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PubMed1997

The heart as a self-regulating system: integration of homeodynamic mechanisms.

In the past the study of mechanical and electrical properties of the heart has been disjointed with minimal overlap and unification. The fact remains that these features are tightly coupled and central to the functioning heart. The maintenance of adequate cardiac output relies upon the highly integrated autoregulatory mechanisms and modulation of cardiac myocyte function. Regional ventricular mechanics and energetics are dependent upon muscle fiber stress-strain rate, the passive properties of myocardial collagen matrix, adequate vascular perfusion, transcapillary transport and electrical activation pattern. Intramural hydraulic "loading" is regulated by coronary arterial and venous dynamics. All of these components are under the constant influence of intrinsic cardiac and extracardiac autonomic neurons, as well as circulating hormones. A brief overview of the putative regulation of these various components is presented in this paper.

Autonomic Pathways↗
PubMed1996

Neural structures within the sheep temporomandibular joint.

To better understand pathologic processes associated with arthritis of the temporomandibular joint (TMJ), detailed information on the innervation of TMJ tissues in normal as well as arthritic joints is needed. The aim of this study was to describe the normal innervation of the sheep TMJ in preparation for using this animal as a model for the study of the effects of arthritis on joint innervation. The macroscopic and microscopic appearance plus the distribution of neural structures within the TMJ were examined using fluorescence histochemistry (glyoxylic acid), immunohistochemistry (calcitonin gene-related peptide), silver, and gold chloride techniques. Joints from 10 mature merino sheep were studied. Calcitonin gene-related peptide-immunoreactive nerve fibers were found in the capsule and the synovial membrane, but not in the disc. Nerve bundles and single nerve fibers in the capsule, synovial membrane, and the peripheral 2 to 3 mm of the disc were stained by glyoxylic acid. Ruffini, paciniform-type, and Golgi organ nerve endings plus free nerve endings were located in the capsule, with the highest density of nerve endings occurring at the site of attachment of the disc to the capsule. The highest density of neural structures (using gold chloride) was in the posterior part of the joint. The highest density of autonomic fibers (using glyoxylic acid) was in the anterior capsule. The highest density of sensory fibers (using calcitonin gene-related peptide) was in the synovial and subsynovial tissues of the anterior capsule. These results confirm the existence of autonomic and sensory nerves in the capsule, synovial membrane, and peripheral disc in healthy adult sheep.

Animals↗
PubMed1997

Effect of steroid therapy on parameters of peripheral autonomic dysfunction in leprosy patients with acute neuritis.

Recent electrophysiological studies on peripheral autonomic dysfunction in leprosy patients show a high prevalence of autonomic dysfunction as measured by abnormal vasomotor reflexes (VMR) and absent sympathetic skin response (SSR). Nothing is known about the reversibility of these autonomic parameters with treatment. Since there is evidence that small fiber function may be the most reversible component in neuropathies, we measured the effect of steroid treatment on autonomic parameters together with motor and sensory functions in leprosy patients with acute neuritis. Control subjects were investigated for repeatability testing of autonomic function. Due to a relatively high variability on repeat VMR testing in the controls, we defined a change in VMR testing as a change of > 30%. With this definition, the VMR of 14.8% of the patients improved, 75% remained unchanged, and 10.2% worsened. Absent SSR became positive in 16.6% and remained unchanged in 83.4%. Improvement in sensory motor functions was seen in 21.2% and 1.3% of the patients, respectively.

Acute Disease↗
PubMed1997

[Chemoradiation for rectal cancer].

Based on the results of the Study Group for Surgical Adjuvant Radiochemotherapy for Rectal Cancer and the Study Group for Surgical Therapy and Combined Irradiation in Rectal Cancer, we examined the clinical aspects of the relatively new field of chemoradiation for rectal cancer and examined improvements in the therapeutic results. Furthermore, we examined the future outlook with particular regard to selection of therapeutic drugs and autonomic nerve preserving operation.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Genetic abnormalities in parathyroid nodules of uremic patients.

