Immune-mediated denervation of the pineal gland underlies sleep disturbance in cardiac disease.

Disruption of the physiologic sleep-wake cycle and low melatonin levels frequently accompany cardiac disease, yet the underlying mechanism has remained enigmatic. Immunostaining of sympathetic axons in optically cleared pineal glands from humans and mice with cardiac disease revealed their substantial denervation compared with controls. Spatial, single-cell, nuclear, and bulk RNA sequencing traced this defect back to the superior cervical ganglia (SCG), which responded to cardiac disease with accumulation of inflammatory macrophages, fibrosis, and the selective loss of pineal gland-innervating neurons. Depletion of macrophages in the SCG prevented disease-associated denervation of the pineal gland and restored physiological melatonin secretion. Our data identify the mechanism by which diurnal rhythmicity in cardiac disease is disturbed and suggest a target for therapeutic intervention.

Implication of P2Y12 receptor in uc.48+-mediated abnormal sympathoexcitatory reflex via superior cervical ganglia in myocardial ischemic rats.

Purinergic 2Y12 (P2Y12) receptor antagonists are used as platelet aggregation inhibitors. Long non-coding RNAs (lncRNAs) play an important role in neuropathological events. Satellite glial cells (SGCs) in the superior cervical ganglia (SCGs) encircle the somata of neurons. This study explored if the upregulated P2Y12 receptor in SCGs was relevant to lncRNA uc.48+ during myocardial ischemia (MI). The results showed that upregulation of P2Y12 receptor was accompanied by increased expression of uc.48+ in the SCGs of MI rats which displayed abnormal changes in cervical sympathetic nerve activity, blood pressure, heart rate, electrocardiograms and cardiac tissue structure. The P2Y12 antagonist clopidogrel improved abnormal alterations in cardiac function and tissue structure in MI rats. Short hairpin RNA (shRNA) against uc.48+ significantly inhibited P2Y12 receptor upregulation and its co-expression with glial fibrillary acidic protein (GFAP) in SCGs, and ameliorated the cardiac dysfunction in MI rats. By contrast, overexpression of uc.48+ increased the expression of P2Y12 in SCGs and enhanced cervical sympathetic nerve activity in control rats. Direct interaction between uc.48+ and the P2Y12 receptor was predicted using the bioinformatic tool CatRAPID and confirmed by RNA immunoprecipitation. Moreover, overexpression of the P2Y12 receptor reversed the protective effect of uc.48+ shRNA on cardiac dysfunction in MI rats. Uc.48 shRNA treatment also inhibited the enhanced rise of intracellular free Ca2+ level ([Ca2+]i) evoked by the P2Y12 agonist 2-methylthio-adenosine-5'-diphosphate (2-MeSADP) in SGCs of SCGs after oxygen-glucose deprivation (OGD) treatment. These data demonstrated that uc.48+ shRNA could counteract the P2Y12 upregulation and improve P2Y12-implicated cardiac dysfunction due to MI.

The effects of sympathetic nerve damage on satellite glial cells in the mouse superior cervical ganglion.

Neurons in sensory, sympathetic, and parasympathetic ganglia are surrounded by satellite glial cell (SGCs). There is little information on the effects of nerve damage on SGCs in autonomic ganglia. We studied the consequences of damage to sympathetic nerve terminals by 6-hydroxydopamine (6-OHDA) on SGCs in the mouse superior cervical ganglia (Sup-CG). Immunostaining revealed that at 1-30 d post-6-OHDA injection, SGCs in Sup-CG were activated, as assayed by upregulation of glial fibrillary acidic protein. Intracellular labeling showed that dye coupling between SGCs around different neurons increased 4-6-fold 1-14 d after 6-OHDA injection. Behavioral testing 1-7 d post-6-OHDA showed that withdrawal threshold to tactile stimulation of the hind paws was reduced by 65-85%, consistent with hypersensitivity. A single intraperitoneal injection of the gap junction blocker carbenoxolone restored normal tactile thresholds in 6-OHDA-treated mice, suggesting a contribution of SGC gap junctions to pain. Using calcium imaging we found that after 6-OHDA treatment responses of SGCs to ATP were increased by about 30% compared with controls, but responses to ACh were reduced by 48%. The same experiments for SGCs in trigeminal ganglia from 6-OHDA injected mice showed no difference from controls, confirming that 6-OHDA acted selectively on sympathetic nerves. However, systemic inflammation induced by lipopolysaccharide did not affect SGCs of Sup-CG, but did influence SGCs in trigeminal ganglia in the same manner as 6-OHDA did on SGCs in Sup-CG. We conclude that even though SGCs in sympathetic and sensory ganglia are morphologically similar, they are quite different functionally, particularly after damage.

