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PubMed2005

A wide role for NOTCH1 signaling in acute leukemia.

NOTCH1 is involved in the pathogenesis of T-acute lymphoblastic leukemia (T-ALL) carrying the very rare translocation t(7;9)(q34;q34.3). We analyzed the expression of genes belonging to NOTCH pathway, in acute leukemia primary samples and lymphoblastoid cell lines. NOTCH1 pathway activation represents a common feature of T-ALL when compared to acute myelogenous leukemia (AML) and B-cell precursor acute lymphoblastic leukemia. The contemporary expression of NOTCH1 and its ligands on cell surface contributes to high levels of pathway activity. AML primary samples show high levels of JAGGED1 expression despite the low NOTCH1 pathway activation, consistent with an autonomous JAGGED1 signaling in myeloid leukemogenesis.

Burkitt Lymphoma↗
PubMed2005

The activin signaling pathway promotes differentiation of dI3 interneurons in the spinal neural tube.

The generation of the appropriate types and numbers of mature neurons during the development of the spinal cord requires the careful coordination of patterning, proliferation, and differentiation. In the dorsal neural tube, this coordination is achieved by the combined action of multiple ligands of both the Wnt and TGF-beta families, and their effectors, such as the bHLH proteins. TGF-beta signaling acting through the BMP receptors is necessary for the generation of several dorsal interneuron types. Other TGF-beta ligands expressed in the dorsal neural tube interact with the Activin receptors, which signal via a different set of SMAD proteins than BMPs. The effects of Activin signaling on the developing neural tube have not been described. Here we have activated the Activin signal transduction pathway in a cell-autonomous manner in the developing chick neural tube. We find that a constitutively active Activin receptor promotes differentiation throughout the neural tube. Although most differentiated cell populations are unaffected by Activin signaling, the number of dorsal interneuron 3 (dI3) cells is specifically increased. Our data suggest that Activin signaling may promote the formation of the dI3 precursor cells within a region circumscribed by BMP signaling and that this function is not dependent upon BMP signaling.

Activin Receptors, Type I↗
PubMed2001

Hedgehog signaling in germ cell migration.

The primitive gonad of the Drosophila embryo is formed from two cell types, the somatic gonad precursor cells (SGPs) and the germ cells, which originate at distant sites. To reach the SGPs the germ cells must undergo a complex series of cell movements. While there is evidence that attractive and repulsive signals guide germ cell migration through the embryo, the molecular identity of these instructive molecules has remained elusive. Here, we present evidence suggesting that hedgehog (hh) may serve as such an attractive guidance cue. Misexpression of hh in the soma induces germ cells to migrate to inappropriate locations. Conversely, cell-autonomous components of the hh pathway appear to be required in the germline for proper germ cell migration.

Animals↗
PubMed1998

Gastrointestinal sensory abnormalities in functional dyspepsia.

Symptoms of functional dyspepsia, such as epigastric pain, bloating or early satiety and nausea, are non-specific and are likely to arise from different mechanisms. Current evidence suggests the presence of at least two subgroups: patients who respond to a prolonged course of acid suppression and patients who show a significant overlap of symptoms with other functional gastrointestinal disorders such as irritable bowel syndrome. An enhanced sensitivity of visceral afferent pathways with or without associated autonomic dysregulation appears to play an important role in the aetiology of symptoms in the second group. In the absence of visceral hypersensitivity, neither the slowing of gastric emptying nor the presence of chronic gastritis appears to be sufficient to cause symptoms of functional dyspepsia. The mechanisms and aetiology of visceral hypersensitivity are incompletely understood. An alteration in the interplay between vagal and spinal afferents, and the inadequate activation of antinociceptive systems in response to tissue irritation, may play a role in symptom generation.

Dyspepsia↗
PubMed2002

Micturition-related electrophysiological properties in the substantia nigra pars compacta and the ventral tegmental area in cats.

