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Release of oxytocin and prolactin in response to suckling.

The oxytocin and prolactin responses to suckling were measured in 10 women in early (n = 5) and established lactation (n = 5). Oxytocin was released in a pulsatile manner during suckling in all women, but the response was not related to milk volume, prolactin response, or parity of the mother. In all 10 women plasma oxytocin concentrations increased three to 10 minutes before suckling began. In five women this occurred in response to the baby crying, in three it coincided with the baby becoming restless in expectation of the feed, while in two it corresponded with the mother preparing for the feed. There was no prolactin response to stimuli other than stimulation of the nipple associated with suckling. These results clearly indicate that the milk ejection reflex, with release of oxytocin, occurs in most women before the tactile stimulus of suckling. A second release of oxytocin follows in response to the suckling stimulus itself. Thus it is important that care is taken to protect breast feeding mothers from stress not only during suckling but also immediately before nursing, when conditioned releases of oxytocin will occur.

Breast Feeding↗

Some shear facts and pure friction related to roughness discrimination and the cutaneous control of grasping.

The question of whether friction contributes to the perception of roughness has been overdebated and underinvestigated. A review of the psychophysical literature suggests that roughness and friction can be subjectively distinguished very effectively, although the same rapidly adapting Meissner corpuscles (RA1s) and slowly adapting Merkel receptors (SA1s) are stimulated by both stimuli. It appears that to achieve the subjective appreciation of roughness, the brain must learn to ignore variations in the speed of movement over the skin, the perpendicular force applied to the receptor surface, and the shear forces tangential to the skin generated by friction. Similarly, the subjective appreciation of slipperiness requires selective attention to tangential forces to the exclusion of speed, perpendicular force, and surface texture. A clearer picture is gradually emerging concerning the detection and appreciation of shear forces from investigations of the grasping and lifting of objects of different surfaces against the force of gravity. Although high shear forces provoke larger responses in almost all skin mechano-receptors, some neurons in both the sensory and motor cortex discharge more vigorously with smooth textures and lower coefficients of friction. Although populations of such neurons sensitive to smooth surfaces and low friction would be very useful in detecting both potential and real slips, just how the afferent signals are derived remains puzzling.

Discrimination Learning↗

Feeble bronchomotor responses in diabetic rats in association with decreased sensory neuropeptide release.

Type I diabetes is associated with a low incidence of asthma. We tested whether a decrease in sensory neuropeptide release is associated with an attenuated bronchoconstrictive response to field stimulation (FS; 100 stimuli, 20 V, 0.1 ms, 20 Hz) in streptozotocin (STZ)-induced diabetes. The organ fluid of the preparations were also tested for substance P, calcitonin gene-related peptide (CGRP), and somatostatin concentrations by RIA. Preparations were from either normal rats or those pretreated with 50 mg/kg STZ iv 8 wk before experiment. A group of STZ-treated animals was supplied with insulin delivery (4 IU/day sc) implants between 4 and 8 wk. A subgroup was formed to study the effect of capsaicin desensitization. The atropine-resistant contraction was attenuated by diabetes without capsaicin-sensitive relaxation response. Exogenous CGRP and substance P potentiated, whereas somatostatin inhibited (1 nM-10 microM) the FS-induced contractions in rings from either group. FS released somatostatin, CGRP, and substance P from 0.17 +/- 0.024, 0.15 +/- 0.022, and 1.65 +/- 0.093 to 0.58 +/- 0.032, 0.74 +/- 0.122, and 5.34 +/- 0.295 in preparations from normal, and from 0.19 +/- 0.016, 0.11 +/- 0.019, and 0.98 +/- 0.116 to 0.22 +/- 0.076, 0.34 +/- 0.099, and 1.84 +/- 0.316 fmol/mg wet wt in preparations from diabetic rats. Insulin supplementation restored neuropeptide release in rings from STZ-treated rats. The results show that the decreased FS-induced contractions occurred with a decrease in sensory neuropeptide release in STZ-diabetic rats.

Animals↗

Evidence for nitric oxide synthase inhibitor-sensitive and insensitive hippocampal synaptic potentiation.