Paradoxic Relations between Basilar Artery Reconfiguration and Superior Cervical Ganglia Ischemia After Bilateral Common Carotid Artery Ligation.

BACKGROUND: The relationship between superior cervical ganglia (SCG) ischemia due to bilateral common carotid artery ligation (BCCAL) and basilar artery (BA) reconfiguration was investigated. METHODS: Twenty-three rabbits were randomly divided into 3 groups: group III rabbits underwent BCCAL (n = 13), group II rabbits were sham-operated controls (n = 5), and group I rabbits did not undergo surgery (n = 5). Degenerated neuron densities (DND) within the SCG were correlated with the BA vasodilatation index (VDI). RESULTS: Mean live and DND in SCG of group I rabbits were 11.235 ± 982/µm3 and 11 ± 3/µm3, respectively, with a mean heart rate of 294 ± 21 beats/min. Mean SCG DND and heart rates were 213 ± 42/µm3 and 242 ± 17 beats/min for the sham group (group II) rabbits and 1743 ± 285/µm3 and 199 ± 19 beats/min for the study group (group III) rabbits, respectively. The BA VDI values in the sham group (group II) (1.32 ± 0.10) and the study group (group III) (0.976 ± 0.112) significantly differed from those in the control group (group I) (1.65 ± 0.12; P < 0.005) versus the sham group (group II) (P < 0.0001) versus the BCCAL applied group (group III) and between group II and group III (P < 0.005). CONCLUSIONS: A meaningful and paradoxic correlation was detected between the BA VDI values and degenerated neuron density of SCG after BCCAL. Although a low degenerated neuron density within SCG may provoke excessive sympathetic activity and prevent excessive BA dilatation with steno-occlusive carotid artery diseases, a high degenerated neuron density may cause dangerous vasodilatation of BA.

Natural compounds acting at P2 receptors alleviate peripheral neuropathy.

Neuropathic pain is generally resistant to currently available treatments, and it is often a consequence of nerve injury due to surgery, diabetes or infection. Myocardial ischemic nociceptive signaling increases the sympathoexcitatory reflex to aggravate myocardial injury. Elucidation of the pathogenetic factors might provide a target for optimal treatment. Abundant evidence in the literature suggests that P2X and P2Y receptors play important roles in signal transmission. Traditional Chinese medicines, such as emodin, puerarin and resveratrol, antagonize nociceptive transmission mediated by purinergic 2 (P2) receptors in primary afferent neurons. This review summarizes recently published data on P2 receptor-mediated neuropathic pain and myocardial ischemia in dorsal root ganglia (DRG), superior cervical ganglia (SCG) and stellate ganglia (SG), with a special focus on the beneficial role of natural compounds.

Serial magnetic resonance imaging evaluations of irradiated superior cervical sympathetic ganglia: Not every retropharyngeal enlarging mass is a sign of malignancy.

INTRODUCTION: To describe serial changes in irradiated superior cervical sympathetic ganglia (SCSGs) on MRI (magnetic resonance imaging) evaluation in patients with head and neck squamous cell carcinoma (HNSCC) and to find the features differentiating them from the metastatic retropharyngeal lymph nodes. MATERIALS AND METHODS: This retrospective study evaluated 52 consecutive patients with definitive radiotherapy with/without chemotherapy for pathologically confirmed HNSCC and pre- and postradiation MRI follow-up evaluations. MR images of SCSGs were analyzed including enhancement pattern, margin, and the presence of intraganglionic hypointensity. RESULTS: MRI evaluations were performed in 36 men and 16 women with HNSCC with an average age of 58 years, range 23-80 years before irradiation (n=52), and at 6 (n=21) and 13-18 (n=52)months follow-up. Mean total radiation dose was 6351±483 cGy (range, 5640-7000 cGy). Intraganglionic hypointensity, homogeneous enhancement pattern, and well-defined margins were observed in 96%, 97%, and 97% of ganglia on the last follow-up, which showed no difference between pretreatment and 6-month follow-up (P>0.05). Mixed linear model analysis revealed significant increases in diameter and normalized T2SI of SCSGs after irradiation (P< 0.05). CONCLUSIONS: Despite of the increase in diameter and normalized T2SI of SCSGs, preservation of intraganglionic hypointensity, well-defined margins and homogeneous enhancement might be helpful for radiologists to identify SCSGs during the follow-up of HNSCC patients.

