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PubMed2006

The centrifugal visual system of vertebrates: a comparative analysis of its functional anatomical organization.

The present review is a detailed survey of our present knowledge of the centrifugal visual system (CVS) of vertebrates. Over the last 20 years, the use of experimental hodological and immunocytochemical techniques has led to a considerable augmentation of this knowledge. Contrary to long-held belief, the CVS is not a unique property of birds but a constant component of the central nervous system which appears to exist in all vertebrate groups. However, it does not form a single homogeneous entity but shows a high degree of variation from one group to the next. Thus, depending on the group in question, the somata of retinopetal neurons can be located in the septo-preoptic terminal nerve complex, the ventral or dorsal thalamus, the pretectum, the optic tectum, the mesencephalic tegmentum, the dorsal isthmus, the raphé, or other rhombencephalic areas. The centrifugal visual fibers are unmyelinated or myelinated, and their number varies by a factor of 1000 (10 or fewer in man, 10,000 or more in the chicken). They generally form divergent terminals in the retina and rarely convergent ones. Their retinal targets also vary, being primarily amacrine cells with various morphological and neurochemical properties, occasionally interplexiform cells and displaced retinal ganglion cells, and more rarely orthotopic ganglion cells and bipolar cells. The neurochemical signature of the centrifugal visual neurons also varies both between and within groups: thus, several neuroactive substances used by these neurons have been identified; GABA, glutamate, aspartate, acetylcholine, serotonin, dopamine, histamine, nitric oxide, GnRH, FMRF-amide-like peptides, Substance P, NPY and met-enkephalin. In some cases, the retinopetal neurons form part of a feedback loop, relaying information from a primary visual center back to the retina, while in other, cases they do not. The evolutionary significance of this variation remains to be elucidated, and, while many attempts have been made to explain the functional role of the CVS, opinions vary as to the manner in which retinal activity is modified by this system.

Animals↗

PubMed1989

Electrophysiological correlates of presynaptic alpha 2-receptor-mediated inhibition of norepinephrine release at locus coeruleus synapses in dentate gyrus.

Despite an abundance of evidence that presynaptic alpha 2-adrenergic receptors mediate inhibitory control of the release of norepinephrine (NE) from the terminals of locus coeruleus (LC) neurons, few studies have demonstrated the physiological significance of this "autoreceptor"-mediated inhibition on NE-mediated synaptic activity within the mammalian brain. This question was addressed by examining the effects of systemic administration of alpha 2-adrenergic agonists and antagonists on the ability of LC stimulation to augment the population spike recorded in the dentate gyrus in response to activation of the perforant path (PP). Extracellular field potentials were recorded in the cell body and dendritic layer of dentate gyrus following single shocks of the entorhinal cortex in halothane-anesthetized rats. Stimulation of the ipsilateral LC 35 msec prior to PP activation produced a short-term enhancement of the population spike amplitude recorded in the cell layer but did not significantly alter dendritic potentials. The effects of LC stimulation were blocked by administration of the beta-adrenergic antagonist propranolol but not the alpha 2-antagonist idazoxan and were abolished by pretreatment of animals with the catecholamine neurotoxin 6-hydroxydopamine. Administration of clonidine reversibly abolished the enhancement produced by LC conditioning. The effect of clonidine was dose dependent and was blocked by administration of idazoxan, which restored the LC potentiative effect. Conditioning stimulation of LC noradrenergic axons in the dorsal bundle also potentiated the PP-evoked population spike, and this effect was equally sensitive to the depressant action of clonidine. In comparison, clonidine, in the range of dosages tested, did not significantly affect the potentials evoked in the dendritic or cell layer by presentations of unconditioned PP test stimuli. We interpret these data to provide evidence for a functional impairment of LC-mediated physiological action on postsynaptic target cells as a result of presynaptic alpha 2-autoreceptor-mediated feedback inhibition of NE release.

Action Potentials↗

PubMed1999

Locus coeruleus neuronal activity and noradrenaline availability in the frontal cortex of rats chronically treated with imipramine: effect of alpha 2-adrenoceptor blockade.

