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Potential mechanisms in chemical intolerance and related conditions.

The symptom of chemical intolerance may occur in isolation, but often occurs in conjunction with other chronic symptoms such as pain, fatigue, memory disturbances, etc. This frequent clustering of symptoms in individuals has led to the definition of several chronic multisymptom syndromes, such as multiple chemical sensitivity, fibromyalgia, chronic fatigue syndrome, and Gulf War illnesses. The aggregate research into these syndromes has suggested some unifying mechanisms that contribute to symptomatology. Multiple lines of evidence suggest that there is aberrant function of numerous efferent neural pathways, such as the autonomic nervous system and hypothalamic-pituitary axes, in subsets of individuals with these conditions. There is perhaps the greatest evidence for abnormal sensory processing in these syndromes, with a low "unpleasantness threshold" for multiple types of sensory stimuli. Psychological and behavioral factors are known to play a significant role in initiating or perpetuating symptoms in some persons with these illnesses. In the field of pain research, the interrelationship between physiologic and psychologic factors in symptom expression has been well studied. Using both established and novel methodologies, studies have suggested that psychologic factors such as hypervigilance and expectancy are playing a relatively minor role in most individuals with fibromyalgia and that clear evidence exists of physiologic amplification of sensory stimuli. These studies need to be extended to more sensory tasks and to larger numbers of subjects with related conditions. It is of note, though, that existing data on this spectrum of illnesses would suggest that there may be greater psychologic contributions to symptomatology if an illness is defined in part by behavior (e.g., avoidance of chemical exposures) rather than on the basis of symptoms alone.

Afferent Pathways↗

Neural control of penile erection in the rat.

The role of autonomic and somatic neural pathways involved in the control of penile erectile tissue was investigated in an in vivo rat model. Intracavernous pressure (ICP) changes were recorded during single or combined electrical stimulation of peripheral nerves in anesthetized rats. Stimulation of the pelvic and cavernous nerves elicited similar ICP increases. Ganglionic blockade abolished the response to pelvic nerve stimulation. Stimulation of the hypogastric nerve, the sensory or motor branches of the pudendal nerve, or the paravertebral sympathetic chain at L4-L5 by themselves did not produce any change in ICP. Stimulation of some of these nerves caused changes in ICP when combined with cavernous nerve stimulation. Stimulation of the paravertebral sympathetic chain reduced the ICP increases elicited by cavernous nerve stimulation. A decrease in ICP in response to cavernous nerve stimulation was also elicited by stimulation of the peripheral cut end of the sensory branch of the pudendal nerve or in paralyzed rats, the motor branch of the pudendal nerve. After sectioning the two branches of the pudendal nerve, stimulation of the sympathetic chain still reduced the ICP increase in response to cavernous nerve stimulation. Stimulation of the motor branch of the pudendal nerve during erection elicited by cavernous nerve stimulation was responsible for an additional ICP increase, which reached suprasystolic values. The present study confirms a proerectile role for parasympathetic pathways. Sympathetic fibers conveyed in both branches of the pudendal nerve exert an antierectile role in the rat. We identified an antierectile sympathetic outflow, originating in the caudal sympathetic chain, the anatomical arrangement of which remains unknown. In this model, penile erection appeared to be dependent on the recruitment of sacral parasympathetic outflow. Additional recruitment of efferent somatic fibers present in the motor branch of the pudendal nerve could participate in more rigid erection. This study provides new information about the organization of the pathways through which the rat penis is innervated, and would be of interest to investigators in the field of male sexual function.

Anesthesia↗

Oxytocin innervation of spinal preganglionic neurons projecting to the superior cervical ganglion in the rat.

