Parasympathetic Origin Research Articles

Neuroanatomy of lymphoid organs: Lessons learned from whole-tissue imaging studies.

Decades of extensive research have documented the presence of neural innervations of sensory, sympathetic, or parasympathetic origin in primary and secondary lymphoid organs. Such neural inputs can release neurotransmitters and neuropeptides to directly modulate the functions of various immune cells, which represents one of the essential aspects of the body's neuroimmune network. Notably, recent studies empowered by state-of-the-art imaging techniques have comprehensively assessed neural distribution patterns in BM, thymus, spleen, and LNs of rodents and humans, helping clarify several controversies lingering in the field. In addition, it has become evident that neural innervations in lymphoid organs are not static but undergo alterations in pathophysiological contexts. This review aims to update the current information on the neuroanatomy of lymphoid organs obtained through whole-tissue 3D imaging and genetic approaches, focusing on anatomical features that may designate the functional modulation of immune responses. Moreover, we discuss several critical questions that call for future research, which will advance our in-depth understanding of the importance and complexity of neural control of lymphoid organs.

Head/neck paragangliomas: focus on tumor location, mutational status and plasma methoxytyramine.

Head and neck paragangliomas (HNPGLs) are tumors of parasympathetic origin that occur at variable locations and are often secondary to germline mutations in succinate dehydrogenase (SDH) subunit genes. Occasionally, these tumors produce catecholamines. Here, we assessed whether different locations of HNPGLs relate to the presence of SDHx mutations, catecholamine production and other presentations. In this multicenter study, we collected clinical and biochemical data from 244 patients with HNPGLs and 71 patients without HNPGLs. We clarified that jugulotympanic HNPGLs have distinct features. In particular, 88% of jugulotympanic HNPGLs arose in women, among whom only 24% occurred due to SDHx mutations compared to 55% in men. Jugulotympanic HNPGLs were also rarely bilateral, were of a smaller size and were less often metastatic compared to carotid body and vagal HNPGLs. Furthermore, we showed that plasma concentrations of methoxytyramine (MTY) were higher (P < 0.0001) in patients with HNPGL than without HNPGL, whereas plasma normetanephrine did not differ. Only 3.7% of patients showed strong increases in plasma normetanephrine. Plasma MTY was positively related to tumor size but did not relate to the presence of SDHx mutations or tumor location. Our findings confirm that increases in plasma MTY represent the main catecholamine-related biochemical feature of patients with HNPGLs. We expect that more sensitive analytical methods will make biochemical testing of HNPGLs more practical in the future and enable more than the current 30% of patients to be identified with dopamine-producing HNPGLs. The sex-dependent differences in the development of HNPGLs may have relevance to the diagnosis, management and outcomes of these tumors.

An origin of carotid vasodilation extends along the full extent of the parasympathetic parvicellular reticular region in the rat brainstem.

During grooming in rats, cranial parasympathetic activation leads to increased carotid artery blood flow, but the brainstem origin of this vasodilation signal is poorly understood. The aim of this study was to map brainstem sites wherein chemical stimulation with l-cysteine, an ionotropic excitatory amino acid receptor activator, can trigger carotid vasodilation in anesthetized intact and superior cervical sympathectomized (SCD) rats. The right side of the brainstem was accessed ventrally; arterial blood pressure and right carotid artery flow resistance were monitored. Employing microinjections of l-cysteine into the ipsilateral brainstem, vasodilation triggering sites were identified dorsal and rostral to the rostral ventrolateral medulla (RVLM) presympathetic pressor area, forming a parasagittal plate-like response zone that varied from rat to rat. In SCD rats (N=6), we observed a vasodilation zone in a region that included the RVLM pressor area, suggesting a parasympathetic origin. A similar zone was identified in intact rats (N=8), except that it did not include part of the RVLM pressor area. Dye injected into vasodilator sites labelled the rostral part of the parvicellular reticular formation (PcRt), consistent with a cranial parasympathetic origin. Employing mapping with L-cysteine, a putative neuromodulator, this study provides the first functional demonstration of a carotid vasodilation area that extends along the full extent of the parasympathetic rostral PcRt region in rats.