BACKGROUND: Previous studies indicate a reduced feedback inhibition of brain noradrenaline (NA) neurons in the locus coeruleus (LC) during chronic administration of antidepressants which inhibit the NA reuptake mechanism due to functional downregulation of somatodendritic alpha 2-adrenoceptors in the LC. Therefore, we have here studied the LC neuronal responsiveness to administration of the alpha 2-adrenoceptor antagonist idazoxan (IDA) after both short-term and long-term imipramine (IMI) administration. METHODS: Rats were treated for different periods with systemic IMI. In these rats, basal activity of central noradrenergic function and the effect of IDA was assessed by means of extracellular single-cell recording from LC neurons and in vivo microdialysis of extracellular NA levels in the frontal cortex (FC). RESULTS: The average firing rate of LC neurons was significantly reduced in rats by short-term IMI treatment compared with long-term treatment. The output of NA in the FC of all IMI-treated animals was significantly increased compared with saline-treated rats. Moreover, the enhancing effect of IDA on both the firing rate of LC neurons and the cortical NA output was larger in rats after long-term treatment with IMI than after short-term administration. CONCLUSIONS: Our results clearly support the notion of development of functional downregulation of alpha 2-autoreceptors on LC neurons during chronic administration of NA reuptake inhibiting antidepressants. Moreover, the data suggest that addition of alpha 2-adrenoceptor antagonists may augment the clinical effect of such drugs in major depression.

Adrenergic alpha-Antagonists↗

PubMed1998

Frequency domain-based models of skeletal muscle.

Models of skeletal muscle based on its response to sinusoidal stimulation have been in use since the late 1960s. In these methods, cyclic excitation at varying frequencies is used to determine force or muscle length amplitude and phase as functions of excitation frequency. These functions can then be approximated by models consisting of combinations of poles and zeros and pure time delays without the need to combine force-length or force-velocity relationships. The major findings of a series of frequency response studies undertaken in our laboratory revealed that: The frequency response models for isometric force including orderly recruitment of motor units were relatively invariant of the particular strategy or oscillation level employed. A critically damped second order model with corner frequency near 2 Hz and a pure time delay best described the relationship between input stimulation and output isometric force. The frequency response models for load-moving muscles consisted of an overall gain which is a function of mass, dependent mostly on the width of the length-force relation at a given load (force), and a frequency-dependent gain component independent of load mass. The phase lag between input and output was also independent of load. Muscle function and architecture are the primary determinants of its isometric force frequency response. Tendon viscoelasticity (excluding the aponeurosis) has no significant effect on isometric force dynamic response, but does have a minor effect on load-moving dynamic response. The effect of tendon in reducing or augmenting the load-moving muscle response bandwidth is muscle-dependent. The joint produces decreased high frequency gain and uniformly increased phase lags between input excitation and output force in isometric conditions. The joint acts as a lag network in load-moving conditions, increasing the phase lag without significant effect on the gain. Despite its inherent non-linear properties, the joint does not significantly deteriorate output signal quality in either isometric or load-moving conditions. Co-contraction strategy has a significant effect on the dynamic response of the joint. These frequency-based models have shown to be robust as long as the excitation type and mechanical conditions under which they are obtained are not varied. They are particularly useful for the design of neuroprostheses, where a dynamic description of muscle output as a function of stimulus input under given conditions is desirable.

Algorithms↗

PubMed1997

Human growth hormone response to repeated bouts of aerobic exercise.

We examined whether repeated bouts of exercise could override growth hormone (GH) auto-negative feedback. Seven moderately trained men were studied on three occasions: a control day (C), a sequential exercise day (SEB; at 1000, 1130, and 1300), and a delayed exercise day (DEB; at 1000, 1400, and 1800). The duration of each exercise bout was 30 min at 70% maximal O2 consumption (VO2max) on a cycle ergometer. Standard meals were provided at 0600 and 2200. GH was measured every 5-10 min for 24 h (0800-0800). Daytime (0800-2200) integrated GH concentrations were approximately 150-160% greater during SEB and DEB than during C: 1,282 +/- 345, 3,192 +/- 669, and 3,389 +/- 991 min.microgram.l-1 for C, SEB, and DEB, respectively [SEB > C (P < 0.06), DEB > C (P < 0.03)]. There were no differences in GH release during sleep (2300-0700). Deconvolution analysis revealed that the increase in 14-h integrated GH concentration on DEB was accounted for by an increase in the mass of GH secreted per pulse (per liter of distribution volume, lv): 7.0 +/- 2.9 and 15.9 +/- 2.6 micrograms/lv for C and DEB, respectively (P < 0.01). Comparison of 1.5-h integrated GH concentrations on the SEB and DEB days (30 min exercise + 60 min recovery) revealed that, with each subsequent exercise bout, GH release apparently increased progressively, with a slightly greater increase on the DEB day [SEB vs. DEB: 497 +/- 162 vs. 407 +/- 166 (bout 1), 566 +/- 152 vs. 854 +/- 184 (bout 2), and 633 +/- 149 vs. 1,030 +/- 352 min.microgram.l-1 (bout 3), P < 0.05]. We conclude that the GH response to acute aerobic exercise is augmented with repeated bouts of exercise.