De la escrófula a la linfoadenitis micobacteriana / From scrophula to mycobacterial lymphadenitis

Resumen En el siglo XIX se pensaba que la tuberculosis y la tumefacción ganglionar cervical llamada escrófula afectaban a individuos predispuestos por una "constitución diatésica" heredada. En 1882 Robert Koch demostró que lesiones tuberculosas y escrofulosas humanas eran causadas por el bacilo Mycobacterium tuberculosis. A principios del siglo XX se estableció que Mycobacterium bovis, bacilo de la tuberculosis del ganado, podía también causar linfoadenitis cervical en humanos, especialmente en niños, por la ingestión de leche de vacas enfermas. La condición disminuyó después que se controló la infección en el ganado y se introdujo la pasteurización de la leche. En 1956 se describió la linfoadenitis cervicofacial granulomatosa necrosante y supurada causada por micobacterias no tuberculosas. Afecta principalmente a niños bajo los cinco años, especialmente en países sin endemia de tuberculosis. Las linfoadenitis cervicales tuberculosas predominan en adultos jóvenes en países con tuberculosis endémica y en individuos infectados por VIH.

In the 19th century it was widely believed that both tuberculosis and cervical lymph node swelling, known as scrophula, affected individuals predisposed to an inherited "diathetic constitution". In 1882 Robert Koch proved that human tuberculosis and scrophulous lesions were caused by the bacillus Mycobacterium tuberculosis. In the early twentieth century it was stated that Mycobacterium bovis, the bacillus of cattle tuberculosis, could also cause cervical lymphoadenitis in humans, especially in children, by the intake of milk from sick cows. The incidence of this condition decreased after the infection was controlled in cattle and pasteurization of the milk was introduced. A type of granulomatous necrotizing and suppurative cervico-facial lymphadenitis associated to non-tuberculous mycobacteria was described in 1956. It mainly affects children younger than 5 years old, particularly those born in countries with non-endemic tuberculosis. Tuberculous cervical lymphadenitis is prevalent in young adults from tuberculosis-endemic countries and in HIV-infected subjects. Infectious etiology displaced the importance of a personal disposition in the development of scrophula. Nevertheless, mutations that confer susceptibility to mycobacterial infection are currently investigated.

[From scrophula to mycobacterial lymphadenitis]. / De la escrófula a la linfoadenitis micobacteriana.

In the 19th century it was widely believed that both tuberculosis and cervical lymph node swelling, known as scrophula, affected individuals predisposed to an inherited "diathetic constitution". In 1882 Robert Koch proved that human tuberculosis and scrophulous lesions were caused by the bacillus Mycobacterium tuberculosis. In the early twentieth century it was stated that Mycobacterium bovis, the bacillus of cattle tuberculosis, could also cause cervical lymphoadenitis in humans, especially in children, by the intake of milk from sick cows. The incidence of this condition decreased after the infection was controlled in cattle and pasteurization of the milk was introduced. A type of granulomatous necrotizing and suppurative cervico-facial lymphadenitis associated to non-tuberculous mycobacteria was described in 1956. It mainly affects children younger than 5 years old, particularly those born in countries with non-endemic tuberculosis. Tuberculous cervical lymphadenitis is prevalent in young adults from tuberculosis-endemic countries and in HIV-infected subjects. Infectious etiology displaced the importance of a personal disposition in the development of scrophula. Nevertheless, mutations that confer susceptibility to mycobacterial infection are currently investigated.

