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Results for “augmented feedback”

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PubMed2001

Modulation of breathing using imperceptible unloading.

We investigated the role of V(T) and V(T)/T(I) modulation of breathing in awake human subjects. We applied a PRBS of volume (incrementing ramp) or flow (decrementing wave) assist at levels below the perceptual threshold in order to stimulate respiratory feedback. We modeled the PRBS data with linear difference equations to obtain impulse-response profiles of V(T), V(T)/T(I), T(I) and factorial(P(MUS)). We limited cortical responses to our stimuli by applying sub-threshold levels of assist, and we limited humoral effects (O2 and CO2) by augmenting mechanical respiratory output intermittently and by small amounts. We found that flow or volume assist elicited similar significant increases in V(T) and V(T)/T(I). During flow assist there was a significant decrease in factorial(P(MUS)) and T(I) was reduced, albeit not significantly; however, volume assist did not modify T(I) or factorial(P(MUS)). The earlier onset of flow assist, relative to volume assist, may explain the difference between the responses. We conclude that vagally mediated inspiratory flow receptors in the chest wall or lungs may modulate breathing on a breath by breath basis when small, imperceptible increases in airflow occur early during inspiration. Furthermore, lung volume feedback during imperceptible unloading (occurring at the end of inspiration) was less effective. Finally, pseudorandom unloading with imperceptible stimuli provides a useful tool to study reflex regulation of ventilation in awake subjects without confounding cortical influences.

Adult↗

PubMed1988

Effect of adenosine analogues on tubuloglomerular feedback responses.

Adenosine has been invoked as a possible mediator of the vasoconstrictor response elicited through the tubuloglomerular feedback mechanism. These experiments were undertaken to study the effect of adenosine analogues on the magnitude of the stop-flow pressure (SFP) feedback response. With a control solution, maximum change of SFP during orthograde perfusion was 6.3 +/- 0.34 mmHg. When the adenosine1 (A1) receptor agonists CHA, CPA, or R-PIA were present in the perfusate in a concentration of 10(-5) M, SFP responses were significantly augmented and averaged 12.6 +/- 1.9 (P less than 0.001), 12.6 +/- 0.8 (P less than 0.001), and 10.3 +/- 1.1 mmHg (P less than 0.02), respectively. Diminished responses were seen at higher concentrations of A1 analogues. The A2-receptor agonist NECA did not significantly modify the control response at 10(-5) M, but reduced its magnitude at higher concentrations. During graded increases in loop flow rate essentially all of the response in the presence of CPA or R-PIA occurred in the 0-10 nl/min flow interval, whereas the most sensitive flow rate range in the control tubules was between 10 and 20 nl/min. In the presence of 10(-4) M furosemide SFP responses were abolished during perfusion with the control and NECA-containing solutions. In contrast, SFP fell by 11.8 +/- 1.26 mmHg and 8.7 +/- 1.25 mmHg with CHA or CPA solutions despite the presence of furosemide. Perfusion with 10(-6) M CPA in an isotonic mannitol solution was associated with a decrease of SFP by 16.3 +/- 1.42 mmHg, whereas the mannitol solution alone decreased SFP by only 0.6 +/- 0.18 mmHg. Our results show that luminal administration of A1-receptor analogues increases SFP feedback response magnitude, an effect that does not require the presence of a luminal NaCl signal.

Adenosine↗

PubMed1994

Role of thrombospondin in mesangial cell growth: possible existence of an autocrine feedback growth circuit.