MON-380 Tinnitus with Unexpected Spanish Roots: Head and Neck Paragangliomas Caused by SDHAF2 Mutation

Introduction: Head and neck paragangliomas (HNPGL) are a subtype of pheochromocytoma/paraganglioma (Pheo/PGL) that originate from the autonomuos nervous system. In contrast to abdominal and thoracic Pheo/PGL, HNPGL are usually non-secretory, of parasympathetic origin and metastasize only rarely. Although HNPGL may occur as sporadic tumors, it is estimated that up to 40% of all cases may have a hereditary background that impacts therapeutic strategies, follow-up of affected patients and diagnostic approaches of family members. The most common mutations are found in the succinate dehydrogenase (SDH) genes with the highest prevalence of mutations in SDH-D, followed by SDH-B and SDH-C. Clinical case: A 15 year old male patient presented with tinnitus and hearing loss of the left ear. Imaging revealed a left sided jugulotympanic tumor (33x34mm) and a tumor of the right carotid body (12x15mm). The patient was normotensive, did not report on spells and plasma free metanephrine/catecholamine were not elevated. The morphological suspicion of a paraganglioma was confirmed histologically following resection of the jugulotympanic lesion. Immunohistochemistry showed a loss of SDHB-expression and genetic testing (somatic and germline) revealed a mutation in the SDH assembly factor 2 (SDHAF2) gene (c.232G>A). The patient's father is of Spanish descent. There was no family history for tumors. The hereditary paraglioma syndrome 2 (PGL2) has first been described in 1982 in a Dutch and later in a Spanish family and was found to be caused by a mutation in the SDHAF2 gene. SDHAF2 is a highly conserved co-factor involved in the flavination of the SDH-A subunit. The inheritence is autosomal dominant with maternal imprinting, leading to tumorigenesis only by paternal transmission. This may explain the seemingly negative family history. As in our case, patients with PGL2 usually present at young age with multiple, benign and non-secretory HNPGL. The penetrance reaches 88-100% by the age of 50 years. Conclusion: Our findings emphasize the relevance of genetic testing in patients with HNPGL, also with negative family history, especially when the patients present at young age and with multiple lesions.

SDHC Promoter Methylation, a Novel Pathogenic Mechanism in Parasympathetic Paragangliomas.

Germline mutations in the succinate dehydrogenase A, B, C, and D genes (collectively, SDHx) predispose to the development of paragangliomas (PGLs) arising at the parasympathetic or sympathetic neuroendocrine systems. SDHx mutations cause absence of tumoral immunostaining for SDHB. However, negative SDHB immunostaining has also been found in a subset of PGLs that lack SDHx mutations. Here, we report the comprehensive molecular characterization of one such a tumor of parasympathetic origin compared with healthy paraganglia and other PGLs with or without SDHx mutations. Integration of multiplatform data revealed somatic SDHC methylation and loss of the 1q23.3 region containing the SDHC gene. This correlated with decreased SDHC messenger RNA (mRNA) and protein levels. Furthermore, another genetic event found affected the VHL gene, which showed a decreased DNA copy number, associated with low VHL mRNA levels, and an absence of VHL protein detected by immunohistochemistry. In addition, the tumor displayed a pseudohypoxic phenotype consisting in overexpression of the hypoxia-inducible factor (HIF)-1α and miR-210, as well as downregulation of the iron-sulfur cluster assembly enzyme (ISCU) involved in SDHB maturation. This profile resembles that of SDHx- or VHL-mutated PGLs but not of PGLs with decreased VHL copy number, pointing to SDHC rather than VHL as the pathogenic driver. Collectively, these findings demonstrate the potential importance of both the SDHC epigenomic event and the activation of the HIF-1α/miR-210/ISCU axis in the pathogenesis of SDHx wild-type/SDHB-negative PGLs. To our knowledge, this is the first case of a sporadic parasympathetic PGL that carries silencing of SDHC, fulfilling the two-hit Knudson's model for tumorigenesis.