Adult↗

PubMed2002

Insulin-like growth factor-binding protein-5 (IGFBP-5) stimulates growth and IGF-I secretion in human intestinal smooth muscle by Ras-dependent activation of p38 MAP kinase and Erk1/2 pathways.

Insulin-like growth factor-binding protein-5 (IGFBP-5) and insulin-like growth factor-I (IGF-I) are produced by human intestinal smooth muscle cells. Endogenous IGF-I stimulates growth and increases IGFBP-5 secretion. IGFBP-5 augments the effects of IGF-I by facilitating interaction of IGF-I with the IGF-I receptor tyrosine kinase. Andress (Andress, D. L. (1998) Am. J. Physiol. 274, E744-E750) and Berfield et al. (Berfield, A. K., Andress, D. L., and Abrass, C. K. (2000) Kidney Int. 57, 1991-2003) have shown that in osteoblasts and kidney mesangial cells, IGFBP-5 stimulates proliferation and filopodia formation independently of IGF-I, presumably by activating a distinct IGFBP-5 receptor serine kinase. The present study determined whether IGFBP-5 exerts direct effects on growth in human intestinal smooth muscle cells and identified the intracellular signaling pathways involved. IGFBP-5 caused a concentration-dependent increase in [(3)H]thymidine incorporation and an increase in IGF-I secretion that occurred independently of IGF-I and the IGF-I receptor tyrosine kinase. IGFBP-5-induced phosphorylation of p38 MAP kinase, which was abolished by SB203580, or expression of a dominant negative Ras mutant, Ras(S17N), and phosphorylation of Erk1/2, which was abolished by a Raf1 kinase inhibitor, U1026, or expression of Ras(S17N). IGFBP-5-stimulated [(3)H]thymidine incorporation and IGF-I secretion were partly inhibited by SB203580 or U1026 and abolished by the combination of the two inhibitors or by expression of Ras(S17N). These data show that IGFBP-5 stimulates growth and IGF-I secretion in human intestinal smooth muscle cells by activation of p38 MAP kinase-dependent and Erk1/2-dependent pathways that are independent of IGF-I. A positive feedback mechanism therefore links IGFBP-5 and IGF-I secretion that reinforces their individual effects on growth.

Cell Division↗

PubMed1994

Neural organization of the ventilatory activity in the frog, Rana catesbeiana. I.

In order to elucidate the neural basis for lung ventilation in the frog, we have investigated the efferent neural activity to oropharyngeal muscles in the decerebrate, paralyzed, unanesthetized bullfrog, Rana catesbeiana. Efferent motor output was recorded from the mandibular branch of the trigeminal (Vmd), the laryngeal branch of the vagus (Xl), and the main and sternohyoid branches of the hypoglossal nerve (Hm and Hsh, respectively). Two types of rhythmic bursting outputs were observed: (1) a high-frequency, low-amplitude, reciprocal oscillation between Vmd, a buccal levator nerve, and Hsh, a buccal depressor nerve; and (2) a low-frequency, high-amplitude, synchronous bursting of Vmd, Hm, Hsh, and Xl. The first type is inferred to represent fictive oropharyngeal ventilation. The second type of burst was divided into four intervals: (a) augmenting activity of Hsh; (b) activation of Xl with continued activation of Hsh; (c) activation of Vmd and Hm (a buccal levator nerve), continued activation of Xl, and termination of Hsh activity; and (d) warning activity in Vmd and Hm associated with a prominent second wave in Xl. This coordinated activity is inferred to represent fictive pulmonary ventilation because the neurograms in these four intervals correspond closely to EMGs and neurograms recorded in the intact frog during the four phases of pulmonary ventilation, namely, buccal depression, pulmonary expiration, pulmonary inspiration, and glottal closure. Hypercapnia, vagotomy, and cutaneous pinching enhanced the high-amplitude, low-frequency rhythm, but not the low-amplitude, high-frequency oscillation. Lung inflation generally inhibited the former and not the latter, but in some cases lung inflation stimulated pulmonary ventilation. We conclude that oropharyngeal and pulmonary ventilation of the frog are produced by one or, possibly, two intrinsically active generators.

Animals↗

PubMed2002

Glucose uptake and adenoviral mediated GLUT1 infection decrease hypoxia-induced HIF-1alpha levels in cardiac myocytes.

