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Histochemistry and function of bombesin-like peptides.

Bombesin-like peptides are a group of brain-gut peptides found in several neuronal groups in the central nervous system and in peripheral intrinsic gut neurons and sensory neurons. The SIF cells (small intensely fluorescent cells) of the sympathetic ganglia also contain immunoreactivity for these peptides. These peptides are present in some pulmonary endocrine cells and tumors originating from these cells. Chromatographic studies suggest that several different peptides, possibly originating from at least two different precursors, are present in mammalian tissues. Authentic amphibian peptide bombesin does not appear to be found in mammalian tissues. Functional studies indicate that these peptides may be involved in many important functions, including sensory transmission, regulation of central autonomic pathways, thermoregulation, secretion of pituitary hormones, gastric and pancreatic secretion, food intake and satiety.

Animals↗

Phorbol ester induction of plasmacytoid and hairy cell leukemia features in B-type lymphocytic leukemias: the relation to B-cell differentiation and maturation.

Mononuclear cells concentrated from 11 patients with chronic lymphocytic leukemia (CLL), 7 with non-Hodgkin's lymphoma in leukemic phase (NHL), 5 with hairy cell leukemia (HCL), 1 with prolymphocytic leukemia (PLL), and 1 with plasma cell leukemia (PCL) were induced to differentiate with various doses of TPA. The degree of induction was followed for up to 6 days by measuring the expression of surface membrane markers (SmIg and GP-70) and Ig secretion, the induction of tartrate-resistant acid phosphatase (TRAP) and by recording ultrastructural changes as seen by electronmicroscopy. The results show a dose and time dependency of the TPA effect and a great heterogeneity in the cellular response, particularly in cells obtained from B-CLL patients. TPA induced two main features, namely the development of "plasmacytoid" or "hairy cell" leukemia features that clearly depended on the dose and duration of treatment with the phorbol ester. The plasmacytoid features were more frequently encountered with lower doses (1 ng/ml) of TPA and were more evident after shorter exposures to TPA (1-2 days). Nevertheless, the hairy cell features were more striking after incubation with higher concentrations of TPA (10-100 ng/ml) after longer periods of incubation (up to 6 days) with lower doses of TPA. The various features of differentiation measured including cell morphology, surface membrane markers, Ig secretion, and TRAP staining, were frequently independent of each other, suggesting an autonomous pathway of differentiation for some of these features. Furthermore, in most of the cases, hairy cell leukemia features were obtained more frequently following TPA exposure than plasmacytic changes.

Acid Phosphatase↗

Heterogeneity in TPA-induced differentiation of B-chronic lymphocytic leukemia cells: development of hairy cell or plasmacytoid features are time and dose dependent.

Cells from 11 chronic lymphocytic leukemic (CLL) patients were induced to differentiate with various doses of tetradecanoyl phorbol-13-acetate (TPA) and the degree of induction was followed up to six days by measuring the expression of two surface membrane markers (SmIg and GP-70), Ig secretion, tartrate-resistant acid phosphatase (TRAP), and ultrastructural changes. The results indicate dose and time dependency of the TPA effect and a great heterogeneity in the response to TPA among cells from different CLL patients. Furthermore, the two main TPA-induced features, the "plasmacytoid" or "hairy cell" features depended on the dose and duration of treatment with the phorbolester. The plasmacytoid features were more frequently encountered at low doses (1 ng/ml) of TPA and were evident after short exposures to TPA (1-2 days). The hairy cell features were more obvious after incubation with higher doses of TPA (10-100 ng/ml) or at Day 6 with lower doses of TPA. The differentiation features measured, including cell morphology, surface membrane markers, Ig secretion, and TRAP staining, appeared to be independent of each other suggesting an autonomous pathway of differentiation for some of these features.

Acid Phosphatase↗

Parasympathetic stimulation as a mechanism for platelet-activating factor-induced contractile responses in the lung.

Platelet-activating factor (PAF) contracts isolated parenchymal tissues from guinea-pig lung at nanomolar concentrations. Previous studies indicate that, although significant quantities of thromboxane A2 are released from lung tissues stimulated with PAF, inhibition of thromboxane synthesis does not significantly diminish the in vitro spasmogenic response. In contrast, treatment of the tissues with the specific neurotoxin tetrodotoxin or with atropine results in significant inhibition of PAF-induced contractions. Contractile responses to the other lipid spasmogens leukotrienes C4 and D4 and prostaglandin F2 alpha and the stable thromboxane A2 analog U-46619 or histamine are not altered by these drugs. In the presence of physostigmine, an acetylcholinesterase inhibitor, the PAF-induced contractions of lung strips were modestly enhanced, consistent with release of endogenous acetylcholine. The rate of degradation of PAF in lung tissue was not altered by physostigmine. Lack of inhibition by the preganglionic blocking agent hexamethonium localizes the site of PAF action to a point at or distal to the parasympathetic ganglion but proximal to the neuromuscular junction. Thus PAF, or a metabolite thereof, acts presynaptically on cholinergic neurons in lung tissues to effect smooth muscle contraction, and this phospholipid may constitute a link between the immunologic humoral and autonomic pathways that lead to bronchoconstriction.

