Sympathetic arousal as a marker of chronicity in childhood stuttering.

PURPOSE: This study investigated whether sympathetic activity during a stressful speaking task was an early marker for stuttering chronicity. METHOD: Participants were 9 children with persisting stuttering, 23 children who recovered, and 17 children who do not stutter. Participants performed a stress-inducing picture-naming task and skin conductance was measured across three time points. RESULTS: Findings indicated that at the initial time point, children with persisting stuttering exhibited higher sympathetic arousal during the stressful speaking task than children whose stuttering recovered. CONCLUSIONS: Findings are taken to suggest that sympathetic activity may be an early marker of heightened risk for chronic stuttering.

Pimentas do gênero Capsicum: propriedades e ações terapéuticas / Pimientos del género Capsicum: propiedades y acciones terapéuticas / Capsicum peppers: properties and therapeutic actions

As especies do genero Capsicum L. vem sendo estudadas por pesquisadores do mundo inteiro. A pungencia e o atributo principal das pimentas e as substancias responséveis por esta ardencia sao denominadas de capsaicinoides. O mais estudado ea capsaicina, sua rota biossintetica e atraves da via dos fenilpropanoides e écidos graxos. A capsaicina e um agonista exogeno do receptor TRPV1(transient receptor potential vanilloid type-7). O TRPV1 contem uma subunidade sensivel ao calor responsével pela sensaçao de queimadura causada pela capsaicina. Quando aplicada na pele, promove uma resposta analgesica devido a dessensibilizaçao dos neuronios sensoriais causados pelo esgotamento da substancia P. A meia vida da capsaicina e vinte e quatro horas quando utilizada por via oral. Sua concentraçao maxima atinge o figado, rins e intestino ern uma hora apos administraçao oral. A capsaicina e principalmente eliminada pelos rins, com uma pequena proporçao nao transformada excretada nas fezes e na urina. Na aplicagao topica, a biotransformaçao da capsaicina foi considerada lenta e a maior parte da mesma permaneceu inalterada. A capsaicina e seus anélogos tem sido utilizados em cremes e patches para tratar sindromes de dor cronica como neuralgia pos-herpetica, dores musculoesqueleticas, neuropatia diabetica, osteoartrite e artrite reumatoide. A capsaicina tambem tem atividade antihiperlipidemica, propiedades anti-inflamatorias, antioxidantes e e efetiva no tratamento da dor associada com artrite e cistite. O capsiato, presente nas pimentas vermelhas nao pungentes tambem estimula o receptor TRPV1, sendo capaz de aumentar o metabolismo por estimulagao do sistema nervoso simpético, alem de ser provido de agao antiinflamatoria, porem por mecanismo ainda desconhecido (AU)

Las especies del género Capsicum, han sido estudiadas por los investigadores de todo el mundo. La pungencia es el principal atributo de los pimientos picantes y las sustancias responsables son los capsaicinoides. La capsaicina es la mas estudiada, su ruta biosintética es a través de la vía de fenilpropanoides y ácidos grasos. La capsaicina es un receptor TRPV1 agonista exógeno (receptor de potencial transitorio vaniloide tipo 1). El TRPV1 contiene una subunidad sensible al calor responsable de la sensación de ardor causada por la capsaicina. Cuando se aplica a la piel se promueve una respuesta analgésica debido a la desensibilización de las neuronas sensoriales causadas por el agotamiento de la sustancia P. La Vida media de la capsaicina es de 24 horas cuando se usa por via oral. Su distribución máxima alcanza el hígado, el riñón y el intestino en una hora después de la administración oral. La capsaicina se elimina principalmente por via renal, con una pequefia proporción no transformada excretada en las heces y en la orina. En la aplicación tópica de capsaicina la biotransformación se consideró lenta, y la mayor parte de la misma permaneció inalterada. La capsaicina y sus análogos han sido utilizados en cremas y apósitos para el tratamiento de síndromes de dolor crónico, tales como neuralgia postherpética, dolor musculo esquelético, neuropatía diabética, la osteoartritis y artritis reumatoide. La capsaicina también tiene actividad hipolipemiante, antiinflamatoria, antioxidante y es eficaz en el tratamiento del dolor asociado a artritis y cistitis. El capsiato, presente en pimientos rojos no picantes, también estimula el receptor TRPV1, siendo capaz de aumentar el metabolismo mediante la estimulación del sistema nervioso simpático, y presentando, además, acción antiinflamatoria, por un mecanismo aun desconocido (AU)

