ABSTRACT
Hirschsprung's disease (HD) is a congenital structural abnormality of the colon seen in approximately 1 to 5000 live births. Despite surgical correction shortly after presentation, up to 60% of patients will express long-term gastrointestinal complaints, including potentially life-threatening Hirschsprung-associated enterocolitis (HAEC). In this study fecal samples from postoperative HD patients (n = 38) and their healthy siblings (n = 21) were analysed using high-resolution liquid chromatography-mass spectrometry aiming to further unravel the nature of the chronic gastrointestinal disturbances. Furthermore, within the patient group, we compared the faecal metabolome between patients with and without a history of HAEC as well as those diagnosed with short or long aganglionic segment. Targeted analysis identified several individual metabolites characteristic for all HD patients as well as those with a history of HAEC and long segment HD. Moreover, multivariate models based on untargeted data established statistically significant (p < 0.05) differences in comprehensive faecal metabolome in the patients' cohort as a whole and in patients with a history of HAEC. Pathway analysis revealed the most impact on amino sugar, lysine, sialic acid, hyaluronan and heparan sulphate metabolism in HD, as well as impaired tyrosine metabolism in HAEC group. Those changes imply disruption of intestinal mucosal barrier due to glycosaminoglycan breakdown and dysbiosis as major metabolic changes in patients' group and should be further explored for potential diagnostic or treatment targets.
Subject(s)
Hirschsprung Disease/metabolism , Metabolome , Case-Control Studies , Child , Child, Preschool , Enterocolitis/etiology , Enterocolitis/metabolism , Feces/chemistry , Female , Ganglia/abnormalities , Hirschsprung Disease/complications , Hirschsprung Disease/surgery , Humans , Intestinal Mucosa/metabolism , Intestine, Large/abnormalities , Intestine, Large/innervation , Male , Metabolic Networks and Pathways , Postoperative Complications/etiology , Postoperative Complications/metabolism , Postoperative PeriodABSTRACT
BACKGROUND: Allied disorders of Hirschsprung's disease (ADHD) have been proposed to be the concept of the functional obstruction of the intestine with the presence of ganglion cells in the terminal rectum. They are classified into two categories based on pathology: (1) abnormal ganglia, including immaturity of ganglia, hypoganglionosis (HG), and intestinal neuronal dysplasia; (2) normal ganglia, including megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS), segmental dilatation (SD), internal anal sphincter achalasia (IASA), and chronic idiopathic intestinal pseudo-obstruction (CIIP). Some of these show poor prognosis, therefore, the establishment of criteria and appropriate treatment strategies is required. METHODS: The questionnaires were sent to the 161 major institutes of pediatric surgery or gastroenterology in Japan, in order to collect the cases of ADHD during 10 years from 2001 and 2010. RESULTS: In total, 355 cases were collected. They included 28 immaturity of ganglia, 130 HG (121 congenital, 9 acquired), 18 intestinal neuronal dysplasia, 33 MMIHS, 43 SD, three IASA, and 100 CIIP. Of the 95 institutes, 69 (72.6%) had their own criteria for ADHD. Criteria were based on clinical symptoms and signs, and conventional pathological examinations. Prognosis was poor in congenital HG, MMIHS, and CIIP, while the others showed good survival rates. CONCLUSION: Almost all Japanese cases of ADHD in the past 10 years were collected. Congenital HG and CIIP showed relatively high incidence, whereas acquired HG and IASA were extremely rare in Japan. The criteria of each disorder were also collected and summarized. Prognosis was poor in congenital HG, MMIHS, and CIIP.