Acetylcholine↗

Effect of ionizing radiation on physiological function in the anesthetized rat.

Exposure of pentobarbital-anesthetized rats to 14.5-MeV electrons results in radiation-induced physiological dysfunction. Responses include transient hypotension, a transient decrease in heart rate, respiratory dysrhythmias, and a prolonged increase in pulse pressure. Magnitudes of these responses are dose related, and maximal responses can be elicited by either whole- or partial-body (head or abdominal) exposure to 10,000 rad. These responses were associated with a fivefold increase in arterial plasma concentration of epinephrine, whereas histamine, norepinephrine, and beta-endorphin did not change during the first minute after the onset of exposure. Administration of diphenhydramine, a histamine receptor antagonist, resulted in a significant decline of baseline cardiovascular function and inhibited radiation-induced cardiovascular dysfunction. The diphenhydramine-induced decrease in preexposure blood pressure was reversed by angiotensin infusion, but this procedure failed to restore the mechanism(s) responsible for the cardiovascular responses to radiation. Results of these experiments and information available in the literature support the hypothesis that these responses are due to an interference in the autonomic pathways that modulate cardiovascular function.

Anesthesia↗

[Activities of 3-hydroxyl-3-methylglutaryl-CoA reductase and acetyl-CoA carboxylase and the rate of mevalonic acid, squalene, sterol and fatty acid biosynthesis from [1-14C]acetyl-CoA and [2-14C]malonyl-CoA in rat liver: effects of Triton WR 1339, starvation and cholesterol diet].

The effects of Triton WR 1339, starvation and cholesterol diet on the activities of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase) and acetyl-CoA carboxylase and on the rates of mevalonic acid (MVA) biosynthesis from acetyl-CoA and malonyl-CoA in the soluble (140 000 g) and microsomal fractions of rat liver, on the rate of incorporation of these substrates into squalene, cholesterol and lanosterol in the rat liver postmitochondrial fraction and on the rate of fatty acid biosynthesis was studied. The administration of Triton WR 1339 (200 mg per 100 g of body weight twice) stimulated the activity of HMG-CoA reductase and MVA biosynthesis from acetyl-CoA and malonyl-CoA in the intact and solubilized microsomal fractions and had no effect on these parameters in the soluble fraction. Starvation for 36 hrs did not cause inhibition of the reductase activity or MVA biosynthesis from both substrates in the soluble fraction. Alimentary cholesterol significantly increased the activity of HMG-CoA reductase, had no effect on the rate of MVA biosynthesis from acetyl-CoA and stimulated the malonyl-CoA incorporation in to MVA in the soluble fraction. Starvation an alimentary cholesterol inhibited the HMG-CoA reductase activity and MVA biosynthesis from both substrates in the solubilized microsomal fraction. Triton WR 1339 stimulated 4--19-fold the lipid formation in the total unsaponified fraction and its components i.e. squalene, lanosterol, cholesterol, from acetyl-CoA and only insignificantly (1,2--1,7-fold) increased malonyl-CoA incorporation into these compounds. Starvation and alimentary cholesterol repressed lanosterol and cholesterol biosynthesis from acetyl-CoA, decreased malonyl-CoA incorporation into these sterols and had no influence on squalene biosynthesis from the two substrates. Triton WR 1339 and starvation inhibited the acetyl-CoA carboxylase activity, unaffected by alimentary cholesterol. No significant changes in the rate of fatty acid biosynthesis from the substrates were observed. The data obtained provide evidence for the existence of autonomic pathways of MVA biosynthesis localized in the soluble and microsomal fractions of rat liver. The pathway of MVA biosynthesis in the soluble fraction is less sensitive to regulatory factors. Sterol biosynthesis from malonyl-CoA is also more resistant to regulatory effects than sterol biosynthesis from acetyl-CoA. This suggests that HMG-CoA reductase localized in the soluble fraction takes part in MVA and sterol biosynthesis from malonyl-CoA.