1. Nitric oxide (NO) has been proposed as a retrograde messenger, mediating the postsynaptic to presynaptic transfer of the effects of conditioning stimulation, responsible for the initiation of hippocampal long-term potentiation (LTP). To further test this hypothesis, we inhibited nitric oxide synthase (NOS) to determine whether synaptic potentiation produced by different conditioning stimulus patterns and intensities was differentially affected by reduction of stimulation-dependent NO production. 2. Synaptic potentiation was produced in hippocampal slices from young F-344 rats by two different conditioning stimulation protocols. Conditioning stimuli were delivered to the Schaffer-collateral commissural system, and moderate levels of potentiation of the population excitatory postsynaptic potential (EPSP) in area CA1 were produced by a single 100 Hz, 1-s conditioning train delivered at half-maximal stimulus intensity. Higher levels of potentiation of the population EPSP were obtained by delivering two 100 Hz, 1-s conditioning stimulus trains, with a 60-s intertrain interval, at high stimulus currents. 3. Application of the nitric oxide synthase inhibitors NG-nitro-L-arginine (NOARG; 0.1-200 microM) and NG-monomethyl-L-arginine (NMMA; 100 microM) produced no significant direct effects on synaptic responses. 4. In slices that received a single conditioning stimulus train, both NOARG and NMMA were ineffective in blocking or reducing potentiation at concentrations between 0.1 and 200 microM. In slices receiving the more intense pair of conditioning stimulus trains, levels of potentiation in control slices were higher, and there was a very significant reduction by both NOARG (50 and 100 microM) and NMMA (100 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

2-Amino-5-phosphonovalerate↗

Intrinsic properties of deep dorsal horn neurons in the L6-S1 spinal cord of the intact rat.

1. Stable intracellular recordings were obtained from neurons (n = 62) in the L6-S1 deep dorsal horn of the spinal cord in pentobarbital-sodium-anesthetized, intact rats (n = 26). All neurons responded to natural mechanical stimuli and/or electrical stimulation of peripheral afferents. 2. Intracellular penetrations were maintained for 30 min-2 h. Action potentials occurred spontaneously in most neurons (n = 50) and could be evoked in the remainder (n = 12) by depolarizing current passage. Mean resting membrane potential was -60.9 mV, mean action potential height amplitude was 75.2 mV, mean half-width of the action potentials was 0.33 ms, mean input resistance was 38 M omega, and mean time constant was 9.1 ms. 3. Action potentials were followed by afterpotentials made up of at least three components; a fast afterhyperpolarization (fAHP), a slow afterhyperpolarization (sAHP), and an afterdepolarization (ADP). Most neurons (n = 40) exhibited all three afterpotentials, although some displayed only a fAHP and an ADP (n = 10) or a fAHP and a sAHP (n = 12). The durations and magnitudes of the afterpotentials varied widely among neurons. 4. Steady-state current-voltage relations were investigated in 14 neurons with depolarizing and hyperpolarizing current pulses. Of these 14 neurons, 5 exhibited inward rectification, 3 had outward rectification, and the remaining 6 showed a predominantly linear change of membrane potential to current injection. In addition, several neurons (n = 9) exhibited a postinhibitory rebound that was sometimes (n = 4) accompanied by a "sag" in voltage during the preceding hyperpolarizing current step. 5. Four patterns of spike frequency adaptation occurred during step depolarizing current passage. The firing of most neurons gradually decreased with a simple, approximately exponential time course (n = 21), in some neurons it decreased with both a fast and a slow time course (n = 8), in several it incremented in rate (n = 3), and one neuron showed a complex combination of multiple decrementing and incrementing adaptations. Time constants, magnitude of adaptation, and the slopes of the steady-state current-voltage relation varied widely. 6. Oscillations in membrane potential and firing rate occurred in three neurons. The oscillations arose from endogenous mechanisms in at least one neuron because manipulation of membrane potentials altered the frequency of oscillation; a depolarizing current increased the period of oscillation and eventually produced tonic firing, and a hyperpolarizing current increased the frequency of oscillation and eventually terminated firing. 7. The results demonstrate that neurons in the L6-S1 region of the dorsal horn exhibit a diversity of cellular mechanisms that may significantly modulate normal somatosensory and visceral input.

Action Potentials↗

Effects of adult neurogenesis on synaptic plasticity in the rat dentate gyrus.

