furthermore, the voltage‐gated properties of these channels may provide biophysically plausible mechanisms for EMF biological effects. Downstream responses of such EMF exposures may be mediated through Ca²⁺/calmodulin stimulation of nitric oxide synthesis. Potentially, physiological/therapeutic responses may be largely as a result of nitric oxide‐cGMP‐protein kinase G pathway stimulation. A well‐studied example of such an apparent therapeutic response, EMF stimulation of bone growth, appears to work along this pathway. However, pathophysiological responses to EMFs may be as a result of nitric oxide‐peroxynitrite‐oxidative stress pathway of action. A single such well‐documented example, EMF induction of DNA single‐strand breaks in cells, as measured by alkaline comet assays, is reviewed here. Such single‐strand breaks are known to be produced through the action of this pathway. Data on the mechanism of EMF induction of such breaks are limited; what data are available support this proposed mechanism. Other Ca²⁺‐mediated regulatory changes, independent of nitric oxide, may also have roles. This article reviews, then, a substantially supported set of targets, VGCCs, whose stimulation produces non‐thermal EMF responses by humans/higher animals with downstream effects involving Ca²⁺/calmodulin‐dependent nitric oxide increases, which may explain therapeutic and pathophysiological effects.     

Intensification of oak sawdust enzymatic hydrolysis by chemical or hydrothermal pretreatment

The activities of cellulases and xylanase were determined in laboratory cultures of Aspergillus terreus F-413 performed on natural and chemically or hydrothermally pretreated oak sawdust. The best stimulation effects were obtained in the cultures containing sawdust treated with dioxane, sodium hydroxide, or phosphoric acid. Moreover, the sawdust pretreatment distinctly affected its enzymatic hydrolysis, especially when the preparation of hydrolase complex was isolated from the culture of A. terreus F-413 growing on the modified sawdust as a sole carbon source. The highest saccharification effect was observed when the sawdust was treated with dioxane, sodium hydroxide, or phosphoric acid. Glucose was the main product of sawdust decomposition found in the hydrolyzates.     

Transcranial Direct Current Stimulation of Right Dorsolateral Prefrontal Cortex Does Not Affect Model-Based or Model-Free Reinforcement Learning in Humans

There is broad consensus that the prefrontal cortex supports goal-directed, model-based decision-making. Consistent with this, we have recently shown that model-based control can be impaired through transcranial magnetic stimulation of right dorsolateral prefrontal cortex in humans. We hypothesized that an enhancement of model-based control might be achieved by anodal transcranial direct current stimulation of the same region. We tested 22 healthy adult human participants in a within-subject, double-blind design in which participants were given Active or Sham stimulation over two sessions. We show Active stimulation had no effect on model-based control or on model-free (‘habitual’) control compared to Sham stimulation. These null effects are substantiated by a power analysis, which suggests that our study had at least 60% power to detect a true effect, and by a Bayesian model comparison, which favors a model of the data that assumes stimulation had no effect over models that assume stimulation had an effect on behavioral control. Although we cannot entirely exclude more trivial explanations for our null effect, for example related to (faults in) our experimental setup, these data suggest that anodal transcranial direct current stimulation over right dorsolateral prefrontal cortex does not improve model-based control, despite existing evidence that transcranial magnetic stimulation can disrupt such control in the same brain region.     

Modulation of interleukin 2 activity by delta 9-tetrahydrocannabinol after stimulation with concanavalin A, phytohemagglutinin, or anti-CD3 antibody.

The effects of delta 9-tetrahydrocannabinol (THC) on lymphocyte proliferation and interleukin (IL) 2 activity was investigated using adult murine spleen cells stimulated with either the mitogens concanavalin A, phytohemagglutinin, or anti-CD3 antibody. THC was found to suppress mitogen-induced proliferation, but to enhance anti-CD3-antibody-induced proliferation. These results reflected THC-induced suppression of Ly2 cells following concanavalin A or phytohemagglutinin stimulation and THC-induced enhancement of Ly2 cells following CD3 stimulation. The combination of THC and concanavalin A or phytohemagglutinin resulted in suppressed IL-2 activity, whereas the combination of THC and anti-CD3 antibody resulted in enhanced IL-2 activity. This drug-related modulation of IL-2 activity corresponded to the changes in blastogenic activity as well as to variations in numbers of Tac positive cells. These results suggest that the dysregulation in immune responses following THC treatment, either suppression or enhancement, may relate to the effects of THC on IL-2 production.     