Subject(s)
Abnormalities, Multiple/epidemiology , Colon/abnormalities , Enteric Nervous System/abnormalities , Ganglia/abnormalities , Hirschsprung Disease/epidemiology , Intestinal Pseudo-Obstruction/epidemiology , Urinary Bladder/abnormalities , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/pathology , Colon/pathology , Diagnosis, Differential , Follow-Up Studies , Health Surveys , Hirschsprung Disease/diagnosis , Hirschsprung Disease/pathology , Humans , Incidence , Intestinal Pseudo-Obstruction/diagnosis , Intestinal Pseudo-Obstruction/pathology , Japan/epidemiology , Prognosis , Retrospective Studies , Urinary Bladder/pathologyABSTRACT
La migraña crónica es una enfermedad que afecta al 0,5-2,5% de la población según las estadísticas que se analicen y la definición de migraña crónica que se adopte. Es extraordinariamente incapacitante, ya que no permite realizar las actividades personales, profesionales o sociales programadas, y tiene un gran impacto sobre la calidad de vida de los pacientes, medido en escalas de discapacidad, calidad de vida e impacto en la actividad diaria. Sin embargo, actualmente se dispone de tratamientos que han demostrado eficacia en la migraña crónica, como la OnabotulinumtoxinA. Es un tratamiento bien tolerado y con una tasa de eficacia elevada. Pero no es sólo una herramienta terapéutica, sino que ha abierto las puertas en el mundo de la cefalea a la realización de tratamientos invasivos, al aprendizaje de técnicas y, en definitiva, a situar la cefalea en unidades de referencia ubicadas, habitualmente, en hospitales de tercer nivel. Además, ha ayudado a eliminar el concepto de que los pacientes con cefalea deben ser atendidos exclusivamente por médicos de atención primaria o neurólogos generales. Ésta es una oportunidad que debe aprovecharse para redimensionar el campo del estudio y asistencia de la cefalea. En el futuro, esto va a complementarse con novedosos tratamientos con neuroestimulación y, probablemente, con anticuerpos monoclonales contra el péptido relacionado con el gen de la calcitonina. Se ha iniciado una revolución en nuestro conocimiento y capacidad de actuación. Es nuestro deber darle la importancia y uso que se merecen tanto para nuestros pacientes como para nosotros como especialistas (AU)
Chronic migraine is a disease that affects 0.5-2.5% of the population, depending on the statistics that are analysed and the definition of chronic migraine that is used. It is extraordinarily disabling, since it does not allow the sufferer to carry out any of their scheduled personal, professional or social activities, and it has a great impact on the patients quality of life, as measured on disability, quality of life and impact on daily activities scales. Yet, nowadays there are treatments that have proven to be effective in cases of chronic migraine, such as OnabotulinumtoxinA. It is a treatment that is well tolerated and with a high rate of efficacy. Yet it is not only a therapeutic tool, but in the world of headaches it has also opened up the doors to invasive treatments, to the learning of techniques and, in short, to placing headaches in referral units that are usually located in tertiary care hospitals. Furthermore, it has also helped to overcome the idea that patients with headache should be visited exclusively by primary care physicians or general neurologists. This is an opportunity to redefine the field of study and the care for headaches that must be seized. In the future, this is going to be complemented by novel treatments with neurostimulation and probably with monoclonal antibodies against the calcitonin gene-related peptide. A revolution has begun in our knowledge and capacity to act. It is our duty to give it the importance and usage it deserves both for our patients and for us as specialists (AU)
Subject(s)
Female , Humans , Male , Migraine Disorders/metabolism , Migraine Disorders/pathology , Neurology/education , Quality of Life/psychology , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/metabolism , Ganglia/abnormalities , Therapeutics/methods , Migraine Disorders/complications , Migraine Disorders/diagnosis , Neurology , Antibodies, Monoclonal/economics , Antibodies, Monoclonal/therapeutic use , Ganglia/injuries , Therapeutics/standardsABSTRACT