The species of the genus Capsicum have been studied by researchers worldwide. Pungency is the main attribute of peppers and it is due to the capsaicinoids. The most studied is capsaicin, biosynthetised through the phenylpropanoid and fatty acid pathway. Capsaicin is an exogenous agonist of TRPV1 receptor (transient receptor potential vanilloid type-1). The TRPV1 contains a subunit sensitive to heat, responsible for the burning sensation caused by capsaicin. When applied to the skin it promotes an analgesic response due to desensitization of sensory neurons caused by the depletion of substance P. The half-life of capsaicin is twenty-four hours when used orally. Its maximum concentration reaches the liver, kidney and intestine one hour after oral administration. Capsaicin is eliminated primarily by kidneys, with a small proportion of untransformed excreted in faeces and urine. After topical application, the biotransformation of capsaicin was considered slow, and it was mostly unchanged. Capsaicin and its analogues have been used in creams and patches to treat chronic pain syndromes, such as postherpetic neuralgia, musculoskeletal pain, diabetic neuropathy, osteoarthritis and rheumatoid arthritis. Capsaicin also has antihyperlipidemic, anti-inflammatory and antioxidant activities, being effective in the treatment of pain associated with arthritis and cystitis. The capsiate, present in non-pungent red peppers, also stimulates the TRPV1 receptor, being able to increase metabolism by stimulating the sympathetic nervous system, and showing, in addition, anti-inflammatory activity by a mechanism still unknown (AU)

Fibrilación auricular paroxística en el contexto de cefalea en racimos / Paroxysmal atrial fibrillation within the context of cluster headaches

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Horner syndrome associated with ipsilateral facial and extremity anhydrosis.

We report a patient with Horner syndrome together with anhidrosis affecting the ipsilateral face and extremities confirmed with starch-iodine and sympathetic skin response testing. No anatomic lesion was apparent. This is the first reported case in which Horner syndrome has been associated with such extensive hemibody sympathetic dysfunction in the absence of other neurologic findings. We propose a developmental disorder of neural crest migration as the cause.

Cardiac sympathetic nerve abnormality predicts ventricular tachyarrhythmic events in patients without conventional risk of sudden death.

PURPOSE: Patients with structural heart disease, severe left ventricular dysfunction, or history of cardiac arrest are at increased risk of sudden cardiac death. However, a useful marker for predicting sudden cardiac death is not clarified in low-risk patients without those conventional risks. We hypothesized that cardiac sympathetic nerve system (SNS) abnormality would be associated with ventricular tachyarrhythmic events in low-risk patients with ventricular tachycardia (VT). METHODS: Iodine-123 metaiodobenzylguanidine ((123)I-MIBG) scintigraphy was performed in 50 patients (mean+/-standard deviation, age 54 +/- 16 years, 52% males) with VT who did not have structural heart disease, severe left ventricular dysfunction, or history of cardiac arrest, and SNS activity was assessed from heart/mediastinal (H/M) ratio on delayed images. RESULTS: Over 11 years of follow-up, three patients had sudden deaths (6%) and nine patients had sustained ventricular tachyarrhythmic events (18%). SNS abnormality, defined as H/M ratio <2.8, was predictive of sudden death or ventricular tachyarrhythmic events (45% in nine of 20 patients with SNS abnormality vs 16.7% in three of 30 patients without SNS abnormality, p = 0.005). After adjustment for potential confounding variables including slight left ventricular dysfunction, SNS abnormality remained independently predictive of ventricular tachyarrhythmic events with a hazard ratio of 5.3 (95% confidence interval = 1.4 to 20.8, p = 0.016). CONCLUSION: SNS abnormality is a readily available and powerful predictor of recurrent ventricular tachyarrhythmic events in patients with VT who did not have conventional risk of sudden cardiac death. (123)I-MIBG scintigraphy can provide prognostic information of VT patients without conventional risk.

Abnormal sympathoadrenal development and systemic hypotension in PHD3-/- mice.

