Analysis of enteric nervous system and intestinal epithelial barrier to predict complications in Hirschsprung's disease.

In Hirschsprung's disease (HSCR), postoperative course remains unpredictable. Our aim was to define predictive factors of the main postoperative complications: obstructive symptoms (OS) and Hirschsprung-associated enterocolitis (HAEC). In this prospective multicentre cohort study, samples of resected bowel were collected at time of surgery in 18 neonates with short-segment HSCR in tertiary care hospitals. OS and HAEC were noted during postoperative follow-up. We assessed the enteric nervous system and the intestinal epithelial barrier (IEB) in ganglionic segments by combining immunohistochemical, proteomic and transcriptomic approaches, with functional ex vivo analysis of motility and para/transcellular permeability. Ten HSCR patients presented postoperative complications (median follow-up 23.5 months): 6 OS, 4 HAEC (2 with OS), 2 diarrhoea (without OS/HAEC). Immunohistochemical analysis showed a significant 41% and 60% decrease in median number of nNOS-IR myenteric neurons per ganglion in HSCR with OS as compared to HSCR with HAEC/diarrhoea (without OS) and HSCR without complications (p = 0.0095; p = 0.002, respectively). Paracellular and transcellular permeability was significantly increased in HSCR with HAEC as compared to HSCR with OS/diarrhoea without HAEC (p = 0.016; p = 0.009) and HSCR without complications (p = 0.029; p = 0.017). This pilot study supports the hypothesis that modulating neuronal phenotype and enhancing IEB permeability may treat or prevent postoperative complications in HSCR.

The Extent of the Transition Zone in Hirschsprung Disease.

BACKGROUND: Retained transition zone is a leading cause of obstructive symptoms after pull-through operation in Hirschsprung's disease. OBJECTIVE: We aimed to evaluate the extent of the histological transition zone in patients with Hirschsprung's disease. DESIGN: We performed an observational study. DAB+ immunohistochemistry for Protein Gene Product 9.5 was used to evaluate the neuronal networks in serial sections of pull-through specimens obtained from children with Hirschsprung's disease (n = 12). Reference ranges for ganglion size/density and nerve trunk diameter were statistically determined using healthy controls obtained from colostomy specimens from children with anorectal malformations (n = 8). The transition zone was defined as ganglionic bowel exhibiting ganglion hypoplasia, hypertrophic nerve trunks, or partial circumference aganglionosis. RESULTS: The mean submucosal nerve trunk diameter in controls was 19.56 µm +/- 3.87 µm. The median age at pull-through for Hirschsprung's disease was 5 months (3-14 months). The median length of the transition zone across the population was 8 cm (4-22 cm). Median transition zone extent was significantly longer in patients with long-segment aganglionosis (n = 6) compared to rectosigmoid aganglionosis (n = 6, 13 cm vs 6 cm, p = 0.041). Due to the age of the patients enrolled, long-term follow-up of bowel function is not yet available. CONCLUSION: Our data suggest that, in children with rectosigmoid Hirschsprung's disease, the transition zone can extend for up to 13 cm. In children with long-segment disease, a longer transition zone is possible. Extended resection at a minimum 5 cm beyond the most distal ganglionic intra-operative biopsy and intra-operative histological examination of the proximal resection margin are required to minimize transition zone pull-through. LEVEL OF EVIDENCE: 2.

