RESUMEN
Delayed cell death in the penumbra region of acute ischemic stroke occurs through apoptotic mechanisms, making it amenable to therapeutic interventions. Fas/CD95 mediates apoptotic cell death in response to external stimuli. In mature neurons, Fas/CD95 signaling is modulated by Fas-apoptotic inhibitory molecule 2 (Faim2), which reduces cell death in animal models of stroke, meningitis, and Parkinson disease. Erythropoietin (EPO) has been studied as a therapeutic strategy in ischemic stroke. Erythropoietin stimulates the phosphatidylinositol-3 kinase/Akt (PI3K/Akt) pathway, which regulates Faim2 expression. Therefore, up-regulation of Faim2 may contribute to neuroprotection by EPO. Male Faim2-deficient mice (Faim2-/- ) and wild-type littermates (WT) were subjected to 30 min of middle cerebral artery occlusion (MCAo) followed by 72 h of reperfusion. EPO was applied before (30 min) and after (24 and 48 h) MCAo. In WT mice application of EPO at a low dose (5000 U/kg) significantly reduced stroke volume, whereas treatment with high dose (90 000 U/kg) did not. In Faim2-/- animals administration of low-dose EPO did not result in a significant reduction in stroke volume. Faim2 expression as measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) increased after low-dose EPO but not with high dose. An extensive phenotyping including analysis of cerebral vessel architecture did not reveal confounding differences between the genotypes. In human post-mortem brain Faim2 displayed a differential expression in areas of penumbral ischemia. Faim2 up-regulation may contribute to the neuroprotective effects of low-dose erythropoietin in transient brain ischemia. The dose-dependency may explain mixed effects of erythropoietin observed in clinical stroke trials.
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Proteínas Reguladoras de la Apoptosis/metabolismo , Eritropoyetina , Ataque Isquémico Transitorio/metabolismo , Proteínas de la Membrana/metabolismo , Neuroprotección/fisiología , Anciano , Animales , Eritropoyetina/metabolismo , Eritropoyetina/farmacología , Femenino , Humanos , Ataque Isquémico Transitorio/patología , Ataque Isquémico Transitorio/fisiopatología , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Proteínas del Tejido Nervioso/metabolismoRESUMEN
Minipigs are frequently used in (neuro-)interventional research. Longitudinal experiments may require repeated vessel access via the femoral artery. Anticoagulation and incompliance of the animals necessitates the use of a vascular closure device (VCD). The effects of the Angio-Seal VCD in minipigs were longitudinally assessed. Minipig (42±8.4 kg body weight) femoral arteries were sealed using the 8F (n = 6) or 6F (n = 7) Angio-Seal VCD. The pre-interventional femoral artery diameter was 5.1±0.4 mm (4.3-5.8 mm). Sealed puncture sites were analysed angiographically as well as by computed tomography angiography (CTA) for a mean period of 14.1±8.0 weeks (1-22 weeks). All animals were constantly treated with acetylsalicylic acid (ASS) (450 mg/d (n = 7) or 100 mg/d (n = 1)) and clopidogrel (75 mg/d (n = 8)). Non-instrumented (n = 2) and arteries sealed using the VCD (n = 2) were examined histologically. No postoperative hemorrhagic complications were observed. Three arteries were occluded after VCD placement (1 animal diagnosed after 4 weeks (8F), 2 animals after 1 week (6F)) and remained so until the end of the experiments after 22, 12 and 4 weeks, respectively. In one artery a 50% stenosis 8 weeks after application of a 6F Angio-Seal was detected. In 69.2% (n = 9) the VCD was applied without complications. Histopathological analysis of the sealed arterial segments showed subtotal obliteration of the vessel lumen, formation of collagenous tissue and partial damage of the internal elastic lamina. The Angio-Seal VCD prevents relevant hemorrhagic complications in minipigs treated with dual platelet inhibition, but is associated with increased vessel occlusion rates.