Cell culture studies have implicated the oxygen-sensitive hypoxia-inducible factor (HIF) prolyl hydroxylase PHD3 in the regulation of neuronal apoptosis. To better understand this function in vivo, we have created PHD3(-/-) mice and analyzed the neuronal phenotype. Reduced apoptosis in superior cervical ganglion (SCG) neurons cultured from PHD3(-/-) mice is associated with an increase in the number of cells in the SCG, as well as in the adrenal medulla and carotid body. Genetic analysis by intercrossing PHD3(-/-) mice with HIF-1a(+/-) and HIF-2a(+/-) mice demonstrated an interaction with HIF-2alpha but not HIF-1alpha, supporting the nonredundant involvement of a PHD3-HIF-2alpha pathway in the regulation of sympathoadrenal development. Despite the increased number of cells, the sympathoadrenal system appeared hypofunctional in PHD3(-/-) mice, with reduced target tissue innervation, adrenal medullary secretory capacity, sympathoadrenal responses, and systemic blood pressure. These observations suggest that the role of PHD3 in sympathoadrenal development extends beyond simple control of cell survival and organ mass, with functional PHD3 being required for proper anatomical and physiological integrity of the system. Perturbation of this interface between developmental and adaptive signaling by hypoxic, metabolic, or other stresses could have important effects on key sympathoadrenal functions, such as blood pressure regulation.

Differential expression of cardiac neurotrophic factors and sympathetic nerve ending abnormalities within the failing heart.

In congestive heart failure (CHF), cardiac sympathetic nerve endings transdifferentiate from a balanced norepinephrine (NE) storage/release/uptake apparatus to a nerve that predominantly releases NE. Little is known about the neurotrophic factors that may trigger this process. In the present study, we evaluated the cardiac expression pattern of nerve growth factor (NGF), neurotrophin-3 (NT-3), brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) in salt-sensitive Dahl rats (DS), which are characterized by profound alterations of the cardiac sympathetic nervous system. Experiments were performed in male DS and salt-resistant Dahl rats (DR) 30, 40 and 50 days after onset of high-salt intake. The sympathetic nerve density was measured by glyoxylic acid-induced histofluorescence. Cardiac NE re-uptake was assessed by isolated heart perfusion with [(3)H]-NE and norepinephrine transporter (NET) mRNA by real-time PCR. Cardiac expression of neurotrophic factors was determined by ribonuclease protection assay and Western blot analysis. DS rats displayed reduced left ventricular sympathetic nerve endings 40 days after onset of high-salt intake, which was preceded by an impaired cardiac [(3)H]-NE uptake. NGF, a positive regulator of NE re-uptake, and NT-3 were down-regulated already 30 days after onset of high-salt intake, whereas BDNF and CNTF protein expression were increased not before 40 days after onset of high-salt intake. In conclusion, during the development of CHF, a dysregulated NE storage/release/uptake apparatus within the sympathetic nerve endings might be triggered by differential expression of cardiac neurotrophic factors.

Topological changes of the human autonomic cardiac nervous system in individuals with a retroesophageal right subclavian artery: two case reports and a brief review.

The topological changes of the human autonomic cardiac nervous system in two cadavers with a retroesophageal right subclavian artery (Rersa) were compared with the normal autonomic cardiac nervous system. The following new results were obtained in addition to the conventional deficient finding of the right recurrent laryngeal nerve. (1) Right superior cardiac nerves arising from the superior cervical ganglion were consistently observed in both cadavers, in addition to the right thoracic cardiac nerves along the Rersa. (2) A segmental accompanying tendency of the right cardiac nerves was recognized: the cardiac nerves arising from the sympathetic trunk cranial to the middle cervical ganglia ran along with the right common carotid artery, whereas the cardiac nerves arising from the sympathetic trunk caudal to the vertebral ganglion ran along the Rersa. (3) The right thoracic cardiac nerves, which have never been observed to accompany the normal right subclavian artery, ran along the proximal part of the Rersa. According to previous reports of individuals with the Rersa, a thick right thoracic cardiac nerve is commonly observed instead of a right superior cardiac nerve. However, all the cardiac nerves were recognized in both the individuals described in the present report. Therefore, we strongly disagree with the previous idea that the origin of the right cardiac nerves from the sympathetic trunk and ganglia is shifted caudally in individuals with the Rersa. The topological changes of the autonomic cardiac nervous system in two cases of Rersa also reflected spatial changes of great arteries.

Abnormal sympathetic innervation of the heart in a patient with Emery-Dreifuss muscular dystrophy.