Impacto del compromiso ganglionar en el pronóstico y la evolución del carcinoma papilar de tiroides / Impact of lymph node involvement on prognosis and outcome of paillary thyroid carcinoma

Las metástasis ganglionares regionales del cuello están presentes en un gran porcentaje de los casos con CPT. Sin embargo, en varios trabajos se pudo observar como no todo compromiso ganglionar tiene igual impacto en la evolución de dicha patología. Recientemente en Argentina, Chile y Brasil se modificaron las guías del manejo del CDT y estas recomiendan una estratificación de riesgo y abordaje terapéutico diferente según el número, el tamaño y la extensión del compromiso ganglionar. En esta monografía se analizaron las características de las metástasis ganglionares y su impacto en la evolución del CDT y esto fue realizado previamente a la reciente publicación de las nuevas guías de la ATA. Dada esta situación, se incorporaron a la monografía original algunos aspectos de las guías de ATA

Cervical lymph node metastases are usually present in a high number of cases with papillary thyroid carcinoma. However, many studies have shown that not all lymph node metastases have the same impact on the outcome of this disease. Argentina, Chile, and Brazil have recently changed their differentiated thyroid carcinoma (DTC) guidelines and recommend a different ranking of risk and therapeutic approach according to the number, size, and extension of lymph node metastasis. An analysis of lymph node metastases is presented in this article, which includes their characteristics and impact on DTC. As this analysis was made before the latest publication of the new American Thyroid Association guidelines, some aspects of these guidelines have also been included

Reduced expression of voltage-gated Kv11.1 (hERG) K(+) channels in aganglionic colon in Hirschsprung's disease.

PURPOSE: The pathophysiology of Hirschsprung's disease (HSCR) is not entirely understood. There is no clear explanation for the occurrence of the spastic or tonically contracted aganglionic segment of bowel. Kv11.1 (hERG) channels play a critical role in the regulation of the resting membrane potential as well as affecting either the force or frequency of contraction of smooth muscles. We designed this study to investigate the expression and distribution of hERG channels in the normal colon and the colon of patients with HSCR. METHODS: We investigated hERG protein expression in both the ganglionic and aganglionic regions of HSCR patients (n = 10) versus normal control colon (n = 10). Protein distribution was assessed using immunofluorescence and confocal microscopy. Gene and protein expressions were quantified using real-time polymerase chain reaction, western blot analysis and densitometry. RESULTS: Confocal microscopy of the normal colon revealed strong hERG channel expression in interstitial cells of Cajal, platelet-derived growth factor-alpha receptor- (PDGFRα(+)) positive cells and enteric neurons. hERG expression was markedly decreased in aganglionic bowel, whereas colonic hERG gene expression levels were significantly decreased in aganglionic compared to ganglionic bowel and controls (p < 0.05). Western blotting revealed decreased colonic hERG protein expression in aganglionic HSCR specimens compared to controls. CONCLUSIONS: We demonstrate, for the first time, the expression and distribution of hERG channels in the human colon. The decreased expression of hERG in the aganglionic colon may be responsible for the increased tone in the aganglionic narrow spastic segment of bowel.

Key-Gaskell syndrome in Brazil: first case report / Síndrome de Key-Gaskell: primeiro relato de caso no Brasil

Feline dysautonomia is a devastating disease characterized by neuronal degeneration in autonomic ganglia that results in clinical signs related to dysfunction of the sympathetic and parasympathetic nervous systems. The cause is unknown and this disease has a poor prognosis and no definitive treatment. Most reports have been described in few countries around the world, but the prevalence may be underestimated in countries like Brazil. This study describes the progression and clinicopathological changes of dysautonomia in a 17-month-old female Brazilian shorthair cat...

Disautonomia felina é uma doença devastadora, caracterizada por degeneração neuronal em gânglios autonômicos, a qual resulta em sinais clínicos relacionados à disfunção dos sistemas simpático e parassimpático. Sua causa é desconhecida, o prognóstico desfavorável e não há tratamento definitivo disponível. A maioria dos relatos foi descrita em países ao redor do mundo, mas sua prevalência pode estar subestimada em países como o Brasil. Este estudo descreve a progressão e as alterações clínico-patológicas da disautonomia em um gato de pelo curto brasileiro, do sexo feminino, de 17 meses de idade...