Parasympathetic vasoactive intestinal peptide (VIP): a likely contributor to clozapine‐induced sialorrhoea

The parasympathetic transmitter vasoactive intestinal peptide (VIP) increases salivary gland blood flow and evokes protein secretion and, in some species, such as rats, a small fluid secretion. It interacts synergistically with muscarinics for protein and fluid output. Human salivary acini are supplied with VIP-containing nerves. We hypothesise that VIP and clozapine, acting together, evoke a volume of saliva greater than the sum of those induced by each drug given separately. It was further considered whether, in the current test situation, circulatory events influenced the magnitude of the secretory response. Saliva from parotid glands deprived of their autonomic innervation, and saliva and blood from innervated submandibular glands were collected in adrenoceptor antagonist-pretreated pentobarbitone-anaesthetised rats. Initially, the individual and then the combined effects of intravenous doses of VIP and clozapine were established. The submandibular volume response to the combination was 2-3 times higher, while blood pressure and glandular blood flow did not differ from those to VIP alone. The synergism occurred independent of nerves as shown in denervated parotid glands. From the current preclinical data, we speculate that VIP of parasympathetic origin, by its synergistic interaction with clozapine, may contribute to the clozapine (muscarinic M1-receptor)-induced sialorrhoea in schizophrenics.

Autonomic Blockade During Sinusoidal Baroreflex Activation Proves Sympathetic Modulation of Cerebral Blood Flow Velocity

Pharmacological blockade showed sympathetic origin of 0.03 to 0.15 Hz blood pressure (BP) oscillations and parasympathetic origin of 0.15 to 0.5 Hz RR-interval (RRI) oscillations, but has not been used to determine origin of cerebral blood flow velocity (CBFV) oscillations at these frequencies. This study evaluated by pharmacological blockade whether 0.1 Hz CBFV oscillations are related to sympathetic and 0.2 Hz CBFV oscillations to parasympathetic modulation. In 11 volunteers (24.6 ± 2.3 years), we monitored RRIs, BP, and proximal middle cerebral artery CBFV, at rest, during 180 s sympathetic BP activation by 0.1 Hz sinusoidal neck suction (NS), and during 180 s parasympathetic RRI activation by 0.2 Hz NS. We repeated recordings after 25 mg carvedilol, and after 0.04 mg/kg atropine. Autoregressive analysis quantified RRI-, BP-, and CBFV-spectral powers at 0.1 Hz and 0.2 Hz. We compared parameters at rest, during 0.1 Hz, or 0.2 Hz NS, with and without carvedilol or atropine (analysis of variance, post hoc testing; significance, P<0.05). Carvedilol significantly increased RRIs and lowered BP, CBFV, and 0.1 Hz RRI-, BP-, and CBFV-powers at baseline (P=0.041 for CBFV-powers), and during 0.1 Hz NS-induced sympathetic activation (P<0.05). At baseline and during 0.2 Hz NS-induced parasympathetic activation, atropine lowered RRIs and 0.2 Hz RRI-powers, but did not change BP, CBFV, and 0.2 Hz BP- and CBFV-powers. Attenuation of both 0.1 Hz CBFV and BP oscillations after carvedilol indicates a direct relation between 0.1 Hz CBFV oscillations and sympathetic modulation. Absent effects of atropine on BP, CBFV, and 0.2 Hz BP and CBFV oscillations suggest that there is no direct parasympathetic influence on 0.2 Hz BP and CBFV modulation.