ANTECEDENTES: el tratamiento del cáncer de recto localmente avanzado (CRLA) y de casos selectivos de estadio IV es la quimioradioterapia (QRT) preoperatoria seguida de la extirpación completa del meso-recto (ETM). A pesar de la reducción en la recurrencia local, la supervivencia libre de enfermedad (SLE) permanece estable en los últimos años. OBJETIVO: el objetivo de este trabajo es analizar el patrón de recidiva, supervivencia a largo plazo y los factores pronósticos en un programa de QRT neoadyuvante y cirugía en el CRLA. MÉTODOS: entre enero de 1992 y diciembre de 2011, 446 pacientes con CRLA y 54 pacientes (con metástasis únicas) fueron tratados con QRT preoperatoria de curso largo y cirugía. Se realizaron 344 (68,8%) resecciones anteriores de recto y 123 (24,6%) amputaciones abdominoperineales. RESULTADOS: con una mediana de seguimiento de 70,06 meses, la recurrencia local fue del 4,8% y a distancia del 25,5%. No se encontraron diferencias en los factores pronósticos histopatológicos entre los tres grupos estudiados dependiendo de la distancia (cm) al margen anal. La afectación del margen circunferencial (MCR+) fue significativamente mayor en el tercio distal (8,5%; p = 0,04). Sesenta y siete pacientes (13,4%) mostraron una respuesta patológica completa. La supervivencia libre de enfermedad a los 5 y 10 años fue significativamente menor en los tumores del tercio distal del recto que en los del tercio medio (61,9% y 57,7%; p = 0,04). En dicha localización se produjo una incidencia significativamente mayor de metástasis pulmonares (p = 0,016)
BACKGROUND: The standard treatment for locally advanced cancer of the rectum (LACR) and selective cases of stage IV disease is preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME). Despite reductions in local recurrence, disease-free survival (DSF) has remained stable in recent years. OBJECTIVE: The objective of this study is to analyze patterns of recurrence, long-term survival and prognostic factors in a program of neoadjuvant CRT and surgery in LACR. METHODS: Between January 1992 and December 2011, 446 patients with LACR and 54 patients (with single metastases) were treated with pre-operative long course CRT and surgery. Three hundred forty four (66.8%) anterior resections of the rectum and 123 (24.6%) abdomino-perineal resections were performed. RESULTS: With a mean follow-up of 70.06 months, local recurrence was 4.8% and distant recurrence 25.5%. No differences were found in the histopathologic prognostic factors across the three groups studied depending on distance (cm) from the anal margin. Involvement of the circumferential resection margin (CRM+) was significantly greater in tumors in the distal third of the rectum (8.5%; p = 0.04). 67 patients (13.4%) showed a complete pathologic response. DSF at 5 and 10 years was significantly lower in patients with tumors affecting the distal third as compared to the middle third of the rectum (61.9% vs. 57.7%; p = 0.04). Tumors at this distal location resulted in a significantly higher incidence of lung metastases (p = 0.016)
Subject(s)
Female , Humans , Male , Rectal Neoplasms/therapy , Survivorship/physiology , Ganglia/abnormalities , Neoplasm Metastasis/diagnosis , Neoplasm Metastasis/pathology , Lung/cytology , Rectal Neoplasms/congenital , Rectal Neoplasms/pathology , Survivorship/psychology , DNA Cleavage , Ganglia/injuries , Neoplasm Metastasis/genetics , Neoplasm Metastasis/prevention & control , Lung/metabolism , Retrospective StudiesABSTRACT
Introducción: Las prionopatías representan hasta el 62% de los casos de demencia rápidamente progresiva (DRP) en los que se alcanza un diagnóstico definitivo. La variabilidad de los síntomas y signos iniciales y las diferencias en su evolución dificultan el diagnóstico precoz. Métodos: Estudio retrospectivo en el que se incluye a pacientes con prionopatía probable o definitiva, que acudieron a la consulta de Neurología de nuestro centro durante el periodo 1999-2012. Se describen las características clínicas y los resultados de las exploraciones complementarias (proteína 14-3-3, EEG, RM, PET-FDG y análisis genético), con la finalidad de identificar qué marcadores permiten un diagnóstico precoz. Resultados: Se describe a 14 pacientes: 6 con enfermedad de Creutzfeldt-Jakob esporádica (ECJe) definitiva, 3 con ECJe probable, 4 con insomnio familiar fatal y uno con la nueva variante de la enfermedad de Creutzfeldt-Jakob. La mediana de edad al diagnóstico fue de 54 años y la mediana de supervivencia de 9,5 meses. El trastorno del ánimo fue el síntoma inicial más frecuente, seguido de inestabilidad de la marcha y deterioro cognitivo. La proteína 14-3-3 fue positiva en el líquido cefalorraquídeo en 7 de 11 pacientes y el EEG mostró signos típicos en 2 de 12 pacientes explorados. El estudio de neuroimagen mostró alteraciones en 13 de los 14 pacientes. Conclusiones: Además de la DRP, el trastorno conductual y de la marcha son síntomas iniciales frecuentes en las prionopatías. En nuestra serie, las pruebas complementarias más útiles para apoyar el diagnóstico fueron la RM y la PET-FDG