Ulnar sensory-motor amplitude ratio: a new tool to differentiate ganglionopathy from polyneuropathy / Razao de amplitude sensitivo-motora ulnar: novo parametro para diferenciar ganglionopatia de polineuropatia

The objective of this study was to evaluate if the ratio of ulnar sensory nerve action potential (SNAP) over compound muscle action potential (CMAP) amplitudes (USMAR) would help in the distinction between ganglionopathy (GNP) and polyneuropathy (PNP). Methods We reviewed the nerve conductions studies and electromyography (EMG) of 18 GNP patients, 33 diabetic PNP patients and 56 controls. GNP was defined by simultaneous nerve conduction studies (NCS) and magnetic resonance imaging (MRI) abnormalities. PNP was defined by usual clinical and NCS criteria. We used ANOVA with post-hoc Tukey test and ROC curve analysis to compare ulnar SNAP and CMAP, as well as USMAR in the groups. Results Ulnar CMAP amplitudes were similar between GNP x PNP x Controls (p=0.253), but ulnar SNAP amplitudes (1.6±3.2 x 11.9±9.1 × 45.7±24.7) and USMAR values (0.3±0.3 × 1.5±0.9 × 4.6±2.2) were significantly different. A USMAR threshold of 0.71 was able to differentiate GNP and PNP (94.4% sensitivity and 90.9% specificity). Conclusions USMAR is a practical and reliable tool for the differentiation between GNP and PNP. .

O objetivo deste estudo foi avaliar se a razão entre as amplitudes dos potenciais de ação sensitivo (SNAP) e motor (CMAP) do nervo ulnar (USMAR) auxiliaria na distinção entre ganglionopatia (GNP) e polineuropatia (PNP). Métodos Revisamos os estudos de neurocondução e eletromiografia de 18 pacientes com GNP, 33 com PNP diabética e 56 controles. GNP foi definida pela presença simultânea de anormalidades na neurocondução e na ressonância magnética cervical. PNP foi definida por critérios clínicos e neurofisiológicos usuais. Usamos o teste ANOVA com Tukey post-hoc e análise da curva ROC para comparar o SNAP e CMAP ulnares, assim como o USMAR entre os grupos. Resultados As amplitudes dos CMAPs ulnares foram similares entre GNP × PNP × Controles (p=0,253), mas as amplitudes dos SNAPs ulnares (1,6±3,2 × 11,9±9,1 × 45,7±24,7) e os valores de USMAR (0,3±0,3 × 1,5±0,9 × 4,6±2,2) foram significativamente diferentes. Um corte de 0,71 para a USMAR foi capaz de diferenciar GNP de PNP (sensibilidade de 94,4% e especificidade de 90,9%). Conclusões A USMAR é um parâmetro útil e confiável para o diagnóstico diferencial entre GNP e PNP. .

Periprostatic implantation of human bone marrow-derived mesenchymal stem cells potentiates recovery of erectile function by intracavernosal injection in a rat model of cavernous nerve injury.

OBJECTIVE: To evaluate whether periprostatic implantation (PPI) of human bone marrow-derived mesenchymal stem cells (hBMSCs) potentiates recovery of erectile function after intracavernosal injection (ICI) of hBMSCs in a rat model of cavernous nerve (CN) injury. METHODS: Sprague-Dawley rats that had undergone bilateral CN injury were treated by ICI with or without PPI of hBMSCs (10 rats per group). hBMSCs were harvested from healthy human donors. Fibrin scaffolds were used for PPI of hBMSCs. After 4 weeks, erectile responses to electric pelvic ganglion stimulation were studied. The expression of neuronal nitric oxide synthase (nNOS)-positive nerve fibers and smooth muscle/collagen ratio was evaluated in each penis. RESULTS: ICI of hBMSCs slightly improved erectile function compared with the control group (maximal intracavernosal pressure/mean arterial pressure, 39.1% vs 21.7%; P=.060), but a combination of PPI and ICI significantly improved erectile function (45.0%, P=.007). After stem cell therapy, the number of nNOS-positive nerve fibers increased significantly in the PPI+ICI group (P=.017). The smooth muscle/collagen ratio increased significantly after stem cell therapy in the ICI and PPI+ICI groups (both P<.001). CONCLUSION: ICI of hBMSCs in a rat model of CN injury results in recovery of penile erection by decreasing corporeal smooth muscle deterioration and collagen deposition. PPI of hBMSCs potentiates recovery of erectile function by ICI of hBMSCs via regeneration of nNOS-containing nerve fibers.