Acetyl Coenzyme A↗

Neurocardiology. Brain mechanisms underlying fatal cardiac arrhythmias.

Chaos theory may have a widespread application in medicine, from the analysis of protein structure at one end of the spectrum to fetal monitoring and the measurement of aging on the other. This application is especially on firm ground in cardiology, where it is simple and precise for the experimenter, and a primer exists for the clinician. As just presented, the point-correlation-dimension analysis of heartbeat variability is able to characterize the patterns of low-dimensional chaos produced by the heartbeat generator, a mechanism that is a composite of the voltage-dependent, neurotransmitter-dependent, and circulation-dependent ionic conductances that are all located in the myocardium where the heartbeat is formed. Most importantly, this deterministic measure of heartbeat variability is able to predict imminent lethal arrhythmogenesis with an accuracy that the more familiar stochastic measures do not have. This may arise because the PD2 is sensitive to the net degrees of freedom of the heartbeat generator, which, under the influence of the nerves and the coronary circulation, can be shifted so the resulting dynamics cause the initiation of lethal arrhythmogenesis. Application of chaos theory in neurology may be equally fruitful because the deterministic measures can discriminate among neuronal firing patterns, reveal subtle changes in brain waves, and be related to higher cognitive processes. Psychiatry also seems quite likely to benefit more and more from the application because the algorithms can discriminate schizophrenic brain functions from normal ones. Thus it can be expected that future applications will enable observation of biologic processes all along the brain-heart axis by which lethal ventricular fibrillation is regulated and perhaps even caused by its determination of the heartbeat dynamics. The subfield of neurocardiology has come a long way since it was first positively identified as an important research area. It took a lot of experiments to show how lethal cardiac arrhythmogenesis is involved with cerebral activities delivered over autonomic pathways. Although we do not yet fully understand the causal mechanism of lethal arrhythmogenesis, we may be getting close. It will become increasingly imperative for the clinical neurologist, along with the cardiologist, to understand the importance of neurocardiology in medical therapy and for the neurologist, along with the cardiologist and psychiatrist, to understand its importance in preventive treatments.

Animals↗

[Neurophysiological methods for the diagnosis of genitourinary dysfunctions].

Genito-urinary function is a watershed field interesting several areas of medical concern. Neurophysiological studies allow objective assessment of central, peripheral and autonomic pathways in the nervous system contributing to topographical localisation of lesions. The authors describe different methods used, namely somatosensory evoked potentials by pudendal nerve stimulation, bulbo-cavernous reflex, cutaneous sympathetic reflex, transcranial cortical or spinal magnetic stimulation and single fiber EMG. Abnormalities in neurological diseases are presented.

Anal Canal↗

Essential role for nuclear phospholipase C beta1 in insulin-like growth factor I-induced mitogenesis.

The nucleus has been shown to be a site for the inositol lipid cycle that can be affected by treatment of quiescent cells with growth factors such as insulin-like growth factor I (IGF-I). Indeed, the exposure of Swiss 3T3 cells to IGF-I results in a rapid and transient increase in nuclear phospholipase C (PLC) beta1 activity. In addition, several other reports have shown the involvement of PLC beta1 in nuclear signaling in different cell types. Although the demonstration of phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate hydrolysis by nuclear PLC beta1 established the existence of nuclear PLC signaling, the significance of this autonomous pathway in the nucleus has yet to be thoroughly clarified. By inducing both the inhibition of PLC beta1 expression by antisense RNA and its overexpression, we show that this nuclear PLC is essential for the onset of DNA synthesis following IGF-I stimulation of quiescent Swiss 3T3 cells.

3T3 Cells↗

[Role of the posterolateral nucleus of the cat thalamus in conducting peripheral and cortical polysensory influences].

The posterior lateral thalamic nucleus (LP) of the cat has separate inputs for ascending signals of different sensory and subcortical origin, as well as for cortifugal activity. With somatic stimuli, only non-specific and reticular signals come to LP. They are not directly involved in the genesis of evoked potentials (EP) in the parietal cortex (P) and the somatic zones I and II (SI and SII). With visual stimuli, specific and reticular impulses directly concerned with the formation of visual EPs in the P and the visual zone (VI) are projected to LP. The cortifugal action of VI, SI and SII influences the same modality in LP. The descending effect of P on visual and somatic signals in LP is actieved along autonomous pathways and consists in dissimilar types of direct (as in VI) and indirect (as in SI and SII) descending influences of different projection zones on impulses of the same modality in the given nucleus.

Animals↗

Stress and immunity: what have we learned from psychoneuroimmunology?