Introduction: Prionopathy is the cause of 62% of the rapidly progressive dementias (RPD) in which a definitive diagnosis is reached. The variability of symptoms and signs exhibited by the patients, as well as its different presentation, sometimes makes an early diagnosis difficult. Methods: Patients withdiagnosis of definite or probable prionopathy during the period 1999-2012 at our hospital were retrospectively reviewed.The clinical features and the results of the complementary tests (14-3-3 protein, EEG, MRI, FDG-PET, and genetic analysis) were evaluated in order to identify some factors that may enable an earlier diagnosis to be made. Results: A total of 14 patients are described: 6 with definite sporadic Creutzfeldt-Jakob (sCJD) disease, 3 with probable sCJD, 4 with fatal familial insomnia, and 1 with the new variant. The median age at diagnosis was 54 years old. The mean survival was 9.5 months. Mood disorder was the most common feature, followed by instability and cognitive impairment. 14-3-3 protein content in the cerebrospinal fluid was positive in 7 of 11 patients, and the EEG showed typical signs in 2 of 12 patients. Neuroimaging (FDG-PET, MRI) studies suggested the diagnosis in 13 of the 14 patients included. Conclusions: Most patients presenting with RPD suffer from a prion disease. In our series the most useful complementary tests were MRI and FDG-PET, being positive in 13 of the 14 patients studied
Subject(s)
Humans , Male , Female , Neuroimaging/instrumentation , Dementia/complications , Dementia/diagnosis , Ganglia/abnormalities , Sleep Initiation and Maintenance Disorders/diagnosis , Sleep Initiation and Maintenance Disorders/metabolism , Urinary Incontinence/diagnosis , Magnetic Resonance Spectroscopy/methods , Neuroimaging/methods , Dementia/metabolism , Dementia/psychology , Ganglia/metabolism , Sleep Initiation and Maintenance Disorders/complications , Sleep Initiation and Maintenance Disorders/genetics , Urinary Incontinence/prevention & control , Magnetic Resonance SpectroscopyABSTRACT
Se describe una creciente incidencia de carcinoma de tiroides en todo el mundo, pero la mayor parte de estos casos corresponde a cánceres de bajo riesgo. Se necesita comprender con precisión la patología tumoral y su comportamiento biológico, para aprovechar estos parámetros en una terapia rentable con utilización adecuada de recursos. La apreciación de la importancia y el significado de los factores pronósticos y la estratificación por grupos de riesgo es esencial para el enfoque actual del carcinoma tiroideo. Se requiere discreción para la selección del tratamiento quirúrgico y la indicación de terapias adyuvantes, así como para las estrategias de vigilancia
Subject(s)
Ganglia/abnormalities , Neoplasm Metastasis/prevention & control , Thyroid Neoplasms/complications , Thyroid Neoplasms/diagnosis , Thyroid Neoplasms/rehabilitation , Thyroid Neoplasms/therapyABSTRACT
Se describe una creciente incidencia de carcinoma de tiroides en todo el mundo, pero la mayor parte de estos casos corresponde a cánceres de bajo riesgo. Se necesita comprender con precisión la patología tumoral y su comportamiento biológico, para aprovechar estos parámetros en una terapia rentable con utilización adecuada de recursos. La apreciación de la importancia y el significado de los factores pronósticos y la estratificación por grupos de riesgo es esencial para el enfoque actual del carcinoma tiroideo. Se requiere discreción para la selección del tratamiento quirúrgico y la indicación de terapias adyuvantes, así como para las estrategias de vigilancia (AU)
Subject(s)
Thyroid Neoplasms/complications , Thyroid Neoplasms/diagnosis , Thyroid Neoplasms/rehabilitation , Thyroid Neoplasms/therapy , Ganglia/abnormalities , Neoplasm Metastasis/prevention & controlABSTRACT
RESUMEN. Las adenopatías son un hallazgo muy común enpediatría y uno de los motivos más frecuentes deconsulta. En general son secundarias a procesosbenignos, pero pueden responder a etiologías demayor gravedad; diferenciarlas es el punto de mayorrelevancia clínica, pues una correcta aproximacióndiagnóstica puede evitar retrasar su manejoadecuado y prevenir así los perjuicios para el paciente.Para ello se revisan las causas más frecuentessegún su localización y distribución anatómica, y seaportan diversos algoritmos de actuación para cadacaso, que pueden orientar al clínico para un diagnósticoy tratamiento adecuados.Palabras clave: adenopatías, ganglio linfático, linfadenopatía.