Whole genome microarray of the major pelvic ganglion after cavernous nerve injury: new insights into molecular profile changes after nerve injury.

UNLABELLED: What's known on the subject? and What does the study add? With the present study, we aimed to provide a global picture of the molecular processes that are activated by CN injury. The present study used genomic expression profiling to identify candidate genes that might be useful targets in the CN recovery process and, thus, the ultimate preservation of penile erection. Regeneration of the CN and axonal outgrowth clearly involve changes in multiple biochemical pathways that have never been investigated by microarray analysis. We analyzed global gene expression in the major pelvic ganglion at early stages (48 h and 14 days) after CN injury and focused on the detection of changes in genes related to nervous tissue repair and proliferation. The findings of the present study provide important insight into the molecular systems affected by CN injury and identify candidate genes that may be utilized for novel molecular-based therapies for the preservation and protection of the CN during RP. OBJECTIVES: To to examine the complexity of the many molecular systems involved in supporting cavernous nerve (CN) repair and regeneration in a rat model of bilateral crush injury utilizing a microarray analysis approach. Erectile dysfunction (ED) is a common clinical complication after prostate cancer treatment by radical prostatectomy, and recovery of erectile function can take as long as 2 years. There are gaps in our understanding of the autonomic pelvic innervation of the penis that still need to be addressed for the development of an adequate treatment strategy for post-prostatectomy ED. The molecular mechanisms of the intrinsic ability of CN to regenerate after an injury have not been elucidated. MATERIALS AND METHODS: We analyzed global gene expression in the major pelvic ganglion 48 h and 14 days after CN injury. Overall, a comparative analysis showed that 325 genes changed at the 48-h time point and 114 genes changed at 14 days. There were 60 changed genes in common with both time points. Using the Ingenuity Pathway Analysis® system (Ingenuity Systems, Inc., Redwood City, CA, USA), we were able to analyze the significantly changed genes that were unique and common to each time point by biological function. We focused on the detection of changes related to nervous tissue repair and proliferation, molecular networks of neurotrophic factors, stem cell regulation and synaptic transmission. RESULTS: There was strong evidence of the early mobilization of genes involved in repair and neuroprotection mechanisms (SERPINF1, IGF1, PLAU/PLAUR, ARG1). Genes related to nervous system development (ATF3 GJA1, PLAU, SERPINE1), nerve regeneration (SERPINE2, IGF1, ATF3, ARG1) and synaptic transmission (GJC1, GAL) were changed. Several genes related to proliferation as well as apoptosis (A2M, ATF3, C3, EGR4, FN1, GJA1, GAL) were also changed, possibly as part of a protective mechanism or the initiation of remodelling. CONCLUSIONS: The results obtained show that multiple biological processes are associated with injury and repair of the CN and provide a systematic genome-wide screen for neurotrophic and/or inhibitory pathways of nerve regeneration. These data identify the candidate genes that may be utilized in novel molecular-based therapies for the preservation and protection of the CN during radical prostatectomy.

Recruitment of intracavernously injected adipose-derived stem cells to the major pelvic ganglion improves erectile function in a rat model of cavernous nerve injury.