Hypoxia causes a large array of adaptive and physiological responses in all cells including cardiac myocytes. In order to elucidate the molecular effects of increased glucose flux on hypoxic cardiac myocytes we focused on the basic helix-loop-helix transcription factor, hypoxia inducible factor 1 alpha (HIF-1alpha), which is rapidly upregulated in hypoxic cells and elicits a number of responses including augmentation of glucose uptake. Primary cultures of neonatal rat cardiac myocytes as well as embryonic rat heart-derived myogenic H9c2 cells demonstrated a significant upregulation of HIF-1alpha when subjected to hypoxia of 6-8h in the absence of glucose. Re-addition of extracellular glucose to the medium resulted in a decrease of HIF-1alpha levels by almost 50%. This glucose effect was blocked by addition of glycolytic inhibitors. In addition, glucose uptake and glycolysis resulted in substantial decreased levels of p53, which is regulated by HIF-1alpha. Adenoviral infection of cultures of cardiac myocytes with the facilitative glucose transporter, GLUT1 followed by hypoxia of 24h also resulted in a significant reduction in the protein expression of HIF-1alpha compared to control vector-infected cultures. GLUT1 infected cultures also demonstrated fewer apoptotic cells and a reduction in the release of cytochrome c after hypoxia. Inhibition of the ubiquitin-proteasomal pathway by a variety of 26S proteasomal inhibitors increased HIF-1alpha to similar levels under both normoxic and hypoxic conditions and in the presence or absence of glucose. This result suggested that glucose induces HIF-1alpha degradation via a proteasomal pathway. This conclusion was substantiated by immunoprecipitation experiments of total cell extracts, which demonstrated an increase of ubiquitinated HIF-1alpha relative to total HIF-1alpha in the presence of glucose during hypoxia. Thus, glucose as well as GLUT1 overexpression diminishes hypoxia-induced HIF-1alpha protein via an ubiquitin-proteasomal pathway in hypoxic cardiac myocytes. This represents a novel feedback mechanism that may play an important role in adaptation of cardiac myocytes to hypoxia and ischemia.

Adenoviridae↗

PubMed2004

The Drosophila metabotropic glutamate receptor DmGluRA regulates activity-dependent synaptic facilitation and fine synaptic morphology.

In vertebrates, several groups of metabotropic glutamate receptors (mGluRs) are known to modulate synaptic properties. In contrast, the Drosophila genome encodes a single functional mGluR (DmGluRA), an ortholog of vertebrate group II mGluRs, greatly expediting the functional characterization of mGluR-mediated signaling in the nervous system. We show here that DmGluRA is expressed at the glutamatergic neuromuscular junction (NMJ), localized in periactive zones of presynaptic boutons but excluded from active sites. Null DmGluRA mutants are completely viable, and all of the basal NMJ synaptic transmission properties are normal. In contrast, DmGluRA mutants display approximately a threefold increase in synaptic facilitation during short stimulus trains. Prolonged stimulus trains result in very strongly increased ( approximately 10-fold) augmentation, including the appearance of asynchronous, bursting excitatory currents never observed in wild type. Both defects are rescued by expression of DmGluRA only in the neurons, indicating a specific presynaptic requirement. These phenotypes are reminiscent of hyperexcitable mutants, suggesting a role of DmGluRA signaling in the regulation of presynaptic excitability properties. The mutant phenotypes could not be replicated by acute application of mGluR antagonists, suggesting that DmGluRA regulates the development of presynaptic properties rather than directly controlling short-term modulation. DmGluRA mutants also display mild defects in NMJ architecture: a decreased number of synaptic boutons accompanied by an increase in mean bouton size. These morphological changes bidirectionally correlate with DmGluRA levels in the presynaptic terminal. These data reveal the following two roles for DmGluRA in presynaptic mechanisms: (1) modulation of presynaptic excitability properties important for the control of activity-dependent neurotransmitter release and (2) modulation of synaptic architecture.

Action Potentials↗

PubMed2000

Influence of nitric oxide and noradrenaline on prostaglandin F(2)(alpha)-induced oxytocin secretion and intracellular calcium mobilization in cultured bovine luteal cells.