Subject(s)
Child , Lymphatic Diseases/diagnosis , Ganglia/abnormalities , Lymphadenitis/diagnosisABSTRACT
RESUMEN. Las adenopatías son un hallazgo muy común enpediatría y uno de los motivos más frecuentes deconsulta. En general son secundarias a procesosbenignos, pero pueden responder a etiologías demayor gravedad; diferenciarlas es el punto de mayorrelevancia clínica, pues una correcta aproximacióndiagnóstica puede evitar retrasar su manejoadecuado y prevenir así los perjuicios para el paciente.Para ello se revisan las causas más frecuentessegún su localización y distribución anatómica, y seaportan diversos algoritmos de actuación para cadacaso, que pueden orientar al clínico para un diagnósticoy tratamiento adecuados.Palabras clave: adenopatías, ganglio linfático, linfadenopatía.(AU)
Subject(s)
Child , Ganglia/abnormalities , Lymphadenitis/diagnosis , Lymphatic Diseases/diagnosisABSTRACT
A 14-yr-old boy with total parenteral nutrition-dependent short-bowel syndrome associated with hypoganglionosis underwent the LR-IT by using a 150 cm segment of distal ileum taken from a healthy donor. The graft vessels were connected to infrarenal aorta and inferior vena cava. The immunosuppressive regimen consisted of daclizumab, tacrolimus, and steroid. The graft surveillance for ACR was accomplished using zoom endoscopy and mucosal biopsy. The blood trough level of tacrolimus was maintained between 20 and 25 ng/mL for the first 2 months, followed by 15-20 ng/mL thereafter. The 50 mg of daclizumab was administered on the day of operation, and same dosage was repeated at 2-wk intervals. The first ACR occurred on POD-9 and was progressive, and required a 14-day course of OKT-3 injection. After the treatment with OKT-3, the graft recovered from the ACR, and began to function well enough to discontinue the intravenous nutrition on POD-55. No infectious complication has occurred. The patient was discharged in POD-112, and currently tolerates full oral intake without requiring intravenous nutritional or fluid supplementation. The donor was discharged without any complications. The LR-IT could successfully be performed with minimal risk to the donor, and it can be a treatment of choice for patients with short-gut syndrome associated with hypoganglionosis.
Subject(s)
Digestive System Surgical Procedures/methods , Ileum/transplantation , Living Donors , Short Bowel Syndrome/surgery , Adolescent , Anastomosis, Surgical , Ganglia/abnormalities , Gastrointestinal Motility , Humans , Immunosuppressive Agents/administration & dosage , Magnetic Resonance Imaging , Male , Nutrition Assessment , Parenteral Nutrition, Total , Short Bowel Syndrome/pathologyABSTRACT
O envelhecimento é caracterizado por um progressivo declínio na função neuronal envolvendo tanto o sistema nervoso central como o periférico. O aumento da idade é verificado por alterações no número e no tamanho dos neurônios. Contudo, estes dados são controversos e pouco conhecidos nos gânglios periféricos. Desta forma, o presente estudo teve como objetivo estudar o gânglio mesentérico caudal (GMC) de cães em dois períodos distintos do desenvolvimento (maturação e envelhecimento), a procura de alterações morfométricas nos neurônios. A importância do GMC esta ligada à inervação simpática do intestino grosso, esfíncter anal interno e parcialmente o aparelho urogenital. Para o estudo, foram utilizados nove cães domésticos sem raça definida e machos, divididos em três grupos etários com idades bem definidas (1-2 meses, 1-3 anos e 5-10 anos). Os gânglios foram processados para o estudo da microscopia e luz e as análises morfométricas (área seccional do neurônio e do núcleo) foram realizadas por meio do software de análise morfométrica KS 400 ZEISS®. O aumento da idade foi caracterizado por um aumento no tamanho do neurônio e do núcleo. Quanto a relação núcleo-citoplasma, esta diminuiu com o aumento da idade.