BACKGROUND: Intracavernous (IC) injection of stem cells has been shown to ameliorate cavernous-nerve (CN) injury-induced erectile dysfunction (ED). However, the mechanisms of action of adipose-derived stem cells (ADSC) remain unclear. OBJECTIVES: To investigate the mechanism of action and fate of IC injected ADSC in a rat model of CN crush injury. DESIGN, SETTING, AND PARTICIPANTS: Sprague-Dawley rats (n=110) were randomly divided into five groups. Thirty-five rats underwent sham surgery and IC injection of ADSC (n=25) or vehicle (n=10). Another 75 rats underwent bilateral CN crush injury and were treated with vehicle or ADSC injected either IC or in the dorsal penile perineural space. At 1, 3, 7 (n=5), and 28 d (n=10) postsurgery, penile tissues and major pelvic ganglia (MPG) were harvested for histology. ADSC were labeled with 5-ethynyl-2-deoxyuridine (EdU) before treatment. Rats in the 28-d groups were examined for erectile function prior to tissue harvest. MEASUREMENTS: IC pressure recording on CN electrostimulation, immunohistochemistry of the penis and the MPG, and number of EdU-positive (EdU+) cells in the injection site and the MPG. RESULTS AND LIMITATIONS: IC, but not perineural, injection of ADSC resulted in significantly improved erectile function. Significantly more EdU+ ADSC appeared in the MPG of animals with CN injury and IC injection of ADSC compared with those injected perineurally and those in the sham group. One day after crush injury, stromal cell-derived factor-1 (SDF-1) was upregulated in the MPG, providing an incentive for ADSC recruitment toward the MPG. Neuroregeneration was observed in the group that underwent IC injection of ADSC, and IC ADSC treatment had beneficial effects on the smooth muscle/collagen ratio in the corpus cavernosum. CONCLUSIONS: CN injury upregulates SDF-1 expression in the MPG and thereby attracts intracavernously injected ADSC. At the MPG, ADSC exert neuroregenerative effects on the cell bodies of injured nerves, resulting in enhanced erectile response.

Colonic soluble mediators from the maternal separation model of irritable bowel syndrome activate submucosal neurons via an interleukin-6-dependent mechanism.

Irritable bowel syndrome (IBS) is characterized by episodic bouts of abdominal pain, bloating, and altered bowel habit. Accumulating evidence has linked immune activation with IBS, including reports of increases in circulating levels of the proinflammatory cytokine interleukin (IL)-6. However, it is unknown whether IL-6 contributes directly to disease manifestation. As enteric nervous activity mediates motility and secretory function, the aims of this study were to determine the effects of IL-6 on submucosal neurons and related gastrointestinal (GI) function. In these studies, we examined the colons of maternally separated (MS) rats, which exhibit elevated circulating levels of IL-6 in addition to GI dysfunction. To our knowledge, these studies are the first to provide evidence of the sensitivity of submucosal neurons to colonic secretions from MS rats (n = 50, P < 0.05), thus recapitulating clinical biopsy data. Moreover, we demonstrated that the excitatory action is IL-6 dependent. Thereafter, the impact of IL-6 on neuronal and glial activation and absorpto/secretory function was pharmacologically characterized. Other proinflammatory cytokines including IL-8 (n = 30, P > 0.05), IL-1ß (n = 56, P > 0.05), and TNF-α (n = 56, P > 0.05) excited fewer neurons. Both muscarinic and nicotinic cholinergic receptors participate in the effect and cause downstream activation of ERK, JAK-STAT, and NF-κB signaling cascades. Functionally, IL-6 increases transepithelial resistance and enhances neurally and cholinergically mediated ion transport. These data provide a role for IL-6 in colonic secretory functions and relate these effects to GI dysfunction in an animal model of IBS, thereby elucidating a potential relationship between circulating levels of IL-6 and aberrant GI function.

Tibial intraneural ganglia at the ankle and knee: incorporating the unified (articular) theory in adults and children.