The paraventricular nucleus of the hypothalamus is a major integrative nucleus for relaying information from the suprachiasmatic nucleus to the autonomic system. The precise pathway by which this information can influence autonomic functions, such as melatonin synthesis in the pineal gland, is not clear. In the present study, we used a retrograde tracer injected in the superior cervical ganglion to identify spinal preganglionic neurons. One of the main neurotransmitters present in descending projections of the paraventricular nucleus of the hypothalamus, oxytocin, was detected with immunocytochemistry to visualise possible contacts with the neurons located in the intermediolateral column of the spinal cord and projecting to the superior cervical ganglion. Although many appositions could be seen at the light-microscopic level, this abundance could not be confirmed at the electron-microscopic level. The implications of these observations for the overall timing message received by the spinal preganglionic neurons are discussed.

Animals↗

Decussations of the descending paraventricular pathways to the brainstem and spinal cord autonomic centers.

Decussations of descending fibers of the hypothalamic paraventricular nucleus (PVN) were investigated by using Phaseolus vulgaris-leucoagglutinin (PHA-L) in intact and brainstem-operated rats. Fibers descend ipsilaterally along the brainstem and spinal cord and decussate at four levels: 1) Supramamillary decussations (SM). PVN fibers reach this area through the lateral hypothalamus and along the third ventricle in the dorsal hypothalamus. In the posterior hypothalamus some fibers crossover in the SM and terminate in the supramamillary region bilaterally. 2) Pontine tegmentum. PVN fibers run in the lateral part of the tegmentum arching to the basis of the pons. Some fibers crossover under the fourth ventricle. The locus ceruleus and the Barrington's nucleus receive bilateral innervation with ipsilateral dominance. 3) Commissural part of the nucleus of the solitary tract (NTS). The major crossover of PVN fibers is found here. The decussated fibers form a dense network here, and loop rostralward to innervate the entire NTS. A midsagittal knife-cut through the NTS eliminated paraventricular-fibers on the contralateral side. Synaptic contacts between PHA-L-labeled boutons and tyrozine hydroxilase-positive neurons were verified in the NTS. The caudal ventrolateral medulla also receives bilateral innervation. 4) Lamina X of the thoracic spinal cord. Paraventricular fibers enter the lateral funiculus ipsilaterally and innervate the intermediolateral cell column (IML). Some fibers cross the midline ventral and dorsal to the central canal running to the contralateral IML, at the level of the decussation. Our results demonstrated that paraventricular projections form a continuous descending pathway on their side of origin, and provide crossover fibers which may terminate segmentally without forming long tracts after crossover.

Animals↗

The effect of local injection of botulinum toxin A on the parotid gland of the rat: an immunohistochemical and morphometric study.

PURPOSE: In this investigation, the effect of a local injection of botulinum toxin A on the concentration of acetylcholinesterase in the parotid gland of the rat was examined. MATERIALS AND METHODS: After local injection into the parotid glands of female Wistar rats, the treated glands were excised, and immunohistochemical staining for acetylcholinesterase was performed. To discover possible changes in cell morphology after local application of botulinum toxin A, morphometric measurements also were performed on the excised parotid glands. RESULTS: In contrast to the untreated, physiologic saline-injected, glands, there was a decrease in the concentration of acetylcholinesterase in the glands treated with botulinum toxin. No persistent changes in the number of acinar cells could be observed. CONCLUSIONS: Because the cholinergic pathway of the autonomic nervous system has great importance in the secretion of fluid from the salivary glands, blocking this pathway and local application of botulinum toxin offers a possible therapeutic option for the treatment of hypersalivation in various otolaryngologic and neurologic diseases.

Acetylcholinesterase↗

Sympathetic predominance of cardiac autonomic regulation in patients with left free wall accessory pathway and orthodromic atrioventricular reentrant tachycardia.