The aging is characterized by a progressive decline of neuronal function that involves both the central and the peripheral nervous system.Aging process is accompanied by changes in the number and size of neurons. However, these data are controvesial and poorly known in the peripheral ganglia. In this way, the present investigation aimed to study the dog's caudal mesenteric ganglion (CMG) in two different phases of aging (maturation and aging), looking for morphometric alterations in the neurons. The importance of the CMG is associated with the innervation of the lower large intestine, internal anal sphincter and partially the urogenital system. To the study, was used nine males, mongrel, domestic dogs, divided into three different well defined aged groups (1-2 months, 1-3 years old, 5-10 years old). The ganglia were processed for light microscopy study and the morphometric analyses were done using morphometric analyses software KS 400 Zeiss®. The increase of age was caractherized by an increased in size of neuron and nucleu. Concerning about nucleus-citoplasmic relation, this decrease with the age.
Subject(s)
Animals , Male , Dogs , Ganglia/anatomy & histology , Ganglia/abnormalities , Neurons/physiologySubject(s)
Chromosome Deletion , Ganglia/abnormalities , Homeodomain Proteins/genetics , Hypoventilation/genetics , Intestine, Large/innervation , Intestine, Small/innervation , Transcription Factors/genetics , Base Sequence , Hirschsprung Disease/genetics , Humans , Hypoventilation/pathology , Infant , Infant, Newborn , Intestine, Large/abnormalities , Intestine, Small/abnormalities , Male , Molecular Sequence Data , SyndromeABSTRACT
La variedad de lesiones que afectan a la cabezay el cuello en niños se pueden subdividir según suetiología en infecciosas, neoplásicas o de origencongénito. Las masas congénitas en el cuello incluyenquistes branquiales, los quistes tiroglosos, losquistes ectópicos del timo, los quistes dermoides,las anormalidades vasculares, y las malformacioneslinfáticas tales como el higroma quístico. Este artículose centra principalmente en las patologíasmás comunes: los quistes branquiales, los quistesdel conducto tirogloso y las malformaciones linfáticas
The variety of lesions involving the head and neckin children can be subdivided by etiology into thosethat result from infection or neoplasm and those ofcongenital origin. Congenital masses in the neck includebranchial cleft cysts, thyroglossal duct cysts,ectopic thymus cysts, dermoid and teratoid cysts,cystic vascular abnormalities, and lymphatic malformationssuch as the cystic lymphangioma. This articlemainly focuses on the common entities of branchialcleft cysts, thyroglossal duct cysts and lymphaticmalformations
Subject(s)
Male , Female , Infant , Child , Child, Preschool , Humans , Head and Neck Neoplasms/congenital , Thyroglossal Cyst/pathology , Branchioma/pathology , Ganglia/abnormalities , Pharynx/abnormalities , Branchial Region/abnormalities , Lymphangioma, Cystic/pathology , Head and Neck Neoplasms/pathologyABSTRACT
Intestinal neuronal dysplasia (IND) has been reported as an innervation disorder that can present as isolated disease or may be associated with Hirschsprung's disease (HD). The interest in this disorder is growing as it mimics HD at clinical level but can be managed with a more conservative approach if an accurate diagnosis can be made. Many workers have tried to set up diagnostic criteria of this condition. But the importance of one criterion varied from one study to another. In our study we analysed seven cases of suspected innervation disorder that had undergone resection. A detailed histological study on these cases was performed and four of them were found to fulfill the diagnostic criteria of IND laid down by Kobayashi and his co-workers. These patients had hyperganglionosis, giant ganglia and ectopic ganglion cells in the lamina propria. In the other three cases some features were highly suggestive of the diagnosis of the IND and can be considered to be so if we follow other workers who have not given much importance to the simultaneous presence of all three criteria in a single case.