Thrombospondin (TSP) is an extracellular matrix glycoprotein involved in mesangial cell (MC) adhesive and migratory function. We have studied the role of TSP in activation and proliferation of rat MC in serum-free media. TSP, in a concentration dependent manner (5 to 20 micrograms/ml), caused an increase in thymidine uptake, first detectable at 28 hours and more prominent at 48 hours. This effect was inhibited by heparin and heparan sulfate. TSP induced epidermal growth factor (EGF) secretion and significantly augmented constitutive platelet-derived growth factor-AB (PDGF-AB) secretion by MC in a concentration dependent fashion. It did not, however, induce TGF-beta, IL-1, IL-6, IL-8, or TNF-alpha production. TSP had an additive effect with exogenous EGF and PDGF on thymidine uptake. Anti-PDGF neutralizing antibody eliminated the effect of TSP on MC growth. MC displayed a single class of heparin-inhibitable TSP binding sites (Bmax 3.8 +/- 1.8 x 10(6)/cell, Kd = 80 +/- 29 nM). Based on these observations, we propose the existence of an autocrine positive feedback loop of MC proliferation involving TSP and growth factors, and regulated by heparan sulfate.

Animals↗

PubMed1990

The interaction of criterion and feedback information in learning a drawing task.

Experiments were designed to examine the influence of criterion and feedback information in the learning of a two-dimensional drawing task. Experiment 1 showed that when the task criterion is well known to the subject, the combined presentation of criterion information and information feedback facilitates the rate of acquisition of the skill but not its overall performance level of achievement. Experiment 2 showed that when the task criterion information is not well known to the subject, presentation of criterion information facilitates both the rate of acquisition and the overall performance level and, furthermore, is essential if configuration information feedback is to be utilized effectively. Experiment 3 showed that it is the combined presentation of criterion and configuration information feedback rather than the isolate presentation of either type of information alone, that facilitates learning and performance. Collectively, the findings from the three experiments suggest an interactive effect of prior knowledge by the learner and type of augmented information in facilitating the acquisition of skill, according to the constraints imposed in the task. The data are consistent with the proposal that the degrees of freedom in the information available to support motor skill learning must match the degrees of freedom to be constraint in the perceptual-motor workspace.

Journal Article↗

PubMed2005

Comparison of the metabolic effects of raloxifene and oral estrogen in postmenopausal and growth hormone-deficient women.

CONTEXT: The endocrine and metabolic functions of the liver are affected by estrogen. Oral estrogen reduces IGF-I and suppresses fat oxidation despite augmenting GH secretion. The aim of this study was to determine whether selective estrogen receptor modulators display similar effects and whether these effects are magnified in GH-deficient (GHD) women because of the loss of GH feedback. DESIGN: This was an open-label, randomized, two-period, crossover study comparing treatment (raloxifene vs. estradiol) and group (normal vs. GHD). SETTING: The setting of this study was a clinical research unit. PARTICIPANTS: Twelve postmenopausal women and 12 women with hypopituitarism participated in this study. INTERVENTION: Two 4-wk treatments with 17beta-estradiol (E2; 2 mg, followed by 4 mg) or raloxifene (60 mg, followed by 120 mg) were given, crossing over to the alternate treatment after a 4-wk washout period. OUTCOME MEASURES: Endocrine [GH, IGF-I, IGF-binding protein-3 (IGFBP-3), GH-binding protein, and SHBG] and metabolic (fat oxidation) end points were used as outcome measures. RESULTS: E2 reduced serum IGF-I levels in a dose-dependent manner in both groups, with effects greater (P < 0.05) than raloxifene. Raloxifene reduced IGF-I levels in the GHD group (P < 0.001), but not in the postmenopausal group. E2 reduced (P < 0.05), and raloxifene increased (P < 0.05), IGFBP-3 levels in both groups. E2, but not raloxifene, increased GH (P < 0.05) in postmenopausal women. The effects of E2 and raloxifene on IGF-I, IGFBP-3, IGF-I/IGFBP-3 molar ratio, GH-binding protein, and SHBG were significantly different (P < 0.05). E2 and raloxifene reduced (P < 0.05) fat oxidation equally in GHD, whereas the decrease in postmenopausal women was not significant. CONCLUSION: E2 and raloxifene exert different hepatic endocrine, but not lipid oxidative, effects. The greater effects seen in GHD women may be explained by the loss of endogenous GH feedback.

Adolescent↗

PubMed1995

Ciliary neurotrophic factor inhibits brain and peripheral tumor necrosis factor production and, when coadministered with its soluble receptor, protects mice from lipopolysaccharide toxicity.