Although prostaglandin (PG) F(2alpha) released from the uterus has been shown to cause regression of the bovine corpus luteum (CL), the neuroendocrine, paracrine, and autocrine mechanisms regulating luteolysis and PGF(2alpha) action in the CL are not fully understood. A number of substances produced locally in the CL may be involved in maintaining the equilibrium between luteal development and its regression. The present study was carried out to determine whether noradrenaline (NA) and nitric oxide (NO) regulate the sensitivity of the bovine CL to PGF(2alpha) in vitro and modulate a positive feedback cascade between PGF(2alpha) and luteal oxytocin (OT) in cows. Bovine luteal cells (Days 8-12 of the estrous cycle) cultured in glass tubes were pre-exposed to NA (10(-5) M) or an NO donor (S-nitroso-N:-acetylpenicillamine [S-NAP]; 10(-4) M) before stimulation with PGF(2alpha) (10(-6) M). Noradrenaline significantly stimulated the release of progesterone (P(4)), OT, PGF(2alpha), and PGE(2) (P: < 0.01); however, S-NAP inhibited P(4) and OT secretion (P: < 0.05). Oxytocin secretion and the intracellular level of free Ca(2+) ([Ca(2+)](i)) were measured as indicators of CL sensitivity to PGF(2alpha). Prostaglandin F(2alpha) increased both the amount of OT secretion and [Ca(2+)](i) by approximately two times the amount before (both P: < 0.05). The S-NAP amplified the effect of PGF(2alpha) on [Ca(2+)](i) and OT secretion (both P: < 0.001), whereas NA diminished the stimulatory effects of PGF(2alpha) on [Ca(2+)](i) (P: < 0.05). Moreover, PGF(2alpha) did not exert any additionally effects on OT secretion in NA-pretreated cells. The overall results suggest that adrenergic and nitrergic agents play opposite roles in the regulation of bovine CL function. While NA stimulates P(4) and OT secretion, NO may inhibit it in bovine CL. Both NA and NO are likely to stimulate the synthesis of luteal PGs and to modulate the action of PGF(2alpha). Noradrenaline may be the factor that is responsible for the limited action of PGF(2alpha) on CL and may be involved in the protection of the CL against premature luteolysis. In contrast, NO augments PGF(2alpha) action on CL and it may be involved in the course of luteolysis.

Animals↗

PubMed1991

Short-term modulation of gonadotropin secretion by progesterone during the luteal phase.

Progesterone (P) levels were acutely augmented by intravenous (IV) infusion in seven women in the midluteal phase to ascertain if short-term changes in P levels have an effect on gonadotropin secretion. During four 6-hour intervals of alternating control and IV P infusion, each subject underwent blood sampling for luteinizing hormone (LH), follicle-stimulating hormone (FSH), and P every 20 minutes for 24 hours. As a result of the P infusions, mean (+/- SE) P levels rose 72% from a control level of 26.24 +/- 2.13 to 45.22 +/- 3.47 nmol/L, whereas mean LH levels were reduced by 20% from a control level of 4.82 +/- 0.67 to 3.85 +/- 0.66 IU/L. During P infusions, mean LH pulse amplitude was reduced by 33% from 3.33 +/- 0.37 to 2.23 +/- 0.28 IU/L. The mean LH interpulse interval increased by 93% (2.56 +/- 0.14 to 4.92 +/- 0.15/h) when the interval between pulses was interdicted by the onset of P infusion. The infusion of P reduced mean FSH levels by 10% from 3.34 +/- 0.41 to 3.01 +/- 0.35 IU/L. These findings suggest that acute elevations in P levels within the physiological range have a short-term inhibitory effect on gonadotropin secretion during the midluteal phase.

Adult↗

PubMed1986

Visual, vestibular and voluntary contributions to human head stabilization.

We have investigated the ability of humans to stabilize their heads in space and assessed the influence of mental set and the relative importance of visual and vestibular cues. Ten normal subjects and 3 patients with bilateral vestibular loss were studied. Subjects were fixed firmly to the chair of a turntable facing a screen on which was projected a target spot. A 'gunsight' spot generated by a small projector fixed to the head provided feedback of head position. Four conditions were studied (1) Gunsight (GU): subjects were instructed to stabilize the head in space by superimposing the 'gunsight' spot on the fixed target spot while chair position was displaced according to a random pattern with a bandwidth from 0-1 Hz. (2) Imagined gunsight (IGU): identical to condition 1 except that the subject was blindfolded and so had to imagine the target position. (3) Mental arithmetic (MA): subjects did mental arithmetic while the chair was displaced. (4) Visual tracking (VT): subjects were instructed to track the target spot with the 'gunsight' spot while the chair was fixed and the target spot driven to follow the chair displacement trajectory used in conditions 1, 2 and 3. In GU normal subjects stabilized their head position extremely well (mean HEAD/CHAIR gain = 0.81). Significant stabilization was present in IGU although the gain (mean gain = 0.61) was reduced compared to GU. There was very little stabilization in MA (mean gain = 0.12). In VT, subjects tracked the target with about the same gain (mean gain = 0.68) as in IGU. By comparison, the vestibular patients could not perform IGU, for which their performance (mean gain = 0.08) was similar to MA (mean gain = 0.06). In GU (mean gain = 0.54), their performance was attributable to visual tracking (mean gain in VT = 0.50). For the frequency bandwidth in which subjects were tested, the results show that: When subjects were distracted by mental arithmetic, the contribution to head stability of the short latency cervico-collic (CCR) and vestibulo-collic (VCR) reflexes is negligible. As expected, vision plays an important role in stabilizing the head. Equally important are long latency stabilizing mechanisms whose onset times (140 ms) are shorter, but still comparable to that of vision. The latter mechanisms are of vestibular origin and their influence is under voluntary control so as to permit augmenting head stability compared to what it would be if vision acted alone.