Enhanced de novo synthesis of phosphatidic acid and phosphatidylinositol in rat pancreatic islets exposed to nutrient or neurotransmitter stimuli

A stimulation of [3H]glycerol incorporation into phosphatidic acid and phosphatidylinositol was observed upon exposure of rat pancreatic islets to the nutrient secretagogues alpha-ketoisocaproate and glucose, or to the neurotransmitter stimuli carbamylcholine and cholecystokinin. These effects were associated with reduced labeling of phosphatidylcholine and, in some cases, phosphatidylethanolamine. The modified patterns of [3H]glycerol incorporation into islet phospholipids persisted in the absence of added Ca2+, but were abolished by excess EDTA. Nutrient, but not neurotransmitter, secretagogues also stimulated the incorporation of [3H]glycerol into triacylglycerols. The results suggest that the stimulation of islets with the above classes of secretagogues is accompanied by enhanced de novo synthesis of acidic phospholipids.     

Ligation or cross-linking of CD40 has different effects on AGS gastric cancer cells

A gastric cancer (GC) cell line, AGS, has high-level expression of CD40, a tumor necrosis factor receptor (TNFR) family member. CD40 is present on the surfaces of a large variety of cells, including B cells, endothelial cells, dendritic cells and some carcinoma cells, and delivers signals regulating diverse cellular responses, such as proliferation, differentiation, growth suppression, and cell death. In this research, we studied the effects of different forms of CD40 stimulation on AGS cells by flow cytometry, Western blotting and siRNA transfection. We found that different forms of CD40 stimulation, either recombinant soluble CD40L (sCD40L, ligation) or agonist anti-CD40 antibody (cross-linking), induced different effects in AGS gastric cancer cells, proliferation or apoptosis. We also showed that VEGF provided a significant contribution to sCD40L-induced proliferation, while agonist anti-CD40 antibody induced GADD45 upregulation and promoted apoptosis.     

Effects of abdominal or cardiopulmonary sympathetic afferents on upper cervical inspiratory neurons

Responses of upper cervical inspiratory neurons (UCINs) to abdominal visceral or cardiopulmonary sympathetic stimulation were studied using extracellular recordings from 213 UCINs in 54 pentobarbital sodium-anesthetized and paralyzed rats. Phrenic nerve activity was used to assess inspiration. The UCINs discharging during inspiration only were mainly in the C(1) segment, whereas phase-spanning UCINs were mostly in the C(2) segment. Phase-spanning activity was typically retained after overventilation or vagotomy. When greater splanchnic nerve (GSN) or cardiopulmonary sympathetic afferent (CPSA) fibers were electrically stimulated, augmented UCIN activity was observed in 65% of cells responding to CPSA stimulation but in only 17% of cells responding to GSN. Response latencies were 10.7 +/- 0.5 and 20.6 +/- 1.5 (SE) ms, respectively. Many augmented responses to CPSA stimulation (64%) and all augmented responses to GSN stimulation were followed by suppression of UCIN discharge (biphasic response). Phrenic nerve activity was suppressed by both GSN and CPSA stimulation, but with shorter latency for the latter (29 +/- 0.7 vs. 14.0 +/- 0.7 ms). Excitation of UCINs using CPSA stimulation occurs more often and by a more direct pathway than for GSN input.     

Noninvasive brain stimulation with transcranial magnetic or direct current stimulation (TMS/tDCS)-From insights into human memory to therapy of its dysfunction

Noninvasive stimulation of the brain by means of transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS) has driven important discoveries in the field of human memory functions. Stand-alone or in combination with other brain mapping techniques noninvasive brain stimulation can assess issues such as location and timing of brain activity, connectivity and plasticity of neural circuits and functional relevance of a circumscribed brain area to a given cognitive task. In this emerging field, major advances in technology have been made in a relatively short period. New stimulation protocols and, especially, the progress in the application of tDCS have made it possible to obtain longer and much clearer inhibitory or facilitatory effects even after the stimulation has ceased. In this introductory review, we outline the basic principles, discuss technical limitations and describe how noninvasive brain stimulation can be used to study human memory functions in vivo. Though improvement of cognitive functions through noninvasive brain stimulation is promising, it still remains an exciting challenge to extend the use of TMS and tDCS from research tools in neuroscience to the treatment of neurological and psychiatric patients.     