BACKGROUND: The receptor of ciliary neurotrophic factor (CNTF) contains the signal transduction protein gp130, which is also a component of the receptors of cytokines such as interleukin (IL)-6, leukemia-inhibitory factor (LIF), IL-11, and oncostatin M. This suggests that these cytokines might share common signaling pathways. We previously reported that CNTF augments the levels of corticosterone (CS) and of IL-6 induced by IL-1 and induces the production of the acute-phase protein serum amyloid A (SAA). Since the elevation of serum CS is an important feedback mechanism to limit the synthesis of proinflammatory cytokines, particularly tumor necrosis factor (TNF), we have investigated the effect of CNTF on both TNF production and lipopolysaccharide (LPS) toxicity. MATERIALS AND METHODS: To induce serum TNF levels, LPS was administered to mice at 30 mg/kg i.p. and CNTF was administered as a single dose of 10 micrograms/mouse i.v., either alone or in combination with its soluble receptor sCNTFR alpha at 20 micrograms/mouse. Serum TNF levels were the measured by cytotoxicity on L929 cells. In order to measure the effects of CNTF on LPS-induced TNF production in the brain, mice were injected intracerebroventricularly (i.c.v.) with 2.5 micrograms/kg LPS. Mouse spleen cells cultured for 4 hr with 1 microgram LPS/ml, with or without 10 micrograms CNTF/ml, were also analyzed for TNF production. RESULTS: CNTF, administered either alone or in combination with its soluble receptor, inhibited the induction of serum TNF levels by LPS. This inhibition was also observed in the brain when CNTF and LPS were administered centrally. In vitro, CNTF only marginally affected TNF production by LPS-stimulated mouse splenocytes, but it acted synergistically with dexamethasone (DEX) in inhibiting TNF production. Most importantly, CNTF administered together with sCNTFR alpha protected mice against LPS-induced mortality. CONCLUSIONS: These data suggest that CNTF might act as a protective cytokine against TNF-mediated pathologies both in the brain and in the periphery.

Animals↗

PubMed1983

Lateral interactions in absence of feedback to cones.

1. The reversal potential of the surround response in cones was measured by inactivating the outer segment, polarizing the cone to different potential levels with extrinsic current, and flashing a full-field stimulus. This elicited a 3- to 4-mV depolarizing response at the normal -40-mV dark level. Its reversal potential was typically near -60 mV. 2. Cones were also polarized by a steady center light while flashing an annulus. The annular response was suppressed when the cone was polarized to near -60 mV. No reversal was measured, presumably because the maximum center light response could not exceed -60 mV. 3. Items 1 and 2 provide a method for measuring surround responses in cells post-synaptic to the cones in the absence of the surround response in the cones themselves; cone surround responses are suppressed although some horizontal cell surround responses are enhanced (item 6) at high center intensities that polarize the cones to near -60 mV. 4. Bipolar cells of both types (depolarizing and hyperpolarizing) generate a surround response that opposes the center response. In both bipolar cell types, the surround response is completely suppressed near center intensities that suppress the surround response in the cones. 5. Narrow-field horizontal cells behave like cones and bipolar cells; the depolarizing surround response is suppressed at high center intensities bright enough to suppress the cone surround response. At higher center intensities the surround response becomes hyperpolarizing, presumably due to direct coupling to peripheral horizontal cells. 6. Broad-field horizontal cells always hyperpolarize in response to surround illumination. The hyperpolarizing surround response is augmented at high center intensities, presumably because the depolarizing component, initiated in the cones, is suppressed, while the direct coupling to peripheral horizontal cells remains intact.

Animals↗

PubMed1996

Insulin-like growth factor I and insulin down-regulate growth hormone (GH) receptors in rat osteoblasts: evidence for a peripheral feedback loop regulating GH action.