Subject(s)
Intestines/abnormalities , Intestines/innervation , Child, Preschool , Digestive System Abnormalities/diagnosis , Digestive System Abnormalities/pathology , Female , Ganglia/abnormalities , Hirschsprung Disease/diagnosis , Hirschsprung Disease/pathology , Humans , Infant , MaleABSTRACT
BACKGROUND: Methanol administered to C57BL/6J mice during gastrulation causes severe craniofacial dysmorphology. We describe dysmorphogenesis, cell death, cell cycle assessment, and effects on development of cranial ganglia and nerves observed following administration of methanol to pregnant C57BL/6J mice on gestation day (GD) 7. METHODS: Mice were injected (i.p.) on GD 7 with 0, 2.3, 3.4, or 4.9 gm/kg methanol, split into two doses. In embryos of mice treated with 0 or 4.9 gm/kg methanol, we used histology and LysoTracker red staining on GD 8 0 hr through GD 8 18 hr to examine cell death and dysmorphogenesis, and we also evaluated cell-cycle distribution and proliferation using flow cytometry (FCM) and BrdU immunohistochemistry. On GD 10, we evaluated the effect of GD 7 exposure to 0, 2.3, 3.4, or 4.9 gm/kg methanol on cranial ganglia and nerve development using neurofilament immunohistochemistry. RESULTS: Methanol treatment on GD 7 resulted in reduced mesenchyme surrounding the fore- and midbrain, and in the first branchial arches, by GD 8 12 hr. There were disruptions in the forebrain neuroepithelium and optic pit. Neural crest cell emigration from the mid- and hindbrain region was reduced in methanol-exposed embryos. Methanol had no apparent effect on BrdU incorporation or cell-cycle distribution on GD 8. Cell death was observed in the hindbrain region along the path of neural crest migration and in the trigeminal ganglion on GD 8 18 hr. Development of the cranial ganglia and nerves was adversely affected by methanol. Development of ganglia V, VIII, and IX was decreased at all dosage levels; ganglion VII was reduced at 3.4 and 4.9 gm/kg, and ganglion X was reduced at 4.9 gm/kg. CONCLUSIONS: These results suggest that gastrulation-stage methanol exposure affects neural crest cells and the anterior mesoderm and neuroepithelium. Cell death was evident in areas of migrating neural crest cells, but only at time points after methanol was cleared from the embryo, suggesting an indirect effect on these cells. Birth Defects Research (Part A), 2004. Published 2004 Wiley-Liss, Inc.
Subject(s)
Craniofacial Abnormalities/chemically induced , Methanol/toxicity , Solvents/toxicity , Animals , Apoptosis/drug effects , Cell Division/drug effects , Cranial Nerves/abnormalities , Cranial Nerves/drug effects , Craniofacial Abnormalities/physiopathology , Female , Ganglia/abnormalities , Ganglia/drug effects , Mice , Mice, Inbred C57BLABSTRACT
AIMS/HYPOTHESIS: Maternal diabetes mellitus increases the risk for fetal malformations. Several of these malformations are found in organs and tissues derived from the neural crest. Previous studies have shown changes in fetal organs of neural crest origin in experimental diabetes and changes in migration of neural crest cells exposed to high glucose in vitro. METHODS: We used whole-mount neurofilament staining of embryos from normal and diabetic mothers to investigate the development of cranial nerve ganglia. Neural tube explants were cultured in 10 and 40 mmol/l glucose and cell death and caspase activity was measured with flow cytometry. RESULTS: The development of cranial ganglia V, VII, VIII, IX and X was impaired in day 10-11 embryos of diabetic rats. There was also a higher rate of cell death of neural crest derived cells cultured in 40 mmol/l glucose for 20 h (35% compared to 12% in 10 mmol/l). However, exposure of cells to 40 mmol/l glucose in culture did not increase the activation of the cell death effector proteins-caspases-measured as cellular binding of the activated caspase marker VAD-FMK. This suggests that the cell death is not caused by caspase-dependent apoptosis or that the caspases are activated at an earlier stage. CONCLUSION/INTERPRETATION: The development of neural crest-derived structures is disturbed already at the organogenic period in embryos of diabetic rats and this deteriorated development could be due to high-glucose induced increase in cell death of neural crest derived cells.