The molecular pathway of autonomous growth of the parathyroid glands in uremic patients is poorly understood. We have analyzed 71 parathyroid lesions from 24 patients with refractory hyperparathyroidism for allelic loss at chromosomes 1, 3, 6, 9, 11, 12, 13, 15, and 17 and at the X chromosome. Microsatellite analysis was performed using 24 highly polymorphic markers. Deletions at chromosomes 1, 3, 6, 11, 12, and 13 and at the X chromosome were detected in only 10 of 67 nodules (15%). No allelic loss of the p16 and p53 tumor suppressor genes or the extracellular calcium receptor gene was found. The X-chromosome inactivation assay revealed a monoclonal pattern in 58% of hyperplastic nodules in females. Our results indicate monoclonal growth in the majority of hyperplastic nodules and suggest that some of these lesions might be considered precursors for adenoma development.

Female↗
PubMed1997

[Gastrointestinal autonomic tumor associated with von Recklinghausen's disease].

Gastrointestinal autonomic nerve (GAN) tumor is a rare type of gastrointestinal stromal tumor that is presumed to arise from the enteric autonomic plexus. Occasionally it develops associated with von Recklinghausen's disease (VRD). A 63-year-old-woman with VRD and two GANs in the ileum is reported, and the literature of this combined findings reviewed.

Autonomic Pathways↗
PubMed1997

c-fos expression in the rat hypothalamic paraventricular nucleus induced by LiCl: descending projections to the dorsal vagal motor nucleus.

Anorexia inducing lithium chloride is believed to involve descending projections from hypothalamus to preganglionic autonomic output neurons. A multiple-labelling technique has presently been used to analyze the anatomical projections of lithium chloride sensitive neurons in the hypothalamus. Immunolabelling of c-fos was performed to stain neurons activated after LiCl administration, while neurons projecting toward vagal parasympathetic preganglionic levels were identified by injection of diamidino yellow in the dorsal motor nucleus of the vagus. Perikarya of descending neurons were mainly observed in the ventral and lateral areas of the paraventricular hypothalamic nucleus. In contrast, lithium chloride activated neurons were observed mainly in the magnocellular division of the paraventricular nucleus and supraoptic nucleus. Double-labelled neurons were not observed. These data provide evidence that lithium chloride sensitive neurons in the paraventricular nucleus are clearly different from those descending toward preganglionic vagal outflow neurons.

Animals↗
PubMed1998

Specific targeting of ganglion cell sprouts provides an additional mechanism for restoring peripheral motor circuits in pelvic ganglia after spinal nerve damage.

The pelvic ganglia contain both sympathetic and parasympathetic neurons and provide an interesting model in which to study the effects of a distributed spinal nerve lesion. Previous animal studies have suggested that after either lumbar or sacral nerve injury, some functional connections are restored between preganglionic and postganglionic neurons. It has been proposed that this is because of intact preganglionic axons sprouting collaterals to supply denervated ganglion cells. However, this has never been demonstrated, and our study has investigated whether the ganglion cells themselves contribute to axogenesis and restoration of peripheral circuitry. We have monitored the growth of axons from pelvic ganglion cells after lumbar or sacral nerve injury (partial decentralization), or a combination of the two (total decentralization). These new processes were distinguished from intact preganglionic terminals by their immunoreactivity for substances present only in pelvic ganglion neurons (vasoactive intestinal peptide, neuropeptide Y, and tyrosine hydroxylase). The proportion of pelvic neurons surrounded by these immunostained fibers was then assessed. Complete removal of preganglionic terminals provides the biggest stimulus for growth of new axon processes (sprouts), which grow profusely within just a few days. These arise from each of the main chemical classes of pelvic neurons but grow at different rates and have different distributions. Importantly, some chemical classes of sprouts preferentially supply neurons of dissimilar histochemistry, suggesting the presence of very specific targeting mechanisms rather than random growth. These sprouts are transient, however, those formed after partial decentralization appear to be maintained. Moreover, after lesion of either lumbar or sacral spinal nerves, many sprouts arise from neurons with intact spinal connections and innervate neurons that have lost their preganglionic inputs. This provides a very different alternative mechanism to reestablish communication between preganglionic and postganglionic neurons. In conclusion, we have demonstrated a rapid and selective axogenesis within the pelvic ganglion after spinal nerve injury. This may allow the development of novel strategies by which autonomic nerve pathways can be experimentally manipulated, to facilitate more rapid return of appropriate peripheral reflex control.