Forskolin suppresses delayed-rectifier K+ currents and enhances spike frequency-dependent adaptation of sympathetic neurons.

In signal transduction research natural or synthetic molecules are commonly used to target a great variety of signaling proteins. For instance, forskolin, a diterpene activator of adenylate cyclase, has been widely used in cellular preparations to increase the intracellular cAMP level. However, it has been shown that forskolin directly inhibits some cloned K+ channels, which in excitable cells set up the resting membrane potential, the shape of action potential and regulate repetitive firing. Despite the growing evidence indicating that K+ channels are blocked by forskolin, there are no studies yet assessing the impact of this mechanism of action on neuron excitability and firing patterns. In sympathetic neurons, we find that forskolin and its derivative 1,9-Dideoxyforskolin, reversibly suppress the delayed rectifier K+ current (IKV). Besides, forskolin reduced the spike afterhyperpolarization and enhanced the spike frequency-dependent adaptation. Given that IKV is mostly generated by Kv2.1 channels, HEK-293 cells were transfected with cDNA encoding for the Kv2.1 α subunit, to characterize the mechanism of forskolin action. Both drugs reversible suppressed the Kv2.1-mediated K+ currents. Forskolin inhibited Kv2.1 currents and IKV with an IC50 of ~32 µM and ~24 µM, respectively. Besides, the drug induced an apparent current inactivation and slowed-down current deactivation. We suggest that forskolin reduces the excitability of sympathetic neurons by enhancing the spike frequency-dependent adaptation, partially through a direct block of their native Kv2.1 channels.

Effects of equine grass sickness on sympathetic neurons in prevertebral and paravertebral ganglia.

Acute equine grass sickness (EGS) is a fatal disease of horses that is thought to be due to ingestion of a neurotoxic agent causing extensive damage to autonomic neurons. The aim of this study was to compare the effects of EGS on neurons in two sympathetic ganglia, the paravertebral cranial cervical ganglion (CCG) and the prevertebral coeliac/cranial mesenteric ganglion (CG/CMG). Specimens from horses with EGS and controls were obtained post mortem and processed using single and double immunofluorescence labelling for PGP 9.5 and HuC/HuD (pan-neuronal markers), TUNEL and caspase 3 (markers for apoptosis), vasoactive intestinal polypeptide (VIP) and galanin (markers of the cell body response to injury following axotomy or exposure to sympathetic neurotoxins) and tyrosine hydroxylase (TH, marker for noradrenaline synthesis). In control horses, all neurons contained PGP 9.5 and HuC/HuD. There was a significant loss of PGP 9.5 and HuC/HuD expression in samples from horses with EGS that occurred to a greater extent in the CG/CMG than the CCG. The number of caspase 3-positive neurons increased significantly in both ganglia, but TUNEL staining of sympathetic neurons was only significantly increased in the CG/CMG in EGS. No VIP was observed in any ganglia; however, there was a significant increase in galanin-positive neurons in both ganglia in EGS. In the CCG, there was a significant shift towards increased fluorescence intensity for TH, possibly indicating an initial accumulation of TH within the cell body. In contrast, TH fluorescence intensity was significantly reduced in the CG/CMG in EGS correlating with the greater loss of neurons. These results demonstrate that EGS can induce a cell body response that is similar to the response of sympathetic neurons to a chemical neurotoxin. EGS also causes loss of sympathetic neurons, some of which occurs via apoptosis. Changes were more marked in the CG/CMG than the CCG indicating that the prevertebral ganglia were affected earlier than the paravertebral ganglia in the pathological process and had undergone greater neurodegeneration.

Hypertrophy and neuron loss: structural changes in sheep SCG induced by unilateral sympathectomy.