Adult↗

PubMed1988

Captopril augments the renal response to an amino acid infusion in diabetic adults.

This study examined whether patients with insulin-dependent diabetes mellitus and normal renal function have an altered response to an amino acid infusion when they are pretreated with a converting-enzyme inhibitor. Three groups of adults received amino acid infusions for 20 min on two occasions separated by a 240-min interval. Groups 1 (6 normals) and 2 (6 diabetics) ingested captopril (12.5 mg) 120 min before starting the second infusion. Group 3 (4 diabetics) did not receive captopril. Diabetics had normal base-line renal plasma flow, as indicated by para-aminohippuric acid clearance (CPAH), and glomerular filtration rate (GFR). In group 1, the maximum increase in CPAH was significant and similar with both infusions, 23 +/- 5 vs. 15 +/- 3% (SE); maximal changes in GFR were also significant and similar, 20 +/- 5 vs. 20 +/- 6%. In Group 2, the maximal increase in CPAH and GFR with the first infusion was 28 +/- 7 and 23 +/- 6%, respectively. After captopril, the increases in CPAH and GFR were significantly greater than with the first infusion (64 +/- 8%, P less than 0.002, and 67 +/- 9%, P less than 0.002, respectively). In Group 3 diabetics, there was no difference in either CPAH or GFR with the first vs. the second infusion. Thus captopril enhances the renal hemodynamic response to an amino acid load in diabetic patients but not in normal adults.

Adult↗

PubMed1998

Protein kinase C inhibition enhances platelet-activating factor-induced eicosanoid production in human eosinophils.

Previous investigations have suggested that protein kinase C (PKC) may regulate guinea pig eosinophil responses through a suppressive "negative feedback" mechanism. Using the selective PKC inhibitors bisindolylmaleimide I (Bis I, GF 109203X) and calphostin C, we examined the role of PKC in platelet-activating factor (PAF)-induced respiratory burst and generation of arachidonic acid metabolites in human peripheral blood eosinophils. Bis I inhibited PAF-induced generation of superoxide anion with substantially lower potency (geometric mean IC50 = 1.41 microM, 95% CI 0.94-2.11 microM) than it exhibited against responses to the phorbol esters 4-beta-phorbol 12-myristate 13-acetate (PMA; IC50 = 0.25 microM, 0.09-0.72 microM; P < 0.01) and 4-beta-phorbol 12,13-dibutyrate (IC50 = 0.48 microM, 0.20-1.14 microM; P < 0.05). The production of thromboxane (measured as TxB2) induced by 1 microM PAF was increased significantly by Bis I at concentrations of 1 microM (162 +/- 7.5% of control PAF response; P < 0.01) and 10 microM (194 +/- 17%; P < 0.001); TxB2 release induced by PMA was unaffected by concentrations of Bis I up to 1 microM and inhibited by 10 microM Bis I (48 +/- 11%; P < 0.05). Bis I (1 microM) significantly increased both thromboxane and leukotriene C4 (LTC4) production induced by 2 microM (P < 0.01 and P < 0.05, respectively) or 20 microM PAF (both P < 0.001). The actions of Bis I on PAF-stimulated thromboxane and leukotriene production were mimicked by a second PKC inhibitor, calphostin C, whereas the non-PKC-inhibitory analog, bisindolylmaleimide V, caused no enhancement of TxB2 or LTC4 production. The increase in intracellular free calcium induced by 1 microM PAF was heightened and prolonged in cells pre-treated with 1 microM Bis I or 1 microM calphostin C (peak increase, P < 0.05 for both drugs; level 60 s after addition of PAF, P < 0.001 and P < 0.05 for Bis I and calphostin C, respectively; time to return to 50% of peak, P < 0.05 for Bis I). We conclude that PKC inhibition causes augmentation of thromboxane and LTC4 production in PAF-stimulated human eosinophils despite suppressing respiratory burst activity, indicating that different signaling pathways predominate in these two responses and that PKC mediates a suppression of an early stage in an alternative pathway of activation.

Arachidonic Acid↗

PubMed2005

Automatic determination of synergies by radial basis function artificial neural networks for the control of a neural prosthesis.