The anabolic actions of GH are mediated by the production of insulin-like growth factor I (IGF-I) from the liver and by local production of IGF-I in extrahepatic tissues. Insulin facilitates the hepatic production of IGF-I by up-regulating GH receptors (GHRs) in the liver and augmenting the IGF-I response to GH. Although GHRs have also been identified in extrahepatic tissues that produce IGF-I, the possibility that IGF-I and insulin might partake in GHR regulation, thereby modulating the effects of GH locally has not received detailed study. The aim of this study was to investigate whether IGF-I and insulin are involved in the local regulation of GHRs, using osteoblasts as a model of GH-responsive extrahepatic tissues. We have used UMR106.06, a well differentiated rat osteoblast-like cell line that expresses GHRs and exhibits a mitogenic response to GH. IGF-I and insulin (0-10 nM) increased cell number and reduced [125I]GH binding in a concentration-dependent manner, with ED50 values of 0.8 and 0.3 nM, respectively. Although IGF-I increased cell number maximally by 36.9 +/- 1.2% (mean +/- SE) above the control value and insulin by 104.8 +/- 5.7% (P < 0.001), they decreased GH binding to 47.0 +/- 9.3% (P < 0.01) and 29.8 +/- 8.7% of the control value (P < 0.001), respectively. Scatchard analysis revealed that the down-regulation of GH binding was attributed to reduced receptor numbers and not binding affinity. The effects of IGF-I and insulin at submaximal concentrations were additive, although the combined effects did not exceed the maximal effect of either growth factor alone. Addition of an anti-IGF-I receptor antibody (alpha IR3) reversed the inhibition of GH binding induced by IGF-I, but not that caused by insulin; similarly, an antiinsulin receptor antibody (29B4) attenuated the inhibitory effect of insulin only. Addition of alpha IR3 alone or an ant-IGF-I antibody (Sm1.2) decreased cell number and increased GH binding in a concentration-dependent mode. GH at 1.5 nM significant increased cell number by 19.3 +/- 2.4% above the control level (P < 0.01), an increase that was reversed by alpha IR3. GH increased GH binding by 32.4 +/- 7.2% (P < 0.05) in cells treated with alpha IR3 to remove the secondary effect of IGF-I. In summary, IGF-I and insulin acted via specific receptors to stimulate cell proliferation and down-regulate GHRs in osteoblasts. GH stimulated cell proliferation, an action mediated by local production of IGF-I, and GH enhanced its own binding. The collective data suggest the presence of a peripheral negative feedback loop that allows IGF-I to limit locally the response of extrahepatic tissues to circulating GH.

Analysis of Variance↗

PubMed1984

Dopaminergic efferent inhibition of carotid body chemoreceptors in chronically hypoxic cats.

The observations that the dopamine concentration of the carotid body and efferent inhibition of carotid chemoreceptors are increased during chronic hypoxia led to the hypothesis that the inhibition was due to the effect of an increased dopamine release by the activity of carotid sinus nerve (CSN) efferents. The hypothesis was tested by measuring the effect of dopamine receptor blockade on efferent inhibition of carotid chemosensory responses to graded levels of arterial O2 partial pressure in chronically hypoxic and normoxic cats. Chronically hypoxic cats were prepared by exposing the cats to 10% O2 at sea level for 30-34 days. Carotid chemosensory activity was first measured from a slip of an otherwise intact CSN. The measurements were then repeated after sectioning the remaining nerve trunk. The effect of sectioning the CSN provided the measure of efferent inhibition. In each group of cats the effects of sectioning the CSN with and without dopamine receptor blockade by haloperidol were also studied. CSN section augmented the chemosensory responses in the chronically hypoxic cats. Haloperidol, a dopamine antagonist, augmented the responses further, indicating that a part of the endogenous dopamine effect was independent of the CSN efferents. After haloperidol treatment CSN section did not influence the chemosensory responses. This study confirmed that the efferent inhibition significantly increased in the chronically hypoxic cats and demonstrated that haloperidol blocked the efferent inhibition, suggesting that the mechanism of the augmented inhibition is dopaminergic.

Animals↗

PubMed1982

Tubuloglomerular feedback response after hypotensive hemorrhage.