Ongoing neurogenesis in the adult hippocampal dentate gyrus (DG) generates a substantial population of young neurons. This phenomenon is present in all species examined thus far, including humans. Although the regulation of adult neurogenesis by various physiologically relevant factors such as learning and stress has been documented, the functional contributions of the newly born neurons to hippocampal functions are not known. We investigated possible contributions of the newly born granule neurons to synaptic plasticity in the hippocampal DG. In the standard hippocampal slice preparation perfused with artificial cerebrospinal fluid (ACSF), a small (10%) long-term potentiation (LTP) of the evoked field potentials is seen after tetanic stimulation of the afferent medial perforant pathway (MPP). The induction of this ACSF-LTP is resistant to a N-methyl-D-aspartate (NMDA) receptor blocker, D,L-2-amino-5-phosphonovaleric acid (APV), but is completely prevented by ifenprodil, a blocker of NR2B subtype of NMDA receptors. In contrast, slices perfused with picrotoxin (PICRO), a GABA-receptor blocker, revealed a larger (40--50%), APV-sensitive but ifenprodil-insensitive LTP. The ACSF-LTP required lower frequency of stimulation and fewer stimuli for its induction than the PICRO-LTP. All these characteristics of ACSF-LTP are in agreement with the properties of the putative individual new granule neurons examined previously with the use of the whole cell recording technique in a similar preparation. A causal relationship between neurogenesis and ACSF-LTP was confirmed in experiments using low dose of gamma radiation applied to the brain 3 wk prior to the electrophysiological experiments. In these experiments, the new cell proliferation was drastically reduced and ACSF-LTP was selectively blocked. We conclude that the young, adult-generated granule neurons play a significant role in synaptic plasticity in the DG. Since DG is the major source of the afferent inputs into the hippocampus, the production and the plasticity of new neurons may have an important role in the hippocampal functions such as learning and memory.

2-Amino-5-phosphonovalerate↗

Tuning of T cell clone size and activation threshold by control of CD25 expression through mitogen-activated protein kinase pathways.

BACKGROUND: Following T cell receptor (TcR) engagement, CD25 expression is upregulated by T cells and controls their proliferation. It is not known how CD25 expression levels differentially influence T helper (Th) 1 and Th2 cell physiology. METHOD: CD25 upregulation, and other T cell functions, were studied in human Th1 and Th2 clones following stimulation with various stimuli. The effects of pharmacological substances were then evaluated to identify the signaling pathways controlling CD25 upregulation. RESULTS: Upon TcR engagement, one Th2 clone was induced to express substantially more CD25 than a Th1 clone, although both clones downregulated CD3 with similar dose responses. It was also found that the amount of antigen needed to elicit proliferation and cytokine production was considerably lowered in the presence of interleukin-2 (IL-2) for the Th2 cells, while for the Th1 cells the threshold of activation was not modified by the presence of IL-2. It was then shown that PP2 and cyclosporin A strongly inhibited CD25 expression in both clones, while wortmannin and Ro-31-8220 had more limited effects. In contrast, mitogen-activated protein kinase (MAPK) inhibitors had strikingly different effects on CD25, blocking its expression in the Th2 cells, while augmenting it, or leaving it unaffected, in the Th1 cells. CONCLUSION: These unexpected observations suggested that in some T cells TcR-mediated activation of the MAPK pathways may inhibit CD25 expression rather than promoting it. Absence of this negative control mechanism may endow Th2 cells with a growth advantage over Th1 cells and their effector functions may be elicited at lower antigen doses.

Calcium↗

Understanding the coronary circulation through studies at the microvascular level.

Studies of the coronary circulation have divided vascular resistances into three large components: large vessels, small resistance vessels, and veins. Studies of the epicardial microcirculation in the beating heart using stroboscopic illumination have suggested that resistance is more precisely controlled in different segments of the circulation. Measurements of coronary pressure in different sized arteries and arterioles have indicated that under normal conditions, 45-50% of total coronary vascular resistance resides in vessels larger than 100 microns. This distribution of vascular resistance can be altered in a nonuniform manner by a variety of physiological (autoregulation, increases in myocardial oxygen consumption, sympathetic stimulation) and pharmacological stimuli (norepinephrine, papaverine, dipyridamole, serotonin, vasopressin, nitroglycerin, adenosine, and endothelin). Studies of exchange of macromolecules in the microcirculation using fluorescent-labeled dextrans have also identified the size of the small pore (35-50 A) in coronary microvessels that can be altered by myocardial ischemia. Studies of the coronary microcirculation have demonstrated that the control of vascular resistance is extremely complex, and mechanisms responsible for these heterogeneous responses need further examination.