RESUMEN
Mutations affecting the mitochondrial DNA-polymerase gamma 1 (POLG1) gene have been shown to cause Alpers-Huttenlocher disease. Ultrastructural data on brain and muscle tissue are rare. We report on ultrastructural changes in brain and muscle tissue of two sisters who were compound heterozygous for the c.2243G>C and c.1879C>T POLG1 mutations. Patient 1 (16 years) presented with epilepsia partialis continua that did not respond to antiepileptic treatment. Neuroimaging showed right occipital and bithalamic changes. Light microscopy from a brain biopsy performed after 3 weeks suggested chronic encephalitis showing astro- and microgliosis as well as perivascular CD8-positive T-cells. However, immunosuppressive therapy failed to improve her condition. When her 17-year-old sister (patient 2) also developed epilepsy, an intensified search for metabolic diseases led to the diagnosis. On electron microscopy mitochondrial abnormalities mainly affecting neurons were detected in the brain biopsy of patient 1, including an increase in number and size, structural changes and globoid inclusions. In patient 2, light and electron microscopy on a muscle biopsy confirmed a mitochondrial myopathy, also revealing an increase in mitochondrial size and number, as well as globoid inclusions. Neurons may be the primary target of mitochondrial dysfunction in brains of patients with Alpers disease related to POLG1 mutations. During early disease stages, brain histopathology may be misleading, showing reactive inflammatory changes.
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Encéfalo/ultraestructura , ADN Polimerasa Dirigida por ADN/genética , Esclerosis Cerebral Difusa de Schilder/patología , Encefalomiopatías Mitocondriales/patología , Músculo Esquelético/ultraestructura , Neuronas/ultraestructura , Adolescente , ADN Polimerasa gamma , Diagnóstico Diferencial , Esclerosis Cerebral Difusa de Schilder/genética , Progresión de la Enfermedad , Resultado Fatal , Femenino , Humanos , Encefalomiopatías Mitocondriales/genéticaRESUMEN
UNLABELLED: The assessment of treatment response in glioblastoma is difficult with MRI because reactive blood-brain barrier alterations with contrast enhancement can mimic tumor progression. In this study, we investigated the predictive value of PET using O-(2-(18)F-fluoroethyl)-l-tyrosine ((18)F-FET PET) during treatment. METHODS: In a prospective study, 25 patients with glioblastoma were investigated by MRI and (18)F-FET PET after surgery (MRI-/FET-1), early (7-10 d) after completion of radiochemotherapy with temozolomide (RCX) (MRI-/FET-2), and 6-8 wk later (MRI-/FET-3). Maximum and mean tumor-to-brain ratios (TBR(max) and TBR(mean), respectively) were determined by region-of-interest analyses. Furthermore, gadolinium contrast-enhancement volumes on MRI (Gd-volume) and tumor volumes in (18)F-FET PET images with a tumor-to-brain ratio greater than 1.6 (T(vol 1.6)) were calculated using threshold-based volume-of-interest analyses. The patients were grouped into responders and nonresponders according to the changes of these parameters at different cutoffs, and the influence on progression-free survival and overall survival was tested using univariate and multivariate survival analyses and by receiver-operating-characteristic analyses. RESULTS: Early after completion of RCX, a decrease of both TBR(max) and TBR(mean) was a highly significant and independent statistical predictor for progression-free survival and overall survival. Receiver-operating-characteristic analysis showed that a decrease of the TBR(max) between FET-1 and FET-2 of more than 20% predicted favorable survival [corrected], with a sensitivity of 83% and a specificity of 67% (area under the curve, 0.75). Six to eight weeks later, the predictive value of TBR(max) and TBR(mean) was less significant, but an association between a decrease of T(vol 1.6) and PFS was noted. In contrast, Gd-volume changes had no significant predictive value for survival. CONCLUSION: In contrast to Gd-volumes on MRI, changes in (18)F-FET PET may be a valuable parameter to assess treatment response in glioblastoma and to predict survival time.