A 33-year-old man was admitted for general malaise and vomiting. An electrocardiogram showed a complete atrioventricular block and an echocardiogram showed right atrial dilatation and normal wall motion of left ventricle (LV). Gene analysis showed nonsense mutation in the STA gene, which codes for emerin, and Emery-Dreifuss muscular dystrophy was diagnosed. An endomyocardial biopsy of right ventricle showed mild hypertrophy of myocytes. Myocardial scintigraphic studies with Tc-99m methoxyisobutylisonitrile (MIBI) and I-123-betamethyl-p-iodophenylpentadecanoic acid (BMIPP) scintigrams showed no abnormalities. In contrast, I-123 metaiodobenzylguanidine (MIBG) scintigrams showed a diffuse and severe decrease in accumulation of MIBG in the heart. Six months later, his LV wall motion on echocardiograms developed diffuse hypokinesis. These results suggest that the abnormality on I-123 MIBG myocardial scintigrams may predict LV dysfunction in Emery-Dreifuss muscular dystrophy.

Cutaneous and sympathetic denervation in neonatal rats with a mutation in the delta subunit of the cytosolic chaperonin-containing t-complex peptide-1 gene.

The mutilated-foot rat (mf rat) is an autosomal recessive mutant with characteristic digit deformities in adult animals, and this phenotype mimics many aspects of human sensory neuropathy. The genetics of mf rats was recently elucidated. To understand whether the genotype is responsible for cutaneous denervation before clinically overt mutilation in adult mf rats, we investigated skin innervation in postnatal day 7 (P7) mf rats and compared the patterns with P7 wild-type rats. The mf rat carries a G-->A mutation in the gene encoding the delta subunit of the cytosolic chaperonin-containing t-complex peptide-1 (Cct4). In the footpad skin of P7 mf rats, there was a >90% loss of epidermal nerves (0.7-7.9% of P7 wild-type rats) as indicated by neuronal markers including protein gene product 9.5 (PGP 9.5), growth-associated protein 43 (GAP43), calcitonin gene-related peptide (CGRP), and substance P (SP). The epidermis of hairy skin in hind feet was completely denervated in mf rats as well. Compared with an approximately 80% reduction in the size of dermal nerve fascicles and a parallel loss of nerve fibers, the nearly complete absence of epidermal innervation suggests further sensory nerve degeneration at the level of nerve terminals in the epidermis. In contrast, the loss of epidermal nerves in the abdominal skin of mf rats was less extensive than that in the footpad skin of mf rats; CGRP (+) and SP (+) fibers were moderately reduced (28.3-56.4% of levels of wild-type rats) with normal amounts of PGP 9.5 (+) and GAP43 (+) nerves. Sympathetic innervation as assessed by tyrosine hydroxylase immunoreactivity was absent from the footpad and abdominal skin of mf rats. In conclusion, there is regional skin denervation with diffuse sympathetic denervation in P7 mf rats. These results suggest that the mutation in Cct4 underlies cutaneous nerve degeneration in mf rats.

Artemin is a vascular-derived neurotropic factor for developing sympathetic neurons.

Artemin (ARTN) is a member of the GDNF family of ligands and signals through the Ret/GFRalpha3 receptor complex. Characterization of ARTN- and GFRalpha3-deficient mice revealed similar abnormalities in the migration and axonal projection pattern of the entire sympathetic nervous system. This resulted in abnormal innervation of target tissues and consequent cell death due to deficiencies of target-derived neurotrophic support. ARTN is expressed along blood vessels and in cells nearby to sympathetic axonal projections. In the developing vasculature, ARTN is expressed in smooth muscle cells of the vessels, and it acts as a guidance factor that encourages sympathetic fibers to follow blood vessels as they project toward their final target tissues. The chemoattractive properties of ARTN were confirmed by the demonstration that sympathetic neuroblasts migrate and project axons toward ARTN-soaked beads implanted into mouse embryos.

Gata3 loss leads to embryonic lethality due to noradrenaline deficiency of the sympathetic nervous system.