This paper describes an automatic method for synthesizing the control for a neural prosthesis (NP) that could augment elbow flexion/extension and forearm pronation/supination in persons with hemiplegia. The basis for the control was a synergistic model of reaching and grasping that uses temporal and spatial synergies between the arm and body segments. The synergies were determined from the movement data measured in nondisabled persons during the performance of functional tasks. The work space was divided into six zones: distance (two attributes) and laterality (three attributes). Radial basis function artificial neural networks (RBF ANN) were used to determine synergies. Sets of RBF ANN characterized with good generalization were selected as control laws for elbow flexion/extension and forearm pronation/supination. The validation was performed for three categories: inter-subject, distance, and laterality generalization. For all of the defined spatial synergies, the correlation was high for inter-subject and distance, yet low for the laterality scenario. This suggests the necessity for implementing different maps for different directions, but the same maps for different distances. The natural movements of the upper arm then drive the lower arm (elbow flexion/extension and forearm pronation/supination) in a way that is very well suited for the administration of functional electrical therapy (FET) in persons with hemiplegia soon after the onset of impairment.

Activities of Daily Living↗

PubMed1989

Ontogeny of pulsatile gonadotrophin secretion and pituitary responsiveness in male puberty in man: a mixed longitudinal and cross-sectional study.

The onset of puberty is characterized by a sleep-associated increase in pulsatile LH secretion which is not observed in adults. The ontogeny of gonadotrophin secretion during pubertal maturation may reflect changes in endogenous LHRH secretion, pituitary sensitivity to LHRH and/or alterations in gonadal steroid feedback. To understand the interplay between these mechanisms, we have examined the pulsatile pattern of plasma LH, FSH, testosterone, oestradiol and prolactin between 20.00 and 09.00 h and the pituitary response to repeated exogenous LHRH stimulation in 16 boys with delayed puberty (age 16.3 +/- 2.7 (S.E.M.) years) on one to four occasions in a mixed longitudinal/cross-sectional analysis. Physical maturity was determined by Tanner G staging (1-5) and clinical progress followed for a mean duration of 22.4 +/- 8.5 months during which 33 hormone profiles were obtained. Nocturnal (23.00-09.00 h) LH pulse frequency increased to a peak of 0.54 +/- 0.03/h at stage 2 which was followed by a gradual decline to 0.42 +/- 0.04/h at stage 5. The appearance of LH pulses in the evening (20.00-23.00 h), probably representative of the rest of the day, was delayed until mid-puberty from which point frequency increased to a peak of 0.53 +/- 0.08/h at stage 5. LH pulse amplitude showed a linear increase from stages 1 to 5, with nocturnal pulse amplitudes being higher than evening pulses throughout. FSH did not show a clear pulsatile pattern. The LH:FSH ratio reversed from less than 1 to greater than 1 at stage 2. The LH response to exogenous LHRH increased in parallel with LH pulse amplitude. There was no difference in the pattern of LH response to repeated LHRH stimulation as puberty advanced; the first stimulus always elicited a greater response than subsequent doses. In contrast, the FSH response to LHRH was maximal at stage 1 and became attenuated thereafter. The estimated mean nocturnal LHRH concentration or amplitude did not show any increase during pubertal maturation from 20.42 +/- 11.57 at stage 1 to 35.96 +/- 20.83 ng/l at stage 5. In conclusion, the sequential changes in this study suggest that the sleep-entrained increase in LHRH pulse frequency plays a key role at the onset of puberty. By enhancing pituitary responsiveness and setting in motion a cascade of events, this peripubertal augmentation of LHRH pulse frequency can account for most of the subsequent changes in LH, FSH and testosterone secretion during pubertal development in the male without any apparent alteration in LHRH pulse amplitude.

Adolescent↗

PubMed2000

PTHrP enhances the secretory response of PTH to a hypocalcemic stimulus in rat parathyroid glands.