Recently, superior cervical ganglionectomy has been performed to investigate a variety of scientific topics from regulation of intraocular pressure to suppression of lingual tumour growth. Despite these recent advances in our understanding of the functional mechanisms underlying superior cervical ganglion (SCG) growth and development after surgical ablation, there still exists a need for information concerning the quantitative nature of the relationships between the removed SCG and its remaining contralateral ganglion and between the remaining SCG and its modified innervation territory. To this end, using design-based stereological methods, we have investigated the structural changes induced by unilateral ganglionectomy in sheep at three distinct timepoints (2, 7 and 12 weeks) after surgery. The effects of time, and lateral (left-right) differences, were examined by two-way analyses of variance and paired t-tests. Following removal of the left SCG, the main findings were: (i) the remaining right SCG was bigger at shorter survival times, i.e. 74% at 2 weeks, 55% at 7 weeks and no increase by 12 weeks, (ii) by 7 weeks after surgery, the right SCG contained fewer neurons (no decrease at 2 weeks, 6% fewer by 7 weeks and 17% fewer by 12 weeks) and (iii) by 7 weeks, right SCG neurons were also larger and the magnitude of this increase grew substantially with time (no rise at 2 weeks, 77% by 7 weeks and 215% by 12 weeks). Interaction effects between time and ganglionectomy-induced changes were significant for SCG volume and mean perikaryal volume. These findings show that unilateral superior cervical ganglionectomy has profound effects on the contralateral ganglion. For future investigations, it would be interesting to examine the interaction between SCGs and their innervation targets after ganglionectomy. Is the ganglionectomy-induced imbalance between the sizes of innervation territories the milieu in which morphoquantitative changes, particularly changes in perikaryal volume and neuron number, occur? Mechanistically, how would those changes arise? Are there any grounds for believing in a ganglionectomy-triggered SCG cross-innervation and neuroplasticity?

Diabetes depresses synaptic transmission in sympathetic ganglia by inactivating nAChRs through a conserved intracellular cysteine residue.

Most people with diabetes develop severe complications of the autonomic nervous system; yet, the underlying causes of many diabetic-induced dysautonomias are poorly understood. Here we explore the idea that these dysautonomias results, in part, from a defect in synaptic transmission. To test this idea, we investigated cultured sympathetic neurons and show that hyperglycemia inactivates nAChRs through a mechanism involving an elevation in reactive oxygen species and an interaction with highly conserved cysteine residues located near the intracellular mouth of the nAChR channel. Consistent with this, we show that diabetic mice have depressed ganglionic transmission and reduced sympathetic reflexes, whereas diabetic mice expressing mutant postsynaptic nAChRs that lack the conserved cysteine residues on the alpha3 subunit have normal synaptic transmission in sympathetic ganglia and normal sympathetic reflexes. Our work suggests a new model for diabetic-induced dysautonomias and identifies ganglionic nAChRs as targets of hyperglycemia-induced downstream signals.

Imaging characteristics of schwannoma of the cervical sympathetic chain: a review of 12 cases.

BACKGROUND AND PURPOSE: SCSCs are rare. This study reviews our experience with CT and MR imaging of SCSCs. MATERIALS AND METHODS: We retrospectively reviewed the CT and MR imaging studies as well as clinical data of 12 patients (6 men, 6 women; mean age, 41 years; range, 27-55 years) with surgicopathologic evidence of SCSC, referred to our institution between January 1999 to October 2008. Images were evaluated with respect to the location, number, morphology, attenuation/signal intensity, enhancement characteristics, and patterns of mass effect of the schwannomas. RESULTS: The schwannomas were solitary, well-circumscribed, and medial to the carotid sheath. Seven were hypoattenuated to skeletal muscle on CT with poor postcontrast enhancement, 4 were isoattenuated, and a single lesion showed intense heterogeneous enhancement. At MR imaging, they were heterogeneously bright on T2WI with intense inhomogeneous postgadolinium enhancement. The ICA was displaced anteriorly in 9 patients with a component of lateral displacement in 8 of these patients. The ICA was in a neutral position in 2 patients and posterolaterally displaced in 1 patient. A single patient demonstrated separation of the ICA and IJV. There was splaying of the carotid bifurcation in 4 patients. CONCLUSIONS: We present the patterns of mass effect and the spectrum of CT and MR imaging characteristics of SCSC, including certain observations that are infrequently described in the published literature.

Cervical sympathectomy causes alveolar bone loss in an experimental rat model.