The tubuloglomerular feedback (TGF) response was studied in control rats and after either hypotensive hemorrhage or aortic clamping (AC). TGF was assessed both by differences in proximally and distally determined single nephron glomerular filtration rate (SNGFR) and by proximally determined SNGFR responses to orthograde microperfusion at 0 or 36 nl/min. Hypotensive hemorrhage was induced by the removal of blood equivalent to 0.5-1% of body weight. In control rats, proximal SNGFR was 29.74 +/- SE 0.87 nl/min and distal SNGFR was 28.64 +/- 0.82 nl/min, values not significantly different from each other. After moderate hemorrhagic hypotension (MH: BP = 86 +/- 1 mm Hg) or AC (BP = 70 +/- 4 mm Hg), both proximal and distal SNGFR decreased, with no significant differences between the values in either group. After severe hemorrhagic hypotension (SH; BP = 70 +/- 1 mm Hg), proximal SNGFR was 25.23 +/- 2.07 nl/min and distal SNGFR was 19.69 +/- 1.50 nl/min, values significantly different from each other and consistent with an enhanced feedback response. Using orthograde microperfusion, a significant reduction in SNGFR at a perfusion rate of 36 nl/min was observed under all circumstances. However, with SH hypotension the percent change in SNGFR at the two perfusion rates was significantly increased to 35.0 +/- 5.5%, compared to 21.6 +/- 6.6% in controls. In contrast, AC with reduction in renal perfusion pressure to a degree comparable to SH hypotension did not augment the relative decrease in SNGFR, the percentage change being 22.2 +/- 7.2%. Neither was TGF enhanced after MH hypotension when similar volumes of blood were removed but a similar decrease in BP was not obtained. These results suggest that some factor related to severe systemic hypotension enhanced the TGF response.

Animals↗

PubMed2004

Testosterone blunts feedback inhibition of growth hormone secretion by experimentally elevated insulin-like growth factor-I concentrations.

The present study tests the hypothesis that a high dose of testosterone (Te) drives GH and IGF-I production, in part, by blunting autonegative feedback by the end-product peptide. To this end, we infused saline or recombinant human IGF-I (10 microg/kg.h iv for 6 h) in seven healthy men ages 51-72 yr after administration of placebo (Pl) and Te in randomized order. GH release was quantitated fasting before and after injection of GHRH (1 microg/kg). Statistical analyses disclosed that Te vs. Pl: 1) increased the mean concentration of GH from 0.15 +/- 0.045 to 0.48 +/- 0.11 microg/liter (P = 0.007) and IGF-I from 108 +/- 5.0 to 124 +/- 4.1 (P = 0.047) without altering GHRH-induced GH release; 2) elevated the GH nadir from 0.13 +/- 0.03 to 0.23 +/- 0.06 microg/liter (P < 0.05) in the control session and from 0.06 +/- 0.02 to 0.14 +/- 0.04 microg/liter (P = 0.038) during IGF-I infusion; 3) augmented GHRH-stimulated GH release from 3.0 +/- 0.56 (Pl) to 3.7 +/- 0.52 microg/liter (Te) (P < 0.05) during IGF-I infusion; and 4) did not influence estimated IGF-I kinetics. In summary, supplementation of a high dose of Te in middle-aged and older men attenuates IGF-I feedback-dependent inhibition of nadir and peak GH secretion. Both effects of Te differ from those reported recently for estradiol in postmenopausal women. Accordingly, we postulate that Te and estrogen modulate IGF-I negative feedback differentially.

Aged↗

PubMed2004

Regional differences in the expression of Fos-like immunoreactivity after central salt loading in conscious rats: modulation by endogenous vasopressin and role of the area postrema.