Asunto(s)
Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/terapia , Glioblastoma/diagnóstico por imagen , Glioblastoma/terapia , Tirosina/análogos & derivados , Adulto , Anciano , Quimioradioterapia , Medios de Contraste , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Gadolinio , Humanos , Estimación de Kaplan-Meier , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Procedimientos Neuroquirúrgicos , Tomografía de Emisión de Positrones , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Radiofármacos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
OBJECTIVE: Despite the introduction of mild therapeutic hypothermia into postcardiac arrest care, cerebral and myocardial injuries represent the limiting factors for survival after cardiac arrest. Administering xenon may confer an additional neuroprotective effect after successful cardiopulmonary resuscitation due to its ability to stabilize cellular calcium homeostasis via N-methyl-D-aspartate-receptor antagonism. DESIGN: In a porcine model, we evaluated effects of xenon treatment in addition to therapeutic hypothermia on neuropathologic and functional outcomes after cardiopulmonary resuscitation. SETTING: Prospective, randomized, laboratory animal study. SUBJECTS: Fifteen male pigs. INTERVENTIONS: Following 10 mins of cardiac arrest and 6 mins of cardiopulmonary resuscitation, ten pigs were randomized to receive either mild therapeutic hypothermia (33°C for 16 hrs) or mild therapeutic hypothermia 1 xenon (70% for 1 hr). Five animals served as normothermic controls. MEASUREMENTS AND MAIN RESULTS: Gross hemodynamic variables were measured using right-heart catheterization. Neurocognitive performance was evaluated for 5 days after cardiopulmonary resuscitation using a neurologic deficit score before the brains were harvested for histopathological analysis. All animals survived the observation period in the mild therapeutic hypothermia 1 xenon group while one animal in each of the other two groups died. Mild therapeutic hypothermia 1 xenon preserved cardiac output during the induction of mild therapeutic hypothermia significantly better than did mild therapeutic hypothermia alone (4.6 6 0.6 L/min vs. 3.2 6 1.6 L/min, p # .05). Both treatment groups showed significantly fewer necrotic lesions in the cerebral cortex, caudate nucleus, putamen, and in hippocampal sectors CA1 and CA3/4. However, only the combination of mild therapeutic hypothermia and xenon resulted in reduced astrogliosis in the CA1 sector and diminished microgliosis and perivascular inflammation in the putamen. Clinically, only the mild therapeutic hypothermia 1 xenon-treated animals showed significantly improved neurologic deficit scores over time (day 1 = 59.0 6 27.0 vs. day 5 = 4.0 6 5.5, p ø .05) as well as in comparison to the untreated controls on days 3 through 5 after cardiopulmonary resuscitation. CONCLUSIONS: These results demonstrate that even a short exposure to xenon during induction of mild therapeutic hypothermia results in significant improvements in functional recovery and ameliorated myocardial dysfunction.
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Paro Cardíaco/terapia , Hipotermia Inducida/métodos , Hipoxia Encefálica/terapia , Fármacos Neuroprotectores/uso terapéutico , Xenón/uso terapéutico , Administración por Inhalación , Animales , Encéfalo/efectos de los fármacos , Encéfalo/patología , Encéfalo/fisiopatología , Reanimación Cardiopulmonar/métodos , Modelos Animales de Enfermedad , Paro Cardíaco/tratamiento farmacológico , Paro Cardíaco/patología , Hipoxia Encefálica/tratamiento farmacológico , Hipoxia Encefálica/etiología , Hipoxia Encefálica/patología , Hipoxia Encefálica/fisiopatología , Masculino , Fármacos Neuroprotectores/administración & dosificación , Porcinos , Xenón/administración & dosificaciónRESUMEN
In this study we describe a case of a term infant with the neurological variant of Waardenburg syndrome type 4 (i.e., PCWH = peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease, as defined in OMIM #609136) due to a novel heterozygous base exchange (c.671C>G) in exon 4 of SOX10. Magnetic resonance imaging suggested central myelin deficiency with cerebral and cerebellar hypoplasia. Hirschsprung disease was confirmed by rectal biopsy. Sural nerve biopsy revealed hypoplasia due to amyelination (with the exception of a single, small myelinated fiber) and severe reduction in the number of axons.