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Case Reports: Paragangliomas are rare neural crest tumors of sympathetic (generally catecholamine producing) or parasympathetic (rarely catecholamine producing) origin. The clinical picture is varied and diagnosis often difficult. Anaesthesia and surgery in unsuspected cases have high mortality. The clinical difficulties and challenges increase manifold in patients with undiagnosed or accidental diagnosis of pheochromocytoma who present to hospital for the treatment of some another disease. We report a similar case who presented with increased per vaginal bleeding. Case report A 49-year-old female, 55 kg, with presented to hospital with history of per vaginal bleeding since 15 days. She was non-hypertensive, non-diabetic & was not suffering from any other illness in the past. She had two living children with uneventful ante & postnatal course. Her menstrual history was normal. She was pale.Her blood pressure was 130/80 mmHg. Haemoglobin was 9.5 g/dl with normal coagulogram. Other routine blood and urine investigations, liver and thyroid function tests, electrocardiogram (ECG) and echocardiogram were normal. USG Abdomen showed about 57 mm × 34 mm × 38 mm diameter oval precaval solid echogenic mass with well-defined margins & smooth surface with 5 mm diameter tiny cystic spaces within, no calcification or sinus tracking. The mass did not show remarkable vascularity on Doppler located in duodenal “C” just caudal to the uncinate process of pancreas, compressing IVC away from aorta & right renal artery. There was no evidence of suprarenal mass. USG pelvis revealed large intramural fibroid. CT abdomen was done which showed enlarged heterogeneous necrotic mass mostly suggestive of precaval lymph node with compression of adjacent IVC. Multiple sub centimeter & centimeter sized necrotic lymph nodes in upper abdomen, gastro hepatic and celiac region. The possibility of lymphoma was strongly thought of. She was posted for excision of a suspected retroperitoneal mass after correction of anemia. GA was induced.Patient was haemodynamically stable during intubation and incision. The retroperitoneal mass 4cm × 4cm × 4cm was found over IVC below the renal vessel extending up to bifurcation of aorta free from duodenal or adrenal origin, suggestive of organ of zukerland. While dissecting the mass, there appeared sudden tachycardia, 150/ min and hypertension, 235/134 mmHg. This was followed by tachyarrhythmia initially and, later, idioventricular rhythms with varying, altered pulse beats. She developed cardiogenic pulmonary edema. These were managed effectively with diuretics & antihypertensive drugs. On excision of mass patient developed sudden hypotension which was managed with vasopressors. Development of severe arrhythmias, ST segment changes and hypertensive spikes during mass handling and dissection suggested the possibility of a catecholamine-secreting tumor. Subsequently, histopathology of the specimen revealed a paraganglioma.

Perioperative Management of Pheochromocytoma/Paraganglioma: Is There a State of the Art?

Pheochromocytoma and paraganglioma are rare tumors of sympathetic or parasympathetic origin, presenting with a highly variable clinical picture. Rarity, as well as biological, clinical, and genetic heterogeneity are barriers to initiate prospective studies that help to establish clinical guidelines. The best management of these patients relies on the experience of a multidisciplinary team. The ultimate outcome can benefit from adequate pre-surgical evaluation and treatment as well as an accurate post-surgical follow-up. Long-term follow-up is mandatory in all patients, but is particularly important in specific familial cases such as those with an SDHB mutation where the risks of recurrence are higher. The surgical approach varies depending on tumor size, location, and surgeon's personal attitude and experience. In this paper, we summarize recommendations, based mostly on authors' and other experts' personal experiences, for the best possible management of patients prior, during and after surgery, as well as when pheochromocytoma is diagnosed during pregnancy.

Anatomic identification of nerve-sparing radical hysterectomy: A step-by-step procedure

The radical hysterectomy is often associated with severe bladder dysfunction and colorectal motility disorders. These issues may arise as a result of damage incurred to the motor and sensory autonomic nerve supply, both of sympathetic and parasympathetic origin, that innervate the uterus, vagina, urinary bladder, and rectum. In this article, we demonstrate a nerve-sparing radical hysterectomy using illustrations and step-by-step instructions.

Mutations associated with succinate dehydrogenase d‐related malignant paragangliomas

Hereditary paraganglioma (PGL) syndromes result from germline mutations in genes encoding subunits B, C and D of the mitochondrial enzyme succinate dehydrogenase (SDHB, SDHC and SDHD). SDHB-related PGLs are known in particular for their high malignant potential. Recently, however, malignant PGLs were also reported among a small minority of Dutch carriers of the SDHD founder mutation D92Y. The aim of the study was to investigate which SDHD mutations are associated with malignant PGL. Case histories; collaborative study between referral centres in France, the USA, and the Netherlands. Six unrelated patients with metastatic PGLs of either sympathetic or parasympathetic origin. Assessment of SDHD mutations underlying malignant PGL. Germline SDHD mutations underlying metastatic PGL were G148D, Y114X, L85X, W43X, D92Y, and IVS2+5G-->A. Our findings indicate that malignant SDHD-related PGL is associated with several mutations besides D92Y.