Parkinson's disease patients are known to have not only motor but also urinary autonomic disorders, suggesting central dopaminergic pathways being involved in the micturition function. However, there is little evidence that the substantia nigra pars compacta (SNC) and the ventral tegmental area (VTA), the major dopamine-containing nuclei in the midbrain, should participate in regulating micturition. We investigated micturition-related electrophysiological properties in the SNC and VTA. In 20 male cats under ketamine anaesthesia, in which spontaneous isovolumetric micturition reflex was generated, we performed electrical stimulation and extracellular single-unit recording in the SNC and the VTA, and correlation analysis of the neuronal firings and antidromic stimulation between the SNC/VTA and the pontine storage centre (PSC). Electrical stimulations in the SNC elicited termination of the micturition reflex, whereas those in the VTA elicited both termination and facilitation of the reflex. Forty-nine neurons in the SNC/VTA showed firing in response to the bladder storage/micturition cycles. The major neurons were tonic storage (55%) and phasic storage neurons (22%), which were found diffusely in th e SNC/VTA. The rest were tonic micturition (16%) and phasic micturition neurons (6%), which were concentrated in the caudal part (A2-4 in the Horsley-Clarke coordinates). These neuronal types were further subclassified into augmenting, constant, binary and decrementing neurons according to their temporal discharge rate change. The decrementing neurons were concentrated in the caudal part (A2-4), whereas the augmenting neurons in the rostral part (A4-6). Some of the recorded neurons had preceding firing pattern, which was more frequently found in the tonic type than in the phasic-type neurons. Twenty-four of the neuronal firings in the SNC/VTA were recorded simultaneously with those in the PSC. However, there was no apparent time-correlation between both sets of neuronal firings. In 15 of the simultaneous recording sites, electrical stimulation was applied to one site to see if antidromic response might be evoked in another site. However, there was no orthodromic or antidromic response in either SNC/VTA or PSC. In conclusion, the present study indicates that neurons in the SNC and the VTA are involved in supra-pontine control of micturition, particularly of urinary storage phase. It is also likely that the major role of the SNC is inhibition of the micturiton reflex, whereas that of the VTA is both facilitation and inhibition of the micturition reflex.

Action Potentials↗
PubMedDate not supplied

Stimulation of noradrenergic sympathetic outflow by calcitonin gene-related peptide.

Alternative splicing of RNA transcripts from the calcitonin gene produces mRNAs that encode different polypeptides. While the mRNA encoding calcitonin predominates in thyroidal 'C' cells, calcitonin gene-related peptide (CGRP) mRNA appears to be the major mRNA component in non-thyroid tissue, including brain. The predicted peptide arising from translation of CGRP mRNA has now been identified immunocytochemically throughout the central and peripheral nervous systems. CGRP, a 37-residue peptide, is distributed in brain pathways subserving sensory, motor and autonomic functions. We report here that CGRP acts in the central nervous system to stimulate selectively noradrenergic sympathetic outflow.

Animals↗
PubMed1996

The effects of hexamethonium on cerebral blood flow and cerebral function during relative cerebral ischaemia in rats.

Cerebral blood flow in either the cortex, thalamic region or the brain stem, as well as somatosensory evoked potentials were measured in a model of moderate cerebral ischaemia in three groups of anaesthetized spontaneously hypertensive rats. The rats were bled to reduce evoked potential amplitudes to approximately 50-60% of pre-haemorrhage control. The consequent blood pressure fall reduced blood flow to approximately 65, 80 and 85% of pre-haemorrhage control in the cortical, thalamic and brain stem regions, respectively, as measured with a laser Doppler flowmeter. Hexamethonium (10 mg kg-1 i.v.), an autonomic ganglion blocker, caused vasodilation and a slight (7-13 units of prebleeding control) increase in blood flow in all the three regions, and the somatosensory evoked potentials normalized. In addition, the latency of the first evoked potential component decreased toward prebleeding values. Heart rate decreased and a transient decrease was also observed in mean arterial pressure despite an attempt to keep it constant with a pressure regulating reservoir. It is possible that the slightly increased regional cerebral blood flow after hexamethonium injection can explain the improved cerebral function as indicated by the enhanced somatosensory evoked potentials. However, the results might also indicate an autonomic regulation of afferent sensory pathways.

Animals↗
PubMed2006

The tomato FT ortholog triggers systemic signals that regulate growth and flowering and substitute for diverse environmental stimuli.

The systemic model for floral induction, dubbed florigen, was conceived in photoperiod-sensitive plants but implies, in its ultimate form, a graft-transmissible signal that, although activated by different stimuli in different flowering systems, is common to all plants. We show that SFT (SINGLE-FLOWER TRUSS), the tomato ortholog of FLOWERING LOCUS T (FT), induces flowering in day-neutral tomato and tobacco plants and is encoded by SFT. sft tomato mutant plants are late-flowering, with altered architecture and flower morphology. SFT-dependent graft-transmissible signals complement all developmental defects in sft plants and substitute for long-day stimuli in Arabidopsis, short-day stimuli in Maryland Mammoth tobacco, and light-dose requirements in tomato uniflora mutant plants. The absence of donor SFT RNA from flowering receptor shoots and the localization of the protein in leaf nuclei implicate florigen-like messages in tomato as a downstream pathway triggered by cell-autonomous SFT RNA transcripts. Flowering in tomato is synonymous with termination of the shoot apical meristems, and systemic SFT messages attenuate the growth of apical meristems before and independent of floral production. Floral enhancement by systemic SFT signals is therefore one pleiotropic effect of FT orthologs.