AIMS: The aim of this study was to compare cardiac autonomic regulation in patients with a history of paroxysmal supraventricular tachyarrhythmias, such as atrioventricular nodal reentrant tachycardia and atrioventricular reentrant tachycardia, and healthy controls. METHODS AND RESULTS: Seventeen patients with paroxysmal atrioventricular nodal reentrant tachycardia (atrioventricular nodal reentrant tachycardia group), 14 patients with overt preexcitation and paroxysmal atrioventricular reentrant tachycardia caused by a left free wall accessory pathway (atrioventricular reentrant tachycardia group) and 14 healthy control subjects, were studied. The patients and the controls were age and gender matched. Cardiac autonomic regulation was assessed by means of frequency domain analysis of heart rate variability at rest, during head-up tilt, active standing, treadmill exercise and after exercise. The high frequency component (0.15-0.5 Hz) of heart rate variability tended to be lower and the low frequency component (0.04-0.15 Hz) tended to be higher among the atrioventricular reentrant tachycardia patients than in atrioventricular nodal reentrant tachycardia patients and controls. The difference reached statistical significance at rest (P < 0.05) and during standing (P < 0.05 atrioventricular reentrant tachycardia vs atrioventricular nodal reentrant tachycardia and P < 0.01 atrioventricular reentrant tachycardia vs controls). Accordingly, the low-to-high frequency ratio--the marker of cardiac sympathetic regulation--was higher in atrioventricular reentrant tachycardia patients than in atrioventricular nodal reentrant tachycardia patients (P < 0.05 at rest and during standing) and controls (P < 0.01 during standing). CONCLUSION: The cardiac autonomic status in atrioventricular reentrant tachycardia patients was suggestive of a higher sympathetic tone than in atrioventricular nodal reentrant tachycardia patients or healthy controls. This may be related to inhomogeneous ventricular activation in the presence of antegrade conduction via the accessory atrioventricular pathway.

Adult↗

Effect of diterpenoid alkaloids on cardiac sympathetic efferent and vagal afferent nerve activity.

The diterpenoid alkaloid, lappaconitine, at a dose of 150 micrograms/kg (i.v.) increased cardiac vagal afferent nerve activity (16.2%) and reduced cardiac sympathetic efferent nerve activity (12.5%). A polar analog, N-deacetyllappaconitine, at this same dose, increased cardiac vagal afferent nerve activity (40%) and reduced cardiac sympathetic efferent nerve activity (23.5%). Both of these agents also reduced arterial blood pressure and heart rate. A larger dose of lappaconitine (300 micrograms/kg i.v.) produced the same changes in nerve activities and cardiac function as the lower dose. Two other structurally related agents, lycoctonine and aconine, failed to alter these variables in doses up to 300 micrograms/kg. These data suggest that certain diterpenoid alkaloids activate autonomic reflex receptors, including cardiac reflex receptors. The polar agent, N-deacetyllappaconitine, appears to be more effective on cardiac reflex receptors than the non-polar agent, lappaconitine. Such agents may be useful in the treatment of hypertension.

Aconitine↗

Visualisation of AMPA binding sites in the brain of mice lacking the adenosine A(2a) receptor.

Adenosine A(2a) receptor knockout mice (A(2a)R k/o) have been characterised as hypertensive, aggressive, anxious and hypoalgesic [12]. Thus, the present study was designed to investigate markers of glutamatergic transmission in specific brain nuclei associated with autonomic regulation. Visualisation of alpha-amino-3-hydroxy-5-methylisoxasole-4-propionic acid binding sites in the brains of A(2a)R k/o mice was achieved by utilising quantitative receptor autoradiography with (S)-[(3)H]-5-fluorowillardiine ([(3)H]FW:10 nM) on slide-mounted sections of mouse-brain. [(3)H]FW binding significantly increased in the nucleus tractus solitarius and area postrema of A(2a)R k/o mice compared with wildtype CD-1 mice. In other autonomic nuclei examined, binding was unchanged between wildtype and knockout mice. The present study suggests that glutamatergic neurotransmission within certain neural pathways involved in autonomic and motor control is altered in the brains of A(2a)R k/o mice.

Animals↗

Time course and predictors of autonomic dysfunction after ablation of the slow atrioventricular nodal pathway.