Management and Treatment of Pheochromocytomas and Paragangliomas

Pheochromocytomas and paragangliomas are rare neural crest-derived tumors of sympathetic (generally catecholamine producing) or parasympathetic (rarely catecholamine producing) origin. Patients affected by these tumors present with a variable clinical picture, often making diagnosis troublesome. Surgery is the treatment of choice, but requires appropriate medical management before, during, and after tumor resection. Appropriate follow-up of patients is particularly important to identify recurrences, remaining disease, or developing malignancy. Currently, however, no firm guidelines exist about what form follow-up should take. There is also a general lack of prospective studies establishing the best approaches for management and treatment of the tumor. Choice of the many available different therapeutic options instead usually depends on institutional experience and clinical setting, which may vary for different groups of patients. At the First International Symposium on Pheochromocytoma (ISP2005), held in Bethesda in October 2005, a panel of experts addressed and discussed the many therapeutic options and problems associated with management and treatment of patients with pheochromocytoma, reporting their personal experience and sharing their opinions with those of patient representatives. The aim of this special Discussion Session was to reconcile differences of opinion and reach agreement about appropriate management and therapeutic options. This article summarizes the discussion and the recommendations derived from that session.

New Developments in the Detection of the Clinical Behavior of Pheochromocytomas and Paragangliomas

Pheochromocytomas (PCC) are catecholamine-producing tumors that are, by definition, located in the adrenal medulla. Extra-adrenal catecholamine-producing tumors are called paragangliomas (PGL), which should be distinguished from head and neck paragangliomas, which are of parasympathetic origin. As is true for many (neuro)endocrine tumors, but unlike most other epithelial tumors, histopathological analysis does not allow a distinction to be made between PCC and PGL that will follow a benign course and those that have metastasized or will do so, a condition associated with poor prognosis. Therefore, many studies have been undertaken in the past decade, with the aim of providing a marker or a set of markers that allows clinical behavior in PCC and PGL to be predicted. Despite promising results in some areas, such as histopathological scoring systems, the use of the MIB-1 labeling index, and the analysis of telomerase activity, no single test or combination of tests has thus far yielded sufficiently high sensitivity and specificity to result in widespread acceptance in every day clinical practice. The relative rarity of PCC and PGL combined with a frequency of malignancy from as low as 2% up to 25% has hampered the power of past research and can only be overcome by multicenter collaborative efforts. In this article, recent attempts at marker detection, such as those mentioned above, as well as emerging knowledge on the molecular abnormalities in benign and malignant PCC and PGL will be presented.

Pheochromocytoma and functional paraganglioma syndrome: No longer the 10% tumor

Pheochromocytomas and abdominal paragangliomas are catecholamine-producing tumors of the sympathetic nervous system, while head and neck paragangliomas are non-secreting tumors of parasympathetic origin. Recent developments in clinical and molecular research on these tumor forms have significantly clarified their genetic backgrounds and challenged the view of "pheochromocytoma as the 10% rule tumor." Firstly, a larger proportion of these tumors are today discovered in normotensive patients during imaging carried out for other reasons than suspicion of pheochromocytoma. Secondly, although the differential diagnosis between malignant and benign tumors remains a challenge, the risk of malignancy well exceeds the classical 10% in patients with extra-adrenal disease, and/or carriers of germ-line SDHB mutations. Finally, up to a third of patients carry a germ-line mutation in a gene predisposing to pheochromocytoma and/or paraganglioma. Identification of a constitutional mutation in RET, VHL, SDHD, or SDHB has implications for clinical screening and follow-up for both the patient and for relatives at risk who can be identified by screening for the same mutation. Genetic testing in apparently sporadic cases is therefore regarded as beneficial, especially in patients diagnosed before 50 years of age, and in patients with bilateral, multifocal, malignant and/or extra-adrenal disease.