Animals↗
PubMed1987

[Role of the autonomic nervous system in the genesis of the electrophysiologic pattern of the double nodal pathway].

Thirty-five patients (age: 53 +/- 13 years) with dual A-V nodal pathways pattern were studied following autonomic blockade (propranolol 0.2 mg/kg and atropine 0.04 mg/kg). Six of them had "idionodal" paroxysmal reentrant supraventricular tachycardia. After autonomic blockade the dual A-V nodal pathways pattern remained in 20 patients (57%) and disappeared in 15; however, in the latter, the effective refractory period of the fast pathway decreased significantly and the disappearance of the slow pathway conduction may not have been real since the marked shortening of the fast pathway refractory period may have masked the slow pathway conduction. The longest A2-H2 interval, the effective and functional refractory periods of the fast pathway did not change significantly after autonomic blockade. Even the electrophysiological measures of the slow pathway in the 20 patients in whom they were comparable did not change significantly. The behaviour of the fast and slow pathways measures varied from patient to patient after autonomic blockade. In the 6 patients with idionodal reentrant tachycardia a discrepancy between jump persistence after autonomic blockade and tachycardia induction was observed. These data suggest that: 1) the dual A-V nodal pathways pattern is mainly related to the anatomic structure of the A-V node; 2) the autonomic system affects in a variable way the conduction velocity and the refractoriness of the fast and slow pathways; 3) the dual A-V nodal pathways pattern and the reentry circuit of idional tachycardia imply two different electrophysiological substrata.

Atrioventricular Node↗
PubMed2001

Cell autonomous regulation of multiple Dishevelled-dependent pathways by mammalian Nkd.

Genetic studies have identified Drosophila Naked Cuticle (Nkd) as an antagonist of the canonical Wnt/beta-catenin signaling pathway, but its mechanism of action remains obscure [Zeng, W., Wharton, K. A., Jr., Mack, J. A., Wang, K., Gadbaw, M., et al. (2000) Nature (London) 403, 789--795]. Here we have cloned a cDNA encoding a mammalian homolog of Drosophila Nkd, mNkd, and demonstrated that mNkd interacts directly with Dishevelled. Dishevelled is an intracellular mediator of both the canonical Wnt pathway and planar cell polarity (PCP) pathway. Activation of the c-Jun-N-terminal kinase has been implicated in the PCP pathway. We showed that mNkd acts in a cell-autonomous manner not only to inhibit the canonical Wnt pathway but also to stimulate c-Jun-N-terminal kinase activity. Expression of mNkd disrupted convergent extension in Xenopus, consistent with a role for mNkd in the PCP pathway. These data suggest that mNkd may act as a switch to direct Dishevelled activity toward the PCP pathway, and away from the canonical Wnt pathway.

Adaptor Proteins, Signal Transducing↗
PubMed1981

Neural pathways involved in the hypothalamic integration of autonomic responses.