In this study, we examined the quantitative relationship between centrally administered hypertonic saline (HS) concentrations and the expression of Fos-like immunoreactivity (FLI) in brain regions involved in the homeostasis of body fluids. The regions examined were the organum vasculosum laminae terminalis (OVLT), the median preoptic nucleus (MnPO), the subfornical organ (SFO), the paraventricular nucleus (PVN), the supraoptic nucleus of the hypothalamus, the nucleus of the solitary tract (NTS), and the area postrema (AP). The experiments were performed in conscious rats with attention to the actual changes in central [Na(+)]. Hypertonic saline (0.3, 0.67, or 1.0 M) was delivered at 1 microl/min for 20 min. The changes in cerebrospinal fluid [Na(+)] during i.c.v. administration of 0.3 M hypertonic saline were compatible with those expected for thermal dehydration. FLI increased in a dose-dependent manner in the dorsomedial cap of the PVN and NTS. Although the pressor responses during central salt loading were not significantly affected by pretreatment with the peripheral vasopressin V(1) receptor antagonist OPC-21268, FLI expression in the PVN was significantly augmented. In addition, in AP-lesioned rats, FLI expression in the lateral magnocellular part of the PVN and NTS was significantly enhanced after central salt loading. These results suggest that the peripheral vasopressin system participates in negative feedback to modulate neuronal activities in the PVN, probably through the AP or direct action at the PVN in response to central osmotic and/or Na(+) stimulation.

Animals↗

PubMed2000

beta(3)-adrenoceptor deficiency blocks nitric oxide-dependent inhibition of myocardial contractility.

The cardiac beta-adrenergic pathway potently stimulates myocardial performance, thereby providing a mechanism for myocardial contractile reserve. beta-Adrenergic activation also increases cardiac nitric oxide (NO) production, which attenuates positive inotropy, suggesting a possible negative feedback mechanism. Recently, in vitro studies suggest that stimulation of the beta(3)-adrenoceptor results in a negative inotropic effect through NO signaling. In this study, using mice with homozygous beta(3)-adrenoceptor deletion mutations, we tested the hypothesis that the beta(3)-adrenoceptor is responsible for beta-adrenergic activation of NO. Although resting indices of myocardial contraction were similar, beta-adrenergic-stimulated inotropy was increased in beta(3)(-/-) mice, and similar hyper-responsiveness was seen in mice lacking endothelial NO synthase (NOS3). NOS inhibition augmented isoproterenol-stimulated inotropy in wild-type (WT), but not in beta(3)(-/-) mice. Moreover, isoproterenol increased myocardial cGMP in WT, but not beta(3)(-/-), mice. NOS3 protein abundance was not changed in beta(3)(-/-) mice, and cardiac beta(3)-adrenoceptor mRNA was detected in both NOS3(-/-) and WT mice. These findings indicate that the beta(3)-adrenergic subtype participates in NO-mediated negative feedback over beta-adrenergic stimulation.

Adrenergic beta-Agonists↗

PubMed2005

Corticofugal feedback for auditory midbrain plasticity elicited by tones and electrical stimulation of basal forebrain in mice.

The auditory cortex (AC) is the major origin of descending auditory projections and is one of the targets of the cholinergic basal forebrain, nucleus basalis (NB). In the big brown bat, cortical activation evokes frequency-specific plasticity in the inferior colliculus and the NB augments this collicular plasticity. To examine whether cortical descending function and NB contributions to collicular plasticity are different between the bat and mouse and to extend the findings in the bat, we induced plasticity in the central nucleus of the mouse inferior colliculus by a tone paired with electrical stimulation of the NB (hereafter referred to as tone-ES(NB)). We show here that tone-ES(NB) shifted collicular best frequencies (BFs) towards the frequency of the tone paired with ES(NB) when collicular BFs were different from tone frequency. The shift in collicular BF was linearly correlated to the difference between collicular BFs and tone frequencies. The changes in collicular BFs after tone-ES(NB) were similar to those found in the big brown bat. Compared with cortical plasticity evoked by tone-ES(NB), the pattern of collicular BF shifts was identical but the shifting range of collicular BFs was narrower. A GABA(A) agonist (muscimol) or a muscarinic acetylcholine receptor antagonist (atropine) applied to the AC completely abolished the collicular plasticity evoked by tone-ES(NB). Therefore, our findings strongly suggest that the AC plays a critical role in experience-dependent auditory plasticity through descending projections.