OBJECT: The etiology of intraneural ganglia has been debated for centuries, and only recently a unifying theory has been proposed. The incidence of tibial nerve intraneural ganglia is restricted to the occasional case report, and there are no reported cases of these lesions in children. While evidence of the unifying theory for intraneural ganglia of the common peroneal nerve is strong, there are only a few reports describing the application of the theory in the tibial nerve. In this report the authors examine tibial nerve intraneural ganglia at the ankle and knee in an adult and a child, respectively, and describe the clinical utility of incorporating the unifying (articular) theory in the management of tibial intraneural ganglia in adults and children. METHODS: Cases of tibial intraneural ganglion cysts were examined clinically, radiologically, operatively, and histologically to demonstrate the application of the unified (articular) theory for the development of these cysts in adults and children. RESULTS: Two patients with intraneural ganglion cysts of the tibial nerve were identified: an adult with an intraneural ganglion cyst of the tibial nerve at the tarsal tunnel and a child with an intraneural ganglion cyst of the tibial nerve at the knee. In each case, preoperative MR imaging demonstrated the intraneural cyst and its connection to the adjacent joint via the articular branch to the subtalar joint and superior tibiofibular joint. At surgery the articular branch was identified and resected, thus disconnecting the tibial nerve intraneural cyst from the joint of origin. CONCLUSIONS: These cases detail the important features of intraneural ganglion cysts of the tibial nerve and document the clinical utility of incorporating the unifying (articular) theory for the surgical management of tibial intraneural ganglia in adults and children.

Tibialis anterior branch involvement in fibular intraneural ganglia.

Fibular (peroneal) intraneural ganglia classically present with predominant tibialis anterior weakness, for which there is no clear anatomical explanation. We identified a new imaging pattern, which consisted of involvement of a proximal tibialis anterior branch, in patients with fibular intraneural ganglia. This study characterizes the cystic involvement of this tibialis anterior branch and evaluates its significance. The magnetic resonance imaging (MRI) and clinical data of 23 patients with fibular intraneural ganglia were retrospectively reviewed. The tibialis anterior branch was consistently involved with the cyst, and this involvement, although variable, was more prominent than the cystic involvement of other terminal branches of the fibular nerve. The finding of cyst extension within a muscle end-organ branch seems likely to explain, in part, the characteristic clinical finding of preferential foot drop in patients with fibular intraneural ganglia.

Routine ganglionic plexi ablation during Maze procedure improves hospital and early follow-up results of mitral surgery.

OBJECTIVE: Ganglionic plexi are claimed to be potentially responsible for atrial fibrillation. We evaluated whether ganglionic plexi isolation improves the results of the Maze procedure during mitral valve surgery. METHODS: A total of 75 patients with atrial fibrillation underwent radiofrequency ablation during mitral valve surgery without (group A) or with (group B) ganglionic plexi ablation with bipolar radiofrequency plus fat pad resection along the Waterston groove, left pulmonary veins, and Marshall's ligament. Ganglionic plexi were intraoperatively mapped, and fat pad specimens were sectioned and analyzed. Hospital and follow-up results were recorded. Amiodarone was discontinued at the sixth month. RESULTS: Active ganglionic plexi were mainly located in the upper parts of fat pads. Active specimens demonstrated more ganglionic plexi than inactive specimens (P

Intraoperative epicardial electrophysiologic mapping and isolation of autonomic ganglionic plexi.

BACKGROUND: Autonomic ganglionic plexi (GPs) have been implicated as triggers in lone atrial fibrillation (AF). The purpose of this study was to describe the technique and results of epicardial electrophysiologic mapping and the early effects of GP isolation. METHODS: Intraoperative epicardial electrophysiologic mapping was performed on 41 consecutive patients during a stand-alone minimally invasive operation for AF. A map labeling anatomic locations was developed to describe the findings. Intraoperative high-frequency stimulation (800/minute, 12 to 16 mA, pulse duration 9.9 ms) was performed using a standard quadripolar catheter placed directly on the epicardium. Locations where stimulation resulted in ventricular slowing with doubling of the electrocardiographic R-R interval were defined as active GPs. These areas were mapped and described. After dry bipolar radiofrequency isolation, the sites were again stimulated to assess isolation. RESULTS: Forty-one patients (mean age of 60.2 years, 31 males) underwent operation for AF (28 intermittent AF, 13 chronic). Active GPs were identified in all patients (24 bilateral, 17 unilateral). There was a mean of 5.0 GPs on the right and 2.7 on the left. More than 50% of patients had active GPs along the interatrial groove on the right and along the ligament of Marshall. All sites were inactive after radiofrequency isolation. Six-month follow-up is available for 15 patients, with 14 patients free of AF. CONCLUSIONS: Autonomic GPs can be routinely identified during AF surgery utilizing high-frequency stimulation. The GPs are clustered around the interatrial groove and the ligament of Marshall, and the cardiac response to GP stimulation can be eliminated with bipolar radiofrequency isolation. The addition of GP isolation to bilateral pulmonary vein isolation may increase freedom from AF.