The old concept that stress depresses immunity must be qualified. There is now evidence that in the same way that different perceptions of stress have different physiological consequences, different ways of coping with stress result in different consequences on immunity, the nature and outcome of which depend on the type of immune response. The mechanisms that are involved in these effects involve neuroendocrine and autonomic pathways. These pathways are actually part of a network of bidirectional interactions between the central nervous system and the immune system, which plays an important role in the physiological regulation of immunity.

Animals↗

[Neurological urology -- a new specialty].

Neuro-urological methods for investigating neurogenic bladder dysfunctions are discussed. A knowledge of central and autonomous pathways of bladder innervation is the basis for an understanding of the pharmacodynamics of the bladder. Successful treatment of neurogenic bladder dysfunction is impossible without urodynamic assessment. Conservative, as well as operative measures of therapy are mentioned. Urinary diversion (ileal conduit) is nowadays no longer undertaken merely as a last resort to prevent chronic upper urinary tract infection, stone formation, contracted kidney and uremia, but is a positive, practicable alternative for the disabled patient. Especially for the younger patient, in whom the social aspects of this situation are of great importance, ileal conduit provides the possibility of a socially-adjusted existence.

Humans↗

The autonomic facial nerve pathway in birds: a tracing study in chickens.

PURPOSE: In birds, the parasympathetic innervation of the choroid is via the ciliary (cranial nerve III) and pterygopalatine (cranial nerve VII) ganglia, the latter consisting of a chain of microganglia within the orbit. Because of the scattered nature of these microganglia, lesions of this nerve pathway in birds have not been attempted, making interpretation of the functional contribution of this parasympathetic input to the avian eye uncertain. The purpose of this study was to find an extraorbital approach to the preganglionic part of cranial nerve VII and to reveal its peripheral terminals and its site of origin in the brain stem. METHODS: The radix autonomica cranial nerve VII was accessed via the tympanic cavity and injected with dextran coupled to Texas red (DTxR). Orbital structures and the brain stem were prepared for tracer detection and immunohistochemistry for neuronal nitric oxide synthase (nNOS), choline acetyl transferase (ChAT), vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptide (CGRP), galanin (GAL), and somatostatin (SOM). For documentation, fluorescence and confocal laser scanning microscopy were used. RESULTS: Anterogradely labeled DTxR-positive nerve fibers were detected within the orbital pterygopalatine microganglionic chain, forming boutons closely associated with nNOS-positive neurons. Retrogradely labeled DTxR-positive neurons with cell diameters of approximately 20 microm were found in the brain stem. These were positive for ChAT, but negative for nNOS, VIP, SOM, GAL, and CGRP. They most likely represent the preganglionic neurons of the superior salivatory nucleus. In close proximity, there were larger (40 microm) unlabeled neurons that were positive for ChAT and CGRP, but negative for GAL. These most likely represent motoneurons of the facial nerve. CONCLUSIONS: This surgical approach offers excellent opportunities for lesioning experiments for the study of the autonomic facial nerve pathway in birds in terms of both its anatomic organization and its function.

Animals↗

FLC, a repressor of flowering, is regulated by genes in different inductive pathways.

The MADS-box protein encoded by FLOWERING LOCUS C (FLC) is a repressor of flowering. Loci in the autonomous flowering pathway control FLC levels. We show the epistatic groupings of autonomous pathway mutants fca/fy and fve/fpa, based on their effects on flowering time, are consistent with their effects on FLC transcript and protein levels. We demonstrate that synergistic increases in FLC mRNA and protein expression occur in response to interactions between the autonomous pathway mutants fca and fpa and mutants in other pathways (fe, ft, fha) that do not regulate FLC when present as single mutants. These changes in FLC levels provide the molecular basis of the interactions previously shown in genetic analyses. The interactions between genes of multiple pathways emphasize the central position of FLC in the control of floral initiation. FLC protein levels match those of its mRNA for a range of genetic, developmental and environmental variables, indicating that control of FLC is at the level of transcription or transcript stability. The autonomous and photoperiod pathways also interact at the level of SOC1. FLC acts as a repressor of SOC1, and SOC1 levels are low when FLC levels are high. In C24 plants which have moderately high FLC levels, flowering occurs without a decrease in FLC level, but the SOC1 level does increase. Thus SOC1 levels can be upregulated through the activities of other pathways, despite the repression by FLC.

Arabidopsis↗

FLOWERING LOCUS C-dependent and -independent regulation of the circadian clock by the autonomous and vernalization pathways.