Recent mapping studies of hypothalamic and autonomic mechanisms have considerably extended our understanding of the anatomy of this system. The pattern of connections emerging from physiological, anatomical, and histochemical experiments suggests several conclusions about the functional organization of the system as well. Recent evidence supports the idea that the hypothalamic (and other limbic) areas involved in the control of ingestion and metabolism form the rostral pole of a longitudinally and hierarchically organized system that elaborates autonomic responses that influence the energy economy of the animal. Substantially the same pathways are apparently responsible for the modulation of ingestive behavior as well. This circuitry, the "visceromotor system" in Nauta's terminology, seems to weld afferent inputs, particularly those of the gustatory and visceral receptors, into a coordinated integrative control strategy influencing autonomic responses. In addition, the system seems to have unique tissue properties, at least at its two periventricularly located sites of integration with special access to both humorally and ventricularly circulated substrates. These nodes, the basomedial hypothalamus and the vagal complex of the medulla, seem to share similar biochemical specializations reflected in susceptibility to goldthioglucose toxicity, specific insulin binding, and susceptibility to alloxan diabetes.

Afferent Pathways↗
PubMed1998

Effects of pharmacological autonomic blockade on dual atrioventricular nodal pathways physiology in patients with slow-fast atrioventricular nodal reentrant tachycardia.

The purpose of this study was to investigate the atrioventricular AV nodal physiology and the inducibility of AV nodal reentrant tachycardia (AVNRT) under pharmacological autonomic blockade (AB). Seventeen consecutive patients (6 men and 11 women, mean age 39 +/- 17 years) with clinical recurrent slow-fast AVNRT received electrophysiological study before and after pharmacological AB with atropine (0.04 mg/kg) and propranolol (0.2 mg/kg). In baseline, all 17 patients could be induced with AVNRT, 5 were isoproterenol-dependent. After pharmacological AB, 12 (71%) of 17 patients still demonstrated AV nodal duality. AVNRT became noninducible in 7 of 12 nonisoproterenol dependent patients and remained noninducible in all 5 isoproterenol dependent patients. The sinus cycle length (801 +/- 105 ms vs 630 +/- 80 ms, P < 0.005) and AV blocking cycle length (365 +/- 64 ms vs 338 +/- 61 ms, P < 0.005) became shorter after AB. The antegrade effective refractory period and functional refractory period of the fast pathway (369 +/- 67 ms vs 305 +/- 73 ms, P < 0.005; 408 +/- 56 ms vs 350 +/- 62 ms, P < 0.005) and the slow pathway (271 +/- 30 ms vs 258 +/- 27 ms, P < 0.01; 344 +/- 60 ms vs 295 +/- 50 ms, P < 0.005) likewise became significantly shortened. However, the ventriculoatrial blocking cycle length (349 +/- 94 ms vs 326 +/- 89 ms, NS) and effective refractory period of retrograde fast pathway (228 +/- 38 ms vs 240 +/- 80 ms, NS) remained unchanged after autonomic blockade. Pharmacological AB unveiling the intrinsic AV nodal physiology could result in the masking of AV nodal duality and the decreased inducibility of clinical AVNRT.

Adrenergic beta-Agonists↗
PubMed1994

Peripheral neural circuits regulating IOP? A review of its anatomical backbone.

The peripheral nervous system is classically separated into a somatic division containing both afferent and efferent pathways and an autonomic division composed of efferents only. The somatic afferent division is divided in A- and B-neurons. The B-neurons are supposed to be autonomic afferents as part of a reflex system involved in homeostasis. Recent data obtained by neuronal tracing and immunohistochemical experiments concerning the eye related peripheral nervous system endorse the existence of these peripheral reflex systems. Somatic afferents of trigeminal origin synaptically innervate parasympathetic neurons in the pterygopalatine ganglion. This probably represents a pathway mediating autonomically regulated ocular activity in response to sensory stimulation. In addition, it has been hypothesized that trigeminal sensory nerve fibres have an efferent function in response to noxious stimuli e.g. the ocular injury response. Sympathetic nerve fibres originating in the superior cervical ganglion course through the trigeminal and pterygopalatine ganglion without forming direct synaptic contacts. These fibres, however, contain clusters of vesicles suggesting some kind of interneural communication. Parasympathetic nerve fibres of pterygopalatine origin course through the ciliary ganglion. These nerve fibre terminals also contain clusters of vesicles without direct synaptic contacts. Experimental data concerning the distribution of neuropeptides revealed a more detailed knowledge of the anterior eye segment innervation. These experimental data are subject to some debate. The pros and cons of different techniques are discussed. Neural circuits regulating IOP have long been postulated. The possible role of peripheral reflex systems in the regulation of IOP is discussed.