Vagal postganglionic origin of vasoactive intestinal polypeptide (VIP) mediating the vagal tachycardia.

Our aim was to confirm the role of postganglionic vagal fibres and vasoactive intestinal polypeptide (VIP) in mediating the vagal tachycardia in anaesthetised dogs. Vagal postganglionic stimulation after atenolol (1 mg/kg) and hexamethonium (10 mg/kg) caused a bradycardia (40 beats/min, n = 2), after atropine (0.5 mg/kg i.v.) the resulting tachycardia (37 beats/min) was attenuated by VIP receptor antagonism with VIP (6-28) (100 mug i.c.) by approximately 50%. VIP release from vagal postganglionic fibres mediates the vagal tachycardia.

Neurophysiological diagnosis of acquired sensory ganglionopathies.

We examined 29 patients with chronic progressive ganglionopathy of different etiology. Neurophysiological abnormalities were dominated by a widespread decrease in sensory nerve action potential amplitudes, which involved both upper and lower limb nerves, even in patients with asymmetrical or patchy clinical presentation. This impairment of sensory nerve conduction, reflecting a nonlenght-dependent pattern of peripheral axon degeneration, should be considered the hallmark of ganglionopathies. The evidence of central sensory pathway impairment, which allows to localize the pathology to the dorsal root ganglion neurons, could be better confirmed by cervical magnetic resonance imaging, which showed a diffuse hyperintensity in the posterior columns in all patients, than by somatosensory evoked potentials, which were undetectable in most of the patients. Few patients showed an impairment of individual motor nerves, which appeared more severe in paraneoplastic associated ganglionopathies. Neurophysiological abnormalities did not appear significantly changed at the 4-year follow-up. We emphasize that distinct abnormalities allow to differentiate ganglionopathies from axonal sensory neuropathies on routine neurophysiological examination.

Oligoneuronal hypoganglionosis in patients with idiopathic slow-transit constipation.

PURPOSE: Several alterations of the enteric nervous system have been described as an underlying neuropathologic correlate in patients with idiopathic slow-transit constipation. To obtain comprehensive data on the structural components of the intramural nerve plexus, the colonic enteric nervous system was investigated in patients with slow-transit constipation and compared with controls by means of a quantitative morphometric analysis. METHODS: Resected specimens were obtained from ten patients with slow-transit constipation and ten controls (nonobstructive neoplasias) and processed for immunohistochemistry with the neuronal marker Protein Gene Product 9.5. The morphometric analysis was performed separately for the myenteric plexus and submucous plexus compartments and included the quantification of ganglia, neurons, glial cells, and nerve fibers. RESULTS: In patients with slow-transit constipation, the total ganglionic area and neuronal number per intestinal length as well as the mean neuron count per ganglion were significantly decreased within the myenteric plexus and external submucous plexus. The ratio of glial cells to neurons was significantly increased in myenteric ganglia but not in submucous ganglia. On statistical analysis, the histopathologic criteria (submucous giant ganglia and hypertrophic nerve fibers) of intestinal neuronal dysplasia previously described in patients with slow-transit constipation were not completely fulfilled. CONCLUSION: The colonic motor dysfunction in slow-transit constipation is associated with quantitative alterations of the enteric nervous system. The underlying defect is characterized morphologically by oligoneuronal hypoganglionosis. Because the neuropathologic alterations primarily affect the myenteric plexus and external submucous plexus, superficial submucous biopsies are not suitable to detect these innervational disorders.