BACKGROUND: The circadian system drives pervasive biological rhythms in plants. Circadian clocks integrate endogenous timing information with environmental signals, in order to match rhythmic outputs to the local day/night cycle. Multiple signaling pathways affect the circadian system, in ways that are likely to be adaptively significant. Our previous studies of natural genetic variation in Arabidopsis thaliana accessions implicated FLOWERING LOCUS C (FLC) as a circadian-clock regulator. The MADS-box transcription factor FLC is best known as a regulator of flowering time. Its activity is regulated by many regulatory genes in the "autonomous" and vernalization-dependent flowering pathways. We tested whether these same pathways affect the circadian system. RESULTS: Genes in the autonomous flowering pathway, including FLC, were found to regulate circadian period in Arabidopsis. The mechanisms involved are similar, but not identical, to the control of flowering time. By mutant analyses, we demonstrate a graded effect of FLC expression upon circadian period. Related MADS-box genes had less effect on clock function. We also reveal an unexpected vernalization-dependent alteration of periodicity. CONCLUSION: This study has aided in the understanding of FLC's role in the clock, as it reveals that the network affecting circadian timing is partially overlapping with the floral-regulatory network. We also show a link between vernalization and circadian period. This finding may be of ecological relevance for developmental programming in other plant species.

Arabidopsis↗

Regulation of flowering time by FVE, a retinoblastoma-associated protein.

The initiation of flowering in plants is controlled by environmental and endogenous signals. Molecular analysis of this process in Arabidopsis thaliana indicates that environmental control is exerted through the photoperiod and vernalization pathways, whereas endogenous signals regulate the autonomous and gibberellin pathways. The vernalization and autonomous pathways converge on the negative regulation of FLC, a gene encoding a MADS-box protein that inhibits flowering. We cloned FVE, a component of the autonomous pathway that encodes AtMSI4, a putative retinoblastoma-associated protein. FVE interacted with retinoblastoma protein in immunoprecipitation assays, and FLC chromatin was enriched in acetylated histones in fve mutants. We conclude that FVE participates in a protein complex repressing FLC transcription through a histone deacetylation mechanism. Our data provide genetic evidence of a new developmental function of these conserved proteins and identify a new genetic mechanism in the regulation of flowering.

Arabidopsis↗

Genetic interactions between FLM and other flowering-time genes in Arabidopsis thaliana.

FLOWERING LOCUS M (FLM) is a MADS-domain gene that acts as an inhibitor of flowering in Arabidopsis. Here we describe the genetic interaction of FLM with genes in the photoperiod and autonomous flowering pathways. Although the sequence of FLM is most similar to that of FLC, FLM and FLC interact with different flowering pathways. It has been previously shown that flc lesions suppress the late-flowering phenotype of FRI-containing lines and autonomous-pathway mutants. However, flm lesions suppress the late-flowering phenotype of photoperiod-pathway mutants but not that of FRI-containing lines or autonomous-pathway mutants. Another MADS-domain flowering repressor with a mutant phenotype similar to FLM is SVP. The late-flowering phenotype of FLM over-expression is suppressed by the svp mutation, and an svp flm double mutant behaves like the single mutants. Thus FLM and SVP are in the same flowering pathway which interacts with the photoperiod pathway.

Arabidopsis↗

Extracellular ATP can activate autonomic signal transduction pathways in cultured equine sweat gland epithelial cells.

Changes in intracellular free calcium concentration ([Ca2+]i) were monitored in a cell line that was derived from the equine sweat gland epithelium. ATP and closely related compounds could increase [Ca2+]i with a rank order of potency of UTP > or = ATP > ADP >> AMP = adenosine = alpha,beta-methylene-ATP. The responses to ATP and to UTP were initiated by the release of calcium from an internal store and subsequently sustained by calcium influx. The rise in [Ca2+]i thus seems to be mediated by P2U receptors that are coupled to phosphoinositidase C. Some desensitisation of this response developed during repeated stimulation with ATP and this was blocked by staurosporine, an inhibitor of protein kinase C, and augmented by a phorbol ester which acts as an exogenous activator of this enzyme. A protein-kinase-C-dependent inhibitory pathway thus seems to become active during repeated stimulation with ATP. ATP and related compounds could also raise cellular cyclic AMP content. The order of potency was ATP > ADP = AMP = adenosine >> UTP, suggesting that this response is mediated via a separate subclass of P2 receptor. The present results demonstrate that ATP can activate autonomic signal-transduction pathways in cultured equine sweat gland cells and suggest that there may be a purinergic component to the control of secretory activity in the equine sweat gland.

Adenosine Triphosphate↗