BACKGROUND AND OBJECTIVE: Periodontal disease, a pathological destructive inflammatory condition, is characterized by alveolar bone loss. Recent studies have suggested a correlation between the sympathetic nervous system and bone remodeling. To confirm the importance of the sympathetic nervous system in bone resorption, we investigated the effects of superior cervical ganglionectomy and oral challenge with Porphyromonas gingivalis on alveolar bone loss in rats. MATERIAL AND METHODS: Rats were divided into three groups: group A underwent a sham operation as the control group; group B underwent superior cervical ganglionectomy; and group C underwent a sham operation and oral challenge with P. gingivalis. Horizontal alveolar bone loss was evaluated by measuring the distance between the cemento-enamel junction and the alveolar bone crest. Cytokine gene expression in the gingival tissues was assessed using reverse transcription-polymerase chain reaction analyses. The furcation areas of the mandibular molars were examined histologically. RESULTS: Both superior cervical ganglionectomy and oral challenge with P. gingivalis resulted in accelerated alveolar bone loss. Gingival tissues in the superior cervical ganglionectomy group showed increased expression of the cytokines interleukin-1 alpha, tumor necrosis factor-alpha and interleukin-6. The density of neuropeptide Y-immunoreactive fibers was decreased following superior cervical ganglionectomy. Osteoclasts were observed in the superior cervical ganglionectomy and P. gingivalis-challenged groups. CONCLUSION: Both superior cervical ganglionectomy and oral challenge with P. gingivalis induced alveolar bone loss. These results provide new information on the occurrence of alveolar bone loss, in that both oral challenge with P. gingivalis and superior cervical ganglionectomy are important accelerating factors for alveolar bone loss. Thus, we suggest that the sympathetic nervous system is linked with the prevention of alveolar bone loss.

First-bite syndrome after parapharyngeal surgery for cervical schwannoma.

BACKGROUND: First-bite syndrome (FBS) is a rare complication that occurs after patients undergo parapharyngeal space surgery. Characteristically, inadvertent ablation of the parotid gland's sympathetic innervation results in the development of severe parotid gland-area pain at the first bite of food. CASE DESCRIPTION: The authors evaluated a patient who underwent parapharyngeal surgery for cervical schwannoma. This surgery involved the sympathetic chain's superior cervical ganglion (SCG). With destruction of the SCG, the patient developed FBS and Horner syndrome. CONCLUSION AND CLINICAL IMPLICATIONS: Destruction of the SCG or the sympathetic postganglionic supply to the parotid gland causes severe parotid pain when food is first introduced into the mouth. The absence of discomfort during mechanical joint movements helps dentists differentiate this pain from myofascial pain or pain caused by temporomandibular dysfunction. The frequent presence of Horner syndrome also facilitates diagnosis.

Neuromuscular specializations within human pharyngeal constrictor muscles.

OBJECTIVES: At present it is believed that the pharyngeal constrictor (PC) muscles are innervated by the vagus (X) nerve and are homogeneous in muscle fiber content. This study tested the hypothesis that adult human PCs are divided into 2 distinct and specialized layers: a slow inner layer (SIL), innervated by the glossopharyngeal (IX) nerve, and a fast outer layer (FOL), innervated by nerve X. METHODS: Eight normal adult human pharynges (16 sides) obtained from autopsies were studied to determine 1) their gross motor innervation by use of Sihler's stain; 2) their terminal axonal branching by use of acetylcholinesterase (AChE) and silver stain; and 3) their myosin heavy chain (MHC) expression in PC muscle fibers by use of immunocytochemical and immunoblotting techniques. In addition, the specialized nature of the 2 PC layers was also studied in developmental (newborn, neonate, and senescent humans), pathological (adult humans with idiopathic Parkinson's disease [IPD]), and comparative (nonhuman primate [adult macaque monkey]) specimens. RESULTS: When nerves IX and X were traced from their cranial roots to their intramuscular termination in Sihler's-stained specimens, it was seen that nerve IX supplied the SIL, whereas branches of nerve X innervated the FOL in the adult human PCs. Use of AChE and silver stain confirmed that nerve IX branches supplying the SIL contained motor axons and innervated motor end plates. In addition to distinct motor innervation, the SIL contained muscle fibers expressing slow-tonic and alpha-cardiac MHC isoforms, whereas the FOL contained muscle fibers expressing developmental MHC isoforms. In contrast, the FOL became obscured in the elderly and in the adult humans with IPD because of an increased proportion of slow muscle fibers. Notably, distinct muscle fiber layers were not found in the human newborn and nonhuman primate (monkey), but were identified in the 2-year-old human. CONCLUSIONS: Human PCs appear to be organized into functional fiber layers, as indicated by distinct motor innervation and specialized muscle fibers. The SIL appears to be a specialized layer unique to normal humans. The presence of the highly specialized slow-tonic and alpha-cardiac MHC isoforms, together with their absence in human newborns and nonhuman primates, suggests that the specialization of the SIL maybe related to speech and respiration. This specialization may reflect the sustained contraction needed in humans to maintain stiffness of the pharyngeal walls during respiration and to shape the walls for speech articulation. In contrast, the FOL is adapted for rapid movement as seen during swallowing. Senescent humans and patients with IPD are known to be susceptible to dysphagia; and this susceptibility may be related to the observed shift in muscle fiber content.