Cell-adhesion molecules and fibroblast growth factor signalling in Hirschsprung's disease.

Hirschsprung's disease (HD) is characterised by the absence of ganglion cells and the presence of hypertrophic nerve trunks in the distal bowel. It has been suggested that aganglionosis may be caused by failure of differentiation as a result of microenvironmental change after neuronal migration has occurred. Recently, it was reported that cell-adhesion molecules (CAMs) and fibroblast growth factors (FGFs) stimulate neurite outgrowth through activation of FGF receptors (FGFRs) in neurons. The aim of this study was to investigate the expression of CAMs FGFs, and FGFRs in ganglionic (NG) and aganglionic (AG) segments of HD in order to understand the role of CAM-FGF signalling in the pathogenesis of HD. Specimens from NG and AG segments of bowel from 11 patients with HD were obtained at the time of definitive pull-through operation, snap-frozen in OCT compound, and stored at -70 degrees C. Aganglionosis was confirmed by Haematoxylin and eosin staining and acetylcholinesterase histochemistry; 8-micron cryosections were immunostained using the standard streptavidinbiotin-immunoperoxidase method. The following antibodies were used as the first antibody; FGF2 and FGF7 for FGFs, FGFR1 and FGFR2 for FGFRs, NCAM, L1CAM, and N-cadherin for CAMs. FGF2, FGF7, and FGFR2 were expressed in neuronal tissue of NG segments as well as in hypertrophic nerves of AG segments. There was a lack of FGFRI expression in neuronal tissue of both NG and AG bowel. Immunoreactivity with all three CAMs was detected in ganglion cells in NG bowel and in hypertrophic nerve trunks in AG bowel. In contrast the numbers of CAM-positive nerve fibres in muscle layers were markedly decreased in AG bowel compared to NG bowel. The markedly decreased expression of CAMs on nerve fibres within the muscle of AG bowel suggests that CAM-FGF signalling is altered in HD, resulting in failure of enteric neuroblast migration.

Downregulation of adenosine and P2X receptor-mediated cardiovascular responses in heart failure rats.

Neurohormonal changes in congestive heart failure (CHF) include an enhanced peripheral sympathetic nerve activity which results in increased release of noradrenaline, neuropeptide Y and ATP. To examine if such changes in CHF would modulate peripheral pre- and postsynaptic receptors of ATP and its degradation product adenosine, experiments were performed in a rat model of ischaemic CHF. In this model, ischaemia was induced in rats by ligation of the left coronary artery. Our results demonstrate that there is a selective downregulation of P2X receptor-mediated pressor effects, while the hypotensive effects mediated by the endothelial P2Y receptors are unaffected in CHF. Moreover, the adenosine-mediated inhibitory effects on heart rate and blood pressure were also attenuated in the CHF rats. The most important changes in adenosine and P2-receptor function induced by ischaemic CHF were the reduced pressor effect mediated by the P2X receptor and the increased heart rate due to an attenuated inhibitory effect of adenosine.

Tarsal tunnel syndrome caused by ganglia.

We describe in 30 feet the occurrence of a tarsal tunnel syndrome caused by a ganglion. The presenting symptom was numbness or pain in the toes and the sole with paraesthesiae in the distribution of the medial plantar nerve in 63% of the patients. Swellings which were not palpable were detected by ultrasonography. Twenty-nine patients were treated by operation. Most ganglia originated from the talocalcaneal joint, and five were associated with a talocalcaneal coalition. The surgical outcome was satisfactory in all patients except one who had a further operation for a recurrence of the ganglion.