Cell Nucleus↗
PubMed2003

The serine/threonine kinase Pim-2 is a transcriptionally regulated apoptotic inhibitor.

Growth factor withdrawal results in the termination of factor-dependent transcription. One transcript that declines rapidly following growth factor deprivation of hematopoietic cells is the serine/threonine kinase pim-2. When constitutively expressed, Pim-2 conferred long-term resistance to a variety of apoptotic stimuli including growth factor withdrawal and endogenous levels of Pim-2 contributed to growth factor-mediated apoptotic resistance. Pim-2 expression maintained cell size and mitochondrial potential independently of the PI3K/Akt/TOR pathway. Pim-2-dependent maintenance of cell size and survival correlated with its ability to maintain rapamycin-resistant phosphorylation of the translational repressor 4E-BP1 and phosphorylation of the BH3 protein BAD. These results establish Pim-2 as a direct link between growth factor-induced transcription and a novel, kinase-dependent pathway that promotes cell-autonomous survival.

Animals↗
PubMed1991

Ultrastructural Relationships Between GABAergic Terminals and Cardiac Vagal Preganglionic Motoneurons and Vagal Afferents in the Cat: A Combined HRP Tracing and Immunogold Labelling Study.

The ultrastructural relationships between gamma-aminobutyric acid-immunoreactive (GABA-ir) neurons and other neurons of the nucleus tractus solitarius (NTS) and motoneurons of the nucleus ambiguus (NA) and dorsal motor vagal nucleus (DMVN), were examined by electron microscopic (EM) immunogold labelling with an anti-GABA antiserum on brain stem sections in which vagal motoneurons and vagal afferent fibres were labelled with horseradish peroxidase (HRP). HRP was applied to the cervical vagus or the cardiac vagal branch of anaesthetized cats. After 24 - 48 h survival, brains were glutaraldehyde-fixed and a stable HRP-tetramethylbenzidine reaction product compatible with EM processing was revealed on 250 microm vibratome sections. Following osmium postfixation, dehydration and resin embedding, GABA-ir was localized on ultrathin sections by an immunogold technique. GABA-ir axon terminals, heavily and specifically labelled with gold particles, were very numerous within NTS, DMVN and NA. All terminals contained small, clear, pleomorphic vesicles and a few also contained larger dense cored vesicles. The density of gold particles over clear vesicles, dense cored vesicles and mitochondria was significantly greater than over the cytoplasm of these terminals. GABA-ir synapses were found on the soma and dendrites of neurons, but rarely on other axon terminals within NTS, where GABA-ir cell bodies and dendrites were also seen. These received synaptic contacts from both GABA-ir terminals and from HRP-labelled vagal afferents. In both the DMVN and NA, similar GABA-ir synapses were present on both the soma and dendrites of HRP-labelled motoneurons. GABA synapses were also present on other cell types in DMVN. These observations provide an anatomical basis for a GABAergic inhibition of neurons forming the central pathways of cardiovascular and other autonomic reflexes.

Journal Article↗
PubMed1999

Coexisting preexcitation syndrome and intermittent heart block presenting as neonatal seizures.

An infant presented with neonatal syncope and seizures. An ECG showed a preexcitation pattern, most compatible with Wolff-Parkinson-White (WPW) syndrome. Rhythm monitoring during an event demonstrated prolonged periods of complete AV block with no ventricular escape mechanism. We postulated that ventricular asystole was initiated by mechanical or autonomic influences on the accessory pathway and sustained by electrophysiologic interactions between the accessory pathway and the junctional escape focus. This is the first case report of a newborn having coexisting congenital AV block and WPW syndrome.

Cardiac Pacing, Artificial↗
PubMed1995

Hypothalamic modulation of laryngeal reflexes in the anaesthetized cat: role of the nucleus tractus solitarii.