Animals↗

Influence of thyroid state on mechanical restitution of rat myocardium.

The purpose of this study was to determine whether thyroid state affects the beat-to-beat regulation of contractile strength in cardiac muscle. Transmembrane action potential and isometric force were simultaneously recorded in right ventricular papillary muscles from euthyroid, hypothyroid, and hyperthyroid rats. Large thyroid state-dependent alterations in the contractile response of the muscles were not accompanied by any significant difference in the action potential. During steady-state stimulation, single test stimuli were interpolated at varying intervals. Action potential duration and peak force of the test responses were plotted against the test stimulus interval to produce electrical and mechanical restitution curves. In all muscles studied, electrical and mechanical restitution followed different time courses; over a wide range of test intervals, action potential duration and peak force of the test responses changed in opposite directions. Thyroid state profoundly affected the recovery of contractile strength, while only minor differences were found among the electrical restitution curves of the three groups of preparations. Mechanical recovery was much faster in hyperthyroid and slower in hypothyroid than in euthyroid muscles. We conclude that electrical and mechanical restitutions occur through separate processes and that the thyroid state affects only the mechanisms responsible for the contractile recovery of rat myocardium. The modifications induced by thyroid dysfunction on contractile recovery might be accounted for by an effect of thyroid state on a time-dependent recycling of calcium by the sarcoplasmic reticulum.

Action Potentials↗

Monocyte IL-10 production during respiratory syncytial virus bronchiolitis is associated with recurrent wheezing in a one-year follow-up study.

Respiratory syncytial virus (RSV) bronchiolitis is associated with subsequent recurrent wheezing episodes. To determine whether cytokine responses during infection can be of predictive value for the development of recurrent wheezing, we performed a follow-up study in 50 hospitalized children with RSV bronchiolitis. Monocyte and lymphocyte cytokine responses in vitro were studied during the acute phase of disease, and again during the convalescent phase, 3 to 4 wk later. Monocyte cytokine responses, including interleukin-10 (IL-10), were measured in whole blood cultures, stimulated with lipopolysaccharide and interferon-gamma (LPS + IFN-gamma). In addition, T-cell cytokine responses, including IFN-gamma and IL-4 production, were measured in whole-blood cultures stimulated with phytohemagglutinin (PHA) or alphaCD2 + alphaCD28. Cytokine responses were analyzed in relation to the development of recurrent episodes of wheezing, documented by parents in a diary during a 1-yr follow-up period. IL-10 responses during the acute phase of RSV bronchiolitis were comparable to those in healthy control subjects. During the convalescent phase, IL-10 responses were significantly increased in patients as compared with those in healthy control subjects (p < 0.001). At follow-up, 27 children (58%) had recurrent episodes of wheezing. IL-10 levels, measured during the convalescent phase, were significantly higher in patients who developed recurrent wheezing during the year after RSV bronchiolitis than in patients without recurrent episodes of wheezing (p = 0.006). Moreover, IL-10 responses during the convalescent phase correlated significantly with the number of wheezing episodes (r = 0.42, n = 46, p = 0.004). Interestingly, no association was found between IFN-gamma responses, IL-4 responses, or IFNgamma/IL-4 ratios and recurrent wheezing. We conclude that monocyte IL-10 responses in vitro upon stimulation with nonspecific stimuli may have predictive value for the development of recurrent wheezing after RSV bronchiolitis. Moreover, our results indicate that not only allergen-driven Th2 cytokine responses can lead to asthmatic symptoms but also virus-induced changes in cytokine responses may result in asthmatic symptoms.

Bronchiolitis, Viral↗

Regulation of glucagon secretion by glucose transporter type 2 (glut2) and astrocyte-dependent glucose sensors.