Acoustic Stimulation↗

PubMed2001

Continuous 24-hour intravenous infusion of recombinant human growth hormone (GH)-releasing hormone-(1-44)-amide augments pulsatile, entropic, and daily rhythmic GH secretion in postmenopausal women equally in the estrogen-withdrawn and estrogen-supplemented states.

How estrogen amplifies GH secretion in the human is not known. The present study tests the clinical hypothesis that estradiol modulates the stimulatory actions of a primary GH feedforward signal, GHRH. To this end, we investigated the ability of short-term (7- to 12-day) supplementation with oral estradiol vs. placebo to modulate basal, pulsatile, entropic, and 24-h rhythmic GH secretion driven by a continuous iv infusion of recombinant human GHRH-(1--44)-amide vs. saline in nine healthy postmenopausal women. Volunteers underwent concurrent blood sampling every 10 min for 24 h on four occasions in a prospectively randomized, single blind, within-subject cross-over design (placebo/saline, placebo/GHRH, estradiol/saline, estradiol/GHRH). Intensively sampled serum GH concentrations were quantitated by ultrasensitive chemiluminescence assay. Basal, pulsatile, entropic (feedback-sensitive), and 24-h rhythmic modes of GH secretion were appraised by deconvolution analysis, the approximate entropy (ApEn) statistic, and cosine regression, respectively. ANOVA revealed that continuous iv infusion of GHRH in the estrogen-withdrawn (control) milieu 1) amplified individual basal (P = 0.00011) and pulsatile (P < 10(-13)) GH secretion rates by 12- and 11-fold, respectively; 2) augmented GH secretory burst mass and amplitude each by 10-fold (P < 10(-11)), without altering GH secretory burst frequency, duration, or half-life; 3) increased the disorderliness (ApEn) of GH release patterns (P = 0.0000002); 4) elevated the mesor (cosine mean) and amplitude of the 24-h rhythm in serum GH concentrations by nearly 30-fold (both P < 10(-12)); 5) induced a phase advance in the clocktime of the GH zenith (P = 0.021); and 6) evoked a new 24-h rhythm in GH secretory burst mass with a maximum at 0018 h GH (P < 10(-3)), while damping the mesor of the 24-h rhythm in GH interpulse intervals (P < 0.025). Estradiol supplementation alone 1) increased the 24-h mean and integrated serum GH concentration (P = 0.047); 2) augmented GH secretory burst mass (P: = 0.025) without influencing pulse frequency, duration, half-life, or basal secretion; 2) stimulated more irregular patterns of GH release (higher ApEn; P = 0.012); and 3) elevated the 24-h rhythmic GH mesor (P = 0.0005), but not amplitude. Notably, combined stimulation of the GH axis with GHRH-(1--44)-amide and estradiol exerted no further effect beyond that evoked by GHRH alone, except for normalizing the acrophase of 24-h GH rhythmic release and elevating the postinfusion plasma insulin-like growth factor I concentration (P = 0.016). Unexpectedly, the two GHRH-infused serum GH concentration profiles monitored after placebo and estradiol pretreatment showed strongly nonrandom synchrony with a 20- to 30-min lag (P < 0.001). In summary, the present clinical investigations unmask a 3-fold (pulsatile, entropic, and daily rhythmic) similitude between the neuroregulatory actions of estradiol and GHRH in healthy postmenopausal women. However, GHRH infusion was multifold more effectual than estradiol, and only GHRH elevated nonpulsatile (basal) GH secretion, shifted the GH acrophase, and synchronized GH profiles. Given the nonadditive nature of the joint effects of estradiol and GHRH on pulsatile and entropic GH release, we hypothesize that estrogen amplifies GH secretion in part by enhancing endogenous GHRH release or actions. In addition, the distinctive ability of GHRH (but not estradiol) to increase basal (nonpulsatile) GH secretion, shift the GH acrophase and synchronize GH output patterns identifies certain divergent hypothalamo-pituitary actions of these two major GH secretagogues.

Aged↗

PubMed1999

Disruption in neuropeptide Y and leptin signaling in obese ventromedial hypothalamic-lesioned rats.