Vaciamiento ganglionar en carcinoma escamoso transglótico / Ganglionic drainage in scaly transglotic carcinoma

Introducción: El manejo de los ganglios cervicales es fundamental en el tratamiento y pronóstico de los pacientes con carcinoma escamoso de laringe. Existe consenso en realizar vaciamiento ganglionar cervical en ausencia de adenopatías clínicas (N0) cuando el riesgo de adenopatías metastásicas ocultas supera el 20 por ciento. El carcinoma laríngeo transglótico (CTG) se caracteriza por presentar una incidencia de metástasis cervicales ocultas de 30 por ciento a 40 por ciento. Objetivo: Evaluar los hallazgos histopatológicos en los ganglios cervicales de los pacientes portadores de CTG, analizando la incidencia de metástasis ocultas y su asociación con factores de riesgo. Material y métodos: Estudio retrospectivo mediante la revisión de las fichas clínicas de pacientes portadores de CTG, sin tratamiento previo, manejados quirúrgicamente en el Hospital San Juan de Dios entre los años 1994 y 2002. Resultados: Se evaluaron 20 pacientes, 4 (20 por ciento) se presentaron con adenopatías clínicas, realizándose en 2 casos vaciamiento radical y en los 2 restantes disección funcional. Los pacientes N0 fueron 16 y se les efectuó un vaciamiento funcional bilateral. Se detectaron metástasis ocultas en 12,5 por ciento de los pacientes N0. Conclusión: Los carcinomas de ubicación transglótica N0 no se beneficiarían de un vaciamiento ganglionar cervical.

Identification of novel human neuronal leucine-rich repeat (hNLRR) family genes and inverse association of expression of Nbla10449/hNLRR-1 and Nbla10677/hNLRR-3 with the prognosis of primary neuroblastomas.

To search for novel prognostic indicators, we previously cloned >2,000 novel genes from primary neuroblastoma (NBL) cDNA libraries and screened for differential expression between the subsets with favorable (stage 1 or 2 with a single copy of MYCN) and unfavorable (stage 3 or 4 with amplification of MYCN) prognosis. From them, we have identified 3 genes of human neuronal leucine-rich repeat protein (NLRR) family: Nbla10449/hNLRR-1, Nbla00061/hNLRR-2/GAC1 and Nbla10677/hNLRR-3. An additional family member, hNLRR-5, was also found by homology search against public database. NLRR family proteins have been proposed to function as a neuronal adhesion molecule or soluble ligand binding receptor like Drosophila toll and slit with multiple domains including 11 sets of extracellular leucine-rich repeat (LRR)-motifs. However, the functional role of the NLRR protein family has been elusive. Our present study shows that hNLRR mRNAs are preferentially expressed in nervous system and/or adrenal gland. In cancer cell lines, hNLRR-1, hNLRR-3 and hNLRR-5 are expressed at high levels in the neural crest-derived cells. Most remarkably, in primary NBLs, hNLRR-1 is significantly expressed at high levels in unfavorable subsets as compared to favorable ones, whereas the expression pattern of hNLRR-3 and hNLRR-5 is the opposite. In order to understand the function of these receptors, we have used newborn mouse superior cervical ganglion (SCG) cells which are dependent on nerve growth factor (NGF) for their survival. Expression of the mouse counterparts of hNLRR-2 and hNLRR-3 is up-regulated after NGF-induced differentiation and down-regulated after NGF depletion-induced apoptosis. On the other hand, expression of hNLRR-1 and hNLRR-5 is inversely regulated in the same system. These results have suggested that the regulation of the hNLRR family genes may be associated with NGF signaling pathway in both SCG cells and neuroblastoma. Our quantitative real-time RT-PCR analysis using 99 primary NBLs has revealed that high levels of hNLRR-1 expression are significantly associated with older age (>1 year, p=0.0001), advanced stages (p=0.0007), low expression of TrkA (p=0.011), and MYCN amplification (p=0.0001), while those of hNLRR-3 expression are significantly correlated with the favorable prognostic indicators. Furthermore, multivariate analysis reveals that expression of hNLRR-1 is an independent prognostic indicator in human neuroblastoma. Thus, our results demonstrate that, despite being members of the same family, hNLRR-1 and hNLRR-3 may share different biological function among the NBL subsets, and that their expression level becomes novel prognostic indicators of NBL.