Withdrawal of parasympathetic tone has been reported after ablation in the posteroseptal right atrium and has been attributed to injury of vagal efferent fibers. The purpose of this study was to assess the time course and predictors of autonomic dysfunction after slow pathway ablation. In 30 patients with AV nodal reentrant tachycardia, time- and frequency-domain measures of heart rate variability (HRV) were measured before, 30 minutes after, and 1 day after slow pathway ablation. There were significant reductions in mean RR interval (724 +/- 163 vs 836 +/- 164 ms, P < 0.05), SD of RR intervals (29 +/- 17 vs 40 +/- 18 ms, P < 0.05), root mean squared difference (15 +/- 8 vs 29 +/- 17 ms, P < 0.05), and high frequency power (4.1 +/- 0.4 vs 4.5 +/- 0.6 log10ms2, P < 0.05) 30 minutes after ablation. However, these parameters returned to baseline 1 day after ablation. Multivariate regression identified isoproterenol dose during the diagnostic study (P = 0.02) and radiofrequency duration (P = 0.02) as statistically significant predictors of heart rate change (R2= 0.45). These findings suggest that changes in autonomic tone after ablation in the posteroseptal right atrium are transitory and resolve within 1 day of the procedure. These short-term changes may be related to procedural variables rather than direct injury to vagal efferent fibers.

Adult↗

Autonomic and sensitive somatic innervation of the ostrich elbow and knee joints articular capsule.

The present research was carried out on the fibrous layer of the ostrich's elbow and knee joints articular capsule, employing opportunely modified gold chloride Ruffini's method, to study the autonomic and sensitive somatic nerve components. The distribution of both nerve components followed frequently the vascular networks. The autonomic innervation was represented by isolated or grouped ganglion cells, frequently placed along the course of nerve trunks, close to the epineurium or located within the perineural connective tissue. The sensitive somatic innervation was constituted by free and encapsulated corpuscles. The last one, morphologically classified as Pacini, Pacini-like and Golgi-Mazzoni's corpuscles, were found isolated or grouped to constitute simple and complex flower sprays, "opposito-polar corpuscles" and "poichilomorphous fibres". The very few Golgi-Mazzoni's corpuscles were found only in the knee joint articular capsule. The two nerve components, found in the considered districts, did not shown significant quanti-qualitative and topographic differences. This datum, at least in appearance, seems to conflict with the ostrich functional aptitudes. In fact, the ostrich is a bird unable to fly but very able to run.

Adrenergic Fibers↗

Sex determination in the Drosophila germline is dictated by the sexual identity of the surrounding soma.

It has been suggested that sexual identity in the germline depends upon the combination of a nonautonomous somatic signaling pathway and an autonomous X chromosome counting system. In the studies reported here, we have examined the role of the sexual differentiation genes transformer (tra) and doublesex (dsx) in regulating the activity of the somatic signaling pathway. We asked whether ectopic somatic expression of the female products of the tra and dsx genes could feminize the germline of XY animals. We find that Tra(F) is sufficient to feminize XY germ cells, shutting off the expression of male-specific markers and activating the expression of female-specific markers. Feminization of the germline depends upon the constitutively expressed transformer-2 (tra-2) gene, but does not seem to require a functional dsx gene. However, feminization of XY germ cells by Tra(F) can be blocked by the male form of the Dsx protein (Dsx(M)). Expression of the female form of dsx, Dsx(F), in XY animals also induced germline expression of female markers. Taken together with a previous analysis of the effects of mutations in tra, tra-2, and dsx on the feminization of XX germ cells in XX animals, our findings indicate that the somatic signaling pathway is redundant at the level tra and dsx. Finally, our studies call into question the idea that a cell-autonomous X chromosome counting system plays a central role in germline sex determination.

Alleles↗

Electrocardiographic manifestations of dual atrioventricular node conduction during sinus rhythm.