Differential relaxing responses to particulate or soluble guanylyl cyclase activation on endothelial cells: a mechanism dependent on PKG-I alpha activation by NO/cGMP

cGMP is generated in endothelial cells after stimulation of soluble guanylyl cyclase (sGC) by nitric oxide (NO) or of particulate guanylyl cyclase (pGC) by natriuretic peptides (NP). We examined whether localized increases in cytosolic cGMP have distinct regulatory roles on the contraction induced by H₂O₂ treatment in human umbilical vein endothelial cells. cGMP concentrations and temporal dynamics were different upon NO stimulation of sGC or C-type NP (CNP) activation of pGC and did not correlate with their relaxing effects measured as planar cell surface area after H₂O₂ challenge. cGMP production due to sGC stimulation was always smaller and more brief than that induced by pGC stimulation with CNP, which was greater and remained elevated longer. The NO effects on cell relaxation were cGMP dependent because they were blocked by sGC inhibition with 1H-(1,2,4)Oxadiazolo(4,3-a)quinoxaline-1-one and mimicked by 8-Br-cGMP. An antagonist of the cGMP-dependent protein kinase type-I (PKG-I) also inhibited the NO-induced effects. The cell contraction induced by H₂O₂ produces myosin light chain (MLC) phosphorylation and NO prevented it completely, whereas CNP only produced a partial inhibition. Transfection with a dominant negative form of PKG type-I completely reversed the NO-induced effects on MLC phosphorylation, whereas it only partially inhibited the effects due to CNP. Taken together, these results demonstrate that the NO/sGC/cGMP pathway induces endothelial cell relaxation in a more efficient manner than does CNP/pGC/cGMP pathway, an effect that might be related to a selective stimulation of PKG-1 by NO-derived cGMP. Consequently, stimulated PKG-I may phosphorylate important protein targets that are necessary to inhibit the endothelial contractile machinery activated by oxidative stress. nitric oxide; C-type natriuretic peptide; myosin light chain; cGMP-dependent protein kinase type I; endothelial cell barrier dysfunction     

Transcranial electrical stimulation for human enhancement and the risk of inequality: Prohibition or compensation?

Non‐invasive brain stimulation is used to modulate brain excitation and inhibition and to improve cognitive functioning. The effectiveness of the enhancement due to transcranial direct current stimulation (tDCS) is still controversial, but the technique seems to have large potential for improvement and more specific applications. In particular, it has recently been used by athletes, both beginners and professionals. This paper analyses the ethical issues related to tDCS enhancement, which depend on its specific features: ease of use, immediate effect, non‐detectability and great variability of effects. If tDCS were to become widespread, there could be some potential side effects, especially the rise of inequality in many selective competitive contexts. I discuss two possible scenarios to counter this effect: that of prohibition and that of compensation, each supported by reasons and arguments that seem plausible and worthy of consideration. In conclusion, I show why I think the scenario of compensation is the preferable one.     

Phospholipase C mimics insulin action on pyruvate dehydrogenase and insulin mediator generation but not glucose transport or utilization

This study investigated the extent to which a purified phosphatidylinositol-specific and a commercial non-specific phospholipase C mimicked acute insulin action in rat adipocytes. The enzymes mimicked insulin stimulation of pyruvate dehydrogenase (PDH) and breakdown of a glycophospholipid proposed as a precursor for an intracellular mediator of insulin action, but were much less effective in stimulating glucose transport and utilization. These observations corroborate recent suggestions that insulin may activate a phospholipase C to generate a mediator that can account for insulin activation of PDH from a mediator precursor with a phosphatidylinositol anchor. This mediator precursor is probably an outer membrane component since effects were obtained with intact cells. It is unlikely that this mechanism accounts fully for insulin action since phosphatidylinositol-specific and commercial phospholipase C stimulation of glucose transport was significantly less than that elicited by insulin.