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Axones/patología , Enfermedades Desmielinizantes , Mutación/genética , Enfermedades del Sistema Nervioso Periférico , Factores de Transcripción SOXE/genética , Axones/ultraestructura , Enfermedades Desmielinizantes/complicaciones , Enfermedades Desmielinizantes/genética , Enfermedades Desmielinizantes/patología , Humanos , Recién Nacido , Masculino , Microscopía Electrónica de Transmisión , Músculo Esquelético/patología , Músculo Esquelético/ultraestructura , Enfermedades del Sistema Nervioso Periférico/complicaciones , Enfermedades del Sistema Nervioso Periférico/genética , Enfermedades del Sistema Nervioso Periférico/patología , Nervio Sural/patología , Nervio Sural/ultraestructuraRESUMEN
RATIONALE: Recently, we provided a technique of chronic high-frequency electric stimulation (HFES) of the right inferior ganglionated plexus for ventricular rate control during atrial fibrillation in dogs and humans. In these experiments, we observed a decrease of the intrinsic ventricular rate during the first 4 to 5 months when HFES was intermittently shut off. OBJECTIVE: We thus hypothesized that HFES might elicit trophic effects on cardiac neurons, which in turn increase baseline parasympathetic tone of the atrioventricular node. METHODS AND RESULTS: In mongrel dogs atrial fibrillation was induced by rapid atrial pacing. Endocardial HFES of the right inferior ganglionated plexus, which contains abundant fibers to the atrioventricular node, was performed for 2 years. Sham-operated nonstimulated dogs served as control. In chronic neurostimulated dogs, we found an increased neuronal cell size accompanied by an increase of choline acetyltransferase and unchanged tyrosine hydroxylase protein expression as compared with unstimulated dogs. Moreover, ß-nerve growth factor (NGF) and neurotrophin (NT)-3 were upregulated in chronically neurostimulated dogs. In vitro, HFES of cultured neurons of interatrial ganglionated plexus from adult rats increased neuronal growth accompanied by upregulation of NGF, NT-3, glial-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) expression. NGF was identified as the main growth-inducing factor, whereas NT-3 did not affect HFES-induced growth. However, NT-3 could be identified as an important acetylcholine-upregulating factor. CONCLUSIONS: HFES of cardiac neurons in vivo and in vitro causes neuronal cellular hypertrophy, which is mediated by NGF and boosters cellular function by NT-3-mediated acetylcholine upregulation. This knowledge may contribute to develop HFES techniques to augment cardiac parasympathetic tone.
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Función del Atrio Derecho/fisiología , Factores de Crecimiento Nervioso/fisiología , Neuronas/fisiología , Neurotrofina 3/fisiología , Fibras Parasimpáticas Posganglionares/fisiología , Regulación hacia Arriba/fisiología , Animales , Células Cultivadas , Perros , Estimulación Eléctrica/métodos , Masculino , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
In the heart, acetylcholine (ACh) slows pacemaker activity, depresses contractility and slows conduction in the atrioventricular node. Beside these cardiovascular effects, ACh has also been associated with an anti-inflammatory and anti-apoptotic pathway. There is no evidence for ACh synthesis and excretion in other cell types than neuronal cells in the heart. Therefore, this study investigates whether cardiomyocytes are able to synthesize, transport and excrete ACh in the heart. We chose a rat model of different aged rats (neonatal, 6-8 week = young, 20-24 month = old). By real-time PCR, Western blot and immunofluorescence experiments we could demonstrate that adult, but not neonatal cardiomyocytes, express the choline acetyltransferase (ChAT). The expression level of ChAT is down-regulated in old cardiomyocytes. Furthermore, we found that young and old cardiomyocytes express the ACh transport proteins choline transporter-1 (CHT-1) and the vesicular acetylcholine transporter (VAChT). The amount of ACh excretion detected by high performance liquid chromatography (HPLC) is significantly down-regulated in old cardiomyocytes. Bromo-acetylcholine (BrACh), a specific ChAT inhibitor, significantly decreased ACh concentrations in cardiomyocyte supernatants demonstrating that ChAT is the main ACh synthesizing enzyme in cardiomyocytes. In conclusion, we could demonstrate that adult, but not neonatal, cardiomyocytes are able to synthesize, transport and excrete ACh in the rat heart. The expression level of ChAT and the ACh excretion amount are significantly down-regulated in old cardiomyocytes. This finding may provide new physiological/pathological aspects in the communication between cardiomyocytes and other cell types in the myocardium, e.g. fibrocytes, neurocytes or endothelial cells.