Mouse embryos deficient in Gata3 die by 11 days post coitum (d.p.c.) from pathology of undetermined origin. We recently showed that Gata3-directed lacZ expression of a 625-kb Gata3 YAC transgene in mice mimics endogenous Gata3 expression, except in thymus and the sympathoadrenal system. As this transgene failed to overcome embryonic lethality (unpublished data and ref. 3) in Gata3-/- mice, we hypothesized that a neuroendocrine deficiency in the sympathetic nervous system (SNS) might cause embryonic lethality in these mutants. We find here that null mutation of Gata3 leads to reduced accumulation of Th (encoding tyrosine hydroxylase, Th) and Dbh (dopamine beta-hydroxylase, Dbh) mRNA, whereas several other SNS genes are unaffected. We show that Th and Dbh deficiencies lead to reduced noradrenaline in the SNS, and that noradrenaline deficiency is a proximal cause of death in mutants by feeding catechol intermediates to pregnant dams, thereby partially averting Gata3 mutation-induced lethality. These older, pharmacologically rescued mutants revealed abnormalities that previously could not be detected in untreated mutants. These late embryonic defects include renal hypoplasia and developmental defects in structures derived from cephalic neural crest cells. Thus we have shown that Gata3 has a role in the differentiation of multiple cell lineages during embryogenesis.

Fetal dexamethasone exposure interferes with establishment of cardiac noradrenergic innervation and sympathetic activity.

Endogenous glucocorticoids provide natural differentiation signals for adrenergic neurons, and exposure to high exogenous steroid levels thus disrupts the timing of neuronal maturation. In the current study, pregnant rats were given 0.05, 0.2, or 0.8 mg/kg dexamethasone on gestational days 17, 18, and 19, and the effects on development of cardiac sympathetic function were assessed postnatally in the offspring. Dexamethasone produced a dose-dependent retardation of body and heart weight gains; at the highest dose, heart weight deficits were smaller than those for body weight, producing a relative cardiomegaly. The weight effects were accompanied by abnormalities of noradrenergic innervation, as assessed with measurements of norepinephrine levels and turnover. Norepinephrine levels were significantly reduced at all doses of dexamethasone, with the magnitude of effect exceeding that on heart or body weights; thus the levels were reduced even when corrected for tissue weight (ng norepinephrine/g heart weight). Norepinephrine turnover, a measure of neuronal impulse activity, showed delayed development at the lowest dose of dexamethasone and displayed profound suppression throughout development at the higher doses. Adverse effects of dexamethasone on norepinephrine turnover were still apparent in young adulthood, despite the recovery of weight variables to within 15% of normal values. In light of the release of steroids during maternal stress and the use of steroids in the therapy of neonatal respiratory distress, developing adrenergic neurons are likely to be targeted for adverse effects even when standard growth indices have normalized.

Congenital Horner syndrome associated with non-cervical neuroblastoma.

Horner syndrome may be caused by a neuroblastoma involving the cervical sympathetic nervous system. A two-year-old girl presented with Horner syndrome and a discrete, distant neuroblastoma, suggesting that these two conditions represent a more widespread dysgenesis of the sympathetic nervous system.

[Classification of malformations of colorectal innervation]. / Zur Klassifikation der kolorektalen Innervationsstörungen.

Inborn errors of colorectal innervation can be classified in four different forms: 1. Aganglionosis (including total aganglionosis of the colon, Hirschsprung's disease, ultrashort Hirschsprung's segment and neurogenic sphincter achalasia) 2. Hypoganglionosis 3. Congenital malformation of sympathetic innervation of the colon (Neuronal Intestinal Dysplasia Typ A or NID A) 4. Congenital malformation of the submucous plexus (Neuronal Intestional Dysplasia Typ B or NID B). We find in 52.2% of our biopsies with a characteristic malformation of the colorectal innervation an aganglionosis. 40.6% are malformations of the submucous plexus (NID B). Half of the cases with Hirschsprung's disease are combined with NID B. 5.0% of the classified colorectal malformations of the innervation are a hypoganglionosis and 2.2% a NID A. An additional half of our biopsies cannot be introduced into the above given classification due to moderate malformations of the colorectal innervation (mild dysganglionosis, hypogenetic nerve cells of the submucous plexus, heterotopic nerve cells of the submucous and myenteric plexus).

[Intestinal ganglioneuromatosis: histochemical, histoenzymological and ultrastructural study of a case]. / La ganglioneuromatose intestinale: étude histochimique, histo-enzymologique et ultrastructurale d'une observation.

Report of a child with disseminated ganglioneuromatosis of the gut. The complexity of the intestinal nervous system malformation is proved by histochemical, histoenzymological and ultrastructural studies. The malformation is characterized by: hyperplasia and hypertrophy of enteric plexus and nerves bundles in the meso, high acetylcholinesterase activity, aplasia of the sympathetic innervation with the exception of perivascular plexus, qualitative and likely quantitative integrity of the endocrine digestive system. These data are compared with similar observations in the literature.