Electrolytic lesions placed in the ventromedial hypothalamus (VMH) of rats induce instant hyperphagia and excessive weight gain. Since neuropeptide Y (NPY) is a potent hypothalamic orexigenic signal, and leptin secreted by adipocytes regulates NPY output, we tested the hypothesis that altered NPYergic-leptin signaling may underlie hyperphagia in VMH-lesioned rats. VMH-lesioned rats exhibiting hyperphagia and excessive weight gain in a time-related fashion were sacrificed on days 2, 7, and 21 post-surgery. Quite unexpectedly, NPY concentrations in the hypothalamic paraventricular nucleus (PVN), a major site of NPY release for stimulation of feeding, and in other sites, such as the dorsomedial nucleus, lateral hypothalamic area and median eminence-arcuate nucleus decreased, with the earliest diminution occurring on day 2 in the PVN only. In vitro basal and K+-evoked NPY release from the PVN of VMH-lesioned rats was significantly lower than that of controls. Analysis of hypothalamic NPY gene expression showed that although the daily decrease in NPY mRNA from 0800 to 2200 h occurred as in control rats, NPY mRNA concentrations were markedly reduced at these times in the hypothalami of VMH-lesioned rats. Leptin synthesis in adipocytes as indicated by leptin mRNA levels was also profoundly altered in VMH-lesioned rats. The daily pattern of increase in adipocyte leptin mRNA at 2200 h from 0800 h seen in controls was abolished, higher levels of leptin gene expression at 2200 h were maintained at 0800 h. The pattern of increase in serum leptin and insulin levels diverged in VMH-lesioned rats. Serum insulin concentration increased to maximal on day 2 and remained at that level on day 21-post-lesion; serum leptin levels on the other hand, increased slowly in a time-related fashion during this period. These results demonstrate that hyperphagia and excessive weight gain in VMH-lesioned rats are associated with an overall decrease in hypothalamic NPY and augmented leptin signaling to the hypothalamus. The divergent time course of increases in serum leptin and insulin levels suggest independent mechanisms responsible for their augmented secretion, and neither these hormones nor VMH lesions altered the daily rhythm in NPY gene expression. These observations underscore the existence of an independent mechanism controlling the daily rhythm in hypothalamic NPY gene expression and suggest that leptin feedback action requires an intact VMH.

Adipocytes↗

PubMed1978

A critique of some of the current concepts on the immunopathogenesis of rheumatoid arthritis.

The interaction of polycations produced during tissue damage and C-reactive protein, and the enzymatic degradation of complement components may be positive mechanisms augmenting immune-complex/complement damage, while reduced phagocytosis and reduced chemotaxis may be negative mechanisms. In cell-mediated immunity, systems consisting of C-reactive protein, proteases, prostaglandins and immune complexes are all potentially capable of negative feedback control.

Arthritis, Rheumatoid↗

PubMed2006

Brain-computer interface technology as a tool to augment plasticity and outcomes for neurological rehabilitation.

Brain-computer interfaces (BCIs) are a rehabilitation tool for tetraplegic patients that aim to improve quality of life by augmenting communication, control of the environment, and self-care. The neurobiology of both rehabilitation and BCI control depends upon learning to modify the efficacy of spared neural ensembles that represent movement, sensation and cognition through progressive practice with feedback and reward. To serve patients, BCI systems must become safe, reliable, cosmetically acceptable, quickly mastered with minimal ongoing technical support, and highly accurate even in the face of mental distractions and the uncontrolled environment beyond a laboratory. BCI technologies may raise ethical concerns if their availability affects the decisions of patients who become locked-in with brain stem stroke or amyotrophic lateral sclerosis to be sustained with ventilator support. If BCI technology becomes flexible and affordable, volitional control of cortical signals could be employed for the rehabilitation of motor and cognitive impairments in hemiplegic or paraplegic patients by offering on-line feedback about cortical activity associated with mental practice, motor intention, and other neural recruitment strategies during progressive task-oriented practice. Clinical trials with measures of quality of life will be necessary to demonstrate the value of near-term and future BCI applications.

Brain↗