The origin of catecholaminergic nerve fibers in the subdiaphragmatic vagus nerve of rat

It is known that the vagus nerve contains catecholaminergic fibers. However, the origin of these fibers has not been systematically examined. In this study, we addressed this issue using retrograde tracing from the subdiaphragmatic vagus nerve combined with immunocytochemistry. The cervical and thoracic sympathetic trunk ganglia, the nodose ganglia and the dorsal motor nucleus of the vagus nerve were examined following injection of Fluoro-Gold or cholera toxin horseradish peroxidase conjugate into the trunks of the subdiaphragmatic vagus nerve of rats. Numerous retrogradely labeled neurons were seen in the nodose ganglion and the dorsal motor nucleus of the vagus nerve. Very few labeled neurons were found in the sympathetic ganglia (less than 0.06% of the neurons in either superior cervical ganglion or cervicothoracic ganglion were retrogradely labeled). Double labeling with immunofluoresence for catecholamine synthesizing enzymes revealed that: (1) 92% of all Fluoro-Gold retrogradely labeled tyrosine hydroxylase immunoreactive neurons were found in parasympathetic sources (75% in the dorsal motor nucleus of the vagus nerve and 17% in the nodose ganglia), and only 8% in the cervicothoracic sympathetic ganglia; (2) 12% of the retrogradely labeled catecholaminergic neurons in the dorsal motor nucleus of the vagus nerve were also dopamine-β-hydroxylase immunopositive neurons; (3) 70% of the retrogradely labeled neurons in the sympathetic ganglia were tyrosine hydroxylase immunopositive and 54% of these catecholaminergic neurons contained dopamine-β-hydroxylase, while 30% of the retrogradely labeled neurons were non-catecholaminergic neurons. These results indicate that catecholaminergic fibers in the abdominal vagus nerve are primarily dopaminergic and of parasympathetic origin, and that only an extremely small number of these fibers, mostly noradrenergic in nature, arise from postganglionic sympathetic neurons.

Neuronal messengers and peptide receptors in the human sphenopalatine and otic ganglia

A majority of the parasympathetic nerve fibers to cranial structures derive from the sphenopalatine and otic ganglia. In particular, blood vessels are invested with a rich supply of dilator fibers of parasympathetic origin. In the present study, we have examined the occurrence of noncholinergic neuromessengers and neuropeptide receptors in the human sphenopalatine and otic ganglia. Vasoactive intestinal peptide (VIP)-immunoreactive (ir) nerve cell bodies occurred in high numbers in the sphenopalatine and otic ganglia. Likewise, high numbers of NOS- and PACAP-containing nerve cell bodies were seen in both ganglia. Autofluorescent lipofuscin, characteristic of adult human nervous tissue, was present within many nerve cell bodies in both ganglia. Receptor mRNA was studied with reverse transcriptase–polymerase chain reaction (RT-PCR). Total RNA from the sphenopalatine and otic ganglia was successfully extracted. By using appropriate sense and antisense primers, oligonucleotides were designed from the human sequences derived from GenBank, corresponding to human NPY Y 1, CGRP 1 and VIP 1 receptors. In the sphenopalatine ganglion, we revealed the presence of mRNA for the human NPY Y 1 and VIP 1 receptors but not the CGRP 1 receptor. The otic ganglion was found to react positively only for primers to mRNA for VIP 1 but not for CGRP 1 or NPY Y 1 receptors.

Development of P2X receptor clusters on smooth muscle cells in relation to nerve varicosities in the rat urinary bladder.

Postnatal development of the distribution of different isoforms of purinergic (P2X) receptors on smooth muscle cells in relation to the development of the innervation of the cells by nerve varicosities in the rat urinary bladder has been determined with immunofluorescence and confocal microscopy. Antibodies against the extracellular domains of the P2X(1) to P2X(6) receptors were used to detect the receptors in the bladder. Several other antibodies were used to identify sympathetic varicosities and Schwann cells. At one day postnatal (D1) there were few strings of varicosities denoting isolated axons, with most axons confined to large nerve trunks. Small size clusters of P2X(1) to P2X(6) receptor subtypes (about 0.4 microm diameter) were observed in the muscle which were independent of each other, and sometimes juxtaposed to the rare isolated varicosity strings. At D4 large numbers of strings of varicosities could be discerned throughout the detrusor. Most of these clouds of small P2X(1) to P2X(6) receptor clusters in their immediate vicinity. Some of these were colocalised with the varicosities, which were of parasympathetic origin as they failed to counter-stain with antibodies to tyrosine hydroxylase. Up to D14 there was a gradual coalescence of many of the isolated P2X(1-6) small receptor clusters so that they became colocalized, often at varicosities. Most of the varicosities in isolated strings possessed receptor clusters at this time. By D21 it was rare to find varicosity strings in the detrusor that were not either in close juxtaposition with P2X small receptor clusters or possessing such clusters in colocalization. However, large numbers of small P2X receptor clusters, many of which consisted of a mixture of isoforms, could be found spatially unrelated to nerve varicosities throughout the detrusor muscle. In the adult, single axons were either coextensive with one or more isoforms of P2X receptor clusters or these were immediately juxtaposed to the axons so that is was rare to find a varicosity that did not possess a receptor cluster. However, different combinations of colocalized P2X receptor isoforms could still be discerned in small clusters unrelated to varicosities. These observations are discussed in relation to the mechanism of formation of the receptor clusters and their migration beneath parasympathetic varicosities during development.