Ripglut1;glut2-/- mice have no endogenous glucose transporter type 2 (glut2) gene expression but rescue glucose-regulated insulin secretion. Control of glucagon plasma levels is, however, abnormal, with fed hyperglucagonemia and insensitivity to physiological hypo- or hyperglycemia, indicating that GLUT2-dependent sensors control glucagon secretion. Here, we evaluated whether these sensors were located centrally and whether GLUT2 was expressed in glial cells or in neurons. We showed that ripglut1;glut2-/- mice failed to increase plasma glucagon levels following glucoprivation induced either by i.p. or intracerebroventricular 2-deoxy-D-glucose injections. This was accompanied by failure of 2-deoxy-D-glucose injections to activate c-Fos-like immunoreactivity in the nucleus of the tractus solitarius and the dorsal motor nucleus of the vagus. When glut2 was expressed by transgenesis in glial cells but not in neurons of ripglut1;glut2-/- mice, stimulated glucagon secretion was restored as was c-Fos-like immunoreactive labeling in the brainstem. When ripglut1;glut2-/- mice were backcrossed into the C57BL/6 genetic background, fed plasma glucagon levels were also elevated due to abnormal autonomic input to the alpha cells; glucagon secretion was, however, stimulated by hypoglycemic stimuli to levels similar to those in control mice. These studies identify the existence of central glucose sensors requiring glut2 expression in glial cells and therefore functional coupling between glial cells and neurons. These sensors may be activated at different glycemic levels depending on the genetic background.

Animals↗

Diary reports of nausea and vomiting during pregnancy.

Nausea and vomiting during pregnancy can have a profound effect on the lives of some women. Symptoms have been reported across cultures and throughout recorded history, but interventions that consistently relieve symptoms have not been documented. As part of a larger study, strategies or situations that stimulate or relieve nausea and vomiting or retching were evaluated qualitatively. Participants (n = 124) who experienced nausea during pregnancy with or without vomiting/retching kept a diary for 7 days, recording any interventions or symptom relief measures that they used, evaluating the effectiveness of these measures, and recording activities or situations that exacerbated their symptoms. Data from the diaries were categorized using content analysis. Rest, particularly napping, was a measure that was universally employed to relieve symptoms. Participants reported that almost any type of sensory perception could stimulate symptoms. Sensory stimuli were often exaggerated or altered, with perceptions of odors being profoundly affected. Implications for nursing practice are discussed.

Adaptation, Psychological↗

Breakdown of accommodation in nerve: a possible role for persistent sodium current.

BACKGROUND: Accommodation and breakdown of accommodation are important elements of information processing in nerve fibers, as they determine how nerve fibers react to natural slowly changing stimuli or electrical stimulation. The aim of the present study was to elucidate the biophysical mechanism of breakdown of accommodation, which at present is unknown. RESULTS: A model of a space-clamped motor nerve fiber was developed. It was found that this new model could reproduce breakdown of accommodation when it included a low-threshold, rapidly activating, persistent sodium current. However, the phenomenon was not reproduced when the persistent sodium current did not have fast activation kinetics or a low activation threshold. CONCLUSION: The present modeling study suggests that persistent, low-threshold, rapidly activating sodium currents have a key role in breakdown of accommodation, and that breakdown of accommodation can be used as a tool for studying persistent sodium current under normal and pathological conditions.

Animals↗

Response of the parathyroid gland to infusion of human parathyroid hormone-(1-34) [PTH-(1-34)]: demonstration of suppression of endogenous secretion using immunoradiometric intact PTH-(1-84) assay.