1. This investigation was initiated because activation of laryngeal afferents, either by electrical stimulation of the superior laryngeal nerve (SLN) or by natural stimulation of receptors in the laryngeal mucosa, results in a cardiorespiratory response comprising bradycardia, hypotension and apnoea (phrenic nerve activity was suppressed). This pattern of response is qualitatively equivalent to the response that is evoked on activation of the arterial baroreceptors. 2. Preliminary studies indicated that the effects of activating the SLN were suppressed during stimulation in the hypothalamic defence area (HDA) at points that also blocked the effects of baroreceptor stimulation. 3. Recordings were taken from seventy-two neurones localized within the ipsilateral nucleus tractus solitarii (NTS) whose activity was modified by SLN stimulation. Sixty neurones responded with an EPSP on SLN stimulation; nine of these had an inspiratory firing pattern. Five neurones were seen to receive an IPSP on SLN stimulation. 4. Five respiratory SLN-activated neurones were unresponsive to stimulation of the other nerve inputs, whilst four received convergent EPSP inputs on sinus nerve (SN) stimulation. One cell of these four also received inputs from the aortic and the vagus nerves. Sixty-one non-respiratory SLN-activated neurones also received convergent inputs from the sinus nerve. Of these, fifty displayed an EPSP, four an IPSP and seven an EPSP-IPSP. Fifteen neurones also received inputs from the aortic nerve and seventeen from the vagus. 5. From the population of neurones affected by SLN stimulation, twenty-four of seventy were also influenced by HDA stimulation (3 were respiratory cells). Sixteen of these responses consisted of an EPSP (2 respiratory cells), five of an IPSP (1 respiratory cell) and three of an EPSP-IPSP. 6. In neurones receiving an IPSP on HDA stimulation, the SLN-evoked excitatory response was reduced throughout the period of HDA-evoked inhibition. These neurones were all shown to receive excitatory inputs from the arterial baroreceptors and laryngeal mechanoreceptors. 7. Additionally, in the thirty-seven neurones that were excited by SLN stimulation but received no direct synaptic input on HDA stimulation, a conditioning stimulus to the HDA evoked a block of SLN-evoked responses without an accompanying change in membrane potential. Several of these neurones were also affected by both baroreceptor and laryngeal mechanoreceptor stimulation. 8. These observations are discussed in the context of the role of the NTS in cardiorespiratory control. The potential importance of these interactions in respiratory distress are highlighted and the implications for the organization of central pathways for the control of autonomic and respiratory function are discussed.

Anesthesia↗
PubMed1998

BCL-2 family: regulators of cell death.

An expanding family of BCL-2 related proteins share homology, clustered within four conserved regions, namely BCL-2 homology (BH1-4) domains, which control the ability of these proteins to dimerize and function as regulators of apoptosis. Moreover, BCL-XL, BCL-2, and BAX can form ion-conductive pores in artificial membranes. The BCL-2 family, comprised of both pro-apoptotic and anti-apoptotic members, acts as a checkpoint upstream of CASPASES and mitochondrial dysfunction. BID and BAD possess the minimal death domain BH3, and the phosphorylation of BAD connects proximal survival signals to the BCL-2 family. BCL-2 and BCL-XL display a reciprocal pattern of expression during lymphocyte development. Gain- and loss-of-function models revealed stage-specific roles for BCL-2 and BCL-XL. BCL-2 can rescue maturation at several points of lymphocyte development. The BCL-2 family also reveals evidence for a cell-autonomous coordination between the opposing pathways of proliferation and cell death.

Animals↗
PubMed1997

Autonomic interactions for control of atrial rate are maintained after SA nodal parasympathectomy.

Autonomic control of atrial rate was evaluated in anesthetized dogs by electrical stimulation of stellate ganglia and/or cervical vagi before and after the intrinsic cardiac right atrial ganglionated plexus (RAGP) was injected with the nicotinic blocker hexamethonium or the membrane stabilizing chemical lidocaine, or the RAGP was surgically removed. Injections of lidocaine or hexamethonium into or surgical removal of the RAGP eliminated the bradycardia elicited by vagal stimulation without reducing the tachycardia induced by stellate stimulation. Yet, after surgical ablation of the RAGP, the tachycardia induced by sympathetic stimulation was still reduced by 94% by parasympathetic stimulation. After injections of hexamethonium or lidocaine into the RAGP were administered, the sympathetically induced tachycardia was reduced by 39 and 85%, respectively, by parasympathetic stimulation. After RAGP ablation, when atrial rate was increased by infusion of beta-adrenergic agonists, parasympathetic stimulation reduced atrial rate by 13%. Sinoatrial (SA) nodal parasympathectomy, produced by disrupting the RAGP, eliminates direct vagal control of the SA node while leaving prejunctional parasympathetic projections to sympathetic afferents innervating the SA node intact.

Animals↗
PubMed2003

Cell fate specification and competence by Coco, a maternal BMP, TGFbeta and Wnt inhibitor.