Subject(s)
Cranial Nerves/abnormalities , Cranial Nerves/embryology , Ganglia/abnormalities , Neural Crest/abnormalities , Pregnancy in Diabetics/physiopathology , Animals , Embryonic and Fetal Development , Female , Ganglia/embryology , Pregnancy , Rats , Rats, Sprague-Dawley , Reference ValuesABSTRACT
Vagal neural crest-derived precursors of the enteric nervous system colonize the bowel by descending within the enteric mesenchyme. Perpendicular secondary migration, toward the mucosa and into the pancreas, result, respectively, in the formation of submucosal and pancreatic ganglia. We tested the hypothesis that netrins guide these secondary migrations. Studies using RT-PCR, in situ hybridization, and immunocytochemistry indicated that netrins (netrins-1 and -3 mice and netrin-2 in chicks) and netrin receptors [deleted in colorectal cancer (DCC), neogenin, and the adenosine A2b receptor] are expressed by the fetal mucosal epithelium and pancreas. Crest-derived cells expressed DCC, which was developmentally regulated. Crest-derived cells migrated out of explants of gut toward cocultured cells expressing netrin-1 or toward cocultured explants of pancreas. Crest-derived cells also migrated inwardly toward the mucosa of cultured rings of bowel. These migrations were specifically blocked by antibodies to DCC and by inhibition of protein kinase A, which interferes with DCC signaling. Submucosal and pancreatic ganglia were absent at E12.5, E15, and P0 in transgenic mice lacking DCC. Netrins also promoted the survival/development of enteric crest-derived cells. The formation of submucosal and pancreatic ganglia thus involves the attraction of DCC-expressing crest-derived cells by netrins.
Subject(s)
Cell Adhesion Molecules/metabolism , Enteric Nervous System/embryology , Nerve Growth Factors/metabolism , Nerve Tissue Proteins/metabolism , Neural Crest/cytology , Neural Crest/metabolism , Tumor Suppressor Proteins/metabolism , Animals , Base Sequence , Cell Adhesion Molecules/antagonists & inhibitors , Cell Adhesion Molecules/deficiency , Cell Adhesion Molecules/genetics , Cell Line , Cell Movement , Chick Embryo , DCC Receptor , DNA/genetics , Enteric Nervous System/cytology , Enteric Nervous System/metabolism , Ganglia/abnormalities , Ganglia/embryology , Gene Expression Regulation, Developmental , Humans , Immunohistochemistry , In Situ Hybridization , Mice , Mice, Transgenic , Nerve Growth Factors/genetics , Nerve Tissue Proteins/genetics , Netrin-1 , Netrins , Neural Crest/embryology , Pancreas/cytology , Pancreas/embryology , Pancreas/metabolism , Receptors, Cell Surface , Transfection , Tumor Suppressor Proteins/antagonists & inhibitors , Tumor Suppressor Proteins/deficiency , Tumor Suppressor Proteins/geneticsABSTRACT
An antibody directed against Kit protein was used to investigate the distribution of interstitial cells of Cajal (ICC) within the murine colon. The ICC density was greatest in the proximal colon and decreased along its length. The distribution of the different classes of ICC in the aganglionic colons of lethal spotted (ls/ls) mice was found to be similar in age-matched wild-type controls. There were marked differences in the electrical activities of the colons from ls/ls mutants compared with wild-type controls. In ls/ls aganglionic colons, the circular muscle was electrically quiescent compared with the spontaneous spiking electrical activity of wild-type tissues. In ls/ls aganglionic colons, postjunctional neural responses were greatly affected. Inhibitory junction potentials were absent or excitatory junction potentials inhibited by atropine were observed. In conclusion, the distribution of ICC in the ganglionic and aganglionic regions of the colons from ls/ls mutants appeared similar to that of wild-type controls. The electrical activity and neural responses of the circular layer are significantly different in aganglionic segments of ls/ls mutants.
Subject(s)
Colon/innervation , Colon/physiology , Ganglia/abnormalities , Ganglia/physiology , Animals , Colon/cytology , Colon/pathology , Congenital Abnormalities/enzymology , Congenital Abnormalities/pathology , Electrophysiology , Mice , Mice, Inbred Strains , Mice, Neurologic Mutants , Neurons/enzymology , Nitric Oxide Synthase/deficiency , Nitric Oxide Synthase Type I , Reference ValuesABSTRACT
We report a 10-year-old boy with multiple congenital anomalies/mental retardation syndrome, who also presented with aganglionosis and neurogenic muscle weakness. Some phenotypic manifestations of our patient overlap with those observed in the Niikawa-Kuroki syndrome; however, the hypothesis of a new distinct entity, with simultaneous involvement of the central and peripheral nervous system, is considered.