BACKGROUND: The secretion of parathyroid hormone (PTH) from the parathyroid glands might be regulated by autocrine/paracrine factors, and a feedback regulatory mechanism of PTH on the secretion of PTH has been suggested. Because of the existence of a common receptor between PTH and PTH-related peptide (PTHrP), the aim of the present study was to examine the possible effects of PTHrP 1-40 and 1-86 on PTH secretion in rats. METHODS: In vivo, the effect of PTHrP on Ca++-regulated PTH secretion was examined by the induction of hypocalcemia and hypercalcemia by an infusion of EGTA and Ca++, with and without PTHrP. The eventual effects of PTHrP on the peripheral metabolism of PTH were examined by infusion of human PTH (hPTH) with and without PTHrP. hPTH was measured by an intact hPTH assay not cross reacting with rat PTH or PTHrP. To examine whether near physiological levels of circulating PTH have an autoregulatory effect in vivo on PTH secretion from the parathyroid gland, an acute reduction of the circulating PTH was induced by an acute unilateral parathyroidectomy (UPTX). PTH secretion from the remaining parathyroid gland was followed in response to EGTA-induced hypocalcemia. In vitro investigations on the effect of PTHrP 1-40 on PTH secretion from whole rat parathyroid glands incubated in media containing a calcium concentration of 0.6 or 1.35 mmol/L were performed to confirm whether the effect of PTHrP was directly on the gland. The rat PTH assay was examined for cross reaction with PTHrP. RESULTS: In vivo, the same rate of decrease of plasma Ca++ was induced in the experimental groups. The maximal response of PTH to hypocalcemia (218 +/- 16 pg/mL, N = 6) was significantly enhanced by PTHrP 1-40 (525 +/- 79 pg/mL, N = 6) and by PTHrP 1-86 (465 +/- 29 pg/mL, N = 6, P < 0.001). No effect of PTHrP on PTH secretion was found during normocalcemia or hypercalcemia. UPTX resulted in a 50% reduction of PTH secretion, and no compensatory increase of PTH was observed. PTHrP had no effect on the metabolism of PTH. In vitro, low-Ca++-induced PTH secretion was significantly augmented by 300% (P < 0.01) when the medium contained PTHrP 1-40. PTHrP did not cross react with the PTH assay. CONCLUSIONS: PTHrP significantly enhanced the low-Ca++-stimulated PTH secretion in vivo and in vitro. An autocrine/paracrine role of PTHrP in the parathyroid glands is suggested. An autoregulatory effect of circulating PTH on the PTH secretion from parathyroid glands seems unlikely. The "maximal secretory capacity" of the parathyroid glands induced by hypocalcemia in vivo and in vitro is not the maximum, as PTH secretion can be increased even further, by several-fold.

Animals↗

PubMed1993

Cholinergic control of growth hormone (GH) responses to GH-releasing hormone in insulin dependent diabetics: evidence for attenuated hypothalamic somatostatinergic tone and decreased GH autofeedback.

OBJECTIVE: We have investigated the effects of cholinergic modulation with pirenzepine and pyridostigmine and of GH pretreatment on the subsequent GH response to a maximal stimulatory dose of GH-releasing hormone (GHRH) in patients with insulin dependent diabetes mellitus (IDDM). We have also investigated the relationship between the differences in metabolic control and other parameters of disease state with the differences in GH responses in IDDM. PATIENTS: Thirteen male subjects with IDDM and no clinical evidence of complications were selected based on HbA1 levels to provide a wide range of metabolic control. Seven normal subjects were also studied. DESIGN: Twelve of the subjects with IDDM and six normal subjects received pirenzepine 200 mg and pyridostigmine 120 mg pretreatment 60 minutes and GH pretreatment 3 hours before an i.v. injection of GHRH (1-44) (80 micrograms) in random order. All subjects underwent a control study with GHRH alone. MEASUREMENTS: Serum GH and plasma glucose were measured at regular intervals throughout the study. Fasting plasma glucose and HbA1 were measured before each study to provide measures of metabolic control. RESULTS: Subjects with IDDM demonstrated exaggerated GH responses to GHRH compared to normals. Pirenzepine significantly reduced GH responses in both normal and diabetic subjects. However, the GH response to GHRH after pirenzepine was higher in subjects with IDDM (mean GH:IDDM vs normals; 8.1 +/- 1.3 vs 2.9 +/- 0.7 mU/l, P < 0.05). Pyridostigmine 120 mg significantly augmented the GH response to GHRH in normal subjects. In diabetic subjects, pyridostigmine failed to increase GH response to GHRH compared to GHRH alone (mean GH: pyridostigmine vs control: 75.7 +/- 12.6 vs 38.9 +/- 5.4 mU/l, P = NS). GH responses to GHRH after pyridostigmine pretreatment in both normal and diabetic subjects did not differ and the GH response to GHRH after pyridostigmine in normal subjects did not differ from the GH response to GHRH alone in diabetic subjects. In normal subjects, GH pretreatment significantly reduced subsequent GH responsiveness to GHRH (delta peak GH 26.4 +/- 5.2 vs 7.7 +/- 5.4 mU/l, P < 0.04). In contrast, GH pretreatment did not cause any significant reduction in GH responsiveness to GHRH in diabetics (delta peak GH 53.6 +/- 9.7 vs 33.4 +/- 11 mU/l, P = NS). No significant correlation was demonstrated between measures of diabetic control and the responses to GHRH alone or after cholinergic modulation and GH pretreatment. CONCLUSION: These data suggest that ambient hypothalamic cholinergic tone in diabetes is high, and of similar degree to the enhanced cholinergic tone in normal subjects pretreated with pyridostigmine. We suggest that in diabetic subjects, the reduced responsiveness to autofeedback may be secondary to the enhanced cholinergic tone demonstrated in these patients. The mechanisms linking the uncontrolled diabetic state to this abnormal neuroregulation of GH remains unknown at present.

Adult↗