Alterations in the sensitivity of the parathyroid gland to both stimulative and suppressive stimuli may be partially responsible for skeletal changes that occur with age, estrogen deficiency, osteoporosis, and estrogen treatment of osteoporosis. We sought to define the changes in intact PTH-(1-84) secretion in normal premenopausal and postmenopausal, osteoporotic and estrogen-treated osteoporotic women during the infusion of human (h) PTH-(1-34). hPTH-(1-34) was infused at 0.55 U/kg.h for 24 h, with serum sampling every 4 h. Serum was analyzed for calcium (ionized and total), hPTH-(1-34), and PTH-(1-84). Basal chemistries were no different among groups, except for serum phosphorus, which was highest in osteoporotic women (1.31 vs. 1.07 mmol/L in premenopausal; P less than 0.02), and hPTH-(1-34), which was slightly higher in normal postmenopausal women (19.31 vs. 13.24 ng/L in estrogen treated; P less than 0.02). No differences in PTH-(1-84) were found among groups. hPTH-(1-34) rose similarly in all patient groups, while the calcemic response was somewhat more sluggish in estrogen-treated women, although statistically significant differences were not found. PTH-(1-84) declined rapidly in all patient groups, although estrogen-treated women had a smaller maximal decrease in PTH-(1-84), and the slope of the decremental change in PTH-(1-84) was lower in estrogen-treated women than in osteoporotic or normal postmenopausal women. Untreated osteoporotic women had less suppression of PTH-(1-84) than normal postmenopausal women at every calcium level. Estrogen treatment decreases the calcemic effects of infused hPTH-(1-34) and at the same time reduces calcium-induced suppression of parathyroid secretion. It is possible that such changes in the set-point of the gland contribute to the alterations in bone turnover that result in osteoporosis and the mechanisms by which estrogen prevents bone loss.

Calcium↗

Olfactory detection and identification performance are dissociated in early Alzheimer's disease.

Ten carefully screened men with very mild symptoms of Alzheimer's disease (AD) and ten healthy controls of similar age were compared on multiple chemosensory tasks: odor detection and identification, and taste detection. The patients scored significantly worse than controls on identification of odors and of a subset of airborne stimuli providing trigeminal stimulation. In contrast, the patients' olfactory detection thresholds as well as taste detection thresholds were not impaired relative to those of controls. The patients' scores on neuropsychological tests and the results 18F-2 deoxy-D-glucose PET studies did not correlate with any of the chemosensory measures. The isolated odor identification deficit suggests that the initial chemosensory impairment in AD is central rather than peripheral.

Aged↗

Atrial lead malposition in a dual chamber (DDD,M) pacemaker.

A model 7000 pacemaker in the DVI mode emitted two stimuli, the first stimulating the right ventricle and the second 110 ms later. The atrial lead was found in the right ventricular outflow tract. The QRS complex produced by the atrial lead fell after the blanking period, and "committed" the ventricular stimulus 110 ms after the "atrial." Intracardiac electrography during the original implant would have enabled proper atrial lead position.

Aged↗

Depolarizing GABAergic conductances regulate the balance of excitation to inhibition in the developing retinotectal circuit in vivo.

Neurotransmission during development regulates synaptic maturation in neural circuits, but the contribution of different neurotransmitter systems is unclear. We investigated the role of GABAA receptor-mediated Cl- conductances in the development of synaptic responses in the Xenopus visual system. Intracellular Cl- concentration ([Cl-]i) was found to be high in immature tectal neurons and then falls over a period of several weeks. GABAergic synapses are present at early stages of tectal development and, when activated by optic nerve stimulation or visual stimuli, induce sustained depolarizing Cl- conductances that facilitate retinotectal transmission by NMDA receptors. To test whether depolarizing GABAergic inputs cooperate with NMDA receptors during activity-dependent maturation of glutamatergic synapses, we prematurely reduced [Cl-]i in tectal neurons in vivo by expressing the Cl- transporter KCC2. This blocked the normal developmental increase in AMPA receptor-mediated retinotectal transmission and increased GABAergic synaptic input to tectal neurons. Therefore, depolarizing GABAergic transmission plays a pivotal role in the maturation of excitatory transmission and controls the balance of excitation and inhibition in the developing retinotectal circuit.

Animals↗

"Kiss-and-run" glutamate secretion in cultured and freshly isolated rat hippocampal astrocytes.

Under physiological conditions, astrocytes not only passively support and nourish adjacent neurons, but also actively modulate neuronal transmission by releasing "glial transmitters," such as glutamate, ATP, and D-serine. Unlike the case for neurons, the mechanisms by which glia release transmitters are essentially unknown. Here, by using electrochemical amperometry and frequency-modulated single-vesicle imaging, we discovered that hippocampal astrocytes exhibit two modes of exocytosis of glutamate in response to various stimuli. After physiological stimulation, a glial vesicle releases a quantal content that is only 10% of that induced by nonphysiological, mechanical stimulation. The small release event arises from a brief (approximately 2 ms) opening of the fusion pore. We conclude that, after physiological stimulation, astrocytes release glutamate via a vesicular "kiss-and-run" mechanism.

Animals↗