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Acetilcolina/metabolismo , Envejecimiento/metabolismo , Miocitos Cardíacos/metabolismo , Neuronas , Acetilcolina/biosíntesis , Envejecimiento/fisiología , Animales , Animales Recién Nacidos , Colina O-Acetiltransferasa/antagonistas & inhibidores , Colina O-Acetiltransferasa/metabolismo , Masculino , Miocardio/enzimología , Miocardio/metabolismo , Miocitos Cardíacos/enzimología , Proteínas del Tejido Nervioso/metabolismo , Neuronas/enzimología , Neuronas/metabolismo , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Electric stimulation of mediastinal sympathetic cardiac nerves increases cardiac contractility but is not selective for the left ventricle because it elicits sinus tachycardia and enhanced atrioventricular conduction. The aim of this study was to identify sympathetic neural structures inside the heart that selectively control left ventricular inotropy and can be accessed by transvenous catheter stimulation. METHODS AND RESULTS: In 20 sheep, high-frequency stimulation (200 Hz) during the myocardial refractory period with electrode catheters inside the coronary sinus evoked a systolic left ventricular pressure increase from 97+/-20 to 138+/-32 mm Hg (P<0.001) without changes in sinus rate or PR time. Likewise, the rate of systolic pressure development (1143+/-334 versus 1725+/-632 mm Hg/s; P=0.004) and rate of diastolic relaxation (531+/-128 versus 888+/-331 mm Hg/s; P=0.001) increased. The slope of the end-systolic pressure-volume relationship increased (2.3+/-0.8 versus 3.1+/-0.6 mm Hg/mL; P=0.04), as did cardiac output (3.5+/-0.8 versus 4.4+/-0.8 L/min; P<0.001). Systemic vascular resistance and right ventricular pressure remained unchanged. There was a sigmoid dose-response curve. Ultrasound analysis revealed an increase in circumferential and radial strain in all left ventricular segments that was significant for the posterior, lateral, and anterior segments. Pressure effects were maintained for at least 4 hours of continued high-frequency stimulation and abolished by beta1-receptor blockade. Histology showed distinct adrenergic nerve bundles at the high-frequency stimulation site. CONCLUSIONS: Cardiac nerve fibers that innervate the left ventricle are amenable to transvenous electric catheter stimulation. This may permit direct interference with and modulation of the sympathetic tone of the left ventricle.
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Ventrículos Cardíacos/inervación , Contracción Miocárdica/fisiología , Sistema Nervioso Simpático/fisiología , Función Ventricular Izquierda/fisiología , Animales , Presión Sanguínea/fisiología , Cateterismo , Estimulación Eléctrica , Electrodos , Modelos Animales , Ovinos , Resistencia Vascular/fisiologíaRESUMEN
Schwann cell tumors arising within the neuraxis and in an intraventricular location are an exceedingly rare tumor entity of the brain. The authors present the first case of a cellular intraventricular schwannoma occurring in the fourth ventricle. The pertinent literature is reviewed. A 71-year-old female was admitted to the hospital with an incidental finding of a ventricular tumor. Computed tomography scanning and magnetic resonance imaging revealed a solitary contrast enhancing exophytic mass lesion within the fourth ventricle. Microsurgical excision via a midline suboccipital craniotomy and tonsillo-nodular approach led to complete tumor removal. Subsequent histopathological examination confirmed the diagnosis of an unsuspected primary intraventricular cellular schwannoma. A unique case of an initially unexpected benign schwannoma arising from the fourth ventricle that could be successfully treated by microsurgery and finally confirmed by histopathological analysis with excellent patient outcome is presented. Although highly uncommon, Schwann cell tumors of both benign and malignant nature may present as ventricular lesions and should be included as a differential diagnosis in patients with either solely intraventricular masses or intra- and extraaxial tumors with extension to the ventricles.
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Neoplasias del Ventrículo Cerebral/patología , Neurilemoma/patología , Anciano , Neoplasias del Ventrículo Cerebral/cirugía , Femenino , Cuarto Ventrículo/patología , Humanos , Imagen por Resonancia Magnética , Neurilemoma/cirugía , Procedimientos Neuroquirúrgicos , Escotoma/etiología , Escotoma/patología , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Xenon (Xe) is neuroprotective when given 1h after cardiopulmonary resuscitation (CPR). Here, we investigated if an earlier administration of Xe or isoflurane (Iso) would also reduce neurological dysfunction. METHODS: 10 min after CPR from 8 min of cardiac arrest 21 pigs were randomized to three groups (n=7/group) and then ventilated for 1h with gas mixtures as follows: (1) control: 30% O(2)+70% N(2); (2) Iso: 30% O(2)+69% N(2)+1% Iso; (3) Xe: 30% O(2)+70% Xe. Physiological variables were obtained before cardiac arrest and 10, 60 and 240 min post-CPR including cardiac output (CO) and mean arterial pressure (MAP). Four days after CPR we assessed functional performance using an established neurocognitive test and overall neurological status using a neurologic deficit score (NDS). On day 5, brains of the re-anaesthetized pigs were harvested for neurohistopathological analyses. RESULTS: Prior to CPR there were no differences in hemodynamics and neurological status between groups. CO and MAP were significantly reduced after starting Iso administration. Both variables were also significantly lower in comparison to Xe and control animals. Control animals presented severe neurological dysfunction as measured by the NDS and the neurocognitive tests. Although Xe and Iso animals showed slightly better functional outcome this trend was not significant. Histopathological evaluation revealed ischaemic damage of neurons predominantly in the CA1 sector of the hippocampus with no differences between groups. CONCLUSIONS: In this study early administration of Xe and Iso did not significantly reduce neurological dysfunction and histopathological alterations induced by cardiac arrest and CPR.