Patterning of the pre-gastrula embryo and subsequent neural induction post-gastrulation are very complex and intricate processes of which little, until recently, has been understood. The earliest decision in neural development, the choice between epidermal or neural fates, is regulated by bone morphogenetic protein (BMP) signaling within the ectoderm. Inhibition of BMP signaling is sufficient for neural induction. Many secreted BMP inhibitors are expressed exclusively within the organizer of the Xenopus gastrula embryo and therefore are predicted to act as bona fide endogenous neural inducers. Other cell-autonomous inhibitors of the BMP pathway are more widely expressed, such as the inhibitory Smads, Smad6 and Smad7. In this report we describe the biological and biochemical characterization of 51-B6, a novel member of Cerberus/Dan family of secreted BMP inhibitors, which we identified in a screen for Smad7-induced genes. This gene is expressed maternally in an animal to vegetal gradient, and its expression levels decline rapidly following gastrulation. In contrast to known BMP inhibitors, 51-B6 is broadly expressed in the ectoderm until the end of gastrulation. The timing, pattern of expression, and activities of this gene makes it unique when compared to other BMP/TGFbeta/Wnt secreted inhibitors which are expressed only zygotically and maintained post-gastrulation. We propose that a function of 51-B6 is to block BMP and TGFbeta signals in the ectoderm in order to regulate cell fate specification and competence prior to the onset of neural induction. In addition, we demonstrate that 51-B6 can act as a neural inducer and induce ectopic head-like structures in neurula staged embryos. Because of this embryological activity, we have renamed this clone Coco, after the Spanish word meaning head.

Activins↗
PubMed1995

The mechanism responsible for hypertension in a patient with Guillain-Barré syndrome.

We report a case of hypertension associated with Guillain-Barré syndrome. In this case, the circadian variation of blood pressure was interrupted. Examination of neurohumoral factors revealed a hyperactive sympathetic nervous system and an increase in plasma renin activity. Clonidine, which acts centrally to inhibit sympathetic outflow, did not suppress serum norepinephrine or epinephrine. These observations suggest that autonomous hyperactivity of the efferent pathway of the sympathetic nervous system may cause the sustained hypertension throughout the day in this case.

Adult↗
PubMed1994

Peripheral neuroendocrinology of the cervical autonomic nervous system.

1. The sympathetic superior cervical ganglia (SCG) provide innervation to the pineal gland and median eminence through the internal carotid nerve and to the thyroid and parathyroid glands through the external carotid nerve. 2. Postsynaptic activation in median eminence nerve endings shortly after superior cervical ganglionectomy (SCGx) was accompanied by a depression of LH and FSH release and by a 3-5 day delay in rat estrous cyclicity. A decrease in TSH and GH release and an increase in ACTH and prolactin release were also found. These effects were accompanied by a) an increase in medial basal hypothalamic (MBH) LHRH, TRH and GHRH, b) a decrease in MBH somatostatin, AVP and CRH, and c) a normal adenohypophyseal response to hypophysiotropic hormones. Neurohypophyseal AVP release decreased during degeneration of sympathetic nerve terminals in the neurohypophyseal lobe after SCGx. The effects were generally mediated by alpha 1-adrenoceptors and were pineal gland. 3. In thyroid and parathyroid tissue the following events were observed during the wallerian degeneration phase after SCGx: a) alpha 1-adrenoceptor inhibition of thyroxine (T4) release, b) alpha 1-adrenoceptor inhibition, together with beta-adrenoceptor stimulation, of calcitonin release, and c) alpha 1-adrenoceptor inhibition of parathyroid hormone release. Thyroid sympathetic nerves also modulate slow phenomena such as compensatory thyroid growth after partial thyroidectomy. 4. In rats subjected to cholinergic decentralization of the thyroid gland, a decrease of plasma T4 and an increase of plasma TSH, as well as an impaired goitrogenic and thyroid compensatory response were detectable. The calcitonin and PTH response to changes in calcium levels increased after regional parasympathetic denervation. 5. The results indicate that cervical autonomic nerves constitute a parallel pathway through which the brain communicates with the endocrine system.

Animals↗
PubMed1993

[Intermittent ventricular pre-excitation in the presence of total atrioventricular block].

An 8 year old child suffering from asthenia and complete atrioventricular block, probably congenital. During the tread-mill test there was a sudden electrocardiogram change to a ventricular preexcitation pattern. Besides this rare association, we emphasize the importance of the autonomic balance over the accessory pathway's electrophysiological properties. The appearance of a latent accessory pathway might be a substitutive mechanism to counterbalance the serious impairment of physiologic atrioventricular conduction.

Child↗