Clinical relevance of heart rate variability changes after heart transplantation.

Heart rate variability (HRV) of the healthy innervated heart is controlled and regulated by the autonomous nervous system and is influenced by respiratory frequency. Physiologically, there are slow and fast variations of heart rate which are of sympathetic or parasympathetic origin respectively. Spectral analysis of heart rate variability permits a selective quantification of these periodic influences of autonomous neural control. In the absence of neural influence on the pacemaker of the donor heart, we do not expect a high periodic heart rate variability (HRV). Due to the almost rigid heart rhythm we only anticipate a slight deviation of the R-R intervals from their mean value. Interventions such as valsalva maneuvers, controlled respiration and tilt table result in a very small but significant change of heart rate variability. These changes are most likely due to local influences at the donor sinus node. Neural influences from reinnervation may also play an important role in patients long after transplantation.

Fluctuations in autonomic nervous activity during sleep displayed by power spectrum analysis of heart rate variability

The use of an efficient noninvasive method to investigate the autonomic nervous system and cardiovascular control during sleep. Beat-to-beat heart rate variability displays two main components: a low-frequency (LF) one representing sympathetic and parasympathetic influence and a high-frequency (HF) component of parasympathetic origin. Sympathovagal balance can be defined as LF/HF ratio. We reviewed normal, standardly staged all-night polysomnograms from 10 healthy children aged 6 to 17 years. Recorded 256-second traces of heart rate and respiration were sampled. Power spectra of instantaneous heart rate and respiration were computed using a fast Fourier transform method. The study revealed a decrease in LF during sleep, with minimal values during non-REM slow-wave sleep and elevated levels similar to those of wakefulness during REM. HF increased with sleep onset, reaching maximal values during slow-wave sleep, and behaved as a mirror image of LF. LF/HF ratio displayed changes similar to those in LF. The sympathetic predominance that characterizes wakefulness decreases during non-REM sleep, is minimal in slow-wave sleep, and surges toward mean awake levels during REM sleep. The autonomic balance is shifted toward parasympathetic predominance during slow-wave sleep. This noninvasive method used to outline autonomic activity achieves results that are in complete agreement with those obtained with direct invasive tools.

The localization of basic fibroblast growth factor (FGF-2) in rat submandibular glands.

The immunohistochemical localization of basic fibroblast growth factor (FGF-2) in the submandibular glands of the rat was investigated by use of an antiserum to FGF-2. Nerve fiber bundles with FGF-2-immunoreactivity were found in association with interlobular ducts and blood vessels; they dissociated into single immunoreactive nerve fibers perhaps to terminate in proximity to acinar cells, or to form a reticular fiber network within the tunica adventitia of blood vessels. The FGF-2-immunoreactive neurons were located in the submandibular ganglia, but not in the superior cervical ganglia; hence, at least some of these immunoreactive nerve fibers probably come from the submandibular ganglia and are of parasympathetic origin. Most of the epithelial cells of the intercalated and collecting ducts showed notable FGF-2 immunoreactivity. The characteristic distribution of FGF-2 immunoreactivity in both the neuronal and epithelial tissues of the salivary glands suggests a role of this growth factor in complex physiological processes within the salivary glands.