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Anestésicos por Inhalación/administración & dosificación , Reanimación Cardiopulmonar/métodos , Paro Cardíaco/terapia , Isoflurano/administración & dosificación , Xenón/administración & dosificación , Animales , Encéfalo/efectos de los fármacos , Encéfalo/patología , Modelos Animales de Enfermedad , Esquema de Medicación , Hipocampo/efectos de los fármacos , Hipocampo/patología , Hipoxia-Isquemia Encefálica/prevención & control , Masculino , Desempeño Psicomotor/efectos de los fármacos , Sus scrofaRESUMEN
Developmental abnormalities of the brain, in particular, the brainstem potentially affecting centers for breathing, circulation and sleep regulation, are thought to be involved in the etiology of sudden infant death syndrome (SIDS). In order to investigate whether leptomeningeal neurons could serve as morphological indicators for a developmental failure or retardation in cerebral maturation, we evaluated the density of isolated leptomeningeal neurons (without associated glia) in 15 brain regions of 24 SIDS and 8 control cases, representing part of the German Study on sudden infant death. Leptomeningeal neurons were encountered in 79% of SIDS and 68% of control cases. More leptomeningeal neurons in SIDS versus control cases were found in lower pons (p = 0.002), upper pons (p = 0.016), cerebellar hemispheres (p = 0.012), lower medulla oblongata (p = 0.039), and temporal lobe (p = 0.041). Summarizing the data according to gross anatomical region of origin (i.e., brainstem, cerebellum or cerebrum), higher numbers of leptomeningeal neurons in SIDS cases were only found in the brainstem (p = 0.006 vs. 0.13 and 0.19, respectively). Our data show that single leptomeningeal neurons are present in most normal infantile brains. The age-dependent increase of leptomeningeal neurons among SIDS cases may either (a) represent a delayed maturation or retardation, i.e., a later or slower reduction of neurons or a delayed peak in occurrence (shift toward an older age), or (b) may be interpreted as a generally increased occurrence of leptomeningeal neurons among SIDS cases as a result of a diffuse developmental abnormality during central nervous system maturation.
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Encéfalo/citología , Encéfalo/patología , Neuronas/patología , Muerte Súbita del Lactante/patología , Autopsia , Tronco Encefálico/citología , Tronco Encefálico/patología , Recuento de Células , Cerebelo/citología , Cerebelo/patología , Femenino , Histología , Humanos , Lactante , Recién Nacido , Masculino , Bulbo Raquídeo/citología , Bulbo Raquídeo/patología , Puente/citología , Puente/patología , Muerte Súbita del Lactante/etiología , Lóbulo Temporal/citología , Lóbulo Temporal/patologíaRESUMEN
A diagnosis of GSD-IV was established in three premature, floppy infants based on characteristic, however unusually pleomorphic polyglucosan bodies at the electron microscopic level, glycogen branching enzyme deficiency in two cases, and the identification of GBE1 mutations in two cases. Pleomorphic polyglucosan bodies in muscle fibers and macrophages, and less severe in Schwann cells and microglial cells were noted. Most of the inclusions were granular and membrane-bound; others had an irregular contour, were more electron dense and were not membrane bound, or homogenous ('hyaline'). A paracrystalline pattern of granules was repeatedly noted showing a periodicity of about 10 nm with an angle of about 60 degrees or 120 degrees at sites of changing linear orientation. Malteser crosses were noted under polarized light in the larger inclusions. Some inclusions were PAS positive and others were not. Severely atrophic muscle fibers without inclusions, but with depletion of myofibrils in the plane of section studied indicated the devastating myopathic nature of the disease. Schwann cells and peripheral axons were less severely affected as was the spinal cord. Two novel protein-truncating mutations (c.1077insT, p.V359fsX16; g.101517_127067del25550insCAGTACTAA, DelExon4-7) were identified in these families. The present findings extend previous studies indicating that truncating GBE1 mutations cause a spectrum of severe diseases ranging from generalized intrauterine hydrops to fatal perinatal hypotonia and fatal cardiomyopathy in the first months of life.