Effects of sympathectomy on experimentally induced pulpal inflammation and periapical lesions in rats.

The role of sympathetic nerves in bone physiology is largely unknown. Recent studies have shown a correlation between sympathectomy and bone remodeling. The present experiments were aimed to study the effects of unilateral sympathectomy on bilateral experimentally induced pulpitis and periapical lesions in the rat maxilla and mandible. Adult male Sprague-Dawley rats were used. Experimental rats (n=11) had the right superior cervical ganglion surgically removed (SCGx) and control rats (n=5) had sham surgery. Pulpal inflammation and periapical bone lesions in the maxilla and mandible were created 14 days later in both experimental and control rats by exposing the dental pulp in the first and second molars and leaving them open to the oral microflora. The rats were perfused 20 days thereafter and the jaws processed for immunohistochemistry with neuropeptide Y (NPY) and ED1 as primary antibodies. Sympathectomy resulted in an almost complete loss of NPY-immunoreactive (IR) fibers in the right SCGx jaws. In the non-sympathectomized (non-SCGx) left side and in the control rats, sprouting of NPY-IR fiber was observed in the inflamed pulp tissue adjacent to reparative dentin formation and in the apical periodontal ligament of the partially necrotic first molars. Significantly more ED1-IR osteoclasts were found in the resorptive lacunae lining the periphery of the periapical lesions on the SCGx side compared with the non-SCGx side (P<0.04) and the controls (P<0.03). The size of the periapical lesions were larger on the SCGx side compared with the non-SCGx side (P<0.03) in the mandible, but not in the maxilla. We conclude that inflammation causes sprouting of NPY-IR nerve fibers and that unilateral removal of the SCG increases both the area of the periapical lesions and the number of osteoclasts in the inflamed region.

Internal carotid plexus schwannoma of the cavernous sinus: case report.

OBJECTIVE AND IMPORTANCE: Schwannomas of the central nervous system usually originate from the vestibular nerve and occasionally originate from the trigeminal nerve. Sympathetic plexus schwannomas are extremely rare and have never been noted within the cavernous sinus. CLINICAL PRESENTATION: A 23-year-old man experienced occasional double vision for a period of 6 months. Magnetic resonance imaging studies revealed an isointense lesion, with enhancement after gadolinium administration, located inferomedial to the internal carotid artery within the left cavernous sinus. INTERVENTION: We explored the cavernous sinus via a left-sided extradural-pterional approach and found the tumor inferomedial to the cavernous segment of the internal carotid artery. Microsurgical gross total resection of the tumor was performed. The IIIrd (oculomotor) to VIth (abducens) cranial nerves within the cavernous sinus were not related to the tumor and were preserved. The operative findings and the anatomic location of the tumor demonstrated that it originated from the internal carotid plexus within the cavernous sinus. The patient's postoperative course was uneventful, and he exhibited no cranial nerve deficits. However, incomplete Horner's syndrome was present on the treated side. CONCLUSION: We present the first reported case of an internal carotid plexus schwannoma, and we describe in detail its anatomic and neuroradiological characteristics. The microneurosurgical resection of this unusual tumor within the cavernous sinus was successful and without morbidity.