OBJECTIVES: The objective of this study was to correlate electrocardiographic (ECG) PR interval changes during normal sinus rhythm with recent observations regarding the anatomy and physiology of the dual, slow and fast atrioventricular (AV) pathways. BACKGROUND: The least common manifestation of dual AV conduction is an abrupt PR interval change in the setting of sinus rhythm. Whereas isolated cases of this phenomenon have been reported, the relatively large series we have collected makes it possible to correlate the ECG findings with the anatomy, composition and electrophysiology of the dual AV pathways. METHODS: The ECGs of 21 patients with sinus rhythm and PR interval changes consistent with dual AV node physiology were studied. Observations include duration of the short and long PR intervals, the difference between the two and the events responsible for the PR interval change. RESULTS: Eighteen of the 21 ECGs exhibited an abrupt and persistent PR interval change. Two of the other three ECGs manifested PR interval alternans, with slow and fast pathway, and a Wenckebach type I AV block; in the third ECG, findings compatible with simultaneous conduction along both pathways in response to a single stimulus were noted. Events responsible for the PR change included atrial premature complexes, atrial tachycardia, interpolated ventricular premature complexes and interpolated junctional premature complexes. In two the PR interval change appeared during a regular sinus rhythm. CONCLUSIONS: The behavior of the PR interval is consistent with dual AV conduction. The PR interval duration hypothesized to represent slow pathway conduction is in keeping with the calculated anatomic length of the slow pathway. The Wenckebach type I block in the slow and fast pathways, as well as the altered conduction time in the slow pathway parallel with changing sinus rate, is evidence that the pathway is influenced by autonomic (?parasympathetic) innervation, supporting the premise that the pathways contain AV node-like tissue.

Arrhythmias, Cardiac↗

Sympathetic inhibition after surgical reversal of renovascular hypertension in rats. Role of vagal nerves.

The present study was undertaken to study the changes in efferent renal sympathetic nerve activity (RSNA) and heart rate (HR) during the acute fall in blood pressure after surgical reversal of two-kidney, one-clip renovascular hypertension in rats, and to explore if cardiopulmonary vagal afferents can influence sympathetic outflow in this situation. In 14 rats with a MAP of 199 +/- 6 mmHg the renal artery clip was surgically removed and after 90 min MAP had decreased to 109 +/- 7 mmHg. The HR had then decreased by 26 +/- 15 beats min-1 (P less than 0.05) and RSNA did not increase as expected, but was somewhat reduced (84 +/- 8% of control). In contrast, lowering pressure with nitroprusside to the same extent produced large and significant increases in HR and RSNA in seven other renal hypertensive rats. Acute bilateral vagotomy was performed in seven of the declipped rats, which induced an immediate increase in MAP (+35 +/- 10 mmHg, P less than 0.05), HR +28 +/- 10 beats min-1, P less than 0.05) and RSNA (+51 +/- 19%, P less than 0.05). A few minutes afterwards the vagotomy pressure again started to fall and was, after another 90 min 107 +/- 10 mmHg together with slight reductions in HR and RSNA. Another group of six rats were initially exposed to bilateral vagotomy. In these vagotomized rats declipping also induced hypotension (204 +/- 10 to 95 +/- 7 mmHg, P less than 0.001), together with tendencies of decreases in HR (425 +/- 17 to 397 +/- 17 beats min-1) and in RSNA (-4 +/- 6%).(ABSTRACT TRUNCATED AT 250 WORDS)

Afferent Pathways↗

Novel retrotransposon analysis reveals multiple mobility pathways dictated by hosts.