Anterior Eye Segment↗
PubMed2005

Neurophysiology of Rett syndrome.

Rett syndrome is a neurodevelopmental disorder that in most cases is consequent to a mutation in the MECP2 gene. The central nervous system is the primary organ system involved in Rett syndrome. Neurophysiologic evaluations provide information concerning the developmental aspects of Rett syndrome and the character and extent of involvement of the central, peripheral, and autonomic nervous system pathways. Evoked potentials typically demonstrate intactness of peripheral auditory and visual pathways and suggest dysfunction of central or "higher" cortical pathways. Somatosensory evoked potentials can be characterized by "giant" responses, suggesting cortical hyperexcitability. Cortical hyperexcitability is further suggested by the findings of the electroencephalogram (EEG), which are primarily characterized by a loss of expected developmental features; the appearance of focal, multifocal, and generalized epileptiform abnormalities; and the occurrence of rhythmic slow (theta) activity, primarily in the frontal-central regions. Epileptic seizures are reported to occur frequently in Rett syndrome. However, many events presumed to be seizures have no EEG correlate during video-EEG monitoring. Impairment of the autonomic nervous system in Rett syndrome is suggested by an increased incidence of long Q-T intervals during electrocardiographic recordings and diminished heart rate variability. Autonomic nervous system dysfunction can contribute to the increased incidence of sudden unexpected death in Rett syndrome.

Afferent Pathways↗
PubMed1992

Specialized functional pathways are the building blocks of the autonomic nervous system.

The autonomic nervous system supplies each type of target organ via separate pathways which consist of sets of pre- and postganglionic neurones with distinct patterns of reflex activity. This has been firmly established for the lumbar sympathetic nervous system to skin, skeletal muscle and viscera, for the thoracic sympathetic outflow to the head and for several parasympathetic systems. In principle, that was already known by Langley. The specificity of the messages that these pathways transmit from the central nervous system arises from integration within precisely organized pathways in the neuraxis. The messages travel along discrete functional pathways and are transmitted to the target tissues via close neuroeffector junctions. Integration in the periphery occurs within each pathway, both in ganglia and at the level of the effector organs. We still need to understand how the central messages get through without distortion and how they control the diverse functions of the vasculature and viscera.

Animals↗
PubMed2005

Analysis of flowering pathway integrators in Arabidopsis.

Flowering is regulated by an integrated network of several genetic pathways in Arabidopsis. The key genes integrating multiple flowering pathways are FT, SOC1 and LFY. To elucidate the interactions among these integrators, genetic analyses were performed. FT and SOC1 share the common upstream regulators CO, a key component in the long day pathway, and FLC, a flowering repressor integrating autonomous and vernalization pathways. However, the soc1 mutation further delayed the flowering time of long day pathway mutants including ft, demonstrating that SOC1 acts partially independently of FT. Although soc1 did not show an obvious defect in flower meristem determination on its own, it dramatically increased the number of coflorescences in a lfy mutant, which is indicative of a defect in floral initiation. Therefore, double mutant analysis shows that the three integrators have both overlapping and independent functions in the determination of flowering time and floral initiation. The expression analysis showed that FT regulates SOC1 expression, and SOC1 regulates LFY expression, but not vice versa, which is consistent with the fact that FT and LFY have the least overlapping functions among the three integrators. The triple mutation ft soc1 lfy did not block flowering completely under long days, indicating the presence of other integrators. Finally, vernalization accelerated flowering of flc ft soc1 and ft soc1 lfy triple mutants, which shows that the vernalization pathway also has targets other than FLC, FT, SOC1 and LFY. Our genetic analysis reveals the intricate nature of genetic networks for flowering.

Arabidopsis↗