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Enzima Ramificadora de 1,4-alfa-Glucano/genética , Glucanos/metabolismo , Enfermedad del Almacenamiento de Glucógeno Tipo IV/genética , Mutación , Enzima Ramificadora de 1,4-alfa-Glucano/metabolismo , Femenino , Glucanos/ultraestructura , Enfermedad del Almacenamiento de Glucógeno Tipo IV/enzimología , Enfermedad del Almacenamiento de Glucógeno Tipo IV/patología , Humanos , Cuerpos de Inclusión/metabolismo , Cuerpos de Inclusión/ultraestructura , Lactante , Recién Nacido , Masculino , Microscopía Electrónica de Transmisión , Músculo Esquelético/metabolismo , Músculo Esquelético/ultraestructura , Embarazo , Médula Espinal/metabolismo , Médula Espinal/ultraestructura , Nervio Sural/metabolismo , Nervio Sural/ultraestructuraRESUMEN
Cogan's syndrome is a rare clinical entity characterized by non-infectious interstitial keratitis with vestibuloauditory dysfunction. The clinical course is extremely variable. In the majority of patients, there appears to be an underlying systemic process, often a "vasculitis". We were able to study for the first time a sural nerve biopsy of a 38-year-old female with clinically suggested Cogan's syndrome associated with a severe multiplex type of neuropathy. There were unusual cells in or below the perineurium and along perineurial extensions into the endoneurium which were usually associated with blood vessels and which have thus far not been described in association with any type of peripheral neuropathy. The unusual cells were identified as perineurial cells because (1) they were frequently associated with the perineurium and its endoneurial extensions; (2) they were immunoreactive for antibodies against epithelial membrane antigen (EMA) but did not react with antibodies against protein S100, GFAP, and CD 68; and (3) they showed focally accumulated pinocytotic vesicles and hemidesmosomes. Some of these cells were clearly immunoreactive with antibodies against collagen VI. Electron microscopic examination revealed numerous intracellular bundles of collagen fibers which were surrounded by an amorphous basal lamina-like material, indicating that they were located within intracellular projections of the surface membrane. The number of myelinated and unmyelinated nerve fibers was severely reduced corresponding to the clinical manifestation of the neuropathy and to the atrophy, especially of the distal arm and leg muscles. It is concluded that the changes were caused by a special type of autoimmune reaction involving blood vessels and perineurial cells of peripheral nerves.
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Colágeno/metabolismo , Trastornos de la Audición/patología , Queratitis/patología , Nervios Periféricos/patología , Enfermedades Vestibulares/patología , Adulto , Matriz Extracelular/metabolismo , Matriz Extracelular/patología , Matriz Extracelular/ultraestructura , Femenino , Trastornos de la Audición/complicaciones , Humanos , Queratitis/complicaciones , Microscopía Electrónica de Transmisión/métodos , Examen Neurológico , Nervios Periféricos/ultraestructura , Enfermedades Vestibulares/complicacionesRESUMEN
Despite a decline in the overall rate of sudden infant death syndrome (SIDS), it remains the leading cause of postneonatal infant mortality. Research into underlying mechanisms of SIDS has still not yielded a morphological, histopathological correlate explaining aetiology and pathophysiology of an infant's sudden death. Of particular interest would be elucidating pathophysiological and molecular events immediately preceding the infant's sudden death. C-jun is an immediate early gene with a physiological role in orchestrating cellular responses following injury including a role in cell death. It is also one of the earliest and most consistent markers for neurons undergoing stress, degeneration and survival. We investigated the immunohistochemical expression of the acute phase protein c-jun within 47 separate cerebral regions of interest in the brains of 23 SIDS and 7 control cases for evidence of acute neuronal injury immediately preceding sudden death and to assess the distribution of cellular damage suggestive of pathophysiologically sensitive or critical cerebral regions. Dividing SIDS-cases and controls into subgroups with (1) no neuronal expression of c-jun at all or (2) some c-jun expression, a statistically significant higher c-jun expression for SIDS compared with control cases was established for the inferior colliculi ( P=0.008), the spinal trigeminal nuclei ( P=0.046) and the premotoric cortex layers II and IV ( P=0.029). The increased expression of c-jun in these areas might be directly related to the pathogenesis of sudden death, or may represent a secondary marker of neuronal injury with the primary event/injury being elsewhere in critical cardioventilatory circuits.