Autonomous non-long-terminal-repeat retrotransposons (NLRs) proliferate by retrotransposition via coordinated reactions of target DNA cleavage and reverse transcription by a mechanism called target-primed reverse transcription (TPRT). Whereas this mechanism guarantees the covalent attachment of the NLR and its target site at the 3' junction, mechanisms for the joining at the 5' junction have been conjectural. To better understand the retrotransposition pathways, we analyzed target-NLR junctions of zebrafish NLRs with a new method of identifying genomic copies that reside within other transposons, termed "target analysis of nested transposons" (TANT). Application of the TANT method revealed various features of the zebrafish NLR integrants; for example, half of the integrants carry extra nucleotides at the 5' junction, which is in stark contrast to the major human NLR, LINE-1. Interestingly, in a cell culture assay, retrotransposition of the zebrafish NLR in heterologous human cells did not bear extra 5' nucleotides, indicating that the choice of the 5' joining pathway is affected by the host. Our results suggest that several pathways exist for NLR retrotransposition and argue in favor of host protein involvement. With genomic sequence information accumulating exponentially, our data demonstrate the general applicability of the TANT method for the analysis of a wide variety of retrotransposons.

Animals↗

The SOC1 MADS-box gene integrates vernalization and gibberellin signals for flowering in Arabidopsis.

The floral transition in Arabidopsis is regulated by at least four flowering pathways: the long-day, autonomous, vernalization, and gibberellin (GA)-dependent pathways. Previously, we reported that the MADS-box transcription factor SUPPRESSOR OF OVEREXPRESSION OF CO 1 (SOC1) integrates the long-day and vernalization/autonomous pathways. Here, we present evidences that SOC1 also integrates signaling from the GA-dependent pathway, a major flowering pathway under non-inductive short days. Under short days, the flowering time of GA-biosynthetic and -signaling mutants was well correlated with the level of SOC1 expression; overexpression of SOC1 rescued the non-flowering phenotype of ga1-3, and the soc1 null mutant showed reduced sensitivity to GA for flowering. In addition, we show that vernalization-induced repression of FLOWERING LOCUS C (FLC), an upstream negative regulator of SOC1, is not sufficient to activate SOC1; positive factors are also required. Under short days, the GA pathway provides a positive factor for SOC1 activation. In contrast to SOC1, the GA pathway does not regulate expression of other flowering integrators FLC and FT. Our results explain why the GA pathway has a strong effect on flowering under short days and how vernalization and GA interact at the molecular level.

Arabidopsis↗

Regulation of flowering time in Arabidopsis by K homology domain proteins.

The transition from vegetative growth to reproductive development in Arabidopsis is regulated by multiple floral induction pathways, including the photoperiodic, the autonomous, the vernalization, and the hormonal pathways. These pathways converge to regulate the expression of a small set of genes critical for floral initiation and different signal transduction pathways can interact to govern the time to flower. One important regulator of floral initiation is the MADS-box transcription factor FLC, which acts as a negative regulator of flowering in response to both endogenous and environmental signals. In this report, we describe a study of the flowering-time gene, FLK [flowering locus K homology (KH) domain] that encodes a putative RNA-binding protein with three KH domains. The flk mutations cause delayed flowering without a significant effect on the photoperiodic or vernalization responses. FLK functions primarily as a repressor of FLC expression, although it also modestly affects expression of genes associated with the photoperiodic pathway. In addition to FLK, the expression of two other KH domain genes are modestly affected by the flk mutation, suggesting a possible involvement of more than one KH domain protein in the regulation of flowering time in Arabidopsis.

Arabidopsis↗

Cholecystokinin-immunoreactive innervation of the ventromedial hypothalamus in the rat: possible substrate for autonomic regulation of feeding.

Cholecystokinin octapeptide (CCK) injected into the medial hypothalamus of the rat has been reported to suppress feeding. In this species, the superior lateral parabrachial subnucleus, which predominantly innervates the ventromedial nucleus of the hypothalamus, is composed primarily of CCK-immunoreactive neurons. Combined retrograde tracing using fluorescent dyes and immunofluorescence for CCK confirms that 80-90% of the neurons in the superior lateral parabrachial nucleus which innervate the ventromedial nucleus of the hypothalamus are CCK-positive. This pathway may underlie autonomic regulation of feeding behavior.

Animals↗